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TRNG I HC Y H NI

B MN DC L

DC L HC
(SCH DNG CHO SINH VIN H BC S A KHOA)

NH XUT BN Y HC
H NI - 2007

TRNG I HC Y H NI
B MN DC L

DC L HC
(SCH DNG CHO SINH VIN H BC S A KHOA)

NH XUT BN Y HC
H Ni - 2007

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CH BIN GS.TS. O VN PHAN THAM GIA BIN SON PGS.TS. NGUYN TRN TH GING HNG GS.TS. O VN PHAN TS. V TH NGC THANH PGS.TS. NGUYN TRNG THNG TH K BIN SON NGUYN KIU VN

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LI NI U
Cun sch ny dng ging dy mn DC L HC cho Trng i hc Y o to Bc s a khoa nh hng cng ng. Ngy nay, trn th trng Vit Nam c ti mi nghn mt hng thuc ang lu hnh. Cc thy thuc lun ng trc th thch rt ln trong vic la chn thuc cho iu tr nhm thc hin phng chm s dng thuc an ton v hp l. Thy thuc iu tr khng chy theo tng tn thuc m cn phi hiu r tc dng ca tng nhm thuc c hng s dng cho ng. Cun sch ny nhm cung cp cho sinh vin nhng kin thc c bn v c ch tc dng ca tng nhm thuc phn theo tc dng sinh l- bnh l- iu tr hc. Trn c s hiu r c ch tc dng, ngi c s hiu r cc p dng lm sng ca thuc nh ch nh, chng ch nh, tc dng khng mong mun. T nhng kin thc c bn ny, trong qu trnh thc hnh, cng vi s pht trin ca cc thuc mi, ngi c hon ton c th hiu thm c i m ca cc thuc c th s dng c an ton v hp l. Khoa hc k thut ang khng ngng pht trin. Cc thuc mi ang lin tc xut hin. Thm ch cn c thuc b loi tr sau vi nm c php lu hnh. V vy cc thy thuc cn lun cp nht thng tin bng cc ngun khc nhau. Cun sch gio khoa khng th lm c vic ny v sau vi nm mi ti bn mt ln. Cc tc gi c gng trnh by nhng kin thc dc l hc c bn cho sinh vin theo ng chng trnh quy nh ca B Y t. Nhng kin thc ny lm c s cho Sinh vin Y a khoa thc hnh v t hc sau khi ra trng. Cc tc gi rt mong nhn c nhng kin ng gp, ch bo ca ngi c v cc ng nghip y dc. Cc tc gi

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MC LC
BI KHI NIM V DC L HC TC GI TRANG

6 8 o Vn Phan o Vn Phan o Vn Phan o Vn Phan trn h o Vn Phan o Vn Phan o Vn Phan Nguyn Trn Th Ging Hng Nguyn Trn Th Ging Hng o Vn Phan o Vn Phan o Vn Phan o Vn Phan o Vn Phan o Vn Phan o Vn Phan Nguyn Trng Thng Nguyn Trn Th Ging Hng Nguyn Trn Th Ging Hng Nguyn Trn Th Ging Hng o Vn Phan 9 31 44 51 52 59 73 92 93 100 108 123 140 144 153 159 160 186 193 198 209 222 230 237

PHN I: DC L HC I CNG Bi 1: i cng v dc ng hc Bi 2: i cng v dc lc hc Bi 3: Tng tc thuc Bi 4: i cng v phn loi Bi 5: Thuc tc cholinnergic dng

PHN II: THUC TC DNG TRN H THN KINH THC VT

Bi 6: Thuc tc dng trn h adrenergic Bi 7: Thuc t Bi 8: Thuc ng v ru Bi 9: Thuc gim au loi morphin Bi 10: Thuc h st -gim au- chng vim Bi 11: Thuc cha gut Bi 12: Thuc an thn kinh, thuc bnh thn Bi 13: Thuc cha ng kinh PHN IV: HA HC TR LIU Bi 14: Thuc khng sinh khng khun Bi 15: Thuc khng virus (nhm khng virus sao chp ngc) Bi 16: Thuc khng nm Bi 17: Thuc chng lao - Thuc iu tr phong Bi 18: Thuc iu tr st rt Bi 19: Thuc chng giun sn Bi 20: Thuc chng amip - Trichomonas Bi 21: Thuc st khun - Thuc ty u

PHN III: THUC TC DNG TRN H THN KINH TRUNG NG

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BI

TC GI

TRANG

PHN V: THUC TC DNG TRN C QUAN V TRN MU Bi 22: Thuc tr tim Bi 23: Thuc iu tr cn au tht ngc Bi 24: Thuc iu tr tng huyt p Bi 25: Thuc li niu o Vn Phan o Vn Phan o Vn Phan o Vn Phan

242 243 252 259 271 261 294 315 329 337 351 352 359 367 374 383 384 413 414

Bi 26: Cc cht in gii chnh v cc o Vn Phan dch truyn Bi 27: Thuc iu chnh ri lon tiu ha V Th Ngc Thanh Bi 28: Thuc iu chnh ri lon h hp Bi 29: Thuc iu tr thiu mu V Th Ngc Thanh Nguyn Trng Thng

Bi 30: Thuc tc dng trn qu trnh ng mu v tiu fibrin Nguyn Trng Thng PHN VI: THUC TC DNG TRN CHUYN HA V M Bi 31: Thuc iu tr ri lon lipoprotein mu Bi 32: Thuc h glucose mu Bi 33: Histamin v thuc khng histamin Bi 34: Vitamin Nguyn Trng Thng Nguyn Trng Thng Nguyn Trng Thng Nguyn Trng Thng

PHN VII: HORMON V CC THUC IU CHNH RI LON NI TIT Bi 40935: Hormon v cc thuc khng hormon Bi 36: iu tr ng c thuc cp tnh o Vn Phan

PHN VIII: IU TR NG C THUC CP TNH o Vn Phan

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KHI NIM V DC L HC Dc l hc (Pharmacology) theo tu t hc l mn khoa hc v thuc. Nhng trnh ngha qu rng ca t ny, Dc l hc ch bao hm m i nghin cu v s tng tc ca thuc vi cc h sinh hc. Thuc l cc cht hoc hp cht c tc dng iu tr hoc d phng bnh tt cho ngi v sc vt, hoc dng trong chn on bnh lm sng, dng khi phc, iu chnh cc chc phn ca c quan. Thuc c th c ngun gc t thc vt (cy Canhkina, cy Ba gc), t ng vt (insulin chit xut t ty tng b, ln), t khong vt, kim loi (kaolin, thu ngn, mu i vng) hoc l cc cht bn tng hp, tng hp ha hc (ampicilin, sulfamid). u tin, thuc phi c nghin cu trn sc vt thc nghim xc nh c tc dng, c ch tc dng, c tnh, liu iu tr, liu c, tc dng gy t bin, gy qui thai, gy ung th... l i tng ca mn Dc l hc thc nghim (Experimental pharmacology). Nhng nghin cu ny nhm m bo an ton n mc ti a cho ngi dng thuc. Ch sau khi c s liu ng tin cy v thc nghim trn sc vt mi c p dng cho ngi. Tuy nhin, sc vt phn ng vi thuc khng hon ton ging ngi ; v vy sau giai on thc nghim trn sc vt, thuc phi c th trn nhm ngi tnh nguyn, trn cc nhm bnh nhn ti cc c s khc nhau, c so snh vi cc nhm dng thuc kinh in hoc thuc v (placebo), nhm nh gi li cc tc dng gp trong thc nghim v ng thi pht hin cc triu chng mi, nht l cc tc dng khng mong mun cha thy hoc khng th th y c trn sc vt (bun nn, chng mt, nhc u, phn ng d ng v.v....). Nhng nghin cu ny l mc tiu ca mn Dc l hc lm sng (Clinical pharmacology). Cun sch gio khoa ny mang tnh cht Dc l Y hc (Medical pharmacology), vit cho Sinh vin trng Y v thy thuc thc hnh, nhm cung cp nhng kin thc v tc dng ca thuc v nhng vn lin quan n iu tr thy thuc c th k n c an ton v hp l. Dc l hc lun da trn nhng thnh tu mi nht ca cc ngnh khoa hc c lin quan nh sinh l, sinh ha, sinh hc, di truyn hc... ngy cng hiu su v c ch phn t ca thuc, gip cho nghin cu sn xut cc thuc mi ngy cng c tnh c hiu, khng ngng nng cao hiu qu iu tr. Dc l hc cn chia thnh: Dc lc hc (Pharmacodynamics) nghin cu tc ng ca thuc trn c th sng. M i thuc, tu theo liu dng s c tc dng sm, c hiu trn mt m, mt c quan hay mt h thng ca c th, c s dng iu tr bnh, c gi l tc dng chnh. Ngoi ra, m i thuc cn c th c nhiu tc dng khc, khng c dng iu tr, tri li cn gy phin h cho ngi dng thuc (bun nn, chng mt, nh trng ngc...), c gi l tc dng ph, tc dng khng mong mun hay tc dng ngoi . Tt c cc tc dng l i tng nghin cu ca Dc lc hc. Trong cun sch ny, n c vit vo mc "tc dng dc l". Dc ng hc (Pharmacokinetics) nghin cu v tc ng ca c th n thuc, l ng hc ca s hp thu, phn ph i, chuyn ha v thi tr thuc. Ngi thy thuc rt cn nhng thng tin ny bit cch chn ng a thuc vo c th (ung, tim bp, tim t nh mch...), s ln dng thuc trong ngy, liu lng thuc tu theo tng trng hp (tui, trng thi bnh, trng thi sinh l...).

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Dc l thi khc (Chronopharmacology) nghin cu nh hng ca nhp sinh hc trong ngy, trong nm n tc ng ca thuc. Hot ng sinh l ca ngi v ng vt chu nh hng r rt ca cc thay i ca mi trng sng nh nh sng, nhit , m ... Cc hot ng ny bin i nhp nhng, c chu k, g i l nhp sinh hc (trong ngy, trong thng, trong nm). Tc ng ca thuc cng c th thay i theo nhp ny. Ngi thy thuc cn bit chn thi im v liu lng thuc ti u. Dc l di truyn (Pharmacogenetics) nghin cu nhng thay i v tnh cm th ca c th, ca gia nh hay chng tc vi thuc do nguyn nhn di truyn. V d ngi thiu G6PD rt d b thiu mu tan mu do dng sulfamid, thuc chng st rt... ngay c vi liu iu tr thng thng. C th ni Dc l di truyn l mn giao thoa gia Dc l - Di truyn - Ha sinh v Dc ng hc. Dc l cnh gic hay Cnh gic thuc (Pharmacovigilance) chuyn thu thp v nh gi mt cch c h thng cc phn ng c hi c lin quan n vic dng thuc trong cng ng. Phn ng c hi l nhng phn ng khng mong mun (ngoi ) xy ra mt cch ngu nhin vi cc liu thuc vn dng d phng, chn on hay iu tr bnh. Phenacetin l thuc h st, phi 75 nm sau khi dng ph bin mi pht hin c tc dng gy c ca thuc; sau 30 nm mi thy c chng suy gim bch cu ca amidopyrin. Nhng mn hc trn l nhng chuyn khoa su ca Dc l hc. Ngi thy thuc cng bit r v thuc cng nm c "ngh thut" k n an ton v hp l. V iu kin thi gian v khun kh, cun sch ny ch yu cung cp nhng kin thc v dc lc hc, dc ng hc v vi mt s thuc c bit, c lu n dc l di truyn, dc l cnh gic... Mc tiu ca mn Dc l hc l Sinh vin sau khi hc xong c th: - Trnh by v gii thch c c ch tc dng, p dng iu tr ca cc thuc i din trong tng nhm. - Phn tch c tc dng khng mong mun v c tnh ca thuc bit cch phng v x tr. - K c cc n thuc ng nguyn tc, ng chuyn mn, ng php l. Ngi thy thuc nn nh rng: . Khng c thuc no v hi. . Ch dng khi tht cn, ht sc trnh lm dng thuc. . Khng phi thuc t tin lun lun l thuc tt nht. . Trong qu trnh hnh ngh, thy thuc phi lun lun hc h i nm c cc kin thc dc l ca cc thuc mi, hoc nhng hiu bit mi, nhng p dng mi ca cc thuc c.

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PHN I DC L HC I CNG Bi 1: I CNG V DC NG HC

MC TIU HC TP: Sau khi hc xong bi ny, sinh vin c kh nng: 1. Phn tch c qu trnh hp thu v phn phi thuc trong c th. 2. Nu c ngha ca cc thng s dc ng hc ca cc qu trnh hp thu v phn phi thuc. 3. Nu c ngha ca vic gn thuc vo protein huyt tng. 4. Trnh by c nhng qu trnh v ngha ca s chuyn ha thuc trong c th. 5. K ra c ngha thng s dc ng hc v h s thanh thi, t/2 v cc ng thi tr thuc khi c th.

Dc ng hc (Pharmacokinetics) nghin cu cc qu trnh chuyn vn ca thuc t lc c hp thu vo c th cho n khi b thi tr hon ton (H1). Cc qu trnh l: - S hp thu (Absorption) - S phn ph i (Distribution) - S chuyn ha (Metabolism)

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- S thi tr (Excretion)

Mu Thuc - protein Hp thu (ung, bi...) Protein + THUC t/m THUC(T) T

M D tr

T - Rec

Tc dng

Chuyn ha M Cht chuyn ha (M)

Thi tr

Hnh 1.1. S chuyn vn ca thuc trong c th

thc hin c nhng qu trnh ny, thuc phi vt qua cc mng t bo. V th trc khi nghin cu 4 qu trnh ny, cn nhc li cc c ch vn chuyn thuc qua mng sinh hc v cc c tnh l ha ca thuc v mng sinh hc c nh hng n cc qu trnh vn chuyn .

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1. CC CCH VN CHUYN THUC QUA MNG SINH HC 1.1. c tnh l ha ca thuc

- Thuc l cc phn t thng c trng lng phn t PM 600. Chng u l cc acid hoc cc base yu. - Kch thc phn t ca thuc c th thay i t rt nh (PM = 7 nh ion lithi) cho ti rt ln (nh alteplase- tPA- l protein c PM = 59.050). Tuy nhin, a s c PM t 100- 1000. gn "kht" vo 1 loi receptor, phn t thuc cn t c mt kch c duy nht vi kch thc ca receptor c hiu thuc khng gn c vo cc receptor khc (mang tnh chn lc). Kinh nghim cho thy PM nh nht phi t khong 100 v khng qu 1000, v ln qu th khng qua c cc mng sinh hc ti ni tc dng. Mt s thuc l acid yu: l phn t trung tnh c th phn ly thun nghch thnh mt anion (in tch (-)) v mt proton (H+). C8H7O2COOH Aspirin trung tnh C8H7O2COO+ Proton H+

Aspirin anion

Mt s thuc l base yu: l mt phn t trung tnh c th to thnh mt cation (in tch (+)) bng cch kt hp vi 1 proton: C12H11ClN3NH3+ Pyrimethamin cation C12H11ClN3NH2 Pyrimethamin trung tnh - Cc phn t thuc c sn xut di cc dng bo ch khc nhau : + H+ Proton

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Tan c trong nc (dch tiu ha, dch khe), do d c hp thu. Tan c trong m thm qua c mng t bo gy ra c tc dng dc l v mng t bo cha nhiu phospholipid. V vy c hp thu vo t bo thun li nht, thuc cn c mt t l tan trong nc/ tan trong m thch hp. - Cc phn t thuc cn c c trng bi hng s phn ly pKa pKa c suy ra t phng trnh Henderson- HasselbACh: dng ion ha pH = pKa + log dng khng ion ha Cho 1 acid: nng phn t pKa = pH + log nng ion

Cho 1 base: nng ion pKa = pH + log nng phn t

K l hng s phn ly ca 1 acid; pKa = - logKa pKa dng cho c acid v base. pKa +pKb=14

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Mt acid hu c c pKa thp l 1 acid mnh v ngc li. Mt base c pKa thp l 1 base yu, v ngc li. Ni mt cch khc, khi mt thuc c hng s pKa bng vi pH ca mi trng th 50% thuc c dng ion ha (khng khuch tn c qua mng) v 50% dng khng ion ha (c th khuch tn c). V khi , nng phn t/ nng ion= 1 v log 1 = 0. Ni chung, mt thuc phn tn tt, d c hp thu khi C trng lng phn t thp t b ion ha: ph thuc vo hng s phn ly (pKa) ca thuc v pH ca mi trng. D tan trong dch tiu ha (tan trong nc) ho tan trong lipid cao d qua mng ca t bo 1.2. Vn chuyn thuc bng cch lc Nhng thuc c trng lng phn t thp (100- 200), tan c trong nc nhng khng tan c trong m s chui qua cc ng dn (d= 4- 40 ) ca mng sinh hc do s chnh lch p lc thu t nh. ng dn ca mao mch c vn c ng knh l 30 , ca mao mch no l 79, v th nhiu thuc khng vo c thn kinh trung ng. 1.3. Vn chuyn bng khuch tn th ng (theo bc thang nng ). Nhng phn t thuc tan c trong nc/ m s chuyn qua mng t ni c nng cao sang ni c nng thp. iu kin ca s khuch tn th ng l thuc t b ion ho v c nng cao b mt mng. Cht ion ha s d tan trong nc, cn cht khng ion ha s tan c trong m v d hp thu qua mng. S khuch tn ca acid v base yu ph thuc vo hng s phn ly pKa ca thuc v pH ca mi trng. Th d: khi ung 1 thuc l acid yu, c pKa = 4, gian 1 d dy c pH= 1 v gian 2 l huyt tng c pH = 7 (H.1)

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Gian 2 pH = 7

Gian 1 pH = 1 pKa = 4

1000

R- COO- + H+ R- COOH

R- COO- + H+

R- COOH

1000

Hnh 1.2: S khuch tn qua mng p dng phng trnh Henderson- Hasselbach, ta c: gian 1 (d dy): [ R- COOH ] log [ R - COO- ] gian 2 (mu): = 4 - 1 = 3; Log ca 3 = 1000

[ R- COOH ] log [ R - COO- ] = 4 - 7 = - 3; Log ca - 3 = 1/1000

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V ch phn khng ion ha v c nng cao mi khuch tn c qua mng cho nn acid ny s chuyn t gian 1 (d dy) sang gian 2 (mu) v c hp thu. Tr s pKa ca mt s thuc l acid yu v base yu c ghi bng1. Nn nh rng base c pKa cao l base mnh v acid c pKa cao l acid yu. Bng 1.1: Tr s pKa ca mt s thuc l acid v base yu ( nhit 250C) Acid yu Salicylic acid Acetylsalicylic acid Sulfadiazin Barbital Boric acid pKa Base yu 3.00 Reserpin 3.49 Codein 6.48 Quinin 7.91 Procain 9.24 Atropin pKa 6.6 7.9 8.4 8.8 9.65

S ion ha ca thuc cn ph thuc vo pH mi trng. Bng 1.2: nh hng ca pH n s ion ha ca salicylic acid c pKa = 3 pH 1 2 3 % khng ion ha 99,0 90,9 50,0

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4 5 6

9,09 0,99 0,10

Nh vy, salicylic acid (aspirin) uc hp thu nhiu d dy v phn trn ca ng tiu ha. Qua bng ny cho thy khi b ng c thuc, mun ngn cn hp thu hoc thuc b hp thu ra ngoi, ta c th thay i pH ca mi trng. Th d phenobarbital (Luminal, Gardenal) l mt acid yu c pKa = 7,2; nc tiu bnh thng c pH cng bng 7,2 nn phenobarbital b ion ha 50%. Khi nng pH ca nc tiu ln 8, ion ha ca thuc s l 86%, do thuc khng thm c vo t bo. iu ny c dng trong iu tr nhim c phenobarbital: truyn dung dch NaHCO3 1,4% base ha nc tiu, thuc s b tng thi tr. i vi mt cht kh (th d thuc m bay hi), s khuch tn t khng kh ph nang vo mu ph thuc vo p lc ring phn ca cht kh gy m c trong khng kh th vo v ha tan ca kh m trong mu. 1.4. Vn chuyn tch cc Vn chuyn tch cc l s ti thuc t bn ny sang bn kia mng sinh hc nh mt "cht vn chuyn" (carrier) c hiu c sn trong mng sinh hc. * c im ca s vn chuyn ny l: - C tnh bo ha: do s lng carrier c hn - C tnh c hiu: m i carrier ch to phc vi vi cht c cu trc c hiu vi n. - C tnh cnh tranh: cc thuc c cu trc gn ging nhau c th gn cnh tranh vi 1 carrier, cht no c i lc mnh hn s gn c nhiu hn.

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- C th b c ch: mt s thuc (nh actinomycin D) lm carrier gim kh nng gn thuc vn chuyn. * Hnh thc vn chuyn: c hai cch - Vn chuyn thun li (Vn chuyn tch cc th pht) : khi km theo carrier li c c s chnh lch bc thang nng , v vy s vn chuyn ny khng cn nng lng. Th d vn chuyn glucose, pyramidon theo bc thang nng ca Na+ - Vn chuyn tch cc thc th (Vn chuyn tch cc nguyn pht): l vn chuyn i ngc bc thang nng , t ni c nng thp sang ni c nng cao hn. V vy i h i phi c nng lng c cung cp do ATP thu phn, thng c gi l cc "bm", th d s vn chuyn ca Na+, K+, Ca++,I-, acid amin.

Hnh 1.3. Cc cch vn chuyn thuc qua mng sinh hc

2. CC QU TRNH DC NG HC 2.1. S hp thu

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Hp thu l s vn chuyn thuc t ni dng thuc (ung, tim) vo mu ri i khp c th, ti ni tc dng. Nh vy s hp thu s ph thuc vo: - ha tan ca thuc. Thuc dng di dng dung dch nc d hp thu hn dng du, dch treo hoc dng cng - pH ti ch hp thu v c nh hng n ion ha v tan ca thuc. - Nng ca thuc. Nng cng cao cng hp thu nhanh. - Tun hon ti vng hp thu: cng nhiu mch, cng hp thu nhanh. - Din tch vng hp thu. Phi, nim mc rut c din tch ln, hp thu nhanh. T nhng yu t cho thy ng a thuc vo c th s c nh hng ln n s hp thu. Ngoi tr ng tim t nh mch, trong qu trnh hp thu vo vng tun hon, mt phn thuc s b ph hu do cc enzym ca ng tiu ha, ca t bo rut v c bit l gan, ni c i lc vi nhiu thuc. Phn thuc b ph hu trc khi vo vng tun hon c gi l "first pass metabolism" (chuyn ha do hp thu hay chuyn ha qua gan ln th nht v thng l ung thuc). Phn vo c tun hon mi pht huy tc dng dc l, c gi l sinh kh dng (bioavailability) ca thuc (xin xem phn sau) Sau y s im qua cc ng dng thuc thng thng v cc c im ca chng. 2.1.1. Qua ng tiu ha u im l d dng v l ng hp thu t nhin. Nhc im l b cc enzym tiu ha ph hu hoc thuc to phc vi thc n lm chm hp thu. i khi thuc kch thch nim mc tiu ha, gy vim lot 2.1.1.1. Qua nim mc ming: thuc ngm di li Do thuc vo thng vng tun hon nn khng b dch v ph hu, khng b chuyn ha qua gan ln th nht

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2.1.1.2. Thuc ung Thuc s qua d dy v qua rut vi cc c im sau: * d dy: - C pH = 1- 3 nn ch hp thu cc acid yu, t b ion ha, nh aspirin, phenylbutazon, barbiturat. - Ni chung t hp thu v nim mc t mch mu, li cha nhiu cholesterol, thi gian thuc d dy khng lu. - Khi i hp thu nhanh hn, nhng d b kch thch * rut non: L ni hp thu ch yu v c din tch hp thu rt rng (> 40 m2), li c ti mu nhiu, pH tng dn ti base (pH t 6 n 8). - Thuc t b ion ha nhng nu t hoc khng tan trong lipid (sulfaguanidin, streptomycin) th t c hp thu. - Thuc mang amin bc 4 s b ion ha mnh kh hp thu, th d cc loi cura. - Cc anion sulfat SO4- - khng c hp thu: MgSO4, Na2SO4 ch c tc dng ty. 2.1.1.3. Thuc t trc trng Khi khng dng ng ung c (do nn, do hn m, hoc tr em) th c dng thuc t vo hu mn. Khng b enzym tiu ha ph hu, khong 50% thuc hp thu qua trc trng s qua gan, chu chuyn ha ban u. Nhc im l hp thu khng hon ton v c th gy kch ng nim mc hu mn. 2.1.2. Thuc tim - Tim di da: do c nhiu si thn kinh cm gic nn au, t mch mu nn thuc hp thu chm

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- Tim bp: khc phc c hai nhc im trn ca tim di da- mt s thuc c th gy hoi t c nh ouabain, calci clorid th khng c tim bp. - Tim t nh mch: thuc hp thu nhanh, hon ton, c th iu chnh liu c nhanh. Dng tim cc dung dch nc hoc cc cht kch ng khng tim bp c v lng mch t nhy cm v mu pha long thuc nhanh nu tim chm. Thuc tan trong du, thuc lm kt ta cc thnh phn ca mu hay thuc lm tan hng cu u khng c tim mch mu. 2.1.3. Thuc dng ngoi - Thm qua nim mc: thuc c th bi, nh git vo nim mc mi, hng, m o, bng quang iu tr ti ch. i khi, do thuc thm nhanh, li trc tip vo mu, khng b cc enzym ph hu trong qu trnh hp thu nn vn c tc dng ton thn: ADH dng bt xng mi; thuc t (lidocain, cocain) bi ti ch, c th hp thu, gy c ton thn. - Qua da: t thuc c th thm qua c da lnh. Cc thuc dng ngoi (thuc m, thuc xoa bp, cao dn) c tc dng nng ti ch st khun, chng nm, gim au. Tuy nhin, khi da b tn thng, vim nhim, bng... thuc c th c hp thu. Mt s cht c d tan trong m c th thm qua da gy c ton thn (thuc tr su ln hu c, cht c cng nghip anilin) Gi m ni bi thuc (bng p), xoa bp, dng thuc gin mch ti ch, dng phng php ion- di (iontophoresis) u lm tng ngm thuc qua da. Hin c dng thuc cao dn mi, lm gii phng thuc chm v u qua da, duy tr c lng thuc n nh trong mu: cao dn scopolamin, estrogen, nitrit Da tr s sinh v tr nh, c lp sng m ng manh, tnh thm mnh, d b kch ng cho nn cn thn trng khi s dng, hn ch din tch bi thuc.

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- Thuc nh mt: ch yu l tc dng ti ch. Khi thuc chy qua ng mi - l xung nim mc mi, thuc c th c hp thu trc tip vo mu, gy tc dng khng mong mun. 2.1.4. Cc ng khc - Qua phi: cc cht kh v cc thuc bay hi c th c hp thu qua cc t bo biu m ph nang, nim mc ng h hp. V din tch rng (80- 100 m2) nn hp thu nhanh. y l ng hp thu v thi tr chnh ca thuc m hi. S hp thu ph thuc vo nng thuc m trong khng kh th vo, s thng kh h hp, ha tan ca thuc m trong mu (hay h s phn ly mu: kh l) Mt s thuc c th dng di dng phun sng iu tr ti ch (hen ph qun). - Tim tu sng: thng tim vo khoang di nhn hoc ngoi mng cng gy t vng thp (chi di, khung chu) bng dung dch c t trng cao (hyperbaric solution) hn dch no tu. 2.1.5. Thng s dc ng hc ca s hp thu: sinh kh dng (F) 2.1.5.1. nh ngha: Sinh kh dng F (bioavailability) l t l phn trm lng thuc vo c vng tun hon dng cn hot tnh v vn tc hp thu thuc (biu hin qua Cmax v Tmax) so vi liu dng. Sinh kh dng phn nh s hp thu thuc. 2.1.5.2. ngha - Khi thay i t dc, cch bo ch thuc s lm thay i ha tan ca thuc (hot cht) v lm thay i F ca thuc. Nh vy, 2 dng bo ch ca cng mt sn phm c th c 2 sinh kh dng khc nhau. Khi nim tng ng sinh hc (bioequivalence) dng so snh cc F ca cc dng bo ch khc nhau ca 1 hot cht: F1/F2. - Khi thay i cu trc ha hc, c th lm F thay i:

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Ampicilin c F = 50% Amoxicilin (gn thm nhm OH) c F = 95% - S chuyn ha thuc khi qua gan ln th nht, hay chuyn ha trc khi vo tun hon (first pass metabolism) lm gim sinh kh dng ca thuc. Song i khi v thuc qua gan li c th c chuyn ha thnh cht c hot tnh nn tuy sinh kh dng ca ng ung l thp nhng tc dng dc l li khng km ng tim chch tnh mch. Th d propranolol c sinh kh dng theo ng ung l 30% nhng gan n c chuyn ha thnh 4- OH propranolol vn c hot tnh nh propranolol. - Cc yu t lm thay i F do ngi dng thuc: . Thc n lm thay i pH hoc nhu ng ca ng tiu ha. . Tui (tr em, ngi gi): thay i hot ng ca cc enzym. . Tnh trng bnh l: to bn, tiu chy, suy gan. . Tng tc thuc: hai thuc c th tranh chp ti ni hp thu hoc lm thay i tan, phn ly ca nhau. 2.2. S phn phi

Sau khi c hp thu vo mu, mt phn thuc s gn vo protein ca huyt t ng (cc protein trong t bo cng gn thuc), phn thuc t do khng gn vo protein s qua c thnh mch chuyn vo cc m, vo ni tc dng (cc receptor), vo m d tr, hoc b chuyn ha ri thi tr (H1). Gia nng thuc t do (T) v phc hp protein - thuc (P- T) lun c s cn bng ng: T+P P-T

Qu trnh phn ph i thuc ph thuc nhiu vo tun hon khu vc. Tu theo s ti mu, thng chia c th thnh 3 gian (H2) Gian II Gian I Gian III

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C quan c ti mu nhiu: tim, thn, gan, no, phi tng

Huyt

C quan c ti mu t hn: m m, da, c

Hnh 1.4. H phn ph i thuc 3 gian Hai loi yu t c nh hng n s phn ph i thuc trong c th: - V pha c th: tnh cht mng t bo, mng mao mch, s lng v tr gn thuc v pH ca mi trng. - V pha thuc: trng lng phn t, t l tan trong nc v trong lipid, tnh acid hay base, ion ha, i lc ca thuc vi receptor. 2.2.1. S gn thuc vo protein huyt tng 2.2.1.1. V tr gn: phn ln gn vo albumin huy t tng (cc thuc l acid yu) v vo a1 glycoprotein (cc thuc l base yu) theo cch gn thun nghch . 2.2.1.2. T l gn: tu theo i lc ca tng loi thuc vi protein huyt tng(bng 1)

Bng 1.3: T l gn thuc vo protein huyt tng T l gn thuc vi protein huyt tng Thuc l acid yu 75-100%: Phenylbutazon, Thuc l base yu 75- 100%: Diazepam

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Warfarin Phenytoin Aspirin 25- 75%: Benzylpenicilin Methotrexat Khng gn: Ethosuximid

Digitoxin Clopromazin Erythromycin 25- 75%: Cloroquin Morphin Khng gn: Isoniasid Ouabain

S gn thuc vo protein huyt t ng ph thuc vo 3 yu t: - S lng v tr gn thuc trn protein huyt t ng - Nng phn t ca cc protein gn thuc - Hng s gn thuc hoc hng s i lc gn thuc 2.2.1.3. ngha ca vic gn thuc vo protein huyt tng - Lm d hp thu, chm thi tr v protein mu cao nn ti ni hp thu, thuc s c ko nhanh vo mch. - Protein huyt t ng l cht m, l kho d tr thuc, sau khi gn thuc, s gii phng t t thuc ra dng t do v ch c dng t do mi qua c cc mng sinh hc pht huy tc dng dc l. - Nng thuc t do trong huyt tng v ngoi dch k lun trng thi cn bng. Khi nng thuc dch k gim, thuc huyt t ng s i ra, protein gn thuc s nh thuc gi cn bng.

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- Nhiu thuc c th cng gn vo 1 v tr ca protein huyt tng, gy ra s tranh chp, ph thuc vo i lc ca thuc. Thuc b y kh i protein s tng tc dng, c th gy c. Th d trn ngi ang dng tolbutamid iu tr i tho ng, nay v au khp, dng thm phenylbutazon, phenylbutazon s y tolbutamid ra dng t do, gy h ng huyt t ngt. C khi thuc y c cht ni sinh, gy tnh trng nhim c cht ni sinh: salicylat y bilirubin, sulfamid h ng huyt y insulin ra kh i v tr gn vi protein. - Trong iu tr, lc u dng liu tn cng bo ha cc v tr gn, sau cho liu duy tr n nh tc dng. - Trong cc trng hp bnh l lm tng - gim lng protein huyt tng (nh suy dinh dng, x gan, thn h, ngi gi...), cn hiu chnh liu thuc. 2.2.2. S phn phi li Thng gp vi cc thuc tan nhiu trong m, c tc dng trn thn kinh trung ng v dng thuc theo ng tnh mch. Th d in hnh ca hin tng ny l gy m bng thiopental, mt thuc tan nhiu trong m. V no c ti mu nhiu, nng thuc t c ti a trong no rt nhanh. Khi ngng tim, nng thiopental trong huyt tng gim nhanh v thuc khuch tn vo cc m, c bit l m m. Nng thuc trong no gim theo nng thuc trong huyt tng. V vy khi m nhanh, nhng tc dng m khng lu. Khi cho cc liu thuc b xung duy tr m, thuc tch ly nhiu m m. T y thuc li c gii phng li vo mu ti no khi ngng cho thuc, lm cho tc dng ca thuc tr nn ko di. 2.2.3. Cc phn phi c bit 2.2.3.1. Vn chuyn thuc vo thn kinh trung ng Phng thc vn chuyn: thuc phi vt qua 3 "hng ro"

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- T mao mch no vo m thn kinh (hng ro mu- no): thuc tan nhiu trong lipid th d thm, thuc tan trong nc rt kh vt qua v cc t bo thn kinh m (astrocyte- t bo hnh sao) nm rt st nhau, ngay ti mng y, ngoi ni m mao mch. - T m ri mng mch vo dch no tu (hng ro mu- mng no hoc mu- dch no tu): nh hng ro trn; thuc cn tan mnh trong lipid. - T dch no tu vo m thn kinh (hng ro dch no tu - no), thc hin bng khuch tn th ng. Cc yu t quyt nh tc vn chuyn thuc vo dch no tu v no th cng ging nh nguyn tc thm qua mng sinh hc, l: - Mc gn thuc vo protein huyt t ng - Mc ion ha ca phn thuc t do (ph thuc vo pH v pKa) - H s phn b lipid/ nc ca phn thuc t do khng ion ha ( tan trong lipid) Thuc ra khi dch no tu c thc hin mt phn bi c ch vn chuyn tch cc trong m ri mng mch (mt h thng vn chuyn tch cc cho cc acid yu v mt h thng khc cho cc base yu). T no, thuc ra theo c ch khuch tn th ng, ph thuc ch yu vo tan trong lipid ca thuc. Hng ro mu - no cn ph thuc vo la tui v vo trng thi bnh l: tr s sinh v tr nh, lng myelin cn t, cu trc "hng ro" cn cha "cht ch" nn thuc d khuch tn c vo no. Penicilin khng qua c mng no bnh thng, nhng khi b vim, penicilin v nhiu thuc khc c th qua c. Hng ro mu no mang tnh cht mt hng ro lipid khng c ng dn, v vy, i vi nhng cht tan mnh trong lipid, coi nh khng c hng ro. Mt s vng nh ca no nh cc nhn bn ca vng di i, sn no tht 4, tuyn tng v thu sau tuyn yn cng khng c hng ro.

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Kt qu ca s vn chuyn - Cc thuc tan nhiu trong m s thm rt nhanh vo no, nhng li khng li c lu (xin xem "s phn ph i li"). Thuc b ion ha nhiu, kh tan trong m, kh thm vo thn kinh trung ng: atropin sulfat, mang amin bc 3, t ion ha, vo c TKT; cn atropin methyl bromid, mang amin bc 4, ion ha mnh, khng vo c TKT. - C th thay i s phn ph i thuc gia huyt tng v no bng thay i pH ca huyt tng: trong iu tr ng c phenobarbital, truyn NaHCO3 nng pH ca mu (7,6) vt ln trn pH ca dch no ty (7,3), lm cho nng dng ion ha trong huyt tng ca phenobarbital tng cao nng dng khng ion ha gim thp s ko dng khng ion ha ca thuc t dch no tu vo mu. 2.2.3.2. Vn chuyn thuc qua rau thai Phng thc - Mao mch ca thai nhi nm trong nhung mao c nhng trong h mu ca m, v vy gia mu m v thai nhi c "hng ro rau thai". Tnh thm ca mng mao mch thai nhi tng theo tui thai. S thm thuc cng theo quy lut chung: - Cc thuc tan trong m s khuch tn th ng: thuc m hi, (protoxyd nit, halothan, cyclopropan), thiopental. - Vn chuyn tch cc: cc acid amin, cc ion Ca++, Mg++. - Thm bo (pinocytosis) vi cc git huyt tng ca m Kt qu - Tr cc thuc tan trong nc c trng lng phn t ln trn 1000 (nh dextran) v cc amin bc 4 (galanin, neostigmin) khng qua c rau thai, rt nhiu thuc c th vo c

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mu thai nhi, gy nguy him cho thai (phenobarbital, sulfamid, morphin), v vy, khng nn coi l c "hng ro rau thai". - Lng thuc gn vo protein- huyt tng mu m cao th nng thuc t do thp, ch c thuc t do ny mi sang c mu con, ti y mt phn thuc ny li gn vo protein huyt tng mu con, v vy nng thuc t do trong mu con cng thp. t c nng thuc t do tng ng nh mu m, cn khong thi gian ti 40 pht. V d tim thiopental cho m trong thi gian chuyn d, v sau 10 pht m c th nng thiopental trong mu con vn cha t c mc m, iu gii thch v sao b m ng m li c th ra a con vn cn thc. - Ngoi ra, rau thai cn c nhiu enzym nh cholinesterase, monoamin oxydase, hydroxylase c th chuyn ha thuc, lm gim tc dng bo v thai nhi. 2.2.4. S tch lu thuc Mt s thuc hoc cht c c m i lin kt rt cht ch (thng l lin kt cng ha tr) vi mt s m trong c th v c gi li rt lu, hng thng n hng chc nm sau dng thuc, c khi ch l 1 ln: DDT gn vo m m, tetracyclin gn vo xng, mm rng, As gn vo t bo sng... Mt s thuc tch ly trong c vn v cc t bo ca m khc vi nng cao hn trong mu. Nu s gn thuc l thun nghch th thuc s li c gii phng t "kho d tr" vo mu (xin xem "s phn ph i li"). Nng quinacrin trong t bo gan khi dng thuc di ngy c th cao hn nng huyt tng vi trm ln do t bo gan c qu trnh vn chuyn tch cc ko quinacrin vo trong t bo. 2.2.5. Thng s dc ng hc ca s phn phi: th tch phn phi (Vd) 2.2.5.1. nh ngha

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Th tch phn phi biu th mt th tch biu kin (khng c thc) cha ton b lng thuc c a vo c th c nng bng nng thuc trong huyt tng. D Vd = Cp D: liu lng thuc a vo c th (mg) theo ng tnh mch. Nu theo ng khc th phi tnh n sinh kh dng : D F Cp: nng thuc trong huyt tng o ngay sau khi phn ph i v trc khi thi tr. Vd: th tch khng c thc, tnh bng L (lt) hoc L/ kg. Th d: mt ngi nng 60 kg, c lng nc trong c th l 36 L (60% trng lng c th), ung 0,5 mg (500 mg) digoxin c F theo ng ung l 0,7. o nng digoxin trong huyt tng thy Cp= 0,7 ng/ mL (0,0007 mg/ mL). Vy: Vd = 0,0007 Vd = 500L , ln bng gn 14 ln lng nc trong c th nn l th tch biu kin. 2.2.5.2. Nhn xt v ngha lm sng - Vd nh nht l bng th tch huyt t ng (3L hoc 0,04L/ kg). Khng c gii hn trn cho Vd. Vd cng ln chng t thuc cng gn nhiu vo m: iu tr nhim khun xng khp nn chn khng sinh thch hp c Vd ln. - Khi bit Vd ca thuc, c th tnh c liu cn dng t nng huyt tng mong mun: D = Vd Cp 0,5 0,7 = 500L hoc 8,3 L/ kg lit

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2.3.

S chuyn ha thuc

2.3.1. Mc ch ca chuyn ha thuc: thi tr cht l (thuc) ra khi c th. Nhng nh ta bit, thuc l nhng phn t tan c trong m, khng b ion ha, d thm qua mng t bo, gn vo protein huyt tng v gi li trong c th. Mun thi tr, c th phi chuyn ha nhng thuc ny sao cho chng tr nn cc phc hp c cc, d b ion ha, do tr nn t tan trong m, kh gn vo protein, kh thm vo t bo, v v th, tan hn trong nc, d b thi tr (qua thn, qua phn). Nu khng c cc qu trnh sinh chuyn ha, mt s thuc rt tan trong m (nh pentothal) c th b gi li trong c th hn 100 nm ! 2.3.2. Ni chuyn ha v cc enzym chnh xc tc cho chuyn ha: - Nim mc rut: protease, lipase, decarboxylase - Huyt thanh: esterase - Phi: oxydase - Vi khun rut: reductase, decarboxylase - H thn kinh trung ng: monoaminoxydase, decarboxylase - Gan: l ni chuyn ha chnh, cha hu ht cc enzym tham gia chuyn ha thuc, s trnh by di y 2.3.3. Cc phn ng chuyn ha chnh Mt cht A c a vo c th s i theo 1 hoc cc con ng sau: - c hp thu v thi tr khng bin : bromid, lithi, saccharin. - Chuyn ha thnh cht B (pha I), ri cht C (pha II) v thi tr - Chuyn ha thnh cht D ( pha II) ri thi tr

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Cht A c th c hoc khng c hot tnh, sinh ra cht B khng c hoc c hot tnh. Cht C v D lun l cht khng c hot tnh sinh hc. Mt cht m A c th sinh ra nhiu cht chuyn ha loi B hoc C.

Hp thu

Sinh chuyn ha

Thi tr

Pha I

Pha II

A B A Tan trong m B C D C D Tan trong nc

Hnh 1.5. Cc phn ng chuyn ha thuc c phn lm 2 pha 2.3.3.1. Cc phn ng pha I Qua pha ny, thuc ang dng tan c trong m s tr nn c cc hn, d tan trong nc hn. Nhng v mt tc dng sinh hc, thuc c th mt hot tnh, hoc ch gim hot tnh, hoc i khi l tng hot tnh, tr nn c hot tnh. Mt s th d: Oxy kh + Prontosil (khng hot tnh "tin thuc") oxy ha + Phenylbutazon (c hot tnh) thu phn + Acetylcholin (c hot tnh) Cholin + A.acetic (mt hot tnh) oxyphenbutazon (cn ho t tnh) Sulfanilamid (c hot tnh)

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Cc phn ng chnh pha ny g m: - Phn ng oxy ha: l phn ng rt thng gp, c xc tc bi cc enzym ca microsom gan, c bit l hemoprotein, cytocrom P450. - Phn ng thu phn do cc enzym esterase, amidase, protease... Ngoi gan, huyt thanh v cc m khc (ph i, thn...) cng c cc enzym ny. - Phn ng kh. Phn ng oxy ha y l phn ng ph bin nht, c xc tc bi cc enzym oxy ha (mixed- function oxydase enzym system- mfO), thy c nhiu trong microsom gan, c bit l h enzym cytochrom P450 (Cyt- P450), l cc protein mng c cha hem (hemoprotein) khu tr li n i bo nhn ca t bo gan v vi m khc. Trong c th ngi hin thy c t i 17 typ v rt nhiu di typ cytochrom P450 tham gia chuyn ha cc cht n i sinh v ngoi sinh t mi trng, thuc. Phn ng oxy ha loi ny i h i NADPH v O2 theo phc sau: C cht (RH) Cytochrom P450 O2 NADPH + H+ Phn ng c thc hin theo nhiu bc: 1) C cht (thuc , RH) phn ng vi dng oxy ha ca Cyt P450 (Fe3+) to thnh phc hp RH- P450 (Fe3+) 2) Phc hp RH- P450 (Fe3+) nhn 1 electron t NADPH, b kh thnh RH- P450 (Fe2+) 3) Sau , phc hp RH- P450 (Fe2+) phn ng vi 1 phn t oxy v 1 electron th 2 t NADPH to thnh phc hp oxy hot ha. 4) Cui cng, 1 nguyn t oxy c gii phng, t o H2O. Cn nguyn t oxy th 2 s oxy ha c cht (thuc): RH ROH, v Cyt.P450 c ti to. Qu trnh phn ng c tm tt s sau: H2O NADP+ C cht (R- OH) oxy ha

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Hnh 1.6: S oxy ha thuc ca cytocrom P450 Phn ng kh Kh cc dn xut nitro, cc aldehyd, carbonyl bi cc enzym nitroreductase, azoreductase, dehydrogenase... (bng 1.4) Phn ng thu phn Cc ng ni este v amid b thu phn bi cc enzym esterase, amidase c trong huyt tng, gan, thnh rut v cc m khc (bng 1.4)

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Bng 1.4: Cc phn ng chnh trong chuyn ha thuc pha I Loi phn ng 1. Phn ng oxy ha - N- mt alkyl - N- oxy ha -Mt amin oxy ha RNHCH3 R- NH2 + CH2O R- NH2 R - NHOH OH R- CHCH3 R- C- CH3 R- C- CH3 NH2 NH2 O + NH2 Imipramin, diazepam, morphin, codein, Clorpheniramin, dapson Diazepam, amphetamin Tolbutamid, ibuprofen, cyclosporin, midazolam Phn ng Th d cc thuc

Hydroxy ha mch R- CH2- CH3 R- CH2- CH3 thng OH

2. Phn ng kh

Prontosil, tartrazin - Azo- kh - Nitro- kh RN=NR1RNH- NHR1RNH2+R1NH2 RNO2 RNO RNHOH R-NH2 Nitrobenzen, chloramphenicol, clorazepam, dantrolen Methadon, naloxon - Carbonyl- kh R- CR' R- CHR' O 3. Phn ng thy phn - Cc este R1COOR2 R1COOH + R2OH OH

Procain, succinylcholin, aspirin, clofibrat Procainamid, lidocain, indomethacin

- Cc amid

RCONHR1 RCOOH + R1NH2

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2.3.3.2. Cc phn ng pha II Cc cht i qua pha ny tr thnh cc phc hp khng cn hot tnh, tan d trong nc v b thi tr. Tuy vy, pha ny, sulfanilamid b acetyl ha li tr nn kh tan trong nc, kt thnh tinh th trong ng thn, gy i mu hoc v niu. Cc phn ng pha II u l cc phn ng lin hp: mt phn t n i sinh (acid glucuronic, glutathion, sulfat, glycin, acetyl) s ghp vi mt nhm ha hc ca thuc to thnh cc phc hp tan mnh trong nc. Thng thng, cc phn ng pha I s to ra cc nhm chc phn cn thit cho cc phn ng pha II, l cc nhm - OH, -COOH, -NH2, -SH... Cc phn ng chnh: cc phn ng lin hp vi acid glucuronic, acid sulfuric, acid amin (ch yu l glycin), phn ng acetyl ha, methyl ha. Cc phn ng ny i hi nng lng v c cht ni sinh, l c im ca pha II. Bng 1.5: Cc phn ng chnh trong chuyn ha thuc pha II Loi phn ng - Glucuro- hp C cht ni sinh Enym chuyn (v tr) Loi c cht Phenol, alcol, acid carboxylic, sulfonamid Th d cc thuc Morphin, diazepam, digitoxin, acetaminophen, sulfathiazol Acid ethacrynic bromobenzen

Acid UDP UDP glucuronosyl glucuronic transferase (microsom)

- Glutathionhp

Glutathion

Glycin - Glycin- hp

- Sulfo- hp

Phosphoaden osyl phosphosulfa t

GSHS- Epoxid, nhm transferase (d ch nitro bo tng, hydroxylamin microsom) Acid salicylic, a.benzoic, a.nicotinic, Acyl- CoA Dn xut acyl- a.cholic transferase (ty CoA ca acid carboxylic th) Estron, anilin, methyldopa, 3OH cumarin, Phenol, alcol, acetaminophen Sulfotransferase (dch bo tng) cc amin vng thm Dopamin, adrenalin, pyridin, histamin Sulfonamid, isoniazid, clonazepam,

-Methyl- ha

S- adenosyl methionin

Transmethylase (dch bo tng)

Catecholamin, phenol amin, histamin

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dapson. Nacetyltrasferase (dch bo tng) Cc amin

- Acetyl- ha

Acetyl- CoA

Ngoi ra, c mt s thuc hon ton khng b chuyn ha, l nhng hp cht c cc cao (nh acid, base mnh), khng thm qua c lp m ca microsom. Phn ln c thi tr nhanh nh hexamethonium, methotrexat. Mt s hot cht khng c cc cng c th khng b chuyn ha: barbital, ether, halothan, dieldrin. Mt thuc c th b chuyn ha qua nhiu phn ng xy ra cng mt lc hoc tip n i nhau. Th d paracetamol b glucuro- hp v sulfo- hp cng mt lc; chlorpromazin b chuyn ha nhn phenothiazin qua nhiu phn ng, sau l nhnh bn cng qua mt lot phn ng cui cng cho ti hn 30 cht chuyn ha khc nhau. 2.3.4. Cc yu t lm thay i tc chuyn ha thuc 2.3.4.1. Tui - Tr s sinh thiu nhiu enzym chuyn ha thuc - Ngi cao tui enzym cng b lo ho 2.3.4.2. Di truyn - Do xut hin enzym khng in hnh khong 1: 3000 ngi c enzym cholinesterase khng in hnh, thu phn rt chm suxamethonium nn lm ko di tc dng ca thuc ny. - Isoniazid (INH) b mt tc dng do acetyl ha. Trong mt nghin cu, cho ung 10 mg/ kg isoniazid, sau 6 gi thy lng isoniazid trong mu mt nhm l 3- 6 mg/ mL, nhm khc ch l 2,5mg/ mL. Nhm u l nhm acetyl ha chm, cn gim liu v d c vi TKT. V di truyn, thuc nhm acetyl ha chm, thy 60% l ngi da trng, 40% l da en v 20% l da vng. Nhm sau l nhm acetyl ha nhanh, cn phi tng liu, nhng sn phm chuyn ha acetyl isoniazid li c vi gan. - Ngi thiu glucose 6 phosphat dehydrogenase (G6PD) s d b thiu mu tan mu khi dng phenacetin, aspirin, quinacrin, vi loi sulfamid... 2.3.4.3. Yu t ngoi lai - Cht gy cm ng enzym chuyn ha: c tc dng lm tng sinh cc enzym microsom gan, lm tng hot tnh cc enzym ny. Th d: phenobarbital, meprobamat, clorpromazin, phenylbutazon, v hng trm thuc khc: khi dng nhng thuc ny vi cc thuc b chuyn ha qua cc enzym c cm ng s lm gim tc dng ca thuc c phi hp, hoc ca chnh n (hin tng quen thuc). Tri li, vi nhng thuc phi qua chuyn ha mi tr thnh c hot tnh ("tin thuc"), khi dng chung vi thuc gy cm ng s b tng c tnh (parathion paraoxon) - Cht c ch enzym chuyn ha: mt s thuc khc nh cloramphenicol, dicumarol, isoniazid, quinin, cimetidin... li c tc dng c ch, lm gim hot tnh chuyn ha thuc ca enzym, do lm tng tc dng ca thuc phi hp. 2.3.4.4. Yu t bnh l

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- Cc bnh lm tn thng chc phn gan s lm suy gim sinh chuyn ha thuc ca gan: vim gan, gan nhim m, x gan, ung th gan... d lm tng tc dng hoc c tnh ca thuc chuyn ha qua gan nh tolbutamid, diazepam. - Cc bnh lm gim lu lng mu ti gan nh suy tim, hoc dng thuc chn b giao cm ko di s lm gim h s chit xut ca gan, lm ko di t/2 ca cc thuc c h s chit xut cao ti gan nh lidocain, propranolol, verapamil, isoniazid. 2.4. Thi tr Thuc c thi tr di dng nguyn cht hoc b chuyn ha 2.4.1. Thi tr qua thn y l ng thi tr quan trng nht ca cc thuc tan trong nc, c trng lng phn t nh hn 300. 2.4.1.1. Qu trnh thi tr - Lc th ng qua cu thn: dng thuc t do, khng gn vo protein huyt tng. - Bi tit tch cc qua ng thn: do phi c cht vn chuyn (carrier) nn ti y c s cnh tranh thi tr. Th d dng thiazid ko di, do phi thi tr thiazid, c th gim thi acid uric, d gy bnh gut (thiazid v a.uric c cng carrier ng thn). Qu trnh bi tit tch cc xy ra ch yu ng ln gn, c 2 h vn chuyn khc nhau, mt h cho cc anion (cc acid carboxylic nh penicilin, thiazid, cc cht glucuro- v sulfo- hp), v mt h cho cc cation (cc base hu c nh morphin, thiamin). - Khuch tn th ng qua ng thn: mt phn thuc thi tr trong nc tiu ban u l i c ti hp thu vo mu. l cc thuc tan trong lipid, khng b ion ha pH nc tiu (pH = 5-6) nh phenobarbital, salicylat. Cc base yu khng c ti hp thu. Qu trnh ny xy ra ng ln gn v c ng ln xa do bc thang nng c to ra trong qu trnh ti hp thu nc cng Na+ v cc ion v c khc. Qu trnh ti hp thu th ng y ph thuc nhiu vo pH nc tiu. Khi base ha nc tiu, th cc acid yu (acid barbituric) s b thi tr nhanh hn v b ion ha nhiu nn ti hp thu gim. Ngc li, khi acid ha nc tiu nhiu hn th cc base (amphetamin) s b thi tr nhiu hn. iu ny c ng dng trong iu tr nhim c thuc. 2.4.1.2. ngha lm sng - Lm gim thi tr tit kim thuc: penicilin v probenecid c chung h vn chuyn ti ng thn. Thn thi probenecid (r tin, t tc dng iu tr) v gi li penicilin (t tin hn, c tc dng iu tr). - Lm tng thi tr iu tr nhim c: base ha nc tiu, lm tng ion ha ca phenobarbital, t ng thi tr khi b nhim c phenobarbital (xin xem"khuch tn th ng"). - Trong trng hp suy thn, cn gim liu thuc dng 2.4.2. Thi tr qua mt

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- Sau khi chuyn ha gan, cc cht chuyn ha s thi tr qua mt theo phn ra ngoi. Phn ln sau khi b chuyn ha thm rut s c ti hp thu vo mu thi tr qua thn. - Mt s hp cht chuyn ha glycuronid ca thuc c trng lng phn t trn 300 sau khi thi tr qua mt xung rut c th b thu phn bi b glycuronidase ri li c ti hp thu v gan theo ng tnh mch gnh li vo vng tun hon, c gi l thuc c chu k rutgan. Nhng thuc ny tch lu trong c th, lm ko di tc dng (morphin, tetracyclin, digitalis tr tim...). 2.4.3. Thi tr qua phi - Cc cht bay hi nh ru, tinh du (eucalyptol, menthol) - Cc cht kh: protoxyd nit , halothan 2.4.4. Thi tr qua sa Cc cht tan mnh trong lipid (barbiturat, chng vim phi steroid, tetracyclin, cc alcaloid), c trng lng phn t di 200 thng d dng thi tr qua sa. V sa c pH hi acid hn huyt tng nn cc thuc l base yu c th c nng trong sa hi cao hn huyt tng v cc thuc l acid yu th c nng thp hn. 2.4.5. Thi tr qua cc ng khc Thuc c th cn c thi tr qua m hi, qua nc mt, qua t bo sng (lng, tc, mng), tuyn nc bt. S lng khng ng k nn t c ngha v mt iu tr. Thng c th gy tc dng khng mong mun (diphenyl hydantoin gy tng sn li khi b bi tit qua nc bt). Hoc dng pht hin cht c (c gi tr v mt php y): pht hin asen trong tc ca Napoleon sau 150 nm! 2.4.6. Thng s dc ng hc ca chuyn ha v thi tr thuc Mc ch ca chuyn ha l lm cho thuc mt hot tnh, d tan trong nc v thi tr. V vy, qu trnh chuyn ha chnh l qu trnh thi tr thuc. C 2 thng s dc ng hc l thanh thi (CL) v thi gian bn thi (t1/2) u nh gi qu trnh chuyn ha v thi tr thuc. 2.4.6.1. thanh thi (clearance CL) nh ngha thanh thi (CL) biu th kh nng ca 1 c quan (gan, thn) trong c th thi tr hon ton mt thuc (hay mt cht) ra khi huyt tng khi mu tun hon qua c quan . Clearance c biu th bng mL/ pht, l s mL huyt tng c thi tr thuc hon ton trong thi gian 1 pht khi qua c quan. Ho c c khi tnh theo kg thn trng: mL/ pht/ kg. V CL = (mL/ pht) Cp V: tc thi tr ca thuc qua c quan (mg/ pht) Cp: nng thuc trong huyt tng (mg/ L)

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Clearance cng l mt tr s o, mang tnh l thuyt v s tun hon ca mu qua c quan c lin tc lp i lp li. Trong thc t, thuc c coi l lc sch kh i huyt tng sau mt khong thi gian l 7 t1/2. Hai c quan chnh thamgia thi tr thuc khi c th l gan (lng thuc b chuyn ha v thi tr nguyn cht qua mt) v thn, v vy, CL ton b c coi l CL gan + CL thn. ngha - Thuc c CL ln l thuc c thi tr nhanh, v th thi gian bn thi (t1/2) s ngn. - Dng CL tnh liu lng thuc c th duy tr c nng thuc n nh trong huyt tng. Nng ny t c khi tc thi tr bng tc hp thu. - Bit CL hiu chnh liu trong trng hp bnh l suy gan, suy thn. 2.4.6.2. Thi gian bn thi (half- life- t1/2) nh ngha Thi gian bn thi t1/2 c phn bit lm 2 loi : - t1/2 a hay t1/2 hp thu l thi gian cn thit 1/2 lng thuc dng hp thu c vo tun hon. nu dng thuc theo ng tim bp th t1/2 a khng ng k. - t1/2 hay t1/2 thi tr l thi gian cn thit nng thuc trong huyt tng gim cn 1/2. Trong thc hnh iu tr, hay dng t1/2 v thng ch vit l t1/2 ho c t/2. ngha - T cng thc trn ta thy t1/2 t l nghch vi clearance. Khi CL thay i theo nguyn nhn sinh l ho c bnh l s lm t1/2thay i, hiu qu ca iu tr b nh hng. Cn phi hiu chnh liu lng hoc khong cch gia cc liu (xem phn Nhng bin i ca dc ng hc). - Trong thc hnh iu tr, thng coi thi gian 5 ln t1/2 (5 ln dng thuc cch u) th nng thuc trong mu t c trng thi n nh (Css), v sau khi ngng thuc khong 7 ln t1/2 th coi nh thuc b thi tr hon ton kh i c th (xem bng). Lng thuc c thi tr theo t/2 S ln t1/2 1 2 3 4 5 6 7 Lng thuc c thi tr (%) 50 75 88 94 97 98 99

- i vi m i thuc, thi gian bn thi l gi ng nhau cho m i liu dng. Do c th suy ra khong cch dng thuc: . Khi t1/2 < 6h: nu thuc t c, cho liu cao ko di c nng hiu dng ca thuc trong huyt tng. Nu khng th cho c liu cao (nh heparin, insulin) th truyn t nh mch lin tc hoc sn xut dng thuc gii phng chm.

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. Khi t1/2 t 6 n 24h: dng liu thuc vi khong cch ng bng t1/2. . Khi t1/2 > 24h: dng liu duy nht 1 ln m i ngy. CU HI T LNG GI 1. S hp thu thuc ph thuc vo nhng yu t no? 2. Phn tch, so snh cc c im ca cc ng hp thu thuc: ng tiu ha, ng tim, ng h hp v ng qua da, nim mc. 3. Trnh by v s vn chuyn thuc vo thn kinh trung ng v qua rau thai. ngha lm sng. 4. Sinh kh dng ca thuc l g? ngha. 5. Trnh by v th tch phn phi (Vd) v ngha lm sng? 6. S gn thuc vo protein huyt tng v ngha? 7. K tn cc phn ng chnh (khng vit cng thc) ca chuyn ha thuc kt qu v ngha? 8. K tn cc phn ng chnh (khng vit cng thc) ca chuyn ha thuc kt qu v ngha? 10. thanh thi l g? ngha? 11. Thi gian bn thi l g? ngha? pha I, pha II,

9. Trnh by cc cch thi tr thuc qua thn, qua gan, qua sa v ngha lm sng.

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Bi 2: I CNG V DC LC HC

MC TIU HC TP: Sau khi hc xong bi ny, sinh vin c kh nng: 1. Trnh by c c ch tc dng ca thuc qua receptor v khng qua receptor. 2. Phn bit c cc cch tc dng ca thuc. 3. Trnh by c nhng yu t thuc v bn thn thuc quyt nh tc dng ca thuc (l ha, cu trc, dng bo ch). 4. Nu c nhng yu t chnh v pha ngi bnh c nh hng n tc dng ca thuc (tui, quen thuc). 5. Trnh by c 5 trng thi tc dng c bit ca thuc. Dc lc hc nghin cu tc dng ca thuc ln c th sng, gii thch c ch ca cc tc dng sinh ha v sinh l ca thuc. Phn tch cng y c cc tc dng, cng cung cp c nhng c s cho vic dng thuc hp l trong iu tr. y l nhim v c bn nht v cng l kh khn ln nht ca dc lc hc. 1. C CH TC DNG CA THUC 1.1. Receptor - Tc dng ca phn ln cc thuc l kt qu ca s tng tc gia thuc vi receptor (th th cm). Receptor l mt thnh phn i phn t (macromolcular) tn ti vi mt lng gii hn trong mt s t bo ch, c th nhn bit mt cch c hiu ch mt phn t "thng tin" t nhin (hormon, cht dn truyn thn kinh), hoc mt tc nhn ngoi lai (cht ha hc, thuc) gy ra mt tc dng sinh hc c hiu, l kt qu ca tc dng tng h . Thnh phn i phn t ca receptor thng l protein v ch c protein mi c cu trc phc tp nhn bit c hiu ca mt phn t c cu trc 3 chiu. Receptor c 2 chc phn: 1) Nhn bit cc phn t thng tin (hay cn gi l ligand) bng s gn c hiu cc phn t ny vo receptor theo cc lin kt ha hc: - Lin kt ion: cc cht ha hc mang in tch (nh nhm amoni bc 4 cu acetylcholin c in tch dng), s gn vo vng mang in tch tri du ca receptor theo lin kt ny, vi lc lin kt khong 5- 10 kcal/ mol. - Lin kt hydro: do s phn b khng ng u electron trong phn t nn c m i lin kt gia nguyn t hydro vi cc nguyn t c in tch m cao nh oxy, nit v fluor. Lc lin kt khong 2- 5 kcal/ mol - Lin kt Van- der- Waals: l lc lin kt ca mi tng h gia cc electron vi cc nhn ca cc phn t st bn. Lc lin kt ph thuc vo khong cch gia cc phn t, lc ny tng i yu, khong 0,5 kcal/ mol. Cc thuc c vng benzen, c mt electron phn b ng u thng c m i lin kt ny. Cc lc lin kt trn u l thun nghch. - Lin kt cng ha tr: l lc lin kt gia cc nguyn t bng nhng cp in t chung. V l lc lin kt ln 50- 150 kcal/ mol nn l lin kt khng thun nghch nhit c th, khng

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c cht xc tc. Loi lin kt ny t gp. Th d lin kt gia cht alkyl ha vi t bo ung th, cc thuc c ch enzym mono- amin oxydase (MAOI), thuc tr su ln hu c vi cholinesterase. Mt phn t thuc c th gn vo receptor theo nhiu kiu lin kt. Th d: acetylcholin gn vo receptor M- cholinergic:

Hnh 2.1. Phc hp acetylcholin- receptor M Acetylcholin gn vo receptor M theo ng ni sau: Hai O ca chc ester to lin kt hydro vi receptor Nhm CH2- CH2 gn vi receptor bng lin kt phn t (lc Van- der- Waals) Hai gc CH3 ca amin bc 4 gn vo cc khoang ca v tr anion cng bng lc Van- der- Waals

2) Chuyn tc dng tng h gia ligand v receptor thnh mt tn hiu gy ra c p ng t bo. Cc receptor nm nhn t bo c hot ha bi cc ligand gn trn cc v tr c hiu ca ADN nm trong cc vng iu ha gen, gy ra s sao chp cc gen c hiu (receptor ca hormon steroid, vitamin D3...). Cc receptor nm mng t bo v xa nhn nn khng tham gia trc tip vo cc chng trnh biu hin ca gen. Khi cc ligand tc ng ln receptor s lm sn xut ra cc phn t trung gian- "ngi truyn tin th 2" (AMPv, GMPv, IP3, Ca2+, diacetyl glycerol...)- Nhng cht ny s gy ra mt lot phn ng trong t bo, dn ti mt thay i chuyn ha trong t bo, cng vi hoc khng c s thay i v biu hin gen (receptor ca adrenalin, ca benzodiazepin...). Nh vy, khi thuc gn vo receptor ca t bo th gy ra c tc dng sinh l. Nhng c khi thuc gn vo t bo m khng gy ra tc dng g, ni gn thuc c gi l ni tip nhn (acceptor) hoc receptor cm, (silent receptor) nh thuc m gn vo t bo m, digitalis gn vo gan, ph i, thn... Thuc gn vo receptor ph thuc vo i lc (affinity) ca thuc vi receptor. Hai thuc c cng receptor, thuc no c i lc cao hn s y c thuc khc ra. Cn tc dng ca thuc l do hiu lc (efficacy) ca thuc trn receptor . i lc v hiu lc khng phi lc no cng i cng nhau: acetylcholin l cht dn truyn thn kinh ca h ph giao cm, khi gn vo receptor M, gy hiu lc lm tng tit nc bt, co ng t, chm nhp tim...; atropin c i lc trn receptor M mnh hn acetylcholin rt nhiu nn y c acetylcholin ra kh i receptor M, nhng bn thn n li khng c hiu lc g. lm sng, tc dng ca atropin quan st c chnh l tc dng ca s thiu vng acetylcholin trn receptor M: kh ming (gim tit nc bt), gin ng t, nhp tim nhanh... 1.2. Cc c ch tc dng ca thuc

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1.2.1. Tc dng ca thuc thng qua receptor Thuc tc dng trc tip trn cc receptor ca cc cht n i sinh (hormon, cht dn truyn thn kinh): nhiu thuc tc dng trn cc receptor sinh l v thng mang tnh c hiu. Nu tc dng ca thuc ln receptor ging vi cht n i sinh, gi l cht ng vn hay cht ch vn (agonists), nh pilocarpin trn receptor M- cholinergic. Nu thuc gn vo receptor, khng gy tc dng ging cht ni sinh, tri li, ngn cn cht n i sinh gn vo receptor, gy tc dng c ch cht ng vn, c gi l cht i khng (antagonists), nh d- tubocurarin tranh chp vi acetylcholin ti receptor N ca c vn. - Mt s thuc thng qua vic gii phng cc cht n i sinh trong c th gy tc dng: amphetamin gii phng adrenalin trn thn kinh trung ng, nitrit lm gii phng NO gy gin mch... Xt trn nhiu mt, protein l mt nhm quan trng ca receptor- thuc. Do , ngoi receptor t bo, cc receptor ca thuc cn l: - Cc enzym chuyn ha hoc iu ha cc qu trnh sinh ha c th b thuc c ch hoc hot ha: . Thuc c ch enzym: captopril c ch enzym chuyn angiotensin I khng hot tnh thnh angiotensin II c hot tnh dng cha cao huyt p; cc thuc chng vim phi steroid c ch cyclooxygenase, lm gim tng hp prostaglandin nn c tc dng h st, chng vim; thuc tr tim digitalis c ch Na+- K+ ATPase... . Thuc hot ha enzym: cc yu t vi lng nh Mg2+, Cu2+, Zn2+ hot ha nhiu enzym protein kinase, phosphokinase tc dng ln nhiu qu trnh chuyn ha ca t bo. - Cc ion: thuc gn vo cc knh ion, lm thay i s vn chuyn ion qua mng t bo. Novocain cn tr Na+ nhp vo t bo thn kinh, ngn cn kh cc nn c tc dng gy t; benzodiazepin lm tng nhp Cl- vo t bo, gy an thn. 1.2.2. Tc dng ca thuc khng qua receptor Mt s thuc c tc dng khng phi do kt hp vi receptor. - Thuc c tc dng do tnh cht l ha, khng c hiu: Cc mu i cha cc ion kh hp thu qua mng sinh hc nh MgSO4, khi ung s "g i nc" thnh rut vo lng rut v gi nc trong lng rut nn c tc dng ty; khi tim vo tnh mch s ko nc t gian bo vo mu nn c dng cha ph no. Isosorbid, mannitol dng liu tng i cao, lm tng p lc thm thu trong huyt tng. Khi l c qua cu thn, khng b ti hp thu ng thn, lm tng p lc thm thu trong ng thn, c tc dng li niu. Nhng cht to chelat hay cn gi l cht "cng cua" do c cc nhm c cc nh -OH, -SH, NH2, d to phc vi cc ion ha tr 2, y chng ra kh i c th. Cc cht "cng cua" nh EDTA (ethyl diamin tetra acetic acid), BAL (British anti lewisit- dimercaprol), d- penicilamin thng c dng cha ng c kim loi nng nh Cu2+, Pb2+, Hg2+ hoc thi tr Ca2+ trong ng c digital. Than hot hp ph c cc hi, cc c t nn dng cha y hi, ng c. Cc base yu lm trung ha dch v acid dng cha lot d dy (khng acid), nh hydroxyd nhm, magnesi oxyd. - Thuc c cu trc tng t nh nhng cht sinh ha bnh thng, c th thm nhp vo cc thnh phn cu trc ca t bo, lm thay i chc phn ca t bo. Thuc ging purin, ging

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pyrimidin, nhp vo acid nucleic, dng chng ung th, chng virus. Sulfamid gn ging paraamino benzoic acid (PABA), lm vi khun dng "nhm", khng pht trin c. 2. CC CCH TC DNG CA THUC Khi vo c th, thuc c th c 4 cch tc dng sau: 2.1. Tc dng ti ch v ton thn: - Tc dng ti ch l tc dng ngay ti ni thuc tip xc, khi thuc cha c hp thu vo mu: thuc st khun ngoi da, thuc lm sn nim mc (tanin), thuc bc nim mc ng tiu ha (kaolin, hydroxyd nhm). - Tc dng ton thn l tc dng xy ra sau khi thuc c hp thu vo mu qua ng h hp, ng tiu ha hay ng tim: thuc m, thuc tr tim, thuc li niu. Nh vy, tc dng ton thn khng c ngha l thuc tc dng khp c th m ch l thuc vo mu "i" khp c th. Tc dng ti ch hoc ton thn c th gy hiu qu trc tip hoc gin tip: tim dtubocurarin vo t nh mch, thuc trc tip tc dng ln bn vn ng lm lit c vn v gin tip lm ngng th do c honh v c lin sn b lit ch khng phi thuc c ch trung tm h hp. Mt khc, tc dng gin tip cn c th thng qua phn x: khi ngt, ngi ammoniac, cc ngn dy thn kinh trong nim mc ng h hp b kch thch, gy phn x kch thch trung tm h hp v vn mch hnh ty, lm ngi bnh h i t nh. 2.2. Tc dng chnh v tc dng ph - Tc dng chnh l tc dng iu tr - Ngoi tc dng iu tr, thuc c th cn gy nhiu tc dng khc, khng c ngha trong iu tr, c gi l tc dng khng mong mun, tc dng dng ngoi (adverse drug reactions- ADR). Cc tc dng ngoi c th ch gy kh chu cho ngi dng (chng mt, bun nn, mt ng), gi l tc dng ph; nhng cng c th gy phn ng c hi (ngay vi liu iu tr) nh xut huyt tiu ha, gim bch cu, tt huyt p th ng... Th d: aspirin l thuc h st, gim au, chng vim (tc dng chnh), nhng gy chy mu tiu ha (tc dng c hi). Nifedipin, thuc chn knh calci dng iu tr tng huyt p (tc dng chnh), nhng c th gy nhc u, nhp tim nhanh (tc dng ph), ho, ph chn, t ng enzym gan, tt huyt p (tc dng c hi). Trong iu tr, thng phi hp thuc lm tng tc dng chnh v gim tc dng khng mong mun. Th d ung thuc chn b giao cm cng vi nifedipin s lm gim c tc dng lm tng nhp tim, nhc u ca nifedipin. Cng c th thay i ng dng thuc nh dng thuc t hu mn trnh tc dng kh ung, gy bun nn. 2.3. Tc dng hi phc v khng hi phc - Tc dng hi phc: sau tc dng, thuc b thi tr, chc phn ca c quan li tr v bnh thng. Sau gy m phu thut, ngi bnh li c trng thi bnh thng, tnh to. - Tc dng khng hi phc: thuc lm mt hon ton chc phn ca t bo, c quan. Th d: thuc chng ung th dit t bo ung th, bo v t bo lnh; thuc st khun bi ngoi da dit vi khun nhng khng nh hng n da; khng sinh cloramphenicol c tai bin gy suy ty xng. 2.4. Tc dng chn lc Tc dng chn lc l tc dng iu tr xy ra sm nht, r rt nht. Th d aspirin ung liu 12 g/ ngy c tc dng h st v gim au, ung liu 4- 6 g/ ngy c c tc dng chng vim;

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digitalis gn vo tim, no, gan, thn... nhng vi liu iu tr, ch c tc dng trn tim; albuterol (Salbutamol- Ventolin) kch thch chn lc receptor b2 adrenergic... Thuc c tc dng chn lc lm cho vic iu tr tr nn d dng hn, hiu qu hn, trnh c nhiu tc dng khng mong mun. 3. NHNG YU T NH HUNG N TC DNG CA THUC: 3.1. V thuc 3.1.1. Thay i cu trc lm thay i dc lc hc ca thuc. Nh ta bit, thuc mun c tc dng, phi gn c vo receptor (i lc vi receptor) v sau l hot ha c receptor (c hiu lc hay tc dng dc l). Receptor mang tnh c hiu cho nn thuc cng phi c cu trc c hiu. Receptor c v nh kha v thuc l cha kha. Mt s thay i nh v cu trc ha hc (hnh dng phn t ca thuc) cng c th gy ra nhng thay i ln v tc dng. Nh vy vic tng hp cc thuc mi thng nhm: - Lm tng tc dng iu tr v gim tc dng khng mong mun. Khi thm F vo v tr 9 v CH3 vo v tr 16 ca corticoid (hormon v thng thn), ta c betametason c tc dng chng vim gp 25 ln v khng c tc dng gi Na+ nh corticoid, trnh phi n nht. - Lm thay i tc dng dc l: thay i cu trc ca isoniazid (thuc chng lao), ta c iproniazid, c tc dng chng trm cm, do gn vo receptor hon ton khc.

Sulfanilamid

PABA (para amino benzoic acid)

Khng histamin H1 c cng thc gn ging vi histamin, tranh chp vi histamin ti receptor H1. - Cc ng phn quang hc hoc ng phn hnh hc ca thuc cng lm thay i cng tc dng, hoc lm thay i hon ton tc dng ca thuc. l. isoprenalin c tc dng kch thch receptor b adrenergic 500 ln mnh hn d. isoprenalin.

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l. quinin l thuc cha st rt, d. quinin (quinidin) l thuc cha lon nhp tim. - Cng ngy ngi ta cng hiu r c siu cu trc ca receptor v sn xut cc thuc rt c hiu, gn c vo di typ ca receptor: receptor adrenergic a1, a2, b1, b2, b3, receptor cholinergic M1, M2, M3, receptor dopaminergic D1, D2, ... D7. 3.1.2. Thay i cu trc thuc, lm thay i dc ng hc ca thuc Khi cu trc ca thuc thay i, lm tnh cht l ha ca thuc thay i, nh hng n s ha tan ca thuc trong nc hoc trong lipid, nh hng n s gn thuc vo protein, ion ha ca thuc v tnh vng bn ca thuc. Mt s v d: - Dopamin khng qua c hng ro mu no, nhng l. dopamin (Levodopa), cht tin thn ca dopamin th qua c. - Estradiol thin nhin khng ung c v b chuyn ha mnh gan. dn xut ethinyl estradiol (-C CH gn v tr 17) rt t b chuyn ha nn ung c. - Tolbutamid b microsom gan oxy ha gc CH3 v tr para, c t/2 huyt t ng l 4- 8 h. Thay gc CH3 bng Cl (Clorpropamid) s rt kh b chuyn ha, lm t/2 ca thuc ko di ti 35 h. - Cc thiobarbituric t b phn ly hn barbituric pH ca ng thn nn b thi tr chm hn. Qua y ta c th nhn thy rng, khi thuc gn vo receptor gy hiu lc, khng phi ton b phn t thuc m ch c nhng nhm chc phn gn vo receptor. Khi thay i cu trc ca nhm hoc vng chc phn, dc lc hc ca thuc s thay i. Cn khi thay i cu trc ngoi vng chc phn, c th thay i dc ng hc ca thuc. 3.2. Dng thuc Dng thuc l hnh thc trnh by c bit ca dc cht a dc cht vo c th. Dng thuc phi c bo ch sao cho tin bo qun, vn chuyn, s dng v pht huy ti a hiu lc cha bnh ca thuc. C th tm tt qu trnh hnh thnh v pht huy tc dng ca mt dng thuc trong c th nh sau: Dc cht K thut bo ch Dng thuc T dc Dng thuc trong c th cht v hp thu Gii phng dc Dc cht vo mu (sinh kh dng) tc dng ti ni Hiu qu iu tr ng dng thuc

Qua s , ta thy t 1 dc cht, cc nh bo ch c th a ra th trng nhiu loi bit dc (dng thuc) khc nhau, c sinh kh dng khc nhau do c nh hng khc nhau ti hiu qu iu tr. 3.2.1. Trng thi ca dc cht - tn nh: thuc cng mn, din tip xc cng tng, hp thu thuc cng nhanh. - Dng v nh hnh v dng tinh th: thuc rn dng v nh hnh d tan, d hp thu.

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3.2.2. T dc T dc khng phi ch l "cht n" bao gi thuc m cn nh hng n ha tan, khuch tn...ca thuc. Khi thay calci sulfat (thch cao, t dc c in) bng lactose dp vin diphenylhydantoin, gy hng lot ng c diphenylhydantoin do lng thuc c hp thu nhiu hn (c, 1968). Nguyn nhn l t dc calci sulfat ch ng vai tr mt khung mang, khng tiu v xp, lm dc cht c gii phng t t trong ng tiu ha. Cn lactose li lm dc cht d tan, nn c hp thu nhanh trong thi gian ngn. 3.2.3. K thut bo ch v dng thuc K thut bo ch l mt yu t khng km phn quan trng c tc ng trc tip n sinh kh dng ca thuc, c th kim sot c s gii phng dc cht v v tr thuc gii phng (gii phng ti ch). V vy n thng c cc nh sn xut gi b mt. Hin c rt nhiu dng thuc khc nhau c sn xut theo cc k thut khc nhau sao cho: - Hot tnh ca thuc c vng bn - Dc cht c gii phng vi tc n nh - Dc cht c gii phng ti ni cn tc ng (gii phng ti ch, targetting medication) - Thuc c sinh kh dng cao. 3.3. V ngi dng thuc 3.3.1. c im v tui (xin xem phn "dc ng hc") 3.3.1.1. Tr em: "Tr em khng phi l ngi ln thu nh li", ngha l khng phi ch gim liu thuc ca ngi ln th thnh liu ca tr em, m tr em cn c nhng c im ring ca s pht trin, l: - S gn thuc vo protein huyt tng cn t, mt khc, mt phn protein huyt t ng cn gn bilirubin, d b thuc y ra, gy ng c bilirubin. - H enzym chuyn ha thuc cha pht trin - H thi tr thuc cha pht trin - H thn kinh cha pht trin, myelin cn t, hng ro mu- no cha bo v nn thuc d thm qua v t bo thn kinh cn d nhy cm (nh vi morphin) - T bo cha nhiu nc, khng chu c thuc gy mt nc. - Mi m v c quan ang pht trin, ht sc thn trng khi dng cc loi hormon. Mt s tc gi a ra cc cng thc tnh liu lng cho tr em: 1. Cng thc ca Young: dng cho tr t 2- 12 tui Tui TE Liu ngi ln Tui TE + 12 2. Cng thc ca Cowling: Dng cho tr em t 2- 12 tui

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Tui TE + 1 Liu ngi ln 24 Th d: liu cho ngi ln l 2,0. Liu cho tr 4 tui l 4+1 2,0 g = 0,41 g 24 3. Cng thc ca Fried: dng cho nh nhi Tui TE (thng) Liu ngi ln 150 (Trng lng trung bnh ca ngi ln)

4. Cng thc ca Clark Trng lng TE (pounds) Liu ngi ln 150

Tuy nhin tnh liu theo din tch c th th tt hn. Khi dng cng thc: BSA (m2) ca tr em Liu ngi ln 1.7 BSA: Body Surface Area-Din tch c th (tra monogram) 1.7: BSA trung bnh ca ngi ln 3.3.1.2. Ngi cao tui Ngi cao tui cng c nhng c im ring cn lu : - Cc h enzym u km hot ng v "lo ha"

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- Cc t bo t gi nc nn cng khng chu c thuc gy mt nc - Ngi cao tui thng mc nhiu bnh (cao huyt p, x va mch, thp khp, tiu ng...) nn phi dng nhiu thuc mt lc. Cn rt ch tng tc thuc khi k n (xin xem phn "tng tc thuc") 3.3.2. c im v gii Nhn chung, khng c s khc bit v tc dng v liu lng ca thuc gia nam v n. Tuy nhin, vi n gii, cn ch n 3 thi k: 3.3.2.1. Thi k c kinh nguyt Khng cm hn thuc. Nu phi dng thuc di ngy, c t ng t ngng thuc th nn sp xp vo lc c kinh. 3.3.2.2. Thi k c thai Trong 3 thng u, thuc d gy d tt bm sinh, to ra qui thai. Trong 3 thng gia thuc c th nh hng xu n s pht trin ca bo thai, n chc phn pht trin ca cc c quan. Trong 3 thng cu i, thuc c th gy xy thai, non. V vy, khi cn ch nh thuc cho ph n c thai, cn cn nhc tht k gia li ch cho ngi m v mc nguy hi cho bo thai. Ni chung, trong 3 thng u, tuyt i trnh dng m i loi thuc. i vi ngi m, khi c thai, lng nc gi li trong c th tng, th tch mu tng, hm lng protein huyt tng c th gim, lng lipid c th tng... lm nh hng n ng hc ca thuc. 3.3.2.3. Thi k cho con b Rt nhiu thuc khi dng cho ngi m s thi tr qua sa v nh vy c th gy c hi cho con. Cc nghin cu v cc loi thuc ny ni chung cn cha c y , do tt nht l ch nn dng nhng loi thuc tht cn thit cho m. Tuyt i khng dng nhng thuc c cha thuc phin v dn xut ca thuc phin (thuc ho, codein, vin ra) v thuc thi tr qua sa v trung tm h hp ca tr rt nhy cm, c th b ngng th. Khng dng cc loi corticoid (lm suy thng thn tr), cc khng gip trng tng hp v iod (gy ri lon tuyn gip), cloramphenicol v thuc phi hp sulfametoxazol + trimethoprim (Co- trimoxazol) v c th gy suy tu xng. Cn rt thn trng khi dng cc thuc c ch thn kinh trung ng (meprobamat, diazepam), thuc chng ng kinh, u gy m mng v li b cho tr. 4. NHNG TRNG THI TC DNG C BIT CA THUC Trong qu trnh s dng thuc, ngoi tc dng iu tr, i khi cn gp nhng tc dng "khng mong mun" do s phn ng khc nhau ca tng c th vi thuc. 4.1. Phn ng c hi ca thuc (Adverse drug reactions- ADR) "Mt phn ng c hi ca thuc l mt phn ng c hi, khng nh c trc v xut hin liu lng thng dng cho ngi" (nh ngha ca Chng trnh gim st thuc quc tWHO). ADR l tn gi chung cho m i triu chng bt thng xy ra khi dng thuc ng liu. C th ch l nhng triu chng rt nh nh nhc u, bun nn... cho n nhng triu chng rt nng dn n t vong nh sc, phn v, suy tu xng. Tu theo nc v tu theo tc gi, ADR c th xy ra khong 8- 30% s ngi dng thuc. 4.2. Phn ng d ng D ng thuc cng l 1 ADR.

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Do thuc l 1 protein l (insulin, thyroxin ly t sc vt), l a peptid, polysaccharid c phn t lng cao, mang tnh khng nguyn. Tuy nhin, nhng thuc c phn t lng thp hoc chnh sn phm chuyn ha ca n cng c th gy d ng, chng c g i l bn khng nguyn hay "hapten". Vo c th, hapten c kh nng gn vi mt protein ni sinh theo ng n i cng ha tr v to thnh phc hp khng nguyn. Nhng thuc c mang nhm NH2 v tr para, nh benzocain, procain, sulfonamid, sulfonylurea... l nhng thuc d gy mn cm v nhm NH2 d b oxy ha v sn phm oxy ha s d gn vi nhm SH ca protein n i sinh thnh khng nguyn. Phn ng min dch d ng c chia thnh 4 typ da trn c s ca c ch min dch: - Typ I hay phn ng phn v (anaphylactic reactions) do s kt hp ca khng nguyn vi khng th IgE, gn trn bch cu a base tun hon hoc cc dng bo. Phn ng lm gii phng nhiu cht ha hc trung gian nh histamin, leucotrien, prostaglandin, gy gin mch, ph v vim. Cc c quan ch ca phn ng ny l ng tiu ha (d ng thc n), da (my ay, vim da d ng), ng h hp (vim mi, hen) v h tim- mch (sc phn v) Cc phn ng ny thng xy ra ngay sau khi dng thuc. Cc thuc d gy phn ng typ I: thuc t procain, lidocain, khng sinh nhm b lactam, aminoglycosid, huyt thanh, g globulin, vaccin, vitamin B1 tim t nh mch. - Typ II hay phn ng hu t bo (cytolytic reactions) xy ra khi c s kt hp khng nguyn vi khng th IgG v IgM ng thi c s hot ha h b th. M ch ca phn ng ny l cc t bo ca h tun hon. Th d: thiu mu tan mu do penicilin, thiu mu tan mu t min do methyl dopa, ban xut huyt gim tiu cu do quinidin, gim bch cu ht do sulfamid, luput ban h thng do procainamid. - Typ III hay phn ng Arthus, trung gian ch yu qua IgG c s tham gia ca b th. Phn ng gia khng nguyn v khng th to thnh phc hp min dch. Phc hp ny lng ng vo n i mc mch, gy tn thng vim hu hoi, c gi l bnh huyt thanh. Biu hin lm sng thng l: my ay, ban , au, vim khp, n i hch, st. Thng xy ra sau 6- 12 ngy. Cc thuc c th gp l sulfonamid, penicilin, mt s thuc chng co git, iod, mui Hg, huyt thanh. Hi chng Stevens- Johnson l biu hin nng ca typ ny. - Typ IV hay phn ng nhy cm mun, trung gian qua t bo lympho T c mn cm v i thc bo. Khi cc t bo mn cm tip xc vi khng nguyn, s gii phng cc lymphokin gy ra phn ng vim. Vim da tip xc l biu hin thng gp ca typ ny. Cc phn ng d ng thuc khng lin quan n liu lng thuc dng, s ln dng v thng c d ng cho. V vy cn h i tin s d ng ca bnh nhn trc khi dng thuc. Vi nhng thuc hay gy d ng (penicilin, lidocain,...) khi dng, phi c sn thuc v phng tin cp cu (adrenalin). Sc phn v c th xy ra do ng dng thuc khc nhau: vitamin B1 dng tim t nh mch c th gy sc cht ngi, trong khi dng ung khng gy phn ng ny. 4.3. Tai bin thuc do ri lon di truyn Thng l do thiu enzym bm sinh, mang tnh di truyn trong gia nh hay chng tc. Ngi thiu enzym glucose- 6- phosphat deshydrogenase (G-6-PD) hoc glutathion reductase d b thiu mu tan mu khi dng primaquin, quinin, pamaquin (xin xem bi "Thuc chng st rt"), sulfamid, nitrofuran...

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Gen kim tra vic to G- 6-PD nm trn chromosom X, v vy, tai bin thng xy ra nam. Ngi ta c lng c khong 100- 200 triu ngi mang gen ny v thng gp trn ngi da en. Ngi thiu enzym methemoglobin reductase l nhng ngi d hp t (khong 1% dn s). Khi dng thuc st rt (pamaquin, primaquin), thuc khng sinh, st khun (cloramphenicol, sulfon, nitrofurantoin), thuc h st (phenazol, paracetamol) rt d b methemoglobin. Ngi thiu acetyl transferase s chm acetyl ha mt s thuc nh hydralazin, isoniazid, phenelzin... nn d b nhim c cc thuc ny. Hin tng c ng (idiosyncrasy) l nhy cm c nhn bm sinh vi thuc chnh l s thiu ht di truyn 1 enzym no . 4.4. Quen thuc Quen thuc l s p ng vi thuc yu hn hn so vi ngi bnh thng dng cng liu. Liu iu tr tr thnh khng c tc dng, i h i ngy cng phi tng liu cao hn. Quen thuc c th xy ra t nhin ngay t ln u dng thuc do thuc t c hp thu, hoc b chuyn ha nhanh, hoc c th km mn cm vi thuc. Thng do nguyn nhn di truyn. Thng gp quen thuc do mc phi sau mt thi gian dng thuc, i h i phi tng dn liu. 4.4.1. Quen thuc nhanh (tAChyphylaxis) Thc nghim dng nhng liu ephedrin bng nhau, tim t nh mch cch nhau tng 15 pht, sau 4- 6 ln, tc dng gy tng huyt p gim dn ri mt hn. Mt s thuc khc cng c hin tng quen thuc nhanh nh amphetamin, isoprenalin, adrenalin, histamin... Nguyn nhn l: - Thuc tc dng gin tip qua s gii phng cht n i sinh ca c th, lm cn kit cht ni sinh. Ephedrin, amphetamin lm gii phng adrenalin d tr ca h giao cm. - Kch thch gn nhau qu lm receptor "mt m i" - To cht chuyn ha c tc dng i khng vi cht m: isoprenalin (cng b giao cm) qua chuyn ha gan, t o ra 3- orthomethylisoprenalin c tc dng hu b. 4.4.2. Quen thuc chm Sau mt thi gian dng thuc lin tc, tc dng ca thuc gim dn, i h i phi tng liu hoc i thuc khc. C nhiu nguyn nhn: - Do gy cm ng enzym chuyn ha thuc, lm nhng liu thuc sau b chuyn ha nhanh, mt tc dng nhanh. Barbiturat, diazepam, tolbutamid, ru ethylic... u l nhng thuc gy cm ng enzym chuyn ha ca chnh n. - Do gim s lng receptor cm ng vi thuc mng t bo (iu ha gim- down regulation): khi dng thuc cng giao cm, ph giao cm ko di... Tri li, khi dng cc thuc phong to ko di s lm tng s lng receptor (iu ha tng- up regulation) nh dng thuc hu b giao cm, thuc an thn c ch h dopaminergic. Khi ngng thuc d gy hin tng h i ng (rebound) - Do c th phn ng bng c ch ngc li dng cc thuc li niu thi Na+ lu, c th mt nhiu Na+ s tng tit aldosteron gi li Na+, lm gim tc dng li niu. trnh hin tng quen thuc, trong lm sng thng dng thuc ngt qung hoc lun phin thay i cc nhm thuc (s trnh by trong phn thuc c th) 4.5. Nghin thuc

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Nghin thuc l mt trng thi c bit lm cho ngi nghin ph thuc c v tm l v th cht vo thuc vi cc c im sau: - Thm thung mnh lit nn xoay s m i cch c thuc dng, k c hnh vi phm php - C khuynh hng tng liu - Thuc lm thay i tm l v th cht theo hng xu: ni iu, li lao ng, bn thu, thiu o c... gy hi cho bn thn v x h i - Khi cai thuc s b thuc " vt" hay ln cn "i thuc" : vt v, ln l n, d cm, v m hi, tiu chy... Nu li dng thuc cn "vt" s ht ngay. Nhng thuc gy nghin u c tc dng ln thn kinh trung ng gy sng khoi lng lng, o nh, o gic ("ph" thuc) hoc trng thi hng phn mnh (thuc lc), c gi chung l "ma ty": morphin v cc cht loi thuc phin (heroin, pethidin, methadon), cocain, cn sa (cannabis, marijuana), metamphetamin, ectasy... Ru v thuc l hin cn c coi l ma ty "hp php". C ch nghin cn cha c hon ton bit r, c nhiu gi thuyt gii thch: do c th khng sn xut morphin n i sinh; lm ri lon chc phn ca nron, gy phn ng b tr ca c th; to ra cht i khng vi ma ty nn i hi phi tng liu... Hin nay khng c phng php cai nghin no c hiu qu, ngoi tr ch ca ngi nghin. V vy, nghin ma tu l mt t nn x h i phi c loi tr. CU HI T LNG GI 1. Trnh by cc c ch tc dng ca thuc. 2. Trnh by cc cch tc dng ca thuc. 3. Phn tch nhng yu t v thuc c nh hng n tc dng ca thuc. 4. Phn tch nhng yu t ca ngi dng thuc c nh hng n tc dng ca thuc. 5. Trnh by nhng tai bin khi dng thuc: phn ng c hi, phn ng d ng, ri lon do di truyn, nghin thuc.

Bi 3: TNG TC THUC

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MC TIU HC TP: Sau khi hc xong bi ny, sinh vin c kh nng: 1. Trnh by c tng tc dc lc hc v dc ng hc. 2. Trnh by c hiu qu v p dng ca tng tc thuc. 1.TNG TC THUC- THUC Nhiu thuc khi cho dng cng mt lc s c tc dng qua li ln nhau, c gi l tng tc thuc. Trong lm sng, thy thuc mun ph i hp thuc lm tng tc dng iu tr, gim cc tc dng khng mong mun. Song trong thc t, nhiu khi khng t c nh th. V vy, khi k n c t 2 thuc tr ln, thy thuc rt cn hiu r s tng tc gia chng. 1.1. Tng tc dc lc hc L tng tc ti cc receptor, mang tnh c hiu 1.1.1. Tng tc trn cng receptor: tng tc cnh tranh Thng lm gim hoc mt tc dng ca cht ng vn (agonist), do cht i khng (antagonist) c i lc vi receptor hn nn ngn cn cht ng vn gn vo receptor: atropin khng acetylcholin v pilocarpin ti receptor M; nalorphin khng morphin t i receptor ca morphin; cimetidin khng histamin ti receptor H2. Thuc cng nhm c cng c ch tc dng, khi dng chung tc dng khng tng bng tng liu ca mt thuc m c tnh li tng hn: CVKS, aminosid vi dy VIII. 1.1.2. Tng tc trn cc receptor khc nhau: tng tc chc phn. - C cng ch tc dng: do lm tng hiu qu iu tr. Th d: trong iu tr bnh cao huyt p, phi hp thuc gin mch, an thn v li tiu; trong iu tr lao, phi hp nhiu khng sinh (DOTS) tiu dit vi khun cc v tr v cc giai on pht trin khc nhau. - C ch tc dng i lp, gy ra c chc phn i lp, dng iu tr nhim c: strychnin liu cao, kch thch ty sng gy co cng c, cura do c ch dn truyn tm vn ng, lm mm c; histamin tc ng trn receptor H1 gy gin mch, tt huyt p, trong khi noradrenalin tc ng ln receptor a1 gy co mch, tng huyt p. 1.2. Tng tc dc ng hc L cc t ng tc nh hng ln nhau thng qua cc qu trnh hp thu, phn phi, chuyn ha v thi tr v th n khng mang tnh c hiu. 1.2.1. Thay i s hp thu ca thuc - Do thay i ion ha ca thuc: Nh ta bit, ch nhng phn khng ion ha ca thuc mi d dng qua c mng sinh hc v d phn tn hn trong lipid. phn ly ca thuc ph thuc vo hng s pKa ca thuc v pH ca mi trng. Cc thuc c bn cht acid yu (nh aspirin) s hp thu tt trong mi trng acid (d dy), nu ta trung ha acid ca dch v th s hp thu aspirin d dy s gim i. - Vi cc thuc dng theo ng ung: khi dng vi thuc lm thay i nhu ng rut s lm thay i thi gian lu gi thuc trong rut, thay i s hp thu ca thuc qua rut. Mt khc

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cc thuc d tan trong lipid, khi dng cng vi parafin (hoc thc n c m) s lm tng hp thu. - Vi cc thuc dng theo ng tim bp, di da: procain l thuc t, khi trn vi adrenalin l thuc co mch th procain s chm b hp thu vo mu do thi gian gy t s c ko di. Insulin trn vi protamin v km (protemin- zinc- insulin- PZI) s lm ko di thi gian hp thu insulin vo mu, ko di tc dng h ng huyt ca insulin. - Do to phc, thuc s kh c hp thu: Tetracyclin to phc vi Ca++ hoc cc cation kim loi khc rut, b gim hp thu. Cholestyramin lm ta mu i mt, ngn cn hp thu lipid, dng lm thuc h cholesterol mu. - Do cn tr c hc: Sucralfat, smecta, maaloc (Al3+) to mng bao nim mc ng tiu ha, lm kh hp thu cc thuc khc. trnh s to phc hoc cn tr hp thu, 2 thuc nn ung cch nhau t nht 2 gi. 1.2.2. Thay i s phn b thuc l tng tc trong qu trnh gn thuc vo protein huyt tng. Nhiu thuc, nht l thuc loi acid yu, gn thun nghch vi protein (albumin, globulin) s c s tranh chp, ph thuc vo i lc v nng ca thuc trong huyt tng. Ch c thuc dng t do mi c tc dng dc l. V vy, tng tc ny c bit c ngha vi thuc c t l gn vo protein huyt tng cao (trn 90%) v c phm vi iu tr hp nh: . Thuc chng ng mu loi khng vitamin K: dicumarol, warfarin . Sulfamid h ng huyt: tolbutamid, clopropamil . Thuc chng ung th, c bit l methotrexat Tt c u b cc thuc chng vim phi steroid d dng y kh i protein huyt tng, c th gy nhim c. 1.2.3. Thay i chuyn ha Nhiu thuc b chuyn ha gan do cc enzym chuyn ha thuc ca microsom gan (xin xem phn dc ng hc). Nhng enzym ny li c th c tng hot tnh (gy cm ng) hoc b c ch bi cc thuc khc. Do s lm gim t/2, gim hiu lc (nu l thuc gy cm ng enzym) hoc lm tng t/2, tng hiu lc (nu l thuc c ch enzym) ca thucdng cng. - Cc thuc gy cm ng (inductor) enzym gan: phenobarbital, phenytoin, carbamazepin, griseofulvin, rifampicin... - Cc thuc c ch (inhibitor) enzym gan: allopurinol, cloramphenicol, cimetidin, MAOI, erythromycin, isoniazid, dicumarol. Cc thuc hay ph i hp vi cc loi trn thng gp l cc hormon (thyroid, corticoid, estrogen), thuc chng ng kinh, thuc h ng huyt, thuc tim mch. Ph n ang dng thuc trnh thai ung, nu b lao dng thm rifampicin, hoc b ng kinh dng phenytoin, c th s b "v k hoch" do estrogen trong thuc trnh thai b gim hiu qu v b chuyn ha nhanh, hm lng tr nn thp. 1.2.4. Thay i thi tr thuc Thi tr (elimination) thuc gm 2 qu trnh l chuyn ha thuc gan ( ni phn trn) v bi xut (excretion) thuc qua thn. Nu thuc bi xut qua thn dng cn hot tnh th s tng/ gim bi xut s c nh hng n tc dng ca thuc. - Thay i pH ca nc tiu: khi mt thuc lm thay i pH ca nc tiu, s lm thay i ion ha ca thuc dng km, lm thay i bi xut ca thuc. Th d barbital c pKa = 7,5;

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pH = 7,5 th 50% thuc b ion ha; pH = 6,5 th ch c 9% b ion ha pH = 9,5 th 91% barbital b ion ha. V vy, khi ng c cc thuc barbiturat, truyn dch NaHCO3 base ha nc tiu s tng bi xut barbiturat. Cc thuc l acid yu (vitamin C, amoni clorid) dng liu cao, lm acid ha nc tiu s lm tng thi tr thuc loi alcaloid (quinin, morphin). - Bi xut tranh chp ti ng thn: do 2 cht cng c c ch bi xut chung ti ng thn nn tranh chp nhau, cht ny lm gim bi xut cht khc. Dng probenecid s lm chm thi tr penicilin, thiazid lm gim thi tr acid uric nn c th gy bnh gut. 1.3. Kt qu v ngha ca tng tc thuc 1.3.1. Tc dng hip ng Thuc A c tc dng l a, thuc B c tc dng l b. Khi kt hp thuc A vi thuc B c tc dng c. Nu c = a + b, ta c hip ng cng (additive effect) c > a + b, ta c hip ng tng mc (synergysm) Hip ng cng thng khng c dng lm sng v nu cn th tng liu thuc ch khng ph i hp thuc. Hip ng tng mc thng dng trong iu tr lm tng tc dng iu tr v lm gim tc dng ph, tc dng c hi. Hai thuc c hip ng tng mc c th qua tng tc dc ng hc (tng hp thu, gim thi tr) hoc tng tc dc lc hc (trc tip hoc gin tip qua receptor) 1.3.2. Tc dng i khng Nh trong nh ngha trn, nhng khi tc dng c ca thuc A + B li nh hn tc dng cng ca tng thuc (c < a + b) ta gi l tc dng i khng. i khng c th ch mt phn (partial antagonism) khi c < a + b, nhng cng c th i khng hon ton khi a lm mt hon ton tc dng ca b. Trong lm sng, thng dng tc dng i khng gii c. - i khng c th xy ra ngoi c th, gi l tng k (incompatibility), mt loi tng tc thun ty l ha: + Acid gp base: to mu i khng tan. Khng tim khng sinh loi acid (nhm b lactam) vo ng dn dch truyn c tnh base. + Thuc oxy ha (vitamin C, B1, penicilin) khng trn vi thuc oxy kh (vitamin B2) + Thuc c bn cht l protein (insulin, heparin) khi gp mu i kim loi s d kt ta. + Than hot, tanin hp ph hoc lm kt ta nhiu alcaloid (quinin, atropin) v cc mu i kim loi (Zn, Pb, Hg...) - i khng xy ra trong c th: Khi thuc A lm gim nng ca thuc B trong mu (qua dc ng hc) hoc lm gim tc dng ca nhau (qua dc lc hc), ta gi l i khng (antagonism) V dc lc hc, c ch ca tc dng i khng c th l: + Tranh chp trc tip ti receptor: ph thuc vo i lc v nng ca thuc ti receptor. Th d: acetylcholin v atropin ti receptor M- cholinergic; histamin v cimetidin trn receptor H2 d dy.

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+ i khng chc phn: hai cht ng vn (agonist) tc dng trn 2 receptor khc nhau nhng chc phn li i khng trn cng mt c quan. Strychnin kch thch tu sng, gy co git; cura c ch dn truyn tm vn ng, gy mm c, chng c co git. Histamin kch thch receptor H1 lm co c trn kh qun, gy hen; albuterol (Ventolin), kch thch receptor b2 adrenergic lm gin c trn kh qun, dng iu tr cn hen. 1.3.3. o ngc tc dng Adrenalin va c tc dng kch tch receptor a adrenergic (co mch, tng huyt p), va c tc dng kch thch receptor b adrenergic (gin mch, h huyt p). Khi dng mt mnh, do tc dng a mnh hn b nn adrenelin gy t ng huyt p. Khi dng phentolamin (Regitin) l thuc c ch chn lc receptor a ri mi tim adrenalin th do ch kch thch c receptor b nn adrenelin gy h huyt p, tc dng b o ngc. ngha ca tng tc thuc Trong lm sng, thy thuc dng thuc phi hp vi mc ch: - Lm tng tc dng ca thuc chnh (hip ng tng mc) - Lm gim tc dng khng mong mun ca thuc iu tr - Gii c (thuc i khng, thuc lm tng thi tr, gim hp thu, trung ha...) - Lm gim s quen thuc v khng thuc Tuy nhin, nu khng hiu r tc dng phi hp, thy thuc c th lm gim tc dng iu tr hoc tng tc dng c ca thuc. Trong cc sch hng dn dng thuc, thng c mc tng tc ca tng thuc. 2. 2.1. TNG TC THUC- THC N- UNG Tng tc thuc- thc n:

Thng hay gp l thc n lm thay i dc ng hc ca thuc. 2.1.1. Thc n lm thay i hp thu thuc: - S hp thu ph thuc vo thi gian rng ca d dy. D dy khng phi l ni c chc nng hp thu ca b my tiu ha. Tuy nhin, do pH rt acid (khi i, pH 1; khi no pH 3) cho nn cn lu : + Ung thuc lc i, thuc ch gi li trong d dy khong 10- 30 pht. + Ung thuc vo lc no, thuc b gi li trong d dy khong 1- 4 gi, do : . Nhng thuc t tan s c thi gian tan, khi xung rut s c hp thu nhanh hn (penicilin V). Tuy nhin, nhng thuc d to phc vi nhng thnh phn ca thc n s b gim hp thu (tetracyclin to phc vi Ca++ v mt s cation ho tr 2 khc). . Cc thuc km bn trong mi trng acid (ampicilin, erythromycin) nu b gi lu d dy s b ph hu nhiu. . Vin bao tan trong rut s b v (cn ung trc ba n 0,5- 1h hoc sau ba n 1- 2 gi) . Nhng thuc d kch ng ng tiu ha, nn ung vo lc no. - S hp thu cn ph thuc vo dng bo ch: aspirin vin nn ung sau khi n s gim hp thu 50%, trong khi vin si bt li c hp thu hon ton. 2.1.2. Thc n lm thay i chuyn ha v thi tr thuc

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Thc n c th nh hng n enzym chuyn ha thuc ca gan, nh hng n pH ca nc tiu, v qua nh hng n chuyn ha v bi xut thuc. Tuy nhin, nh hng khng ln. Ngc li, thuc c th nh hng n chuyn ha mt s cht trong thc n. Thuc c ch enzym mono- amin- oxydase (MAOI) nh iproniazid- l enzym kh amin- oxy ha ca nhiu amin n i, ngoi sinh- c th gy cn tng huyt p kch pht khi n cc thc n c nhiu tyramin (nh khng c chuyn ha kp, lm gii phng nhiu noradrenalin ca h giao cm trong thi gian ngn. 2.2. Tng tc thc n ung 2.2.1. Nc - Nc l ung (dung mi) thch hp nht cho m i loi thuc v khng xy ra tng k khi ha tan thuc. - Nc l phng tin dn thuc (dng vin) vo d dy- rut, lm tng tan r v ha tan hot cht, gip hp thu d dng. V vy cn ung nc (100 - 200 mL cho m i ln ung thuc) trnh ng vin thuc ti thc qun, c th gy kch ng, lot. - c bit cn ch : + Ung nhiu nc trong qu trnh dng thuc (1,5- 2 l/ ngy) lm tng tc dng ca thuc (cc loi thuc ty), lm tng thi tr v lm tan cc dn xut chuyn ha ca thuc (sulfamid, cyclophosphamid). + Ung t nc hn bnh thng duy tr nng thuc cao trong rut khi ung thuc ty sn, ty giun (niclosamid, mebendazol). + Trnh dng nc qu, nc khong base hoc cc loi nc ngt ng hp c gas v cc loi nc ny c th lm hng thuc hoc gy hp thu qu nhanh. 2.2.2. Sa Sa cha calci caseinat. Nhiu thuc to phc vi calci ca sa s khng c hp thu (tetracyclin, lincomycin, mu i Fe...) Nhng thuc d tan trong lipid s tan trong lipid ca sa chm c hp thu. Protein ca sa cng gn thuc, lm cn tr hp thu. Sa c pH kh cao nn lm gim s kch ng d dy ca cc thuc acid. 2.2.3. C ph, ch - Hot cht cafein trong c ph, nc ch lm tng tc dng ca thuc h st gim au aspirin, paracetamol; nhng li lm tng tc dng ph nh nhc u, tng nhp tim, t ng huyt p nhng bnh nhn ang dng thuc loi MAOI. - Tanin trong ch gy ta cc thuc c Fe hoc alcaloid - Cafein cng gy ta aminazin, haloperidol, lm gim hp thu; nhng li lm tng ha tan ergotamin, lm d hp thu. 2.2.4. Ru ethylic Ru c rt nhiu nh hng n thn kinh trung ng, h tim mch, s hp thu ca ng tiu ha. Ngi nghin ru cn b gim protein huyt tng, suy gim chc nng gan, nhng li gy cm ng enzym chuyn ha thuc ca gan (xin xem bo "ru"), v th ru c tng tc vi rt nhiu thuc v cc tng tc ny u l bt li. Do khi dng thuc th khng ung ru. Vi ngi nghin ru cn phi dng thuc, thy thuc cn kim tra chc nng

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gan, tnh trng tm thn... chn thuc v dng liu lng thch hp, trong thi gian dng thuc cng phi ngng ung ru. 3. THI IM UNG THUC Sau khi nhn r c tng tc gia thuc- thc n- ung, vic chn thi im ung thuc hp l t c nng cao trong mu, t c hiu qu mong mun cao v gim c tc dng ph l rt cn thit. Nn nh rng: ung thuc vo lc i, thuc ch b gi li d dy 10- 30 pht, vi pH 1; ung lc no (sau n), thuc b gi li 1- 4 gi vi pH 3,5. Nh vy, tu theo tnh cht ca thuc, mc ch ca iu tr, c mt s gi chn thi im ung thuc nh sau: 3.1.Thuc nn ung vo lc i (trc ba n 1/2- 1 gi) - Thuc "bc" d dy cha lot trc khi thc n c mt, nh sucralfat. - Cc thuc khng nn gi li lu trong d dy nh: cc thuc km bn vng trong mi trng acid (ampicilin, erythromycin), cc lo i vin bao tan trong rut hoc cc thuc gii phng chm. 3.2. Thuc nn ung vo lc no (trong hoc ngay sau ba n) - Thuc kch thch bi tit dch v (ru khai v), cc enzym tiu ha (pancreatin) chng i tho ng loi c ch gluconidase nn ung trc ba n 10- 15 pht. - Thuc kch thch d dy, d gy vim lot ng tiu ha: cc thuc chng vim phi steroid, mu i kali, quinin. - Nhng thuc c thc n lm tng hp thu, hoc do thc n lm chm di chuyn thuc nn ko di thi gian hp thu: cc vitamin, cc vin nang amoxicilin, cephalexin, cc vin nn digoxin, sulfamid. - Nhng thuc c hp thu qu nhanh lc i, d gy tc dng ph: levodopa, thuc khng histamin H1. 3.3. Thuc t b nh hng bi thc n, ung lc no cng c: prednisolon, theophylin, augmentin, digoxin. 3.4. Thuc nn ung vo bui sng, ban ngy - Cc thuc kch thch thn kinh trung ng, cc thuc li niu trnh nh hng n gic ng. - Cc corticoid: thng ung 1 liu vo 8 gi sng duy tr c nng n nh trong mu. 3.5. Thuc nn ung vo bui ti, trc khi i ng. - Cc thuc an thn, thuc ng - Cc thuc khng acid, chng lot d dy. Dch v acid thng tit nhiu vo ban m, cho nn ngoi vic dng thuc theo ba n, cc thuc khng acid dng cha lot d dy nn c ung mt liu vo trc khi i ng. Cn nh rng khng nn nm ngay sau khi ung thuc, m cn ngi 15- 20 pht v ung nc (100- 200 mL nc) thuc xung c d dy. Dc l thi khc (chronopharmacology) cho thy c nhiu thuc c hiu lc hoc c tnh thay i theo nhp ngy m. Tuy nhin, trong iu tr, vic cho thuc cn tu thuc vo thi gian xut hin triu chng.

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CU HI T LNG GI 1. Trnh by tng tc dc ng hc ca thuc. 2. Trnh by tng tc dc lc hc. 3. Trnh by ngha v p dng lm sng ca tng tc thuc. 4. Trnh by tng tc thuc vi thc n v ung.

PHN II THUC TC DNG TRN H THN KINH THC VT Bi 4: I CNG V PHN LOI MC TIU HC TP: Sau khi hc xong bi ny, sinh vin c kh nng: 1. Phn bit c v gii phu, sinh l v dc l cc h giao cm, ph giao cm, adrenergic, cholinergic 2. Phn bit c cc tc dng sinh l ca h M- N- cholinergic H thn kinh thc vt (cn gi l h thn kinh t ng) chuyn iu khin cc hot ng ngoi mun, c vai tr iu ha chc phn ca nhiu c quan, h thng cho gii hn sng ca c th gi c s n nh trong mi trng sng lun lun thay i. H thng thn kinh thc vt hnh thnh t nhng trung tm trong no v tu sng, xut pht nhng si thn kinh ti cc tng, mch mu v c nhn. Trc khi ti c quan thu nhn, cc si ny u dng mt xinap ti hch, v vy c si trc hch (hay tin hch) v si sau hch (hay hu hch). Khc vi nhng b phn do h thn kinh trung ng iu khin, cc c quan do h thn kinh thc vt chi phi vn c th hot ng t ng khi ct t nhng si thn kinh n chng. H thng thn kinh thc vt c chia thnh 2 h giao cm v ph giao cm khc nhau v c gii phu v chc phn sinh l. 1. PHN LOI THEO GII PHU 1.1. im xut pht

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- H giao cm xut pht t nhng t bo thn kinh sng bn ca tu sng t t sng ngc th nht n t sng tht lng th 3 (T1- L3). - H ph giao cm xut pht t no gia, hnh no v tu cng. no gia v hnh no, cc si ph giao cm i cng vi cc dy thn kinh trung ng: dy III vo mt; dy VII vo cc tuyn nc bt; dy IX vo c mi, cc tuyn tit nc mt, nc bt, tuyn tit nim mc mi, ming, hu; dy X vo cc tng trong ngc v bng. tu cng, xut pht t cc t sng cng th 2 n th 4 (S2- S4) chi ph i cc c quan trong h chu. 1.2. Hch - H giao cm c 3 nhm hch: . Chui hch cnh ct sng nm hai bn ct sng . Nhm hch trc ct sng, gm hch tng, hch mc treo v hch h v, u nm trong bng. . Nhm hch tn cng gm nhng hch nm cnh trc trng v bng quang. - H ph giao cm: cc hch nm ngay cnh ho c ngay trong thnh c quan. 1.3. Si thn kinh - H giao cm: mt si tin hch thng tip n i vi khong 20 si hu hch cho nn khi kch thch giao cm, nh hng thng lan rng. - H ph giao cm: mt si tin hch thng ch tip n i vi mt si hu hch, cho nn xung tc thn kinh thng khu tr hn so vi xung tc giao cm. Tuy nhin, i vi dy X th m ri AuerbACh v m ri Meissner (c coi l hch) th mt si tin hch tip n i vi khong 8000 si hu hch. V hch nm ngay cnh c quan, cho nn cc si hu hch ph giao cm rt ngn.

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Hnh 4.1. Cu to gii phu ca h thn kinh thc vt 2. CHC PHN SINH L 2.1. Chc phn sinh l Chc phn sinh l ca hai h giao cm v ph giao cm trn cc c quan ni chung l i khng nhau (bng 4.1) Bng 4.1: p ng ca c quan vi h thn kinh thc vt C quan Kch thch giao cm Loi receptor p ng Kch thch ph giao cm p ng

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Mt C nan hoa C co ng t Tim Nt nh- tht Tm nh Mao ng mch Mch vnh C vn Da, nim mc No Tng Thn Tnh mch Ph qun Rut Nhu ng C tht Bi tit Thn Tit renin T cung C quan sinh dc nam Bng quang C bng quang b2 C trn Gan Ty Acini T bo b a a1 b2 Gim tit + Gim tit +++ tng tit ++ Tng tit ++ a1 a1, b2 Gin + Co ++ Hu glycogen v tn t o glucose +++ Co +++ Gin ++ a1, b1 a1, b2 a1 Gim +; tng ++ Cha: co (a1); gin (b2) Khng cha; gin (b2) Phng tinh +++ Thay i theo chu k kinh... Cng +++ a1, a2, b2 a1 a2 Gim + Co + c ch Tng +++ Gin + Tng +++ a1, a2, b2 a, b2 a1, a2 a1 a1, , b2 a1, a2, b1, b2 a1, b2 b2 Co +; gin ++ Co ++; gin ++ Co +++ Co nh Co +++; Gin + Co +++; gin + Co ++; gin ++ Gin + Gin + Gin + Gin Gin Co ++ b1 (b2) b1(b2) Tng tn s ++ Tng bin ++ Gim tn s ngng tim Gim bin ++ a1 Co (gin ng t) ++ Co (co ng t ) +++

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T bo m Ghi ch:

a2, b1 (b3)

Hu lipid +++

- Cc receptor ca h ph giao cm u l cc loi receptor M Mc p ng t thp (+) n cao (+++)

2.2.

Xinap v cht dn truyn thn kinh

Khi ta kch thch cc dy thn kinh (trung ng v thc vt) th u mt ca cc dy s tit ra nhng cht ha hc lm trung gian cho s dn truyn gia cc dy tin hch vi hu hch, hoc gia dy thn kinh vi cc c quan thu nhn. Cht ha hc lm trung gian cho s dn truyn gi l cht dn truyn thn kinh. H thng thn kinh ca ngi c hng chc t nron. S thng tin gia cc nron cng da vo cc cht dn truyn thn kinh. Cc thuc nh hng n chc phn thn kinh thng l thng qua cc cht dn truyn thn kinh . Cht dn truyn thn kinh hch giao cm, ph giao cm v hu hch ph giao cm u l acetylcholin, cn hu hch giao cm l noradrenalin, adrenalin v dopamin (gi chung l catecholamin). Cc cht dn truyn thn kinh tc ng n mng sau xinap lm thay i tnh thm ca mng vi ion Na+, K+ hoc Cl- do gy ra hin tng bin cc (kh cc hoc u cc ha). Ion Ca++ ng vai tr quan trng trong s gii phng cht dn truyn thn kinh.

2.3.

Cc cht dn truyn khc

Trong nhng nm gn y, nhiu nghin cu cho thy rng phn ln cc nron trung ng v ngoi bin c cha 2 hoc nhiu cht dn truyn, c th c gii phng ra cng mt lc xinap khi dy thn kinh b kch thch. Nh vy, h thn kinh thc vt, ngoi acetylcholin (ACh) v noradrenalin (NA), cn c nhng cht dn truyn thn kinh (neurotransmitters) khc cng c gii phng v c th c vai tr nh cht cng dn truyn (cotransmitters),

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cht iu bin thn kinh (neuromodulators) hoc chnh n cng l cht dn truyn (transmitters). Ngi ta tm thy trong tu thng thn, trong cc si thn kinh, trong hch thn kinh thc vt hoc trong cc cu trc do h thn kinh thc vt chi ph i mt lot cc peptid sau: enkephalin, cht P, somatostatin, hormon gii phng gonadotropin, cholecystokinin, vasoactive intestinal peptide (VIP), neuropeptid Y (NPY)... Vai tr dn truyn ca ATP, VIP v NPY trong h thn kinh thc vt dng nh c coi l nhng cht iu bin tc dng ca NA v ACh. Nh vy, bn cnh h thn kinh thc vt vi s dn truyn bng ACh v NA cn tn ti mt h thng dn truyn khc c gi l dn truyn khng adrenergic, khng cholinergic [Nonadrenergic, non cholinergic (NANC) transmission]. Burnstock (1969, 1986) thy c cc si thn kinh purinergic chi ph i c trn ng tiu ha, ng sinh dc- tit niu v mt s mch mu. Adenosin, ATP l cht dn truyn, cc receptor gm receptor adenosin (A hoc P1) v receptor ATP (P2). Cc di typ receptor u hot ng thng qua protein G, cn receptor P2x li thng qua knh ion (Fredholm v cs, 1994). Methylxantin (cafein, theophylin) l cht c ch cc receptor ny. Nitric oxyd cng l mt cht dn truyn ca h NANC c tc dng lm gin mch, gin ph qun. Nitric oxyd c ni m thnh mch, khi c gii phng s hot ha guanylyl cyclase, lm tng tng hp GMPv, gy gin c trn thnh mch. Cc cht dn truyn thn kinh c tng hp ngay ti t bo thn kinh, sau c lu tr di th phc hp trong cc ht c bit nm ngn dy thn kinh trnh b ph hu. Di tc dng ca nhng lung xung tc thn kinh, t cc ht d tr , cht dn truyn thn kinh c gii phng ra di dng t do, c hot tnh tc ng ti cc receptor. Sau chng c thu hi li vo chnh cc ngn dy thn kinh va gii phng ra, hoc b ph hu rt nhanh bi cc enzym c bit. Acetylcholin b cholinesterase thu phn, cn noradrenalin v adrenalin th b oxy ha v kh amin bi catechol- oxy- methyl- transferase (COMT) v mono- amin- oxydase (MAO). c bit: - Dy giao cm i ti tu thng thn khng qua mt hch no c. tu thng thn, dy ny tit ra acetylcholin kch thch tuyn tit ra adrenelin. V vy, thng thn c coi nh mt hch giao cm khng l. - Cc ngn dy hu hch giao cm chi ph i tuyn m hi ng l phi tit noradrenalin, nhng li tit ra acetylcholin. - Cc dy thn kinh vn ng i n cc c xng (thuc h thn kinh trung ng) cng gii phng ra acetylcholin. - Trong no, cc xung tc gia cc nron cng nh acetylcholin. Ngoi ra cn c nhng cht trung gian ha hc khc nh serotonin, catecholamin, acid- gama- amino- butyic (GABA)... 2.4. H thng thn kinh thc vt trong no Khng th tch ri hot ng ca h thn kinh trung ng vi h thn kinh thc vt. Gia 2 h lun lun c m i lin quan cht ch vi nhau m bo tnh thng nht ca c th. Nhng m i lin quan v ang c tm thy vng di i, h vin (systema limbicus), h i hi m (hyppocampus), l nhng ni c cc trung tm iu ha thn nhit, chuyn ha nc, ng, m, iu ha huyt p, ni tit, hnh vi... Trong h thn kinh trung ng cng thy cc cht dn truyn thn kinh v cc receptor nh ca h thng thn kinh thc vt ngoi bin.

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3. PHN LOI THEO DC L Nhng thuc c tc dng ging nh tc dng kch thch giao cm c gi l thuc cng giao cm (sympathicomimetic), cn nhng thuc c tc dng ging nh kch thch ph giao cm c g i l thuc cng ph giao cm (para- sympathicomimetic). Thuc no c tc dng km hm tc dng ca giao cm hay ph giao cm th gi l hu giao cm (sympathicolytic) hay hu ph giao cm (parasympathicolytic). Nh chng ta thy, hot ng ca thn kinh l nh nhng cht trung gian ha hc, cho nn cch phn loi v gi tn theo gii phu v sinh l khng ni ln c y v chnh xc tc dng ca thuc. V vy, mt cch hp l hn c, ng v phng din dc l, ta chia h thn kinh thc vt thnh 2 h: h phn ng vi acetylcholin, gi l h cholinergic (gm cc hch giao cm, ph giao cm; hu hch ph giao cm; bn vn ng c vn; mt s vng trn thn kinh trung ng) v h phn ng vi adrenalin, gi l h adrenergic (ch g m hu hch giao cm) Phn loi cc thuc tc dng trn h thng thn kinh thc vt Cc thuc tc dng trn h thn kinh thc vt cng mang tnh c hiu, tc dng chn lc trn cc receptor ring i vi chng. Cc receptor ca h cholinergic cn c chia lm 2 loi: - Loi nhn cc dy hu hch (v d tim, cc c trn v tuyn ngoi tit) cn b kch thch bi muscarin v b ngng hm bi atropin, nn c gi l h cm th vi muscarin (hay h M). - Loi nhn dy tin hch cn b kch thch bi nicotin, nn cn c gi l h cm th vi nicotin (hay h N), h ny phc tp, bao gm cc hch giao cm v ph giao cm, tu thng thn, xoang ng mch cnh (b ngng hm bi hexametoni), v bn vn ng c vn thuc h thn kinh trung ng (b ngng hm bi d- tubocurarin). Cng trn nhng c s tng t, cc receptor ca h adrenergic c chia lm 2 loi: alpha (a) v beta (b). Cc thuc kch thch c th tc ng theo nhng c ch: . Tng cng tng hp cht dn truyn thn kinh . Phong to enzym phn hu cht dn truyn thn kinh . Ngn cn thu h i cht dn truyn thn kinh v ngn dy thn kinh. . Kch thch trc tip cc receptor Dn truyn xinap thn kinh ngoi bin

Trung gian acetylcholin (cholinergic)

Trung gian noradrenalin (adrenergic)

H muscarinic(M)

H nicotinic (N)

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Hu hch ph giao cm

Hch thc vt

C vn

Hu hch giao cm

Receptor a Cc thuc c ch c th l: - Ngn cn tng hp cht dn truyn thn kinh - Ngn cn gii phng cht dn truyn thn kinh - Phong to ti receptor. CU HI T LNG GI

Receptor b

1. Trnh by c im gii phu v chc phn sinh l ca h giao cm v ph giao cm. 2. Phn bit h cholinergic (M,N) v h adrenergic v gii phu v dc l.

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Bi 5:THUC TC DNG TRN H H CHOLINERGIC MC TIU HC TP: Sau khi hc xong bi ny, sinh vin c kh nng: 1. Trnh by c tc dng v p dng iu tr ca acetylcholin, pilocarpin v atropin 2. Phn tch c c ch tc dng ca nicotin v thuc lit hch 3. Ni r c tc dng, c ch v p dng ca 2 loi cura 4. Trnh by c c ch, triu chng v cch iu tr nhim c cc cht phong to khng hi phc cholinesterase. 1. THUC KCH THCH H MUSCARINIC (H M) 1.1. Acetylcholin 1.1.1. Chuyn ha Trong c th, acetylcholin (ACh) c tng hp t cholin coenzym A vi s xc tc ca cholin- acetyltransferase. Acetylcholin l mt base mnh, to thnh cc mui rt d tan trong nc CH3 CH3 - CO - O - CH2 - CH2 - N OH Sau khi tng hp, acetylcholin c lu tr trong cc nang c ng knh khong 300- 600 A0 ngn dy cholinergic di th phc hp khng c hot tnh. Di nh hng ca xung ng thn kinh v ca ion Ca++, acetylcholin c gii phng ra dng t do, ng vai tr mt cht trung gian ha hc, tc dng ln cc receptor cholinergic mng sau xinap, ri b thu phn mt hot tnh rt nhanh di tc dng ca cholinesterase (ChE) thnh cholin (li tham gia tng hp acetylcholin) v acid acetic. Chol.acetyltransferase Cholin + Acetyl CoA ChE ACh cholin a.acetic CH3 CH3

C hai loi cholinesterase: - Acetylcholinesterase hay cholinesterase tht (cholinesterase c hiu), khu tr cc nron v bn vn ng c vn lm mt tc dng ca acetylcholin trn cc receptor.

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- Butyryl cholinesterase, hay cholinesterse gi (cholinesterase khng c hiu, thy nhiu trong huyt tng, gan, t bo thn kinh m (nevroglia). Tc dng sinh l khng quan trng, cha hon ton bit r. Khi b phong to, khng gy nhng bin i chc phn quan trng. Qu trnh tng hp acetylcholin c th b c ch bi hemicholin. c t ca vi khun botulinus c ch gii phng acetylcholin ra dng t do.

Hnh 5.1. Chuyn vn ca ACh ti tn cng dy ph giao cm Cholin c nhp vo u tn cng dy ph giao cm bng cht vn chuyn ph thuc Na+ (A). Sau khi c tng hp, ACh c lu gi trong cc nang cng vi peptid (P) v ATP nh cht vn chuyn th hai (B). Di tc ng ca Ca2+, ACh b y ra khi nang d tr vo khe xinap. 1.1.2. Tc dng sinh l Acetylcholin l cht dn truyn thn kinh c nhiu ni trong c th, cho nn tc dng rt phc tp: - Vi liu thp (10 mg/ kg tim t nh mch ch), ch yu l tc dng trn hu hch ph giao cm (h muscarinic): . Lm chm nhp tim, gin mch, h huyt p . Tng nhu ng rut . Co tht ph qun, gy cn hen . Co tht ng t

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. Tng tit dch, nc bt v m hi Atropin lm mt hon ton nhng tc dng ny. - Vi liu cao (1mg/ kg trn ch) v trn sc vt c tim trc bng atropin sulfat phong to tc dng trn h M, acetylcholin gy tc dng ging nicotin: kch thch cc hch thc vt, tu thng thn (h N), lm tng nhp tim, co mch, tng huyt p v kch thch h hp qua phn x xoang cnh. V c amin bc 4 nn acetylcholin khng qua c hng ro mu- no vo thn kinh trung ng. Trong phng th nghim, mun nghin cu tc dng trung ng, phi tim acetylcholin trc tip vo no, nhng cng b cholinesterase c rt nhiu trong thn kinh trung ng ph hu nhanh. Acetylcholin l mt cht dn truyn thn kinh quan trng trong h thng thn kinh trung ng, c tng hp v chuyn ha ngay ti ch, c vai tr kch thch cc yu t cm th (nh cc receptor nhn cm ha hc), tng phn x ty, lm gii phng cc hormon ca tuyn yn, tc dng trn vng di i lm h thn nhit, p trc tip vo v no gy co git... 1.1.3. Cc receptor ca h cholinergic Receptor Nicotinic muscle (Nm) (N- c vn) Nicotinic nron (Nn) (hch tk) Cht ch vn Phenyltrimet hyl ammonium Dimethylphe nyl piperazin (DMPP) Cht i khng a tubocurarin Trimethapha n T chc (m) Tm vn ng thn kinh - c Hch thc vt Tu thng thn Trung ng TK p ng Kh cc ti tm vn ng, co c Kh cc si sau hch Tit catecholam in Cha xc nh Hu hch ph giao cm M1 Oxotremorin Atropin Pirenzepin Hch thc vt Trung ng TK Kh cc chm Cha xc nh Tim Xoang nh Nt nh tht Tm tht Chm kh cc t pht Gim dn truyn Gim lc co bp Hot ha knh K+ c ch adenylcyclas e (tc dng trn protein Gi) Kch thch phospholipas e C to IP3 v DAG; tng Ca2+ trong cytosol C ch phn t M knh cation ti receptor Nm M knh cation ti receptor Nn

M2 (M4)

Atropin AF; DX 15

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M3

Atropin Hexahydro siladifenidol

C trn Tuyn tit

Co tht tng tit

Hot ha knh K+ c ch adenylcyclas e (tc dng trn protein Gi)

1.1.4. p dng lm sng V acetylcholin b ph hu rt nhanh trong c th nn t c dng trong lm sng. Ch dng lm gin mch trong bnh Ray- n (Raynaud- tm ti u chi) hoc cc biu hin hoi t. Tc dng gin mch ca ACh ch xy ra khi n i m mch cn nguyn vn. Theo Furchgott v cs (1984), ACh v cc thuc cng h M lm gii phng yu t gin mch ca n i m mch (endothelium- derived relaxing factor- EDRF) m bn cht l nitric oxyd nn gy gin mch. Nu n i m mch b tn thng, ACh khng gy c gin mch. Tim di da hoc tim bp 0,05- 0,1 g, m i ngy 2- 3 ln ng 1 mL = 0,1 g acetylcholin clorid 1.2. Cc este cholin khc Nu thay th nhm acetyl bng nhm carbamat th bo v c thuc khi tc dng ca cholinesterase, do ko di c thi gian tc dng ca thuc. Cc thuc u c amin bc 4 nn kh thm c vo thn kinh trung ng. 1.2.1. Betanechol (Urecholin)- Dn xut tng hp Tc dng chn lc trn ng tiu ha v tit niu. Dng iu tr chng bng, y hi v b i sau khi m.

Chng ch nh: hen, lot d dy- t trng. Ung 5- 30 mg. Vin 5- 10- 25- 50 mg Tim di da: 2,5- 5 mg, 3- 4 ln mt ngy. 1.2.2. CarbAChol Dng cha bnh tng nhn p, nh dung dch 0,5-1% Cn dng lm chm nhp tim trong cc cn nhp nhanh kch pht, ri lon tun hon ngoi bin (vim ng mch, bnh Raynaul), to bn, chng bng, b i sau m. Ung 0,5- 2,0 mg/ ngy. Tim di da 0,5- 1 mg/ ngy. 1.3. Muscarin C nhiu trong mt s nm c loi Amanita muscaria, A.pantherina

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- Tc dng in hnh trn h thng hu hch ph giao cm, v vy c gi l h muscarinic. Mnh hn acetylcholin 5- 6 ln v khng b cholinesterase ph hu. - Khng dng cha bnh. Nhng c th gp ng c muscarin do n phi nm c: ng t co, si bt mp, m hi lnh lng, kh th do kh o co tht, nn e, a chy, i dm, tim p chm, huyt p h... iu tr: atropin liu cao. C th tim t nh mch tng liu 1 mg atropin sulfat. 1.4. Pilocarpin c, bng A L alcaloid ca l cy Pilocarpus jaborandi, P.microphylus- Rutaceae, mc nhiu Nam M. tng hp c. Kch thch mnh hu hch ph giao cm, tc dng lu hn acetylcholin; lm tit nhiu nc bt, m hi v tng nhu ng rut. Khc vi muscarin l c c tc dng kch thch hch, lm gii phng adrenalin t tu thng thn, nn trn ng vt c tim trc bng atropin, pilocarpin s lm tng huyt p. Trong cng thc, ch c amin bc 3 nn thm c vo thn kinh trung ng, liu nh kch thch, liu cao c ch. Liu trung bnh 0,01- 0,02g Thng ch dng nh mt dung dch du pilocarpin base 0,5- 1% hoc dung dch nc pilocarpin nitrat hoc clohydrat 1- 2% cha tng nhn p hoc i lp vi tc dng gin ng t ca atropin. 2. THUC I KHNG H MUSCARINIC (H M) 2.1. Atropin c, bng A. Atropin v ng loi l alcaloid ca l cy Belladon (Atropa belladona), c c dc (Datura stramonium), thin tin t (Hyoscyamus niger)... 2.1.1. Tc dng Atropin v ng loi l nhng cht i khng tranh chp vi acetylcholin receptor ca h muscarinic (i lc > 0; hiu lc n i ti = 0). Ch vi liu rt cao v tim vo ng mch th mi thy tc dng i khng ny trn hch v bn vn ng c vn. V vy, cc tc dng thng thy l: - Trn mt, lm gin ng t v mt kh nng iu tit, do ch nhn c xa. Do lm c mi gin ra nn cc ng thng dch nhn cu b p li, lm tng nhn p. V vy, khng c dng atropin cho nhng ngi tng nhn p. - Lm ngng tit nc bt lng, gim tit m hi, dch v, dch rut - Lm n kh o, nht l khi n b co tht v cng ph giao cm. t c tc dng trn kh o bnh thng. Km theo l lm gim tit dch v kch thch trung tm h hp, cho nn atropin thng c dng ct cn hen. - t tc dng trn nhu ng rut bnh thng, nhng lm gim khi rut tng nhu ng v co tht. - Tc dng ca atropin trn tim th phc tp: liu thp do kch thch trung tm dy X hnh no nn lm tim p chm; liu cao hn, c ch cc receptor muscarinic ca tim, li lm tim p nhanh. Tim th khng chu s chi ph i ca ph giao cm nn atropin khng c nh hng.

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- Atropin t nh hng n huyt p v nhiu h mch khng c dy ph giao cm. Ch lm gin mch da, nht l mi trng nng, v thuc khng lm tit m hi c, nn mch cng gin ra chng vi xu hng tng nhit. - Liu c, tc ng ln no gy tnh trng kch thch, thao cung, o gic, st, cui cng l hn m v cht do lit hnh no. iu tr nhim c bng thuc khng cholinesterase (physostignin) tim t nh mch cch 2 gi 1 ln v chng triu chng kch thch thn kinh trung ng bng benzodiazepin. 2.1.2. Chuyn ha D hp thu qua ng tiu ha v ng tim di da. C th hp thu qua nim mc khi dng thuc ti ch, cho nn tr c th gp tai bin ngay c khi nh mt. Khong 50% thuc b thi tr nguyn cht qua nc tiu. 2.1.3. p dng lm sng - Nh mt dung dch atropin sulfat 0,5- 1% lm gin ng t ti a sau 25 pht, dng soi y mt hoc iu tr vim m ng mt, vim gic mc. Phi vi ngy sau ng t mi tr li bnh thng. C th dng eserin salicylat (dung dch 0,2%) hay pilocarpin hydrat hoc nitrat (dung dch 1%) rt ngn tc dng ca atropin. - Tc dng lm gin c trn c dng ct cn hen, cn au ti mt, cn au thn, au d dy. - Tim trc khi gy m trnh tit nhiu m di, trnh ngng tim do phn x ca dy ph v. - Ri lon dn truyn nh tc nh tht (Stockes- Adams) hoc tim nhp chm do nh hng ca dy X. - iu tr ng c nm loi muscarin v ng c cc thuc phong to cholinesterase. Chng ch nh: bnh tng nhn p, b i do ph i tuyn tin lit. 2.1.4. Ch phm v liu lng Dng di dng base hoc sulfat. Tim t nh mch 0,1- 0,2 mg; tim di da 0,25- 0,50 mg (liu ti a 1 ln: 1 mg; 24gi: 2 mg); ung 1- 2 mg (liu ti a 1 ln: 2 mg; 24 gi: 4 mg). Atropin sulfat ng 1 mL = 0,25 mg; vin 0,25 mg Atropin sulfat ng 1 mL = 1 mg (c bng A), ch dng iu tr ng c cc cht phong to cholinesterase. 2.2. Homatropin bromhydrat (homatropini hydrobromidum) c, bng A Tng hp. Lm gin ng t thi gian ngn hn atropin (trung bnh 1 gi). Dng soi y mt, dung dch 0,5- 1%. 2.3. Scopolamin (scopolaminum; hyoscinum) c, bng A - L alcaloid ca cy Scopolia carniolica. Tc dng gn ging atropin. Thi gian tc dng ngn hn. Trn thn kinh trung ng, atropin kch thch cn scopolamin th c ch cho nn c dng cha bnh Parkinson, cc cn co git ca bnh lit rung, phi hp vi thuc khng histamin chng nn khi say tu, say sng. Ung hoc tim di da 0,25- 0,5 mg

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Liu ti a m i ln 0,5mg; 24 gi: 1,5mg Vin Aeron c scopolamin camphonat 0,1mg v hyoscyamin camphonat 0,4mg; dng chng say sng, say tu: ung 1 vin 30 pht trc lc khi hnh. 2.4. Thuc bn tng hp mang amoni bc 4: Ipratropium Do gn thm nhm isopropyl vo nguyn t N ca atropin, ipratropium mang amoni bc 4, khng hp thu c qua ng ung v khng vo c thn kinh trung ng. Thng dng di dng kh dung iu tr bnh ph i tc nghn mn tnh v ct cn hen. Ch 1% hp thu vo mu v khong 90% liu kh dung c nut vo ng tiu ha v thi tr theo phn. Tc dng ti a sau 30- 90 pht v t/2 > 4 gi. Ch phm: Ipratropium bromid (Atrovent, Berodual) dng kh dung nh liu, 20 mg/ nht bp 200 liu. Ngi ln m i ln bp 2 nht, mi ngy 3- 4 ln. 3. THUC KCH THCH H NICOTINIC (H N) Cc thuc ny t c dng trong iu tr, nhng li quan trng v mt dc l v c dng nghin cu cc thuc tc dng trn hch. Hin nay cc thuc kch thch hch c chia thnh hai nhm: nhm u gm nicotin v cc thuc tng t, tc dng kch thch trn cc receptor nicotinic ca hch, b hexametoni c ch; nhm sau gm muscarin, pilocarpin, oxotremorin, thuc phong to cholinesterase... tc dng kch thch trn cc receptor muscarinic (h M1) ca hch, khng b hexametoni, m b atropin c ch. Serotonin, histamin v cc a peptid kch thch hch c th l trn cc receptor c hiu ring. Trong phn ny ch ni ti cc cht thuc loi nicotin. 3.1. Nicotin (a- pyridyl- metyl pyrrolidin) c, bng A C trong thuc l, thuc lo di hnh thc acid hu c (0,58,0%). Khi ht thuc, nicotin c gii phng ra di dng base t do. Trung bnh, ht 1 iu thuc l, hp thu khong 1- 3 mg nicotin. Liu cht khong 60mg. Trn hch thc vt, liu nh (0,02- 1,0mg/ kg ch, tim t nh mch) kch thch; liu cao (10- 30 mg/ kg trn ch) lm lit hch do gy bin cc v sau l tranh chp vi acetylcholin. Tc dng: - Trn tim mch, gy tc dng ba pha: h huyt p tm thi, tng huyt p mnh ri cui cng l h huyt p ko di. - Trn h hp, kch thch lm tng bin v tn s - Gin ng t, tng tit dch, t ng nhu ng rut Nguyn nhn ca nhng tc dng l do: - Lc u nicotin kch thch hch ph giao cm v trung tm c ch tim hnh no nn lm tim p chm, h huyt p. - Nhng ngay sau , nicotin kch thch hch giao cm, trung tm vn mch v cc c trn, lm tim p nhanh, tng huyt p, gin ng t v tng nhu ng rut. ng thi kch thch tu thng thn (coi nh hch giao cm khng l) lm tit adrenalin, qua cc receptor nhn cm ha hc xoang cnh kch thch phn x ln trung tm h hp.

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- Cui cng l giai on lit sau khi b kch thch qu mc nn lm h huyt p ko di. Nicotin khng dng trong iu tr, ch dng trong cc phng th nghim hoc git su b. Nicotin gy nghin, nhng khi cai thuc th khng gy bin chng nh cai thuc phin. Ht thuc l c hi n tim, mch, nim mc ng h hp v khi thuc c oxyd carbon (gy carboxyhemoglobin trong mu ngi nghin), c cc base nit, cc acid bay hi, cc phenol... l nhng cht kch thch mnh nim mc. Ngoi ra cn c hc n (c hot cht l 3,4benzpyren, c th l mt trong nhng nguyn nhn gy ung th ph i). 3.2. Cc thuc khc - Lobelin: L alcaloid ca l cy lobelia inflata. Tc dng km nicotin rt nhiu. Hu nh khng cn c dng trong lm sng na. - Tetramethylamoni (TMA) v dimethyl- phenyl- piperazin (DMPP) Tc dng ging nicotin, kch thch c hch giao cm v ph giao cm nn tc dng phc tp, khng c dng trong iu tr. Hay c dng trong thc nghim. DMPP cn kch thch thng thn tit nhiu adrenalin. 4. THUC PHONG B H NICOTINIC (H N) c chia lm 2 loi: loi phong b hch thc vt, nh hng n hot ng ca c trn, v loi phong b trn bn vn ng ca c vn. 4.1. Loi phong b h nicotinic ca hch Cn gi l thuc lit hch, v lm ngn cn lung xung tc thn kinh t si tin hch ti si hu hch. C ch chung l tranh chp vi acetylcholin ti receptor mng sau ca xinap ca hch. Nh ta bit, cc hch thn kinh thc vt cng c c hai loi receptor cholinergic l N v M1. Khi ni ti cc thuc lit hch l c ngha ch bao hm cc thuc c ch trn receptor N ca hch m thi. Tuy cc c quan thng nhn s chi ph i ca c hai h giao cm v ph giao cm, song bao gi cng c mt h chim u th. V vy, tc dng ca cc thuc lit hch trn c quan thuc vo tnh u th y ca tng h (xem bng di): C quan ng mch nh Tnh mch Tim ng t Rut Bng quang Tuyn nc bt H thn kinh chim u th Giao cm Giao cm Ph giao cm Ph giao cm Ph giao cm Ph giao cm Ph giao cm Tc dng ca thuc lit hch Gin mch, h huyt p Gin: tr tun hon , gim cung lng tim p nhanh Gin Gim trng lc v nhu ng, to bn B tiu tin Gim tit, kh ming

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Trong lm sng, cc thuc lit hch thng c dng lm h huyt p trong cc cn tng huyt p, h huyt p iu khin trong m x, v i khi iu tr ph ph i cp, do chng c nhng c im sau: - Cng c ch giao cm gy gin mch t l vi liu dng - Tc dng mt i nhanh sau khi ngng thuc, do d kim tra c hiu lc ca thuc - Cc receptor adrenergic ngoi bin vn p ng c bnh thng nn cho php d dng iu tr khi c tai bin Nhng tai bin v tc dng ph thng gp l: - Do phong b hch giao cm, nn: . D gy h huyt p khi ng (phi ngi bnh nm 10- 15 pht sau khi tim) iu tr tai bin bng adrenalin v ephedrin. . Ri lon tun hon mch no, mch vnh. . Gim tit niu. - Do phong b hch ph giao cm nn: . Gim tit dch, gim nhu ng rut, lm kh ming v to bn. . Gin ng t, ch nhn c xa. . B i do gim trng lc bng quang. Cc thuc c (tetra ethyl amoni- TEA v hexametoni) u mang amoni bc 4, kh hp thu. Hin cn 2 thuc c s dng. 4.1.1. Trimethaphan (Arfonad) Phong b hch trong thi gian rt ngn. Truyn tnh mch dung dch 1 mg trong 1 mL, huyt p h nhanh. Khi ngng truyn, 5 pht sau huyt p tr v bnh thng Dng gy h huyt p iu khin trong phu thut hoc iu tr ph ph i cp. ng 10 mL c 500 mg Arfonad, khi dng pha thnh 500 mL trong dung dch mn ng trng c 1 mg trong 1 mL. 4.1.2. Mecamylamin (Inversin) Mang N ha tr 2, cho nn d hp thu qua ng tiu ha, c th ung c. Tc dng ko di 4- 12 gi. Dng lu tc dng s gim dn Ung m i ln 2,5 mg, m i ngy 2 ln. Tng dn cho ti khi t c hiu qu iu tr, c th ung ti 30 mg m i ngy. Vin 2,5 mg v 10 mg Liu cao c th kch thch thn kinh trung ng v phong to bn vn ng c vn. 4.2. Loi phong b h nicotinic ca c vn Cura v cc ch phm c, bng B 4.2.1. Tc dng Cura tc dng u tin trn h nicotinic ca cc c xng (c vn), lm ngn cn lung xung tc thn kinh ti c bn vn ng (Claude Bernard, 1856) nn lm gin c. Khi kch thch trc tip, c vn p ng c. Di tc dng ca cura, cc c khng b lit cng mt lc, m

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ln lt l cc c mi (gy sp mi), c mt, c c, c chi trn, chi di, c bng, cc c lin sn v cui cng l c honh, lm bnh nhn ngng h hp v cht. V tc dng ngn nn nu c h hp nhn to, chc phn cc c s c h i phc theo th t ngc li. Ngoi ra, cura cng c tc dng c ch trc tip ln trung tm h hp hnh no v lm gin mch h huyt p hoc co tht kh qun do gii phng histamin Hu ht u mang amin bc 4 nn rt kh thm vo thn kinh trung ng, khng hp thu qua thnh rut. 4.2.2. Cc loi cura v c ch tc dng. Theo c ch tc dng, chia lm hai loi: 4.2.2.1. Loi tranh chp vi acetylcholin bn vn ng, lm cho bn vn ng khng kh cc c, gi l loi cura chng kh cc (antidpolarisant), hoc loi ging cura (curarimimetic) hay pakicura (Bovet). Gii c bng cc thuc phong to cholinesterase (physostigmin, prostigmin tim tnh mch tng 0,5 mg, khng vt qu 3 mg. C th tim thm atropin 1 mg ngn cn tc dng cng h muscarinic ca thuc). Loi ny c tc dng hip ng vi thuc m, thuc ng loi barbiturat, thuc an thn loi benzodiazepin - d- Tubocurarin: l alcaloid ly t cc cy loi Chondodendron tementosum v Strychnos m th dn Nam M dng tm tn c. Tc dng ko di vi gi. Khng dng trong lm sng - Galamin (flaxedil): tng hp. C thm tc dng gi ng atropin nn lm tim p chm, khng lm gii phng histamin v km c hn d- tubocurarin 10- 20 ln. Tc dng pht trin chm trn cc nhm c khc nhau, thi gian lm gin c bng n lit c honh kh di nn gii hn an ton rng hn. Ch phm: Remiolan ng 5 mL = 0,1g galamin triethyl iodid. Liu 0,5 mg/ kg - Pancuronium (Pavulon): l steroid mang 2 amoni bc 4. Tc dng khi pht sau 4- 6 pht v ko di 120- 180 pht. u im chnh l t tc dng trn tun hon v khng lm gii phng histamin. - Pipecuronium (Arduan): khi pht tc dng sau 2- 4 pht v ko di 80- 100 pht. L cha bt pha tim 4 mg + 2 mL dung mi. Tim t nh mch 0,06- 0,08 mg/ kg 4.2.2.2. Loi tc ng nh acetylcholin, lm bn vn ng kh cc qu mnh, (depolarisant) gi l loi gi ng acetylcholin, (acetylcholinomimetic) hoc leptocura (Bovet). Cc thuc phong b cholinesterase lm tng c tnh. Khng c thuc gii c, tuy d- tubocurarin c tc dng i khng. Trc khi lm lit c, gy git c trong vi giy. -Decametoni bromid: gy git c v au c, c th gy tai bin ngng th ko di nn c xu hng dng succinylcholin thay th. Succinylcholin: l thuc duy nht ca nhm cura kh cc c dng lm sng. C cu trc ha hc nh 2 phn t ACh gn vo nhau:

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Succinylcholin Khi pht tc dng sau 1- 1,5 pht v ko di ch khong 6- 8 pht, do b cholinesterase trong huyt tng thu phn. Succinylcholin y K+ t trong t bo ra nn c th lm tng K+ mu 30- 50%, gy lon nhp tim. Ch phm: Myo- relaxin ng 0,25g succinylcholin bromid. Tim t nh mch t kg. 4.2.3. Ch nh v liu lng - Lm mm c trong phu thut, trong chnh hnh, t ng ni kh qun. - Trong tai mi hng, dng soi thc qun, gp d vt... - Chng co git c trong chong in, un vn, ng c strychnin. Khi dng phi t ng ni kh qun. Khng hp th qua nim mc tiu ha nn phi tim t nh mch. Liu lng tu theo tng trng hp, c th tim 1 ln hoc truyn nh git vo tnh mch. Liu mm c u tin thng l: d- Tubocurarin Methyl d- tubocurarin Galamin (flaxedyl) Decametoni Succinylcholin diiodua 15 mg 5 mg 20- 100 mg 4 mg 30- 60 mg 1 mg/

Ch : mt s thuc khi dng cng vi cura loi curarimimetic (d- tubocurarin) c th c tc dng hip ng, lm tng tc dng lit c ca cura, nn cn gim liu: - Cc thuc m nh ether, halothan, cyclopropan. - Cc khng sinh nh neomycin, streptomycin, polimycin B, kanamycin. - Quinin, quinidin 5. THUC KHNG CHOLINESTERASE Cholinesterase l enzym thu phn lm mt tc dng ca acetylcholin. Mt phn t acetylcholin s gn vo hai v tr hot ng ca enzym; v tr anion (anionic site) s gn vi cation N+ ca acetylcholin, cn v tr gn este (esteratic site) gm mt nhm base v mt nhm acid proton (-- H) to nn mt lin kt hai ha tr vi nguyn t C ca nhm carboxyl ca este:

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Physostigmin 5.1.1. Physostigmin (physotigminum; eserin) c, bng A L alcaloid ca ht cy Physostigma venenosum. V c amin bc 3, nn d hp th v thm c c vo thn kinh trung ng Dng cha tng nhn p (nh mt dung dch eserin sulfat hoc salicylat 0,25- 0,5%) , hoc kch thch nhu ng rut (tim di da, ng 0,1%- 1 mL, m i ngy 1- 3 ng). Khi ng c, dng atropin liu cao. 5.1.2. Prostigmin (neostigmin, proserin) c, bng A V mang amin bc 4 nn khc physostigmin l c i lc mnh hn vi cholinesterase, v khng thm c vo thn kinh trung ng. Tc dng nhanh, t tc dng trn mt, tim v huyt p. Ngoi tc dng phong to cholinesterase, prostigmin cn kch thch trc tip c vn, tc dng ny khng b atropin i khng. p dng:

Prostigmin

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- Ch nh tt trong bnh nhc c bm sinh (myasthenia gravis) v thiu ht acetylcholin bn vn ng c vn. Cn c dng trong cc trng hp teo c, lit c. - Lit rut, b i sau khi m - Nh mt cha tng nhn p - Cha ng c cura loi tranh chp vi acetylcholin Liu lng, ch phm: - Tim di da m i ngy 0,5- 2,0 mg - Ung m i ngy 30-90 mg v thuc kh thm qua d dy v d b ph hu ng 1 mL = 0,5 mg prostigmin methyl sulfat 5.1.3. Edrophonium clorid (Tensilon) Cht tng hp Tc dng mnh trn bn vn ng c vn, l thuc gii c cura loi tranh chp vi acetylcholin. Tc dng ngn hn prostigmin. Trong bnh nhc c, tim tnh mch 2- 5 mg; gii c cura: 5- 20 mg ng 1 mL = 10 mg edrophonium clorid. 5.2. Loi c ch khng hi phc hoc rt kh hi phc Tensilon

5.2.1. Cc hp cht ca phospho hu c: cc cht ny kt hp vi cholinesterase ch v tr gn este. Enzym b phosphoryl ha rt vng bn, kh c thu phn h i phc tr li, i h i c th phi tng hp li cholinesterase mi. V vy lm tch lu nhiu acetylcholin ton b h cholinergic t vi ngy ti hng thng. c ch mnh c cholinesterase tht cng nh gi. Trong lm sng, nh gi tnh trng nhim c bng nh lng cholinesterase gi trong huyt tng. Cc cht c ch cholinesterase loi phospho hu c c cng thc chung l: R1 O P R2 X Trong X c th l halogen, cyanid (CN), thiocyanat, alkoxy, thiol, pyrophosphat... Ch c DFP (di- isopropyl- fluo- phosphat) c dng nh mt cha bnh tng nhn p (dung dch 0,01- 0,05%). Cc dn xut khc c dng lm thuc tr su (TEPP, parathion,...), hoc s dng lm hi c chin tranh (tabun, sarin, soman...). 5.2.2. Du hiu nhim c cp: cc du hiu nhim c cp phn nh s trn ngp acetylcholin ton b h cholinergic. - Du hiu kch thch h M: co ng t, sung huyt gic mc, chy nc mi, nc bt, dch kh qun, co kh qun, nn, au bng, tiu chy, tim p chm, h huyt p.

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- Du hiu kch thch h N: mt m i, git c, cng c, lit v nguy him hn c l lit h hp. - Du hiu kch thch thn kinh trung ng: l ln, mt ng tc, mt phn x, nhp th Cheyne- Stokes, co git ton thn, hn m, lit h hp, h huyt p do trung tm hnh tu b c ch. Nguyn nhn dn ti t vong l do suy h hp v tim mch do c 3 c ch kch thch h M, N v trung ng. 5.2.3. iu tr nhim c 5.2.3.1. Thuc hu h M: atropin sulfat liu rt cao. Tim t nh mch liu 1- 2 mg, cch 5- 10 pht mt ln cho n khi ht triu chng kch thch h M, hoc bt u c du hiu nhim c atropin (gin ng t). Ngy u c th tim ti 200 mg. 5.2.3.2. Dng thuc hot ha cholinesterase: mt s cht a nhn (nucleophylic agents) nh hydroxylamin (NH2OH), acid hydroxamic (R- CO- NHOH) v oxim (R- CH = NOH) c kh nng gii phng c enzym b phospho hu c phong ta v hot ha tr li. Cht thng dng l pralidoxim (2- PAM) tc dng ln ChE phosphoryl ha, to oximphosphonat b thi tr v gii phng cholinesterase. Pralidoxim (2- PAM): l 1g km ng nc 20 mL. Mi u, tim t nh mch 1- 2g, sau truyn nh git tnh mch m i gi 0,5g. 5.2.3.3. iu tr h tr Thay qun o, ra cc vng da c tip xc vi cht c, ra d dy nu ng c do ng ung. H hp h tr, th oxy. Chng co git bng diazepam (5- 10 mg tim t nh mch) hoc natri thiopental (2,5% tim t nh mch). iu tr sc. CU HI T LNG GI 1. Trnh by sinh chuyn ha, c ch tc dng v p dng iu tr ca acetylcholin. 2. Trnh by tc dng ca muscarin v iu tr ng c muscarin. 3. So snh acetylcholin v pilocarpin. 4. Trnh by c ch tc dng v p dng iu tr ca atropin 5. Phn tch c ch tc dng ca nicotin. 6. Phn tch c ch tc dng ca thuc lit hch (ngng hm h N ca hch) v p dng lm sng. 7. Phn bit 2 loi cura v c ch tc dng, tc dng v p dng lm sng. 8. Phn tch c ch tc dng, tc dng v cch iu tr ng c thuc phong ta khng hi phc cholinnesterase. Bi 6: THUC TC DNG TRN H ADRENERGIC MC TIU HC TP: Sau khi hc xong bi ny, sinh vin c kh nng: 1. Trnh by c chu trnh chuyn ha ca catecholamin ti ngn dy thn kinh giao cm 2. Phn bit c tc dng ca adrenalin, noradrenalin v DA

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3. Phn bit c tc dng ca thuc cng 1 v 2: Isoproterenol, dobutamin v salbutamol 4. Phn tch c c ch tc dng ca cc thuc hu giao cm 5. Trnh by c tc dng v p dng iu tr ca thuc hy a giao cm 6. Phn bit c c ch tc dng v p dng iu tr ca thuc hy 1 H adrenergic l h hu hch giao cm, gii phng cht trung gian ha hc gi chung l catecholamin v u mang nhn catechol (vng benzen c hai nhm -OH v tr ortho v mt gc amin chu i bn. Cc catecholamin g m c adrenalin (c sn xut ch yu tu thng thn) noradrenalin ( u tn cng cc si giao cm) v dopamin ( mt s vng trn thn kinh trung ng).

Hnh 6.1. Sinh tng hp catecholamin 1. CHUYN HA CA CATECHOLAMIN Catecholamin c sinh tng hp t tyrosin di tc dng ca mt s enzym trong t bo a crm tu thng thn, cc nron hu hch giao cm v mt s nron ca thn kinh trung ng theo s trn (hnh 6.2)

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Hnh 6.2. Chuyn vn ca catecholamin ti tn cng dy giao cm Tyrosin c vn chuyn vo u tn cng dy giao cm nh cht vn chuyn ph thuc Na+ (A). Tyrosin c chuyn ha thnh dopamin (DA) ri c cht vn chuyn (B) a vo cc ti d tr (cc ht). Cht vn chuyn ny cng vn chuyn c noradrenalin (NA) v vi amin khc. Trong ti d tr, DA c chuyn ha thnh NA. in th hot ng lm m knh calci, Ca2+ vo t bo, gii phng NA t ti d tr. Sau khi c tng hp, mt phn catecholamin s kt hp vi ATP hoc vi mt dng protein ha tan l chromogranin tr thnh dng khng c hot tnh, khng b cc enzym ph hu, lu li trong cc kho d tr l nhng ht c bit nm bo t ng (khong 60%), cn mt phn khc (khong 40%) vn dng t do trong bo tng, d di ng, nm ngoi ht. Gia hai dng ny lun c s thng bng ng, khi dng t do gim i th li c b sung ngay t cc kho d tr. Lng noradrenalin trong bo tng iu chnh hot tnh ca tyrosin

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hydroxylase theo c ch iu ha ngc chiu: khi noradrenalin tng th hot tnh ca enzym gim, v ngc li. Mt khc, cc cht cng receptor a2 lm gim gii phng noradrenalin ra khe xinap v do tr lng ca noradrenalin trong bo tng s tng ln. Theo gi thit ca Burn v Rand (1959- 1962) di nh hng ca xung tc thn kinh, ngn dy giao cm lc u tit ra acetylcholin, lm thay i tnh thm ca mng t bo, do Ca++ t ngoi t bo thm nhp c vo trong t bo, ng vai tr nh mt enzym lm v lin kt ATP- catecholamin, gii phng catecholamin ra dng t do. Sau khi c gii phng, mt phn noradrenalin s tc ng ln cc receptor (sau v trc xinap), mt phn chuyn vo mu tun hon tc dng xa hn ri b ging ha, cn phn ln (trn 80%) s c thu hi li, phn nh khc b mt hot tnh ngay trong bo tng.

Hnh 6.3. S phn ca noradrenalin khi c gii phng 1. 2. 3. 4. Tc dng trn receptor sau (1a) v trc (1b) xinap Thu hi Vo tun hon v b chuyn ha bi COMT Chuyn ha trong bo tng bi MAO

Catecholamin b mt hot tnh bi qu trnh oxy ha kh amin do hai enzym MAO (monoamin oxydase) v COMT (catechol- oxy- transferase) cui cng thnh acid 3- methoxy4 hydroxy mandelic (hay vanyl mandelic acid- VMA) thi tr qua nc tiu. MAO c nhiu trong ti th (mitochondria), v vy n ng vai tr ging ha catecholamin trong t bo hn l tun hon. Phong to MAO th lm tng catecholamin trong m nhng khng nh hng n tc dng ca catecholamin ngoi lai. COMT l enzym ging ha catecholamin ngoi t bo, c mng xinap v nhiu ni nhng m cao hn c l gan v thn. Phong to COMT th ko di c thi gian tc dng ca catecholamin ngoi lai. Receptor: Adrenalin v noradrenalin sau khi c gii phng ra s tc dng ln cc receptor ca h adrenergic. Ahlquist (1948) chia cc receptor thnh hai loi a v b do chng c tc dng khc nhau trn cc c quan (bng sau). Ta thy rng tc dng cng a c tnh cht kch thch, lm co tht cc c trn, ch c c trn thnh rut l gin. Ngc li, tc dng cng b c tnh cht c ch, lm gin c, tr c tim li lm p nhanh v p mnh.

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Land, Arnold v Mc Auliff (1966) cn chia cc receptor b thnh hai nhm b1 (tc dng trn tim v chuyn ha m) v nhm b2 (lm gin mch, gin kh o v chuyn ha ng). b2 trc xinap kch thch lm tng gii phng NA, c vai tr iu ha ngc vi a2. Theo xut ca Langer (1974), cc receptor a c chia thnh hai loi: loi a1 l receptor sau xinap, lm co mch tng huyt p, loi a2 l receptor trc xinap, c tc dng iu ha, khi kch thch s lm gim gii phng noradrenalin ra khe xinap, ng thi lm gim tit renin, gy h huyt p. Cc receptor a2 c nhiu h giao cm trung ng. Hin cng thy c receptor a2 sau xinap ca mch mu v t bo c trn (lm co), m m v cc t bo biu m xut tit (rut, thn, tuyn n i tit) Dopamin ch yu tc dng thn kinh trung ng, thn v cc tng, trn cc receptor c hiu i vi n gi l cc receptor dopaminergic (receptor delta- d) Bng 6.1: Cc receptor adrenergic Recepto r a1 Cht ch vn Adr NA >>Iso Phenylephrin Chti khng Prazosin M - C trn thnh mch - C trn sinh dc tit niu - Gan - C trn rut - Tim a2 AdrNA >> Iso Clonidin Yohimbi n - T bo b ca ty - Tiu cu - Tn cng si TK - C trn thnh mch p ng Co tht Co tht Hu glycogen Tn to ng u cc ha v gin C ch phn t Kch thch phospholipase C to IP3 v DAG; tng Ca++ cytosol - Hot ha knh K+ ph thuc vo Ca++

Tng co bp, lon - c ch dng K+ nhp Gim tit insulin Ngng kt Gim tit NA Co - c ch adenylcyclase (Gi) - Hot ha knh K+ - c ch knh Ca++ -Tng lung Ca, tng Ca++ trong cytosol Hot ha adenylcyclase v knh Ca

b1

Iso>Adr =NA Dobutamin

Metoprol - Tim ol

Tng tn s, bin v tc dn truyn A-V Tng tit renin

- T bo gn cu thn b2 Iso>Adr >> NA Terbutalin ICI 118551 - C trn (mch kh qun, rut...)

- Gin - Hu glycogen gn K+

Hot ha adenylcyclase

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- C vn - Gan b3 Iso=NA>Adr BRL 37344 ICI 118551 CGP 20712A Iso*: Isoproterenol Ghi ch ca bng 3:

- Hy glycogen - Tn to ng Hu lipid Hot ha adenylcyclase

Adr: adrenalin

NA: noradrenalin

- Mi receptor b u kch thch adenylcyclase thng qua protein GS v lm tng AMPv, ngoi ra cn lm knh calci cm ng vi in th ca c vn v c tim. - Receptor a2, tri li, c ch adenylcyclase thng qua protein Gi, ng thi hot ha knh kali, c ch knh calci. - Receptor a1 kch thch lm tng calci ni bo thng qua 2 cht trung gian Diacylglycerol (DAG) v Inositol triphosphat (IP3). 2. THUC CNG H ADRENERGIC L nhng thuc c tc dng ging adrenalin v noradrenalin , kch thch hu hch giao cm nn cn gi l thuc cng giao cm. Theo c ch tc dng c th chia cc thuc ny lm hai loi: - Loi tc dng trc tip trn cc receptor adrenergic sau xinap nh adrenalin, noradrenalin, isoproterenol, phenylephrin - Loi tc dng gin tip do kch thch cc receptor trc xinap, lm gii phng catecholamin n i sinh nh tyramin (khng dng trong iu tr), ephedrin, amphetamin v phenyl- ethylamin. Khi dng reserpin lm cn d tr catecholamin th tc dng ca cc thuc s gim i. Trong nhm ny, mt s thuc c tc dng kch thch thn kinh trung ng theo c ch cha hon ton bit r (nh ephedrin, amphetamin), reserpin khng nh hng n tc dng ny; hoc c ch mono- amin- oxydase (MAOI), lm vng bn catecholamin. 2.1.Thuc cng receptor alpha v beta 2.1.1.Adrenalin c, bng A L hormon ca tu thng thn, ly ng vt hoc tng hp. Cht t nhin l ng phn t tuyn c tc dng mnh nht. 2.1.1.1.Tc dng Adrenalin tc dng c trn a v b receptor. - Trn tim mch: Adrenalin lm tim p nhanh, mnh (tc dng b) nn lm tng huyt p ti a, tng p lc t ngt cung ng mch ch v xoang ng mch cnh, t pht sinh cc phn x gim p qua dy thn kinh Cyon v Hering lm cng trung tm dy X, v vy lm tim p chm dn v huyt p gim. Trn ng vt th nghim, nu ct dy X hoc tim atropin (hoc methylatropin) trc ct phn x ny th adrenalin ch lm tim p nhanh mnh v huyt p tng rt r.

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Mt khc, adrenalin gy co mch mt s vng (mch da, mch tng- receptor a) nhng li gy gin mch mt s vng khc (mch c vn, mch ph i- receptor b...) do huyt p ti thiu khng thay i hoc c khi gim nh, huyt p trung bnh khng tng hoc ch tng nh trong thi gian ngn. V l adrenalin khng c dng lm thuc tng huyt p. Tc dng lm gin v tng lu lng mch vnh ca adrenalin cng khng c dng trong iu tr co tht mch vnh v tc dng ny li km theo lm tng cng nng v chuyn ha ca c tim. Di tc dng ca adrenalin, mch mu mt s vng co li s y mu ra nhng khu vc t chu nh hng hn, gy gin mch th ng nhng ni (nh mch no, mch ph i) do d gy cc bin chng t mch no, hoc ph ph i cp. - Trn ph qun: t tc dng trn ngi bnh thng. Trn ngi b co tht ph qun do hen th adrenalin lm gin rt mnh, km theo l co mch nim mc ph qun, lm gim ph cho nn nh hng rt tt ti tnh trng bnh. Song adrenalin b mt tc dng rt nhanh vi nhng ln dng sau, v vy khng nn dng ct cn hen. - Trn chuyn ha: Adrenalin lm tng hu glycogen gan, lm tng glucose mu, lm tng acid bo t do trong mu, tng chuyn ha c bn, tng s dng oxy ca m. Cc c ch tc dng ca adrenalin hay catecholamin ni chung l lm t ng tng hp adenosin 3'- 5'- monophosphat (AMP- vng) t ATP do hot ha adenylcyclase (xem s ) S tc ng ca catecholamin ln chuyn ha ng v m Catecholamin Adenylcyclase ATP 3', 5'- AMP (AMP vng) Cafein Diazoxid (-) Phosphodiesterase AMP

Glycogen Phosphorylase Glucose- 1- phosphat (-) Glycogen synthetase

Triglycerid lipase

Triglycerid

Diglycerid

Acid bo

Glucose- 6- phosphat

Monoglycerid

Acid bo

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Glucose mu 2.1.1.2. p dng iu tr:

Nng lng Glycerol Acid bo

Acid lactic

- Chng chy mu bn ngoi (p ti ch dung dch adrenalin hydroclorid 1% lm co mch). - Tng thi gian gy t ca thuc t v adrenalin lm co mch ti ch nn lm chm hp thu thuc t. - Khi tim b ngng t ngt, tim adrenalin trc tip vo tim hoc truyn mu c adrenalin vo ng mch hi t nh. - Sc ngt: dng adrenalin tng huyt p tm thi bng cch tim t nh mch theo phng php trng bm tim. Liu trung bnh: tim di da 0,1- 0,5 mL dung dch 0,1% adrenalin hydroclorid. Liu ti a: m i ln 1 mL; 24 gi : 5 mL ng 1 mL = 0,001g adrenalin hydroclorid 2.1.2. Noradrenalin (arterenol) c, bng A L cht dn truyn thn kinh ca cc si hu hch giao cm. Tc dng mnh trn cc receptor a, rt yu trn b, cho nn: - Rt t nh hng n nhp tim, v vy khng gy phn x cng dy ph v. - Lm co mch mnh nn lm tng huyt p ti thiu v huyt p trung bnh (mnh hn adrenalin 1,5 ln) - Tc dng trn ph qun rt yu, v c trn ph qun c nhiu receptor b2. - Tc dng trn dinh dng v chuyn ho u km adrenalin. Trn nhiu c quan, tc dng ca NA trn receptor a km hn adrenalin mt cht. Nhng do t l cng tc dng gia a v b khc nhau nn tc dng chung khc nhau r rt. Trn thn kinh trung ng, noradrenalin c nhiu vng di i. Vai tr sinh l cha hon ton bit r. Cc cht lm gim d tr catecholamin no nh reserpin, a methyldopa u gy tc dng an thn. Tri li, nhng thuc c ch MAO, lm tng catecholamin th u c tc dng kch thn. iu ha thn nhit ph thuc vo s cn bng gia NA, serotonin v acetylcholin phn trc ca vng di i. C th cn tham gia vo c ch gim au: thuc lm gim lng catecholamin tim vo no tht c ch c tc dng gim au ca morphin. Ch nh: nng huyt p trong mt s tnh trng sc: sc nhim c, nhim khun, sc do d ng... Ch truyn nh git tnh mch t 1- 4 mg pha long trong 250- 500 mL dung dch glucose ng trng. Khng c tim bp hoc di da v lm co mch ko di, d gy hoi t ti ni tim. ng 1 mL = 0,001g 2.1.3. Dopamin

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Dopamin l cht tin thn ca noradrenalin v l cht trung gian ha hc ca h dopaminergic. C rt t ngn dy giao cm. Trong no, tp trung cc nhn xm trung ng v b en vn. Trn h tim mch, tc dng ph thuc vo liu: - Liu thp 1- 2 mg/ kg/ pht c gi l "liu thn", tc dng ch yu trn receptor dopaminergic D1, lm gin mch thn, mch tng v mch vnh. Ch nh tt trong sc do suy tim hoc do gim th tch mu (cn phc h i th tch mu km theo). - Ti thn, "liu thn" ca dopamin lm tng nc tiu, t ng thi Na+, K+, Cl-, Ca++, tng sn xut prostaglandin E2 nn lm gin mch thn gip thn chu ng c thiu oxy. - Liu trung bnh > 2- 10 mg/ kg/ pht, tc dng trn receptor b1, lm tng bin v tn s tim. Sc cn ngoi bin ni chung khng thay i. - Liu cao trn 10mg/ kg/ pht tc dng trn receptor a1, gy co mch tng huyt p. Trong lm sng, tu thuc vo tng loi sc m chn liu. Dopamin khng qua c hng ro mu no Ch nh: cc loi sc, km theo v niu ng 200 mg trong 5 mL. Truyn chm t nh mch 2- 5 mg/ kg/ pht. Tng gim s git theo hiu qu mong mun. Chng ch nh: cc bnh mch vnh 2.2. Thuc cng receptor a 2.2.1. Metaraminol (Aramin) Tc dng u tin trn receptor a1. Lm co mch mnh v lu hn adrenalin, c th cn do kch thch gii phng noradrenalin, khng gy gin mch th pht. Lm tng lc co bp ca c tim, t lm thay i nhp tim. Khng kch thch thn kinh trung ng, khng nh hng n chuyn ha. V mt gc phenol trn vng benzen nn vng bn hn adrenalin. Dng nng huyt p trong cc trng hp h huyt p t ngt (chn thng, nhim khun, sc). Tim t nh mch 0,5- 5,0 mg trong trng hp cp cu. Truyn chm t nh mch dung dch 10 mg trong 1 mL. C th tim di da hoc tim bp. ng 1 mL= 0,01g metaraminol bitartrat. 2.2.2. Phenylephrin (neosynephrin) Tc dng u tin trn receptor a1. Tc dng co mch tng huyt p ko di, nhng khng mnh bng NA. Khng nh hng n nhp tim, khng kch thch thn kinh trung ng, khng lm tng glucose huyt. Ch nh: nh noradrenalin Tim bp 5- 10 mg Truyn chm vo tnh mch 10- 15 mg trong 1000 mL dung dch glucose ng trng Cn dng chng xung huyt v gin ng t trong mt s ch phm chuyn khoa. 2.2.3. Clonidin (Catapressan) Clonidin (dicloro- 2, 6 phenyl- amino- imidazolin) c tc dng cng receptor a2 trc xinap trung ng v thuc qua c hng ro mu- no. Tc dng cng a2 sau xinap ngoi bin

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ch thong qua nn gy tng huyt p ngn. Sau , do tc dng cng a2 trung ng chim u th, clonidin lm gim gii phng NA t cc nron giao cm hnh no, gy gim nhp tim, gim trng lc giao cm, gim lu lng mu no, tng, thn v mch vnh, a n h huyt p. Clonidin lm cn bi tit nc bt, dch v, m hi, lm gim hot tnh ca renin huyt tng, gim l i niu. ng thi c tc dng an thn, gim au v gy mt m i. Mt s tc gi cho rng clonidin gn vo receptor imidazolin thn kinh trung ng, l loi receptor mi ang c nghin cu. Tc dng khng mong mun: ng g, kh ming Ch nh: tng huyt p th va v nng (xin xem bi "Thuc cha t ng huyt p") Chng ch nh: trng thi trm cm. Khng dng cng vi guanetidin hoc thuc lit hch v c th gy cn tng huyt p. Liu lng: vin 0,15 mg. Ung liu tng dn ti 6 vin mt ngy, tc dng xut hin chm. Dng cng vi thuc li niu, tc dng h huyt p s tng. 2.3. Thuc cng receptor b C 4 tc dng dc l chnh - Tc dng gin ph qun, dng cha hen: loi cng b2. - Tc dng gin mch: loi cng b2 - Tc dng kch thch b1 lm tng tn s, tng lc co bp ca c tim, tng tc dn truyn trong c tim, tng ti mu cho c tim. - Trn t cung c cha, thuc cng b2 lm gim co bp c dng chng da xy thai. 2.3.1. Isoproterenol (Isoprenalin, Isuprel, Aleudrin, Novodrin, Isopropyl noradrenalin) Tc dng u tin trn b receptor (b1 v b2). Lm tng nhp tim, tng sc co bp ca c tim v cung lng tim, gy gin mch, h huyt p, lm gin kh qun nhanh v mnh (gp 10 ln adrenalin), ng thi lm gim tit dch nim mc nn ct cn hen rt tt. Dng trong cc trng hp nhp tim chm thng xuyn, nghn nh tht hon ton, lon nhp do nh i mu c tim: truyn t nh mch 0,5mg trong 250- 500 ml dung dch glucose 5%. Tc dng tng ng huyt km adrenalin v cn trc tip kch thch t bo ty tit insulin. Trong hen ph qun v trn kh ph mc mn tnh, t di li vin 10 mg, 2- 3 ln/ ngy. Khng ung v b chuyn ha nhanh. ng Novodrin 1 mL= 0,5 mg isoprenalin clohydrat Vin 10- 20 mg isoprenalin sulfat Phun dch 1 phn nghn 2.3.2. Dobutamin (Dobutrex) Cng thc gn ging dopamin: tc dng u tin trn b1 receptor. Tc dng phc tp do dobutamin raxemic c 2 ng phn; ng phn (-) dobutamin c tc dng cng a1 mnh, gy tng huyt p; trong khi ng phn (+) dobutamin li c tc dng i lp hy a1. C hai ng phn u c tc dng cng b, nhng ng phn (+) 10 ln mnh hn ng phn (-). Tc dng ca dobutamin raxemic l tng hp ca c hai ng phn.

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Trn tim, do dobutamin lm tng co bp mnh v t lm tng nhp , v vy khng lm tng nhu cu s dng oxy ca c tim. Tc dng km isoproterenol. t tc dng trn mch nhng lm gin mch vnh. Tc dng li niu ch yu l do tng lu lng tim. Ch nh: suy tim cp sau m tim, nh i mu c tim V thi gian bn thi ch khong 2 pht nn ch dng bng ng truyn chm t nh mch. Ch phm: Dobutamin hydroclorid (Dobutrex) l 20 mL cha 250 mg dobutamin. Khi dng, ha long trong 50 mL dung dch dextrose 5%, truyn tnh mch vi liu 2,5- 10 mg/ kg/ pht. Nu nhp tim tng nhanh, gim tc truyn. 2.3.3. Thuc cng u tin (chn lc) receptor b2 L thuc thng c dng iu tr ct cn hen. Tuy nhin, liu cao cng vn kch thch c b1, lm tng nhp tim. V vy hng nghin cu ti vn l tm cch thay i cu trc c cc thuc tc dng ngy cng chn lc trn b1 hn v c sinh kh dng cao hn. ng thi dng thuc di dng kh dung trnh hp thu nhiu thuc vo ng ton thn, d gy tc dng ph (tim p nhanh, run tay) Cc thuc cng b2 dng di dng kh dung, ngoi tc dng lm gin ph qun cn c th c ch gii phng leucotrien v histamin kh i dng bo phi (xem thm bi "Thuc iu chnh ri lon h hp") Chng ch nh: bnh mch vnh, lon nhp tim, cao huyt p nng, i tho ng, cng gip. Dng ko di lin tc, tc dng c th gim dn do s lng receptor b2 mng t bo sau xinap gim ("down regulation") 2.3.3.1. Terbutalin Do c vng resorcinol trong cu trc nn khng b COMT metyl ha. Sau kh dung, tc dng ko di c 3- 6 gi. 2.3.3.2. Albuterol (Salbutamol- Ventolin) Tnh cht dc l v ch nh iu tr nh terbutalin. Dng ng ung hoc kh dung. Sau kh dung, tc dng ti a vo pht th 15 v duy tr c 3- 4 gi. - Vin gii phng chm (Volmax): 4- 8 mg 2 ln/ ngy - Kh dung nh liu (Ventolin): 100 mg/ nht bp 2 nht/ ln 3- 4ln/ ngy cch nhau 4 ting. 2.3.2.3. Ritodrin Dng lm gin t cung, chng non (xem bi " Thuc tc dng trn t cung"). Hp thu nhanh qua ng ung nhng sinh kh dng ch c 30%. Thi tr qua nc tiu 90% di dng lin hp. Tim tnh mch, 50% thi tr di dng nguyn cht. 2.4. Thuc cng giao cm gin tip 2.4.1. Ephedrin (ephedrinum) c, bng B Ephedrin l alcaloid ca cy ma hong (Ephedra equisetina v Ephedra vulgaris). Hin nay tng hp c. Trong y hc, dng loi t tuyn v raxemic. L thuc va c tc dng gin tip lm gii phng catecholamin ra kh i ni d tr, va c tc dng trc tip trn receptor.

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Trn tim mch, so vi noradrenalin, tc dng chm v yu hn 100 ln, nhng ko di hn ti 10 ln. Lm tng huyt p do co mch v kch thch trc tip trn tim. Dng nhiu ln lin nhau, tc dng tng p s gim dn (hin tng quen thuc nhanh: tAChyphylaxis) Thng dng chng h huyt p v kch thch h hp trong khi gy t tu sng, trong nhim c ru, morphin, barbiturat. Kch thch trung tm h hp hnh no v lm gin ph qun nn dng ct cn hen, tc dng tt trn tr em. Trn thn kinh trung ng, vi liu cao, kch thch lm mt ng, bn chn, run, tng h hp. Ephedrin d dng hp thu theo m i ng. Vng bn vi MAO. Chuyn ha gan, khong 40% thi tr nguyn cht qua nc tiu. Dng di th mu i clohydrat hoc sulfat d ha tan. Ung 10- 60 mg / ngy. Liu ti a 24h l 150 mg Tim di da, bp tht hoc tnh mch 10- 20 mg/ ngy Nh nim mc (mt, mi) dung dch 0,5- 3% ng 1 mL= 0,01g ephedrin clohydrat Vin 0,01g ephedrin clohydrat Pseudoephedrin l ng phn lp th ca ephedrin, t gy tim nhanh, t ng huyt p v kch thch thn kinh trung ng hn ephedrin. Thng c dng trong cc ch phm nh mi chng xung huyt nim mc. 2.4.2. Amphetamin L thuc tng hp phenylisopropanolamin. Tc dng dc l theo kiu ephedrin, gin tip lm gii phng noradrenalin (v c th cn c dopamin v serotonin) ra kh i ni d tr. Khc ephedrin l thm vo thn kinh trung ng nhanh, tc dng kch thch mnh tm trng v s nhanh nhn do tc ng ln v no v h lin vng hot ha (v vy, c xp vo loi doping, cm dng trong thi u th thao). Cn c tc dng gy chn n, dng chng bo ph. Mt s dn xut ca amphetamin (methamphetamin, dimethoxyamphetamin...) kch thch thn trung ng rt mnh, gy lon thn, u xp vo cht ma tu. 2.4.3. Phenylpropanolamin t tc dng trung ng hn. ngoi bin, tc dng co mch thng c dng chng ngt mi, l thuc phi hp trong vin thuc chng cm cm (Atussin, Decolgen). Tuy nhin, gn y thy nhiu tc dng ph trn tim mch nn c xu hng khng dng na. 3. THUC HU H ADRENERGIC L nhng thuc lm mt tc dng ca adrenalin v noradrenalin. Cc thuc ny thng c dng iu tr chng tng huyt p, bnh Raynaud, lon nhp tim, hi chng cng tuyn gip (tim nhp nhanh, l i mt, gin ng t, tng h hp; chnh l nhng du hiu cng giao cm). Cc thuc c chia thnh hai nhm: - Thuc hy giao cm (sympatholytic): l nhng thuc phong to nron adrenergic trc xinap, lm gim gii phng catecholamin, khng c tc dng trn receptor sau xinap, khi ct cc dy hu hch giao cm th thuc mt tc dng. Do thiu cht dn truyn thn kinh n i sinh, tnh cm th ca cc receptor sau xinap vi catecholamin ngoi lai s tng ln.

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- Thuc hu adrenalin (adrenolytic) l nhng thuc phong to ngay chnh cc receptor adrenergic sau xinap, cho nn khi ct t cc si hu hch giao cm, tc dng ca thuc khng thay i. Catecholamin c n i sinh ngoi lai u b mt tc dng. 3.1. Thuc hu giao cm Cc thuc c th c tc dng nhng khu sau: 3.1.1. c ch tng hp catecholamin Thuc hay c dng l a methyl dopa (Aldomet) phong ta dopa decarboxylase, lm dopa khng chuyn thnh dopamin v 5- hydroxytryptophan khng chuyn thnh 5hydroxytryptamin (5 HT- serotonin). Do s lng catecholamin v serotonin c ngoi bin v thn kinh trung ng u gim. Mt khc cn ngn cn kh nng gn catecholamin vo cc ht lu tr. Ngoi ra, trong c th a methyldopa cn c th chuyn thnh a methyl noradrenalin, tc dng nh mt cht trung gian ha hc gi chim ch ca noradrenalin (xem bi "Thuc cha tng huyt p") Tc dng ph: m mng, c ch tm thn, chng mt, nhc u, kh ming, ph. Khng dng khi c ri lon tun hon no v mch vnh, cc trng thi trm cm, ri lon gan, thn. Liu lng: ung vin 250 mg. C th dng ti 8 vin/ ngy. Ch phm: Dopegyt vin 0,25 g a methyl dopa. Carbidopa v bemerazid, c ch dopa decarboxylase ngoi bin. c dng phi hp vi ldopa iu tr bnh Parkinson. 3.1.2. Lm gim d tr catecholamin trong cc ht * Reserpin: Lm gii phng t t catecholamin t cc ht lu tr ra ngoi bo tng MAO ph hu, do lng catecholamin gim c trn thn kinh trung ng (gy an thn), c ngoi bin (lm h huyt p). Reserpin cn cn tr qu trnh gn catecholamin (c n i sinh ln ngoi sinh) vo cc ht lu tr. * Guanetidin (Ismelin) Chim ch noradrenalin trong cc ht lu tr v tr thnh cht trung gian ha hc gi. Khc reserpin l lc u guanetidin gy tng nh huyt p do lm gii phng nhanh noradrenalin ra dng t do, mt khc guanetidin khng thm c vo thn kinh trung ng nn khng c tc dng an thn. Tc dng ti a xut hin sau 2- 3 ngy v mt i 6- 10 ngy sau khi ngng thuc. Khng dng cho ngi bnh c lot d dy, suy mch vnh, suy thn. Khng dng cng vi clonidin. Liu lng: lc u ung 10 mg/ ngy, sau tng dn ti 50- 75mg/ ngy Ch phm: vin 10 v 20 mg 3.1.3. Ngn cn gii phng catecholamin Bretylium (Darentin) C ch cha tht r. c ch gii phng catecholamin, nhng khng nh hng n tc dng ca adrenalin v noradrenalin ngoi lai. C th l bretylium lm cho mng cc ht lu tr gim tnh thm vi ion Ca++ m lm cho catecholamin khng c gii phng ra.

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C tc dng gy t ti ch. V c nhiu tc dng ph (nh xung huyt nim mc mi, kh th, a lng, h huyt p, nhc c) cho nn cn t c s dng lm sng. 3.1.4. Thay th catecholamin bng cc cht trung gian ho hc gi Mt s cht khng c tc dng dc l, nhng chim ch ca catecholamin v cng c gii phng ra di xc tc kch thch dy giao cm nh mt cht trung gian ha hc, c gi l cht trung gian ha hc gi: - a methyldopa t o thnh a methyl noradrenalin - Thuc c ch MAO: tyramin chuyn thnh octopamin - Guanetidin 3.2. Thuc hu adrenalin Cc thuc phong ta tc dng trn receptor tng i c hiu hn thuc kch thch, ngha l nhiu thuc kch thch c tc dng c trn hai loi receptor a v b, cn thuc phong to thng ch tc dng trn mt loi receptor m thi. Do thuc loi ny c chia thnh hai nhm: thuc hu a v thuc hu b adrenergic. 3.2.1. Thuc hu a- adrenergic V phong to cc receptor a nn lm gim tc dng tng huyt p ca noradrenalin, lm o ngc tc dng tng p ca adrenalin. Khng c ch tc dng gin mch v tng nhp tim ca cc thuc cng giao cm v u l tc dng trn cc receptor b. Hin tng o ngc tc dng tng p ca adrenalin c gii thch l cc mao mch c c hai loi receptor a v b, adrenalin tc dng trn c hai loi receptor , nhng bnh thng, tc dng a chim u th nn adrenalin lm tng huyt p. Khi dng thuc phong to a, adrenalin ch cn gy c tc dng kch thch trn cc receptor b nn lm gin mch, h huyt p. Nhm thuc ny c ch nh trong cc cn tng huyt p, chn on u tu thng thn, iu tr bnh Raynaud. Hin ang nghin cu thuc hu a1A iu tr ph i lnh tnh tuyn tin lit. Nhc im chung l d gy h huyt p khi ng, nhp tim nhanh, xung huyt nim mc mi, co ng t, bun nn, nn v tiu chy do tng nhu ng d dy- rut. Cc thuc ch khc nhau v cng tiu chy v thi gian tc dng. 3.2.1.1. Nhm haloalkylamin: C phenoxybenzamin (dibenzylin) v dibenamin. V ha hc, c cng thc gn ging nh m tc nit (nitrogen mustard). Khi vo c th, amin bc 3 c chuyn thnh etylen amoni, cht ny gn cht vo cc receptor a theo lin kt cng ha tr (ch yu l receptor a1), gy c ch rt mnh v ko di (ti 24 gi cho mt ln dng thuc) theo kiu c ch mt chiu. Liu lng: phenoxybenzamin, vin nang 10 mg, ung 2- 10 vin/ ngy 3.2.1.2. Dn xut imidazolin C tolazolin (Priscol, Divascon) v phentolamin (Regitin) c ch tranh chp vi noradrenalin receptor a1 v a2 nn tc dng yu v ngn hn phenoxybenzamin nhiu. Liu lng: Priscol ung hoc tim bp 25- 50 mg/ ngy. Regitin ung 20- 40 mg/ ngy

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Cn dng chn on u tu thng thn: nghim php c coi l dng tnh nu ngi bnh ngh ngi, hon ton yn tnh, tim bp ho c tim t nh mch 5 mg phentolamin, sau vi pht lm huyt p ti a v ti thiu h khong 4- 5 cmHg, duy tr c 7 pht ri tr li huyt p ban u trong 10- 15 pht. 3.2.1.3. Prazosin (Minipress): cht in hnh phong to a1. Dng iu tr tng huyt p, ung 1- 20 mg mt ngy. (xin xem bi "Thuc cha tng huyt p") 3.2.1.4. Alcaloid nhn indol: Cc alcaloid ca nm ca g (ergot de seigle; Secale cornutum; Claviceps purpurea), c chia thnh hai nhm: loi hu giao cm v lm co bp t cung (gm ergotamin, ergotoxin) v loi lm co bp t cung n thun (ergometrin). Vi liu thp, ergotamin c tc dng cng giao cm nh v ngn cn thu hi noradrenalin ngn dy giao cm. Liu cao, tri li c tc dng phong to receptor a. Ngoi ra cn c tc dng trc tip lm co c trn, nn c th lm co mch tng huyt p, hoc hoi t u chi v vch mi trong trng hp nhim c mn tnh do n la mch m mc, lm co tht rut, ph qun v t cung. Ch nh: ct cn migren, ri lon thi k mn kinh, chy mu t cung sau s rau Dn xut hydro ha ca cc ergot (nh dihydroergotamin, hydroergotoxin) c tc dng phong to a tng ln trong khi tc dng co c trn gim xung. Ngoi tc dng phong to receptor a, tc dng h huyt p ca ergotamin cn c gii thch l lm gim trng lc trung tm vn mch v kch thch trung tm ph giao cm. Do c dng lm thuc gin mch, h huyt p: ung 4- 6 mg/ ngy, hoc tim di da 0,1- 0,5 mg/ ngy. Chng ch nh: c thai, ri lon mch vnh - Yohimbin: l alcaloid ca Corynantheyo himbe c nhiu Chu Phi. Cu trc ha hc gn ging reserpin, tranh chp vi NA ti receptor a2. D vo thn kinh trung ng. Tc dng yu v ngn, nn t c dng trong iu tr. Trong lm sng cn dng lm thuc cng dng, v ngoi tc dng gin mch cn kch thch phn x tu. Liu lng: Yohimbin clorhydrat 5- 15 mg/ ngy 3.2.2. Thuc hu b adrenergic Cn gi l thuc "phong to b" ("b blocking agent") c tc dng c ch tranh chp vi isoproterenol cc receptor. Cht u tin c tm ra l dicloisoproterenol (Powell v Slater, 1958). c dng nhiu trong lm sng. 3.2.2.1. Tc dng dc l: c 4 tc dng dc l chnh vi mc khc nhau gia cc thuc:

* Kh nng hu giao cm b: l tnh cht chung duy nht ca tt c cc thuc hu b: - Trn tim: lm gim nhp tim (20- 30%), gim lc co bp ca c tim, gim lu lng tim, gim cng nng v gim s dng oxy ca c tim, gim tc dn truyn ca t chc nt. Ch yu l do hu b1. - Trn kh qun: lm co, d gy hen. Ch yu l do hu b2, gy tc dng khng mong mun. - Trn thn: lm gim tit renin, h huyt p trn ngi c HA cao - Trn chuyn ha: c ch hu glycogen v hu lipid

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+Tc dng lm n nh mng: gi ng quinidin, lm gim tnh thm ca mng t bo vi s trao i ion nn c tc dng chng lon nhp tim. + C hot tnh n i ti kch thch receptor b: mt s thuc phong to b khi gn vo cc receptor li c tc dng kch thch mt phn. Hiu qu thc t t quan trng, nhng c th hn ch tc dng lm gim nhp tim, gim co bp c tim, gim co kh qun ca chnh n. + Tnh chn lc: nhiu thuc phong to b i lp vi tt c cc tc dng cng giao cm ca b (b1: tim v b2: mch, kh qun). Nhng mt s thuc li ch phong to c mt trong hai loi receptor (b1hoc b2), v th phn bit thnh cc loi phong to chn lc trn giao cm b: - Loi tc dng chn lc trn b1 hay loi chn lc trn tim ("cardioselectifs"), nh practolol, acebutalol, atenolol. Thng dng metoprolol (Lopressor) v atenolol (Tenormin) Li ch ca loi thuc ny l: - Do rt km tc dng trn b2 ca kh qun nn hn ch c tai bin co tht kh qun. - Km tc dng trn b2 ca thnh mch s c li cho iu tr cao huyt p (gim co mch ngoi bin) - Do rt km tc dng trn b2 ca thnh mch vnh nn khng bc l tc dng cng aadrenergic (tc dng co mch vnh ca CA tun hon trong mu). Bnh thng, do c tc dng b th tc dng ca a b lu m. Khi b b phong to th tc dng ca a s c bc l ra. - Do khng nh hng n cc receptor trong hu glycogen nn khng lm nng thm tnh trng h ng huyt. - Loi c tc dng chn lc trn b2, ng u l Butoxamin, t c ngha trong lm sng. 3.2.2.2. Ch nh chnh - Cn au tht ngc, ch yu do lm gim s dng oxy ca c tim. Trong nh i mu c tim, tim t nh mch ngay t gi u s lm gim lan rng nh i mu v ci thin c tin lng bnh. - Lon nhp tim: nhp nhanh xoang, nhp nhanh trn tht, tim cng gip, cung ng nh do nhim c digital. - Tng huyt p: do lm gim lu lng tim, gim sc cn ngoi bin, gim tit renin v gim gii phng noradrenalin (xin xem thm bi "Thuc cha t ng huyt p") - Mt s ch nh khc; cng gip, migren, glocom gc m (do lm gim sn xut thu dch), run tay khng r nguyn nhn. 3.2.2.3. Chng ch nh: - Suy tim l chng ch nh chnh v n c ch c ch b tr ca tim. - Bloc nh- tht v thuc c tc dng lm gim dn truyn n i ti trong c tim. - Hen ph qun. Loi c tc dng chn lc trn receptor b1 dng cho ngi hen t nguy him hn, nhng vi liu cao, trong iu tr tng huyt p th cng b mt tnh chn lc. - Khng dng cng vi insulin v cc sulfamid h ng huyt v c th gy h ng huyt t ngt. - C thai: khng chng ch nh tuyt i, nhng gp tr mi b chm nhp tim, h ng huyt, suy h hp, thai chm pht trin. 3.2.2.4. Cc tc dng khng mong mun c chia lm hai loi:

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* Loi tai bin l hu qu ca s phong to receptor b - Tim: suy tim do lm yu co bp ca c tim, chm nhp tim, nh tht phn ly. - Mch: h i chng Raynaud, tm lnh u chi, i khp khing, (thng gp vi propranolol, do b b phong to th a s cng). Cc thuc chn lc trn b1 v c hot tnh kch thch n i ti th t tai bin ny hn - Phi: cc thuc c tc dng hu b2 > b1 s gy co kh qun, kh th. Khng dng cho ngi hen. - Thn kinh trung ng: mt m i, mt ng, hay ng m, o nh, trm cm, thng gp hn vi cc thuc d tan trong m v d thm vo t bo thn kinh (propranolol, metoprolol), loi t tan trong m (atenolol, nadolol) t tai bin hn. - Chuyn ho: lm h ng huyt (cn thn trng vi ngi b i tho ng), tng triglycerid trong mu. * Loi tai bin khng lin quan n tc dng phong to b - Hi chng mt- da- tai: xut hin ring hoc phi hp vi cc tn thng ca mt (vim gic mc, vim cng mc), da (sn nga lng bn tay, bn chn, dy da), tai (ic v vim tai nng). gp vi practolol, iu tr trong 1- 2 nm - Vim phc mc x cng: au cng bng phc mc c nhng mng dy do t chc x. Sau khi ngng thuc hoc iu tr bng corticoid s khi. Gp sau khi iu tr ko di trn 30 thng. - Trn thc nghim, gp ung th tuyn c, ung th v, lymphosarcom. Do cn theo di trn ngi khi dng liu cao ko di. 3.2.2.5. Tng tc thuc - Cc thuc gy cm ng cc enzym chuyn ha gan nh phenytoin, rifampin, phenobarbital, ht thuc l, s lm tng chuyn ha, gim tc dng ca thuc hu b. - Cc mu i nhm, cholestyramin lm gim hp thu - Cc thuc hu b c tc dng hip ng vi thuc chn knh calci, cc thuc h huyt p - Indomethacin v cc thuc chng vim phi steroid lm gim tc dng h huyt p ca cc thuc hu b. 3.2.2.6. Phn loi Khng c tc dng "chn lc trn tim" n nh mng Khng cng ni ti b C cng ni ti b Propranolol Khng n nh mng Sotalol Timolol Alprenolol Oxprenolol Pindolol Acebutolol Metoprolol Practolol C tc dng "chn lc trn tim" n nh mng Khng n nh mng Esmolol Atenolol

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S phn loi ny gip cho chn thuc trong iu tr. Th d bnh nhn c ri lon co tht ph qun th nn dng loi c tc dng "chn lc trn tim"; bnh nhn c nhp tim chm th dng loi "c cng n i ti b" 3.2.2.7. Mt s thuc chnh * Propranolol (Inderal, Avlocardyl) L isopropyl aminonaphtyl oxypropranolol. C tc dng phong to nh nhau trn c b1 v b2, khng c hot tnh n i ti kch thch. Tc dng: - Trn tim:lm gim tn s, gim lc co bp, gim lu lng tim ti 30%. c ch tim l do tc dng ring ca propranolol ngn cn calci nhp vo t bo c tim, gim nng calci trong ti li n i bo. - Trn mch vnh: lm gim lu lng 10- 30% do c ch gin mch. Lm gim tiu th oxy ca c tim. - Trn huyt p: lm h huyt p r sau 48 gi dng thuc. Huyt p ti thiu gim nhiu. - Ngoi ra cn c tc dng chng lon nhp tim, gy t (do tc dng n nh mng) v an thn Ch nh: - Tng huyt p, lon nhp tim, nhp nhanh xoang, cung ng nh, nhp nhanh trn tht, bnh cng gip, suy mch vnh. Ung liu hng ngy 120- 160 mg Vin 40 v 160 mg - Dng trong cp cu lon nhp tim do nhim c digital hay do thng tim, do t ng ni kh qun. Tim t nh mch 5- 10 mg. ng 5 mg Chng ch nh: ngoi chng ch nh chung, propranolol khng c dng cho ngi c thai hoc lot d dy ang tin trin. Thuc c d dng hp thu qua ng tiu ha do tan nhiu trong m. Gn vo protein huyt tng ti 90- 95%, m ti a trong mu t c sau khi ung t 1- 2 gi. Chuyn ha thnh hydroxy- 4- propranolol v acid naphtoxyl acetic rt nhanh ti gan nn ch khong 25% liu ung vo c vng tun hon, t/2: 3- 5 gi. Vin 40 mg. Ung trung bnh 2- 4 vin / ngy, chia lm nhiu ln ng 1 mL= 1 mg. Dng cp cu, tim tnh mch rt chm, t 1- 5 mg/ ngy * Pindolol (Visken); C tc dng cng n i ti b v khng nh hng n vn chuyn ca ion Ca++ nn lm tng lc co bp v tn s ca tim. Thng dng trong cc trng hp c lon nhp chm vi liu ung 5- 30 mg/ ngy. Tan va trong m, sinh kh dng 75% v t/2 = 3- 4 gi. * Oxprenolol (Trasicor): Dng iu tr cao huyt p, cn au tht ngc, lon nhp tim. Ung 160- 240 mg/ ngy. * Atenolol (Tenormin): Tc dng chn lc trn b1- rt tan trong nc nn t thm vo thn kinh trung ng, sinh kh dng 50%, t/2 = 5- 8 gi. Ung 50- 100 mg/ ngy. * Metoprolol (Lopressor). C tc dng chn lc trn tim (b1) nn gy cn hen ph qun (b2). Ung 50- 150 mg/ ngy. Hp thu nhanh qua ng ung, sinh kh dng 40% v t/2 = 34 gi.

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CU HI T LNG GI 1. Trnh by sinh chuyn ha ca catecholamin ti ngn dy giao cm. 2. Trnh by s phn loi cc receptor ca h giao cm: v tr, p ng v cht ch vn. 3. Phn tch, so snh tc dng v p dng iu tr ca adrenalin, noradrenalin v dopamin. 4. Phn bit tc dng ca thuc cng 1 v 2 giao cm. 5. Trnh by c ch tc dng, tc dng v p dng lm sng ca isoproterenol, dobutamin v albuterol (Salbutamol, Ventolin). 6. Phn tch c ch ca cc thuc hu giao cm. 7. Trnh by c im tc dng v p dng iu tr ca thuc hu a giao cm, nu 2 thuc th d. 8. Trnh by tc dng dc l v p dng lm sng ca thuc hu . 9. Trnh by cc tc dng khng mong mun ca thuc hu .

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PHN III THUC TC DNG TRN H THN KINH TRUNG NG Bi 7: THUC T MC TIU HC TP: Sau khi hc xong bi ny, sinh vin c kh nng: 1. Trnh by c c ch tc dng v tc dng ca thuc t 2. Phn tch c nhng tc dng khng mong mun v c tnh ca thuc t 3. Phn bit c c im tc dng ca cocain, procain lidocain, bupivacain v ethylclorid. 1. TNH CHT CHUNG CA THUC T 1.1. nh ngha Thuc t lm mt cm gic (au, nhit ) ca mt vng c th, ti ch dng thuc, trong khi chc phn vn ng khng b nh hng. Carl Koller (1884) dng dung dch cocain gy t gic mc, m u thi k ca cc thuc t. Ngy nay, v tnh cht c v gy nghin ca thuc, cocain dn dn b b. Vi vic tm ra procain (novocaine), Einhorn (1904) m u thi k th hai, rt quan trng v dng tim gy t. 1.2. c im ca thuc t tt Nhiu thuc c tc dng gy t, nhng mt thuc t tt cn t c cc tiu chun sau: - Ngn cn hon ton v c hiu s dn truyn cm gic. - Sau tc dng ca thuc, chc phn thn kinh c h i phc hon ton. - Thi gian khi t ngn, thi gian tc dng thch hp (thng l khong 60 pht). - Khng c, khng kch thch m v khng gy d ng. - Tan trong nc, vng bn di dng dung dch, kh khun xong vn cn hot tnh. 1.3. Lin quan gia cu trc v tc dng Cc thuc t u c cu trc gn gi ng nhau, t ng t lidocain, g m ba phn chnh: cc a m, cc a nc v chu i trung gian:

Cc a m

Chui trung gian

Cc a nc

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- Cc a m l nhn thm, c nh hng n s khuch tn v hiu lc ca tc dng gy t. Tnh a m lm tng i lc ca thuc vi receptor nn lm tng cng t; ng thi lm chm thu phn ca cc esterase nn lm ko di thi gian t. Tuy nhin, c tnh ca thuc li tng. - Cc a nc l nhm amin bc 3 (- N ) hoc bc 2 (- NH -) quy nh tnh tan trong nc v s ion ha ca thuc. Nhm amin l cht nhn H+ theo phn ng: R - NH2 + H2O R - NH3 + OH- Chu i trung gian: c 4-6 nguyn t (di 6-9nm) nh hng n c tnh ca thuc, chuy n ha v thi gian tc dng ca thuc. Ngoi gii hn , tc dng s km dn. Trong chu i ny c th c : . Nhm mang ng n i ester (-COO-, nh procain) b thu phn nhanh gan v mu do cc esterase, nn c thi gian tc dng ngn. . Nhm mang ng n i amid (-NH-CO-, nh lidocain), kh b thu phn, tc dng di. 1.4. C ch tc dng Cc thuc t tng hp lm gim tnh thm ca mng t bo vi Na+ do gn vo receptor ca knh Na+ mt trong ca mng, khc vi cc c t thin nhin nh ttrodotoxin gn mt ngoi ca knh. Nh vy, thuc t c tc dng lm n nh mng, ngn cn Na+ i vo t bo, lm t bo khng kh cc c. Ngoi ra, thuc t cn lm gim tn s phng xung tc ca cc si cm gic. Hu ht cc thuc t u c pKa l 8,0 - 9,0, v vy, pH ca dch c th u phn ln dng cation, l dng c hot tnh gn vo c receptor, nhng li khng qua c mng t bo nn khng c tc dng, v receptor ca thuc t nm mt trong mng t bo. Qu trnh thm nhp qua mng t bo ti c receptor din bin nh s : R1 H thng m ca m R2 - N + - HCl- + NaHCO3 R3 Trong ng tim, thuc di dng mu i t do, hydroclorid, tan, l ion, khng qua c mng t bo R1 R2 - N - + HOH R3 R1 R2 - N + NaCl + H2CO3 R3 Chuyn thnh dng base qua c mng Mng t bo R1 R2 - NH+ + OH R3 B ion ha thnh amoni bc 4, mang in (+), gn c vo receptor.

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Hnh 7.1. Qu trnh thm nhp ca thuc t qua mng t bo gn vo receptor Thuc t t c hiu qu m nhim khun v pH thp nn ch c t l rt thp thuc t qua c mng. Mun lm t nhanh th cn tng nng ca thuc. Nhng khi s c hi cho m v d dn ti nhim c ton thn, cho nn trong thc hnh, cn chn nng ti u. 1.5. Tc dng dc l 1.5.1. Tc dng ti ch: Thuc t tc dng trn tt c cc si thn kinh trung ng (cm gic, vn ng) v thn kinh thc vt, ln lt t si b n si to tu theo nng ca thuc. Th t mt cm gic l au, lnh, nng, xc gic nng, ri n xc gic su. Khi ht thuc, tc dng h i phc theo chiu ngc li. Tu theo mc ch lm sng m s dng cc ng a thuc khc nhau: - Gy t b mt: bi hoc thm thuc ti ch (0,4-4%). - Gy t thm nhim = tim di da thuc ngm c vo t n cng thn kinh (dung dch 0,1 - 1%). - Gy t dn truyn: tim thuc vo cnh ng dn truyn ca thn kinh (gy t thn th n kinh, phong ta hch, gy t ngoi mng cng, gy t tu sng (xem s ).

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1.5.2. Tc dng ton thn Ch xut hin khi thuc t thm c vo vng tun hon vi nng hiu dng: - Tc dng c ch thn kinh trung ng xut hin sm nht vi trung tm c ch nn gy cc du hi kch thch: bn chn, lo u, run c, cn co git (iu tr bng diazepam), mt nh hng. - c ch dn truyn thn kinh- c gy nhc c, lit h hp. - Lm gin c trn do tc dng lit hch v tc dng trc tip trn c trn. - Trn tim - mch: do tc dng lm n nh mng, thuc t lm gim tnh kch thch, gi m dn truyn v gim lc co bp ca c tim. C th gy lon nhp, thm ch rung tm tht. Trn mch, hu ht gy gin mch, h huyt p (tr cocain). - Trn mu: liu cao (trn 10 mg/ kg) prilocain tch t cht chuyn ha O- toluidin gy oxy ha, bin Hb thnh metHb. 1.6. Tc dng khng mong mun v c tnh 1.6.1. Loi tc dng do thuc ngm vo vng tun hon vi nng cao, gy nhng biu hin thn kinh (bun nn, nn, mt nh hng, ng tc git rung, lit h hp), hoc tim mch (ri lon dn truyn, bloc nh tht...). 1.6.2. Loi tc dng c hiu, lin quan n k thut gy t: h huyt p, ngng h hp do gy t tu sng, tn thng thn kinh do kim tim m phi hoc do thuc chn p. 1.6.3. Loi phn ng qu mn hay d ng ph thuc vo tng c th. Thng gp vi cc dn xut c thay th v tr para ca nhn thm (ester ca acid para aminobenzoic), loi ng n i ester (procain). Rt t gp vi loi c ng ni amid (lidocain). 1.7. Dc ng hc Cc thuc t u l base yu, t tan trong nc, nhng khi kt hp vi acid (nh HCl) s cho cc mu i rt tan v hon ton n nh (dung dch c pH acid). Khng thm qua da lnh. Cc thuc t tng hp kh thm qua nim mc. Ging ha v thi tr ph thuc ch yu vo cu trc. Cc thuc t c chc amid (nh lidocain) hoc chc ether (-O-), (nh quinisocain) ch b chuyn ho rt t gan bi cyt P450, phn ln thi tr nguyn cht qua thn. Tc chuyn ho t nhanh n chm l prilocain >etidocain>lidocain>mepivacain>bupivacain. ngi bnh thng, t/2 ca lidocain l 1,8 gi; ngi suy gan nng c th ti >6gi. Cc thuc t c chc ester (procain) b thu phn bi cc esterase ca c gan v huyt tng, nn ging ho v mt tc dng nhanh, t/2 vi procain ch khong 1 pht. Loi ester b chuyn ho thnh para amino benzoic acid (PABA) nn d gy d ng. Cn loi amid khng b chuyn thnh PABA nn rt him gy d ng. 1.8. Tng tc thuc - khc phc tc dng gy gin mch ca thuc t (tr cocain gy co mch), thng ph i hp vi adrenalin, nht l khi gy t thm nhim. Adrenalin lm co mch, c tc dng ngn cn s ngm thuc t vo tun hon chung v ko di c thi gian gy t. - Cc thuc lm tng tc dng ca thuc t: cc thuc gim au loi morphin, cc thuc an thn kinh (clopromazin). - Cc thuc d lm tng c tnh ca thuc t: quinidin, thuc phong to b adrenergic (lm ri lon dn truyn c tim).

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- Thuc t hip ng vi tc dng ca cura. Sulfamid i khng 2 chiu vi cc thuc t dn xut t acid para amino benzoic (nh procain). 1.9. p dng lm sng 1.9.1. Ch nh - Gy t b mt: Vim ming, vim hng, chun b ni soi, s dng trong nhn khoa. - Gy t dn truyn: Mt s chng au, phu thut chi trn, trong sn ph khoa (gy t ngoi mng cng). - Cc ch nh khc: Lon nhp tim (xem bi thuc cha lon nhp tim). 1.9.2. Chng ch nh - Ri lon dn truyn c tim - C d ng (tm nhm thuc khc). 1.9.3. Thn trng khi dng thuc - Dng ng tng liu v chn ng nng ti u. Khng dng thuc qu long v khng vt qu 1% nu tim tu sng. - Tim ng vng cn gy t. Khng tim vo mch hoc trc tip vo thn kinh. - Ngng ngay thuc nu c bt k mt biu hin bt thng no. 2. CC LOI THUC T THNG DNG 2.1. Cocain Bng A-nghin. V vy ngy cng t dng. L thuc t duy nht c ngun gc thc vt (l cy Erythroxylon coca) c nhiu Nam M. 2.1.1. Tc dng - Gy t: thm qua c nim mc, dng trong tai mi hng (dung dch 10-20%) hoc khoa mt (dung dch 1-2%). - Trn thn kinh trung ng: gy kch thch, sng khoi, o gic, gim mt m i (d gy nghin). Liu cao gy run chi v co git. - Trn thn kinh thc vt: cng giao cm gin tip do ngn cn ti thu h i noradrenalin ngn dy giao cm, lm tim p nhanh, co mch, tng huyt p. 2.1.2. c tnh - Cp: co mch mnh (tm ti, h i hp, lo s, d b ngt), kch thch thn kinh trung ng (o gic, co git). - Mn: d gy quen thuc v nghin, mt nht nht, ng t gin, hoi t vch mi. 2.2. Procain (novocaine) Bng B. Tng hp (1905) - L thuc t mang ng n i este, tan trong nc. - Tc dng gy t km cocain 4 ln, t c hn 3 ln. - Khng thm qua nim mc, khng lm co mch, ngc li, do c tc dng phong ta hch li lm gin mch, h huyt p. Khi gy t nn ph i hp vi adrenalin lm co mch, tng thi gian gy t.

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- Dng lm thuc gy t dn truyn, dung dch 1%-2% khng qu 3mg/kg cn nng. - c tnh: d ng, co git ri c ch thn kinh trung ng. - Hin c nhiu thuc tt hn nn ngy cng t dng. 2.3. Lidocain (xylocain): Tng hp (1948). Hin dng rt rng ri. - L thuc t mang ng n i amid, tan trong nc. - L thuc gy t b mt v gy t dn truyn tt. Tc dng mnh hn procain 3 ln, nhng c hn hai ln. - Tc dng nhanh v ko di do b chuyn ha chm. Hai cht chuyn ha trung gian l monoethylglycin xylidid v glycin xylidid vn cn tc dng gy t. V khng gy co mch nn nu dng cng vi adrenalin, thi gian tc dng s lu m c tnh li gim. - c tnh: + Trn thn kinh trung ng: lo u, vt v, bun nn, nhc u, run, co git v trm cm, c ch thn kinh trung ng. + Trn h hp: th nhanh, ri kh th, ngng h hp. + Trn tim mch: tim p nhanh, tng huyt p, tip theo l cc du hiu c ch: tim p chm, h huyt p, do tc dng c ch trung ng. 2.4. Bupivacain (Marcain) L nhm thuc t c ng n i amid nh lidocain. Dng t 1963. - c im gy t: thi gian khi t chm, tc dng gy t lu, cng mnh gp 16 ln procain, nng cao phong ta cn ng kinh vn ng. - Dng gy t tng vng, gy t thn thn kinh, m ri thn kinh v gy t tu sng. Dung dch gy t ty sng c t trng 1,020 370 (ng 4ml = 20mg bupivacain clohydrat): tim tu sng 3ml t th ng i, tc dng t v mm c (c bng, c chi di ko di 2-2,5 gi). - D tan trong m, gn vo protein huyt tng 95%, hon ton chuyn ha gan do Cyt.P450 v thi tr qua thn. - c tnh: c tnh trn tim mnh hn lidocain: gy lo n nhp tht nng v c ch c tim, do bupivacain gn mnh vo knh Na+ ca c tim v c ch c trn trung tm vn mch. - Gy t tng vng, tu thuc mc ch, tu thuc tui ca ngi bnh, dng dung dch 0,25-0,50% (c th km theo adrenalin gy co mch), tim t vi ml ti 20 ml. Tng liu cho 1 ln gy t khng vt qu 150mg. 2.5. Ethyl clorid (Klne) C2H5Cl L dung dch khng mu, si nhit 120C. C tc dng gy m nhng c ch mnh h hp, tun hon nn khng dng. Do bc hi nhit thp, nn c tc dng lm lnh rt nhanh vng da c phun thuc, gy tc dng t mnh, nhng rt ngn. - Ch nh: trch p xe, mn nht, chn thng th thao. - Thuc ng trong l thy tinh, c van kim loi, tin s dng khi phun vo ni cn gy t. CU HI T LNG GI 1. Trnh by c ch tc dng v tc dng dc l ca thuc t.

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2. Trnh by dc ng hc v tc dng khng mong mun ca thuc t. 3. Phn bit c im tc dng v p dng lm sng ca cocain, procain, lidocain, bupivacain v ethyl clorid.

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Bi 8: THUC NG V RU MC TIU HC TP: Sau khi hc xong bi ny, sinh vin c kh nng: 1. Nu c mi lin quan gia cu trc ha hc v tc dng ca barbiturat. 2. Trnh by c cc tc dng dc l ca barbiturat. 3. Nu c triu chng ng c cp v cch x l ng c ca thuc ng barbiturat (phenobarbital). 4. Trnh by c tc dng, ng c cp v mn, iu tr ng c ru ethylic. 1. I CNG Gic ng l nhu cu rt cn thit cho c th. nhng ng vt bc cao, cho qu trnh sng c th din ra bnh thng phi c s lun phin ca hai trng thi thc v ng. Do c ch thn kinh trung ng, thuc ng to mt gic ng gn gic ng sinh l. Khi dng liu thp, thuc gy tc dng an thn, vi liu cao c th gy m. Thuc c th gy ng c v cht khi dng liu rt cao. chng mt ng, lm gim trng thi cng thng thn kinh... trc y thng dng barbiturat v mt s thuc ng khc nh dn xut piperidindion, carbamat, ru, paraldehyd, dn xut benzodiazepin. Ngy nay, hay dng thuc an thn- gy ng loi benzodiazepin v t gy quen thuc v t tc dng khng mong mun. 2. BARBITURAT Cc barbiturat u l thuc c bng B, hin nay t dng. 2.1. Cu trc Acid barbituric (2, 4, 6- trioxohexahydropyrimidin) c to thnh t acid malonic v ure. NH2 O=C + NH2 Ur HOOC CH2 HOOC acid malonic O =C2 3 NH - OC 4 H acid barbituric NH - OC 1 6 5C H

V l acid mnh, d b phn ly nn acid barbituric cha khuch tn c qua mng sinh hc v cha c tc dng. Khi thay H C5 bng cc gc R1 v R2, c cc barbiturat (l acid yu, t phn ly) c tc dng c ch thn kinh trung ng. 2.2. Lin quan gia cu trc v tc dng Khi thay i cu trc, s nh hng n ion ha v kh nng tan trong lipid ca thuc, do mc khuch tn ca thuc vo no v i lc ca thuc i vi lipid ca c th cng b thay i, nn cng tc dng cng thay i. Tc dng s rt yu khi ch thay th mt H C5. Nu thay hai H C5 bng cc chu i R1 v R2 s tng tc dng gy ng.

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Tc dng c ch thn kinh trung ng s mnh hn khi R1 v R2 l chu i nhnh hoc gc carbua hydro vng hoc cha no. Khi mt H C5 c thay bng mt gc phenyl, s c phenobarbital c tc dng chng co git. Thay O C2 bng S, c thiobarbiturat (thiopental) gy m nhanh v ngn. Khi thay H N1 hoc N3 bng gc methyl ta c barbiturat c ch thn kinh trung ng mnh v ngn (hexobarbital). 2.3. Tc dng dc l 2.3.1. Trn thn kinh Barbiturat c ch thn kinh trung ng. Tu vo liu dng, cch dng, tu trng thi ngi bnh v tu loi barbiturat m c tc dng an thn, gy ng hoc gy m. Barbiturat to ra gic ng gn gi ng gic ng sinh l, lm cho gic ng n nhanh, gi m lng ton th ca gic ng nghch thng (pha ng nhanh, in no c sng nhanh, ng rt say nhng c hin tng vn ng nhn cu nhanh nn pha ny cn c g i l pha ng c vn ng nhn cu nhanh), gim t l ca gic ng nghch thng so vi gic ng sinh l. Vi liu gy m, barbiturat c ch ty sng, lm gim phn x a synap v c th lm gi m p lc dch no tu khi dng liu cao. Barbiturat (v d phenobarbital) cn chng c co git, chng ng kinh, do lm gim tnh b kch thch ca v no. Barbiturat i lp vi cn co git do strychnin, picrotoxin, cardiazol, c t un vn... C ch tc dng: Gia hnh no v c no sinh t c h li ca no gia g m phn trc (phn i ln) hot ha v phn sau (phn i xung) c tnh c ch. Barbiturat tc ng bng cch c ch chc phn ca h li m vai tr l dn dt, chn lc nhng thng tin t ngo i bin vo v no. Thuc c th ngn cn xung tc thn kinh qua cc trc h li- v no, ngoi bin- i nov no, h li- c nga, v no- i no... Barbiturat tc dng gin tip thng qua GABA, lm tng thi lng m knh Cl -. Vi liu cao, barbiturat tc dng trc tip trn knh Cl -, gip m knh, Cl - tin o t vo trong t bo thn kinh, gy u cc ha. Picrotoxin i lp vi barbiturat knh Cl -, c ch vn chuyn Cl , gy co git. Barbiturat c kh nng tng cng hoc bt chc tc dng c ch synap ca GABA, tuy nhin tnh chn lc km cc benzodiazepin. 2.3.2. Trn h thng h hp Do c ch trc tip trung tm h hp hnh no nn barbiturat lm gim bin v tn s cc nhp th. Liu cao, thuc hu hoi trung tm h hp, lm gim p ng vi CO2, c th gy nhp th Cheyne- Stockes. Ho, ht hi, nc v co tht thanh qun l nhng du hiu c th gp, khi dng barbiturat gy m. Cc barbiturat lm gim s dng oxy no trong lc gy m (do c ch hot ng ca neuron). 2.3.3. Trn h thng tun hon Vi liu gy ng barbiturat t nh hng n tun hon. Liu gy m, thuc lm gim lu lng tim v h huyt p. Barbiturat c ch tim liu c. 2.4. c tnh

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Trong bi ny chng ti ch cp n c tnh ca phenobarbital, mt barbiturat cn c dng nhiu trn lm sng. 2.4.1. Tc dng khng mong mun Khi dng phenobarbital, t l ngi gp cc phn ng c hi chim khong 1%. - Ton thn: bun ng - Mu: c hng cu khng l trong mu ngoi vi. - Thn kinh: rung git nhn cu, mt iu ha ng tc, b kch thch, lo s, l ln (hay gp ngi bnh cao tui). - Da: ni mn do d ng (hay gp ngi bnh tr tui). Him gp h i chng au khp, r i lon chuyn ha porphyrin do phenobarbital. 2.4.2. Ng c cp Ng c cp phenobarbital phn ln do ngi bnh ung thuc vi mc ch t t. Vi liu gp 5- 10 ln liu ng, thuc c th gy nguy him n tnh mng. T vong thng xy ra khi nng phenobarbital trong mu cao hn 80 microgam / ml. 2.4.2.1. Triu chng nhim c - Ngi bnh bun ng, mt dn phn x. Nu ng c nng c th mt ht phn x gn xng, k c phn x gic mc. - ng t gin, nhng vn cn phn x vi nh sng (ch mt nu ngi bnh ngt th do tt li hoc suy h hp). - Gin mch da v c th h thn nhit (v thuc lm gim chuyn ha chung nn gy gim sinh nhit). - Ri lon h hp, nhp th chm v nng, gim lu lng h hp, gim thng kh ph nang. - Ri lon tun hon: gim huyt p, try tim mch. Cu i cng, ngi bnh b hn m v cht do lit h hp, ph no, suy thn cp. 2.4.2.2. X tr X tr cp cu ph thuc vo mc nng khi bnh nhn vo vin: loi b cht c trc hay h i sc trc. - m bo thng kh: t ng ni kh qun, ht m, h hp nhn to, m kh qun nu c ph thit hu, thanh mn. - Hn ch ng c: . Ra d dy bng dung dch NaCl 0,9% hoc KMnO4 0,1%, ngay c khi ng c t lu v khi ng c barbiturat, nhu ng d dy b gim nn thuc li lu trong d dy. Ly dch ra d dy ln u xt nghim c cht. . Ung than hot tng o thi thuc v rt ngn thi gian hn m hoc thuc ty sorbitol 1- 2 g/kg. - Tng o thi: . Gy bi niu cng bc: truyn dung dch mn ng trng hoc dung dch glucose 5% (46 lt/ ngy) Dng thuc li niu thm thu (truyn t nh mch chm dung d ch manitol 100 g/ lt) tng thi barbiturat.

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. Base ho huyt tng: truyn t nh mch dung dch base natribicarbonat 0,14% (0,5- 1 lt) . Lc ngoi thn: l bin php thi tr cht c rt c hiu qu nhng khng phi tuyn no cng c th lm c, gi thnh cao. . Khi bnh nhn ng c nng, nng barbiturat trong mu cao nn chy thn nhn to (phi m bo huyt p bng truyn dch, dopamin hay noradrenalin). . nhng bnh nhn c t t huyt p, suy vnh hoc suy tim, lc mng bng s c hiu qu hn thn nhn to. - m bo tun hon. . Hi phc nc in gii, thng bng acid base. . Nu try mch: chng sc, truyn noradrenalin, plasma, mu. - Chng b i nhim, ch ti cng tc h l v chm sc c bit trong trng hp bnh nhn b hn m. 2.4.3. Ng c mn tnh Ng c mn tnh barbiturat thng gp cc bnh nhn lm dng thuc dn n nghin thuc. Biu hin ca ng c gm cc triu chng: co git, hong lon tinh thn, m sng... 2.5. Tng tc thuc - Barbiturat gy cm ng mnh microsom gan, do s lm gim tc dng ca nhng thuc c chuyn ha qua microsom gan khi dng phi hp, v d nh dng phenobarbital cng vi sulfamid chng i tho ng, thuc chng th thai, estrogen, griseofulvin, cortison, corticoid tng hp, diphenylhydantoin, dn xut cumarin, aminazin, diazepam, doxycyclin, lidocain, vitamin D, digitalin... - C mt s thuc c th lm thay i tc dng ca barbiturat nh ru ethylic, reserpin, aminazin, haloperidol, thuc chng i tho ng, thuc c ch microsom gan (cimetidin, cloramphenicol...) lm tng gic ng barbiturat. 3. DN XUT BENZODIAZEPIN c tng hp t 1956, ngy nay c dng nhiu hn barbiturat v t c, t tng tc v i thuc khc. Benzodiazepin c tc dng an thn, gii lo, lm d ng, gin c v chng co git. Thng dng cha mt ng hoc kh i vo gic ng do u t lo lng (xem bi"Thuc bnh thn"). 4. RU 4.1. Ru ethylic (ethanol) 4.1.1. Tc dng - Thn kinh trung ng: ru c ch thn kinh trung ng. Tc dng ca ru trn thn kinh trung ng ph thuc vo nng ru trong mu: nng thp ru c tc dng an thn, lm gim lo u, nng cao hn ru gy r i lon tm thn, mt iu ha, khng t ch c hnh ng v c th b hn m, c ch h hp, nguy him n tnh mng khi nng ru trong mu qu cao. C ch tc dng: Trc y ngi ta cho rng tc dng c ch thn kinh trung ng l do ru lm tan r lp lipid ca mng, nn nh hng n hot ng ca cc knh ion v cc protein tc ng trn cc knh. Nhng nghin cu gn y cho thy ru lm tng kh nng gn ca GABA trn receptor GABAA. Ru cn tc ng trn receptor NMDA glutamat (N- methyl- D- aspartat), c ch kh nng m knh Ca++ ca glutamat.

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- Ti ch: khi bi ngoi da ru c tc dng st khun, tt nht l ru 700. Ru 900 lm ng protein da, lm hp cc l tit m hi, do ru khng thm su vo trong da c. - Tim mch: ru nh t nh hng n tim mch. Dng ru mnh trong thi gian di c th gy gin c tim, ph i tm tht v x ha. - Tiu ha: ru nh (di 100) lm tng tit dch v, dch v c nhiu acid v t pepsin, tng nhu ng rut, tng kh nng hp thu thc n nim mc rut. V vy, dng ru nh c iu s lm tng th trng. Ngc li, ru 200 c ch s bi tit d ch v. Ru mnh (400) gy vim nim mc d dy (do nh hng ti lp cht nhy d dy), nn, co tht vng h v, lm gim s hp thu ca mt s thuc qua rut. - C trn: do c ch trung tm vn mch nn ru gy gin mch. Tc dng gin mch ca ru cn do kh nng lm gin c trn ca acetaldehyd (cht chuyn ha ca ru). Do , ngi ng c ru d b h thn nhit v khi gp lnh d b cht cng. Ru cn lm gin c t cung. 4.1.2. Dc ng hc Ru hp thu nhanh qua ng tiu ha. Sau khi ung 30 pht, ru t nng ti a trong mu. Thc n lm gim hp thu ru. Sau khi hp thu, ru c phn ph i nhanh vo cc t chc v dch ca c th (qua c rau thai). Nng ru trong t chc tng ng vi nng trong mu. Trn 90% ru c oxy ha gan, phn cn li c thi tr nguyn vn qua ph i v thn. C 2 con ng chuyn ha ru thnh acetaldehyd. - Chuyn ha qua alcool dehydrogenase (ADH): (l con ng chnh). ADH l mt enzym cha km, c nhiu gan. Ngi ta cn tm thy ADH no v d dy. ADH chuyn ru thnh acetaldehyd vi s tham gia ca NAD+ (nicotinamid adenin dinucleotid). - Chuyn ha qua h microsomal ethanol oxidizing system (MEOS) khi nng ru trong mu trn 100 mg/ dL (22 mmol/ L), ru c chuyn ha qua h MEOS. nhng ngi nghin ru, hot tnh ca cc enzym tng ln, lm tng chuyn ha ca chnh ru v mt s thuc c chuyn ha qua h ny nh phenobarbital, meprobamat, carbamazepin, diphenylhydantoin... 4.1.3. ng dng ca ru - Ngoi da: dng st khun - Gim au: c th tim ru vo dy thn kinh b vim gim au. 4.1.4. Ng c mn nhng ngi dng ru lu di, mt s c quan nh gan, thn kinh, d dy, tim mch... s b tn thng. - Gan d b vim, nhim m gan, x gan. Ph n d nhy cm vi c tnh ca ru hn nam gii. - Ru lm tng s bi tit dch v, dch ty, nh hng ti lp cht nhy nim mc dn ti vim d dy. Ngi nghin ru hay b tiu chy (ru gy thng tn rut non), chn n, gy yu v thiu mu. - Vim dy thn kinh, r i lon tm thn, co git, gim kh nng lm vic tr c, m sng... thng gp ngi nghin ru nng.

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- Ung ru mnh v ko di, c tim d b tn thng v x ha. 5% ngi nghin ru b tng huyt p. - Ru c nh hng ti h thng min dch (thay i s ha ng ng bch cu, s lng t bo limpho T, hot tnh ca NK (natural killer cell) do ngi nghin ru d mc cc bnh nhim khun nh vim ph i, lao... Kh nng b ung th ming, thc qun, thanh qun v gan ngi nghin ru thng cao hn ngi bnh thng. 4.1.5. iu tr ng c 4.1.5.1. Ng c cp - Ra d dy nu bnh nhn mi b ng c - m bo thng kh trnh suy h hp - Gii quyt tnh trng h ng mu, tng ceton mu bng truyn glucose. - Bnh nhn nn nhiu, c th dng thm kali (nu chc phn thn bnh thng) - Vitamin B1 v mt s vitamin khc nh acid folic, vitamin B6 c th lm gim bt cc thng tn thn kinh do ru gy ra. 4.1.5.2. Ng c mn tnh Dng disulfiram cha nghin ru Disulfiram (tetraethylthiuram) c ch aldehyd dehydrogenase, lm tng nng acetaldehyd (gp 5 n 10 ln) nn gy c. Sau khi ung, khong 80% disulfiram c hp thu nhanh qua ng tiu ha nhng nng thuc trong mu thp v disulfiram b chuyn ha thnh diethyldithiocarbamate (cht chuyn ha cn tc dng). Liu thng dng: 250 mg/ ngy (ti a 500 mg/ ngy) trong 1- 2 tun, sau chuyn sang liu duy tr 125 mg/ ngy (tu thuc vo mc nhy cm ca bnh nhn). Sau khi dng disulfiram 1 gi, ngi nghin ung ru s b bng mt, nhc u d d i, bun nn, nn, v m hi, tt huyt p v b i r i. Cc du hiu ny c th ko di t 30 pht n vi gi, sau bnh nhn ng thip i. Mt s thuc nh metronidazol, cephalosporin, sulfamid chng i tho ng, khi ph i hp vi ru ethylic cng gy nhng phn ng nh disulfiram. Cc nghin cu gn y cho thy c th ph i hp Naltrexon (cht i khng trn receptor opioid) vi disulfiram cha nghin ru. S ph i hp ny s lm gim c c tnh ca thuc i vi gan. Naltrexon c dng 50 mg/ ln/ ngy. 4.1.6. Tng tc thuc - Cc thuc an thn, thuc ng, chng co git, thuc c ch tm thn, thuc gim au lo i opioid lm tng tc dng ca ru trn thn kinh trung ng. - Ru lm tng tc dng ph trn ng tiu ha nh vim, lot, chy mu ca cc thuc chng vim phi steroid (aspirin...), ung ru cng vi paracetamol lm tng nguy c vim gan. - Khi ung ko di, ru gy cm ng mt s enzym chuyn ha thuc microsom gan, lm tng chuyn ha v gim hiu qu iu tr ca mt s thuc: sulfamid h ng huyt, thuc chng ng mu loi cumarin, meprobamat, diphenylhydantoin, carbamazepin...

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- Do tc dng gin mch ngoi vi ca ru, nu ung ng thi vi cc thuc chng tng huyt p, c th c nguy c gy tt huyt p t ngt qu mc cn thit. - Cc thuc h ng huyt nhm biguanid c th gy tng acid lactic mu nu ung nhiu ru trong thi gian iu tr. 4.2. Methanol (ru methylic) Loi ru ny dng trong cng nghip, khng dng trong y t v c. Trong c th, di s xc tc ca alcool dehydrogenase, methanol c oxy ha thnh formaldehyd rt c (gy au u, bun nn, nn, da lnh, hemoglobin niu v c th dn n m nu khng c iu tr kp thi). Alcool CH3OH methanol H2CO dehydrogenase formaldehyd format HCOOCO2+ H2O

4.3. Ethylen glycol (CH2OHCH2OH) c s dng nhiu trong cng nghip, trong my iu kh ca xe t... Khng dng trong y t. Khi ng c, ethylenglycol c th gy acid chuyn ha v suy thn (do lng ng cc tinh th oxalat ng thn). CU HI T LNG GI 1. Phn tch cu trc ha hc v cc c tnh l ha ca cc barbiturat. 2. Phn tch mi lin quan gia cu trc ha hc v tc dng dc l ca barbiturat. 3. Trnh by cc tc dng dc l ca thuc ng barbiturat. 4. Trnh by cc tc dng khng mong mun ca phenobarbital. 5. Trnh by triu chng ng c cp v cch x tr ng c phenobarbital. 6. Trnh by cc tc dng dc l ca ru ethylic. 7. Trnh by triu chng ng c v cch x tr ng c ru ethylic. 8. Trnh by cc tng tc ca ru ethylic vi cc thuc khc.

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Bi 9: THUC GIM AU LOI MORPHIN MC TIU HC TP: Sau khi hc xong bi ny, sinh vin c kh nng: 1. Nu c mi lin quan gia cu trc v tc dng ca morphin. 2. Phn tch c cc tc dng ca morphin, t nu c p dng iu tr ca morphin. 3. Trnh by c triu chng v cch iu tr ng c cp v mn ca morphin. 4. Nu c c im tc dng ca mt s opioid tng hp: pethidin, pentazoxin, methadon, fentanyl. 1. I CNG au l mt c ch bo v c th. au l do cc ngn dy thn kinh cm gic b kch thch qu bi tc nhn vt l hay ha hc (nhit, c, in, cc acid hay base...). Di nh hng ca cc kch thch au, c th gii phng ra mt hoc nhiu cht gy au nh histamin, cht P, cc cht chuyn ha acid, cc kinin huyt tng (bradykinin, kallidin...). Thuc gim au c chia lm 3 loi: - Thuc gim au loi morphin. - Thuc gim au khng phi loi morphin: paracetamol v thuc chng vim khng steroid. - Thuc gim au h tr: l nhng thuc c tc dng lm tng hiu qu gim au hoc gim nh tc dng khng mong mun ca cc thuc trn. 2. THUC GIM AU LOI MORPHIN Thuc gim au loi morphin c chung mt c tnh l gy nghin, v vy u thuc "bng A, gy nghin", khng k n qu 7 ngy. Nhm thuc ny bao gm: - Opiat: l cc dn xut ca thuc phin (opium), c tnh cht ging nh morphin. - Opioid: l cc cht tng hp, bn tng hp, c tc dng ging morphin hoc gn c vo cc receptor ca morphin. Nha kh ca qu cy thuc phin c cha khong 25 alcaloid, trong morphin chim 10%, codein gn 0,5%, papaverin 0,8%... Da vo cu trc ha hc, cc alcaloid ca thuc phin c chia lm 2 loi: - Nhn piperidin- phenanthren: morphin, codein..., tc dng u tin trn thn kinh trung ng. - Nhn benzyl- isoquinolein: papaverin Papaverin khng gy ng, tc dng ch yu l lm gin c trn (mch vnh, tiu ng mch ca tim, phi, no, si c trn ca ph qun, rut, ng mt v niu qun). 2.1. Morphin Trong lm sng dng mu i morphin clohydrat d tan trong nc, cha 75% morphin. 2.1.1. Tc dng

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Morphin c tc dng chn lc vi t bo thn kinh trung ng, c bit l v no. Mt s trung tm b c ch (trung tm au, trung tm h hp, trung tm ho), trong khi c trung tm li b kch thch gy co ng t, nn, chm nhp tim. Tc dng ca thuc thay i theo loi, gy hng phn mo, chut nht, loi nhai li, c... nhng c ch r ngi, ch, th, chut lang. 2.1.1.1. Receptor ca morphin (v cc opioid) Receptor c hiu ca morphin c tm thy t cui 1973, c 3 loi chnh v m i loi li c cc phn loi nh. Gn y, mt receptor mi c pht hin, c tn l N/ OFQ receptor. Cc receptor ny c rt nhiu sng sau tu sng ca ng vt c xng sng, nhiu vng trong thn kinh trung ng: i th, cht xm quanh cu no, no gia. Cc receptor ca morphin cn tm thy trong vng chi ph i hnh vi (hnh nhn, h i hi m, nhn lc, v no), vng iu ha h thn kinh thc vt (hnh no) v chc phn n i tit (l i gia). ngoi bin, cc receptor c tu thng thn, tuyn ngoi tit d dy, m ri thn kinh tng. V mt iu tr, m i receptor c coi nh c chc phn ring. Tc dng ca cc receptor

Tc dng Gim au Trn ty sng Ty sng H hp Nhu ng rut Tm thn

Loi receptor

Tc dng ca cht ng vn

Tc dng ca cht i khng

m1, k3, d1, d2 m2, k2, d2 m2 m2 , k k

Gim au Gim au Gim Gim Tng hot ng

Khng Khng Khng Khng Khng

2.1.1.2. Tc dng trn thn kinh trung ng * Tc dng gim au Morphin l thuc gim au mnh do lm tng ngng nhn cm gic au, thuc cn lm gim cc p ng phn x vi au. Tc dng gim au ca morphin l do thuc kch thch trn receptor muy v kappa. Morphin c ch tt c cc im cht trn ng dn truyn cm gic au ca h thn kinh trung ng nh tu sng, hnh tu, i th v v no. Nh vy, v tr tc dng ca morphin v cc opioid ch yu nm trong h thn kinh trung ng. Khi dng morphin, cc trung tm v no vn hot ng bnh thng, nhng cm gic au mt, chng t tc dng gim au ca morphin l chn lc. Khc vi thuc ng, khi tt c cc trung tm v no b c ch, bnh nhn mi ht au. Tc dng gim au ca morphin c tng cng khi dng cng thuc an thn kinh. Morphin lm tng tc dng ca thuc t. * Gy ng Morphin lm gim hot ng tinh thn v gy ng. Vi liu cao c th gy m v lm mt tri gic. * Gy sng khoi

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Cng vi tc dng gim au, morphin lm mt mi lo lng, bn chn, cng thng do au gy ra nn ngi bnh cm thy thanh thn, th gin v d dn ti sng khoi. Morphin lm thay i t th, lm tng tr tng tng, ngi bnh lun trng thi lc quan v mt cm gic i. * Trn h hp Morphin tc dng trn receptor m2 v nh hng trc tip n trung tm h hp. Morphin c ch trung tm h hp hnh tu, lm trung tm ny gim nhy cm vi CO2 nn c tn s v bin h hp u gim. Khi nhim c, nu ch cho th O2 nng cao, c th gy ngng th. tr mi v tr cn b, trung tm h hp rt nhy cm vi morphin v cc dn xut ca morphin. Morphin qua c hng ro rau thai, hng ro mu- no. V vy, cm dng morphin v cc opioid cho ngi c thai hoc tr em. Morphin cn c ch trung tm ho nhng tc dng ny khng mnh bng codein, pholcodin, dextromethorphan... * Tc dng trn vng di i Morphin lm mt thng bng c ch iu nhit lm thn nhit gim nh. Tuy nhin, khi dng liu cao ko di, thuc c th gy tng nhit c th. * Tc dng ni tit Morphin tc ng ngay ti vng di i, c ch gii phng GnRH (Go nadotropin- releasing hormone) v CRF (corticotropin- releasing factor) do lm gim LH, FSH, ACTH, TSH v beta endorphin. Cc opioid kch thch receptor muy, lm t ng tit ADH (hormon khng niu), trong khi cht ch vn ca receptor kappa li lm gim tit ADH, gy li niu. * Co ng t Do kch thch cc receptor muy v kappa trn trung tm thn kinh III, morphin v opioid c tc dng gy co ng t. Khi ng c morphin, ng t co rt mnh, ch cn nh nh u anh ghim. * Tc dng gy bun nn v nn Morphin kch thch trc tip trung tm nn sn no tht IV, gy cm gic bun nn v nn. Khi dng liu cao thuc c th c ch trung tm ny. 2.1.1.3. Tc dng ngoi bin * Trn tim mch: liu iu tr morphin t tc dng trn tim mch. Liu cao lm h huyt p do c ch trung tm vn mch. * Trn c trn: - C trn ca rut: trn thnh rut v m ri thn kinh c nhiu receptor vi morphin ni sinh. Morphin lm gim nhu ng rut, lm gim tit mt, dch ty, dch rut v lm tng hp thu nc, in gii qua thnh rut, do gy to bn. Lm co c vng (mn v, hu mn....) co tht c oddi ch ni rut t- ng mt ch - Trn cc c trn khc: morphin lm tng trng lc, tng co bp nn c th gy b i (do co tht c vng bng quang), lm xut hin cn hen trn ngi c tin s b hen (do co kh qun). * Trn da: vi liu iu tr morphin gy gin mch da v nga, mt, c, na thn trn ngi bnh b .

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* Trn chuyn ha: lm gim oxy ha, gim d tr base, gy tch lu acid trong mu. V vy, ngi nghin mt b ph, mng tay v mi thm tm. 2.1.2. Lin quan gia cu trc v tc dng Hai nhm nh hng nhiu n tc dng ca morphin l: - Nhm phenol v tr 3: tc dng gim au gy nghin s gim i khi alkyl ha nhm ny, v d codein (methyl morphin). Ngc li, tc dng ca morphin s c tng cng nu nhm phenol v tr 3 b ha ester, nh acetyl morphin (acetyl ha). Cng thc:

- Nhm ru v tr 6: tc dng gim au v c tnh s tng ln nhng thi gian tc dng li gim i khi nhm ny b kh H cho nhm ceton (hydro morphin) hay b ha ester, ha ether. Tc dng gim au v gy nghin s tng mnh khi c 2 nhm phenol v ru u b acetyl ha, v d heroin (diacetyl morphin). 2.1.3.Dc ng hc 2.1.3.1. Hp thu Morphin d hp thu qua ng tiu ha, ch yu t trng, hp thu qua nim mc trc trng song v phi qua chuyn ha ban u gan nn sinh kh dng ca morphin dng ng ung thp hn ng tim (ch khong 25%). Morphin hp thu nhanh sau khi tim di da hoc tim bp v c th thm nhp tt vo tu sng sau khi tim ngoi mng cng hoc trong mng cng (trong ng sng). 2.1.3.2. Phn phi Trong huyt tng, khong 1/3 morphin gn vi protein. Morphin khng lu trong cc m. Mc d v tr tc dng ch yu ca morphin l h thn kinh trung ng, nhng ch c mt lng nh qua c hng ro mu- no v morphin t tan trong m hn cc opioid khc, nh codein, heroin v methadon. 2.1.3.3. Chuyn ha Con ng chnh chuyn ha morphin l lin hp vi acid glucuronic v tr gn OH (3 v 6), cho morphin - 3- glucuronid khng c tc dng dc l v morphin - 6- glucuronid (cht chuyn ha chnh ca morphin) c tc dng gim au mnh hn morphin. Khi dng lu, morphin - 6- glucuronid cng c tch lu. Thi gian bn thi ca morphin khong 2- 3 gi; morphin - 6- glucuronic c thi gian bn thi di hn. 2.1.3.4. Thi tr

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Morphin thi tr di dng nguyn cht rt t. Trn 90% liu dng c thi tr qua thn trong 24 gi u di dng morphin - 3- glucuronid. Morphin c chu k gan- rut, v th nhiu ngy sau vn cn thy cht chuyn ha trong phn v nc tiu. 2.1.4. Tc dng khng mong mun Khi dng morphin c th gp mt s tc dng khng mong mun: * Thng gp: bun nn v nn (khong 20%), to bn, c ch thn kinh, co ng t, b i... * t gp: c ch h hp, nga, tot m hi, l ln, c mng, o gic, co tht ti mt, co tht ph qun... Morphin tim ngoi mng cng t gy bun nn, nn, co tht ng mt hoc ng niu hn khi dng qua cc ng khc. 2.1.5. p dng iu tr 2.1.5.1. Ch nh - Gim au: dng trong nhng cn au d di cp tnh hoc au khng p ng vi cc thuc gim au khc (au sau chn thng, au sau phu thut, au thi k cu i ca bnh, au do ung th...). gim au nhng bnh khng cha khi c (nh ung th thi k cu i), c th dng morphin qu 7 ngy. - Phi hp khi gy m v tin m 2.1.5.2. Chng ch nh - Tr em di 30 thng tui - Triu chng au bng cp khng r nguyn nhn - Suy h hp - Suy gan nng - Chn thng no hoc t ng p lc ni s - Hen ph qun (morphin gy co tht c trn ph qun) - Ng c ru cp - ang dng cc cht c ch monoaminoxidase 2.1.5.3. Thn trng Cn ch khi dng morphin ngi cao tui, suy gan, suy thn, thiu nng tuyn gip, suy thng thn, ngi c ri lon tit niu- tin lit (nguy c b i), bnh nhc c. - Thuc lm gim s tnh to, v vy khng nn li xe hoc vn hnh my khi dng morphin. - Khng nn dng morphin trong thi k mang thai v cho con b. 2.1.6. Tng tc thuc - Cm ph i hp vi thuc c ch monoaminoxidase v c th gy try tim mch, tng thn nhit, hn m v t vong. Morphin ch c dng sau khi ngng thuc MAOI t nht 15 ngy. - Cc cht va ch vn va i khng morphin nh buprenorphin, nalbuphin, pentazocin lm gim tc dng gim au ca morphin (do c ch cnh tranh trn receptor) - Cc thuc chng trm cm lo i 3 vng, khng histamin H1 loi c in, cc barbiturat, benzodiazepin, ru, clonidin lm tng tc dng c ch thn kinh trung ng ca morphin. 2.1.7. c tnh

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2.1.7.1. c tnh cp * Triu chng ng c: Cc biu hin ca ng c cp morphin xut hin rt nhanh: ngi bnh thy nng u, chng mt, ming kh, mch nhanh v mnh, nn. Sau ng ngy cng su, ng t co nh nh u anh ghim v khng phn ng vi nh sng. Th chm (2- 4 nhp/ pht), nhp th Cheyne- Stokes, c th cht nhanh trong vi pht sau tim hoc 1- 4 gi sau ung trong trng thi ngng th, mt tm xanh, thn nhit h, ng t gin v try mch. Nu hn m ko di c th cht v vim ph i. Hn m, ng t co nh nh u anh ghim v suy gim h hp l 3 triu chng thng gp khi ng c cc opioid. * X tr Cp cu bnh nhn ng c cp morphin phi da vo tnh trng bnh nhn lc c a vo bnh vin. u tin phi m bo thng kh cho bnh nhn bng th oxy, h hp nhn to... Truyn dch gi vng huyt p, nu bnh nhn hn m phi cho th my. Gii c bng naloxon (thuc i khng vi morphin). Tim t nh mch naloxon 1 mL = 0,4 mg cho c ngi ln v tr em, c th cho liu ban u 2 mg nu ng c nng. Hai- ba pht sau bnh nhn khng tnh, dng thm 0,4 mg (c th ti 4 liu), sau dng naloxon qua ng tim bp. Tng liu naloxon c th ti 10- 20 mg/ 24 gi. Trong x tr ng c cp morphin nn dng naloxon qua ng truyn tnh mch lin tc d phng suy h hp tr li v naloxon c thi gian bn thi ngn. 2.1.7.2. c tnh mn * Quen thuc Quen thuc ph thuc vo liu dng v s dng lp li. Ngi quen thuc c th dng morphin vi liu gp 10- 20 ln liu ban u v cao hn nhiu so vi ngi bnh thng. T khi tm ra morphin n i sinh, ngi ta ct ngha c hin tng quen thuc: cht ch vn n i sinh ca receptor morphinic l enkephalin b ging ha qu nhanh, nn khng gy quen thuc. Enkephalin (v c morphin) kch thch receptor, c ch gii phng mt s cht trung gian ho hc, c ch adenylcyclase, lm gim sn xut AMP vng. Khi dng thuc lp i lp li, c th phn ng bng tng tng hp AMP vng, v vy liu morphin sau i h i phi cao hn liu trc receptor p ng mnh nh c, l hin tng quen thuc. * Nghin thuc Mt s tc gi cho rng khi dng morphin ngoi sinh lu s dn ti 2 hu qu: - Receptor gim p ng vi morphin - C th gim sn xut morphin n i sinh S thiu ht morphin n i sinh lm ngi dng phi l thuc vo morphin ngoi lai, l nghin thuc. Ngi nghin morphin thng c ri lon v tm l, ni iu, li bing, t ch v sinh thn th. Hay b to bn, co ng t, mt ng, chn n nn st cn, thiu mu, run... Kh nng khng km, v vy h d b cht v cc bnh truyn nhim. Ngi nghin lun "i morphin", khi thi thuc t ngt, morphin n i sinh khng , cc receptor morphinic ang trong tnh trng chng li s tc ng thng xuyn ca morphin b ri vo trng thi "mt thng bng" ; t l GMPv/ AMPv b o ngc, dn n mt s ri lon lm sng: vt v, au c, au qun bng, v m hi, nn, a l ng, chy nc mi, run,

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sn gai c, d cm, tng nhp tim, tng huyt p, tng thn nhit, gin ng t, mt nc, st cn. Ngoi ra, cn gp mt s du hiu v thn kinh nh: thao thc, bn chn, chn n, ngp vt, u su. Cc biu hin ny nng nht l 36- 72 gi sau khi dng liu thuc cui cng v mt dn sau 2- 5 tun. * Cai nghin morphin Ngi nghin cn c cch ly, kt hp gia lao ng chn tay vi tm l liu php v dng thuc. Trong thc t, d cai c cng d b nghin li. - Dng thuc loi morphin Phng php c in cai nghin morphin l dng methadon, mt opioid c tc dng ko di. Methadon c tc dng lm nh cn i ma ty, phong ta tc dng gy khoi cm ca cc cht dng thuc phin do lm cc triu chng ca h i chng cai xy ra m m hn, nh nhng hn v khng thi thc tm ma ty cp bch ngi nghin. Vic iu tr bng methadon c chia lm 2 giai on: iu tr tn cng: liu thng dng t 10 - 40 mg/ngy (khng qu 120 mg/ngy), ko di 3 5 ngy, sau bt u gim liu tng t, m i t gim 5 mg. iu tr duy tr: ko di t 9 - 12 thng, sau gim dn liu ri ngng hn. Hin nay, ang dng th levomethadyl acetat (L - a - acetylmethadon) trong cai nghin heroin v thuc c thi gian tc dng rt di, 3 ngy m i cn ung 1 ln. - Khng dng thuc loi morphin . iu tr triu chng: chng bn chn, vt v bng benzodiazepin hay thuc an thn kinh. Chng au bng cc thuc gim au phi steroid (aspirin, paracetamol). Dng loperamid (l opioid t tc dng trn thn kinh trung ng) chng tiu chy. Chng nn, chng mt ng... . iu tr bng clonidin: ti vng nhn lc (locus ceruleus) c nhiu nron ca noradrenalin, cc nron ny bnh thng b cc opioid tc ng trn cc receptor muy c ch. Khi cai thuc, cc nron noradrenalin c thot c ch, gy nn cc triu chng cng giao cm, v th s rt hiu qu nu dng clonidin, thuc cng a2 adrenergic trc synap, c tc dng lm gim tit noradrenalin. Clonidin thng c dng 0,1 mg/ ln, m i ngy 2 ln (ti a 0,4 mg/ngy), trong 3- 4 tun. Ngoi ra c th dng cc thuc i khng vi morphin nh naloxon, naltrexon. 2.2. Dn xut ca morphin Mt s dn xut ca morphin nh thebain, dionin, dicodid, eucodal... c tc dng gim au, gy sng khoi, gy nghin nh morphin. Ngi nghin morphin c th dng nhng dn xut ny thay th. c bit c heroin gy nghin mnh hn hn nhng dn xut khc nn khng dng lm thuc. Khng cai heroin c. 2.3. Cc opioid thng dng 2.3.1. Pethidin (meperidin, dolosal, dolargan) 2.3.1.1. Tc dng - Sau khi ung 15 pht, pethidin c tc dng gim au mc d khng mnh bng morphin (km 7- 10ln). t gy nn, khng gy to bn. Khng gim ho, pethidin cng gy an thn, lm du, c ch h hp nh morphin. - Pethidin lm gim huyt p, nht l t th ng, do lm gim sc cn ngoi vi v lm gim hot ng ca h giao cm.

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Khi dng qua ng tnh mch, pethidin lm tng lu lng tim, lm tim p nhanh, do c th nguy him cho ngi b bnh tim. - ng mt, thuc lm co tht c oddi, v vy khi au ng mt phi dng thm atropin. 2.3.1.2. Dc ng hc Hp thu d qua cc ng dng. Sau khi ung, khong 50% pethidin phi qua chuyn ha ban u gan. Thi gian bn thi l 3 gi. Gn vi protein huyt tng khong 60% Pethidin t tan trong lipid, nn c i lc vi thn kinh trung ng yu hn morphin. 2.3.1.3. Tc dng khng mong mun Pethidin t c hn morphin Thng gp: Bun nn, nn, kh ming. Him gp cc tc dng khng mong mun trn thn kinh trung ng nh bun ng, suy gim h hp, ngt. 2.3.1.4. p dng iu tr - Ch nh: gim au, tin m - Chng ch nh nh morphin - Liu lng: ung hoc t hu mn 0,05g m i ln, ngy dng 2- 3 ln Tim bp 1 mL dung dch 1%, liu ti a: 0,05 g m i ln, 0,15g trong 24 gi. 2.3.1.5. Tng tc thuc - Dng pethidin cng MAOI gy nguy him: c ch mnh h hp, hn m, st cao, h huyt p, co git .... - Clopromazin lm tng tc dng c ch h hp ca pethidin - Scopolamin, barbiturat v ru lm tng c tnh ca pethidin, do phi gim liu pethidin khi dng ng thi. 2.3.2. Methadon (dolophin, amidone, phenadon) L thuc tng hp, tc dng ch yu trn receptor muy 2.3.2.1.Tc dng Methadon c tc dng tng t morphin nhng nhanh hn v ko di hn, t gy to bn. Gy gim au mnh hn pethidin. D gy bun nn v nn. 2.3.2.2.Dc ng hc Hp thu tt qua ng tiu ha, 90% gn vi protein huyt tng. Nh c nhm ceton v amin trong cu trc nn methadon c lin kt ng ha tr bn vi protein no. Thuc c th tch lu nu dng lin tip. Chuyn ha qua gan vi phn ng N- kh methyl. Thi tr qua nc tiu v mt. Thi gian bn thi khong 15- 40 gi. 2.3.2.3.Tc dng khng mong mun Tc dng khng mong mun v c tnh gi ng nh morphin. Khi dng ko di, methadon c th lm ra nhiu m hi, tng bch cu lympho, tng nng prolactin, albumin v globulin trong mu. 2.3.2.4.p dng iu tr

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Trn lm sng, methadon c dng gim au v cai nghin morphin, heroin Liu lng: ung m i ln 2,5 mg, ngy 2- 3 ln, tu thuc mc au v phn ng ca bnh nhn. 2.3.3.Fentanyl (Submimaze, Fentanest, leptanal) Thuc tng hp, tc dng ch yu trn receptor muy 2.3.3.1.Tc dng Fentanyl gim au mnh gp 100 ln morphin, tc dng nhanh (khong 3- 5 pht sau khi tim tnh mch) v ko di 1- 2 gi. 2.3.3.2.Dc ng hc Thuc ch dng tim bp hoc tnh mch. 80% fentanyl gn vi protein huyt tng; phn b mt phn trong dch no tu, rau thai v sa. Fentanyl b chuyn ha gan v mt hot tnh. Thi tr qua nc tiu (khong10% di dng cha chuyn ha). 2.3.3.3.Tc dng khng mong mun Khong 45% trng hp iu tr vi fentanyl c th xut hin tc dng khng mong mun. - Ton thn: chng mt, ng l m, l ln, o gic, ra m hi, bng mt, sng khoi. - Tiu ha: bun nn, nn, to bn, co tht ti mt, kh ming. - Tun hon: chm nhp tim, h huyt p thong qua, nh trng ngc, lon nhp . - H hp: th nhanh, suy h hp, ngt th - C xng: co cng c bao gm c lng ngc, git rung - Mt: co ng t 2.3.3.4.p dng iu tr * Ch nh - Gim au trong phu thut. - Phi hp vi droperidol gim au, an thn - Phi hp trong gy m. * Chng ch nh - Cc trng hp au nh (c th dng cc thuc gim au khc nh acetaminophen) - Nhc c - Thn trng trong cc trng hp: bnh phi mn tnh, chn thng s no v tng p lc s no, bnh tim, trm cm, ph n c thai. Fentanyl c ch nh i vi ph n cho con b, mc d thuc c mt trong sa m nhng vi liu iu tr fentanyl khng nh hng n tr ang b. * Liu lng - Dng cho tin m: 50- 100 mg, c th tim bp 30- 60 pht trc khi gy m. - Gim au trong phu thut: 0,07- 1,4 mg/ kg th trng, c th nhc li trong 1- 2 gi nu cn. 2.3.3.5.Tng tc thuc

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- Cc thuc c ch thn kinh trung ng nh ru, thuc ng, thuc m, phenothiazin... lm tng tc dng gim au ca fentanyl. - Fentanyl lm gim hp thu ca mt s thuc nh metoclopamid, mexiletin... khi dng ph i hp. - Huyt p gim mnh khi ph i hp fentanyl vi thuc c ch b- adrenergic v thuc chn knh calci. Sulfentanyl (Sufenta) - Tc dng v ch nh tng t fentanyl. Mnh hn fentanyl 10 ln, cng gy cng c. - Gn vi protein huyt tng trn 90%, thi gian bn thi 2- 3 gi. - Thng tim t nh mch 8 mg/ kg Alfentanil (Alfenta) Tc dng nhanh v ngn hn sufentanyl nn cn dng theo ng truyn tnh mch. Thng c dng khi m v gim au, ph i hp vi thuc m loi barbiturat, nitoxyd. 2.3.4.Propoxyphen 2.3.4.1.Tc dng Propoxyphen c cng thc gn gi ng methadon, tc ng ch yu trn receptor muy. Tc dng gim au km, ch bng 1/2 n 2/3 codein: 90- 120 mg propoxyphen hydroclorid theo ng ung, c tc dng gim au tng t 60 mg codein hoc 60 mg aspirin. 2.3.4.2.Dc ng hc Sau khi ung 1- 2 gi, thuc t c nng ti a trong mu. Chuyn ha ch yu qua gan, nh phn ng N- kh methyl. Thi gian bn thi t 6- 12 gi. Cht chuyn ha l norpropoxyphen c thi gian bn thi di hn (khong 30 gi). 2.3.4.3. Tc dng khng mong mun Propoxyphen c th gy c ch h hp, co git, hoang tng, o gic, c vi tim... khi dng. 2.3.4.4. p dng iu tr Dng gim au nh v trung bnh. Propoxyphen thng c phi hp vi aspirin hoc acetaminophen. 2.3.5.Cc opioid c tc dng hn hp: va hip ng- va i lp, hoc hip ng mt phn (Agonist- antagonist; partial agonist) C nhiu thuc gn trn receptor muy, tranh chp vi morphin v cc opioid khc nhng khng gy tc dng g, c gi l thuc i lp tranh chp, v d naloxon, cyclazocin... Ngc li, mt s thuc sau khi tranh chp c receptor cn c th gy ra mt s tc dng dc l, hoc trn receptor muy, hoc trn cc receptor khc nh delta v kappa. Cc thuc c gi l thuc c tc dng hn hp hoc hip ng mt phn, v d: pentazocin, nalbuphin... 2.3.5.1. Pentazocin Pentazocin l mt dn xut benzomorphan, cu trc c nhiu im gi ng morphin. * Tc dng Thuc c tc dng i khng ti receptor muy nhng li c tc dng hip ng ti receptor kappa 1, gy an thn , gim au v c ch h hp Tc dng gim au nh morphin nhng khng gy sng khoi.

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Khi dng liu cao, pentazocin lm tng huyt p v nhp tim. * Dc ng hc Hp thu d qua ng tiu ha. Sau khi ung 1- 3 gi, thuc t c nng ti a trong mu. Thi gian bn thi khong 4- 5 gi. V phi qua chuyn ha ln u gan nn ch 20% pentazocin vo c vng tun hon. Thuc qua c hng ro rau thai. * Tc dng khng mong mun Pentazocin c th gy ra mt s tc dng khng mong mun: an thn, v m hi, chng mt, bun nn v nn... Thuc c ch h hp khi dng liu cao. * p dng iu tr Thuc c ch nh trong nhng cn au nng, mn tnh hoc khi ngi bnh khng dng c cc thuc gim au khc. Thng dng dung dch pentazocin lactat cha 30 mg pentazocin base/ 1 mL. Tim tnh mch hoc di da 30 mg m i ln, sau 4 gi c th tim li. Hin nay c nhng ch phm ph i hp gia pentazocin vi aspirin hay acetaminophen. 2.3.5.2. Buprenorphin L thuc tng hp, dn xut ca thebain. Buprenorphin hip ng 1 phn trn receptor muy, c tc dng gim au mnh hn morphin t 25- 50 ln. Hp thu d qua cc ng dng: ung, di li, tim bp... Gn vi protein huyt t ng khong 96%, thi gian bn thi 3 gi. c dng gim au trn lm sng. Thng tim bp hoc tnh mch 0,3 mg m i ln, ngy dng 3- 4 ln. 2.4. Thuc i khng vi opioid Thay i cng thc ha hc ca morphin, c bit v tr 17 mang nhm N- methyl, nhm c hiu kch thch receptor muy, s c cc cht i khng. V d: Morphin Levorphanol Oxymorphon nalorphin levallorphan naloxon, naltrexon

Cc cht ny i lp c cc tc dng do morphin gy ra, ch yu l nhng du hiu c ch nh gim au, c ch h hp, an thn, sng khoi. Thi gian tc dng ni chung ngn hn morphin. Nalorphin khng c dng trn lm sng v c ch h hp, lm chm nhp tim, co ng t, sng khoi. 2.4.1. Naloxon (nalonee, narcan, narcanti) 2.4.1.1.Tc dng Khc vi levallorphan hoc nalorphin, naloxon t hoc khng c ho t tnh ch vn. ngi dng liu ln opioid, naloxon i khng phn ln nhng tc dng khng mong mun ca opioid nh c ch h hp, an thn, gy ng... Khi dng, naloxon c th gy ra h i chng thiu thuc sm ngi nghin opioid, tuy vy dng liu cao s ngn chn c triu chng suy h hp trong hi chng ny. 2.4.1.2. Dc ng hc

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Mc d c hp thu d qua ng tiu ha nhng naloxon b chuyn ha gan trc khi vo vng tun hon nn liu ung phi ln hn nhiu so vi liu tim. Thuc c tc dng nhanh (1- 2 pht sau khi tim t nh mch) thi gian tc dng ph thuc vo liu v ng dng. Sau khi tim, naloxon phn b nhanh vo cc m v dch c th. Thi gian bn thi l 60- 90 pht. 2.4.1.3. Tc dng khng mong mun - Tim mch: tng huyt p (c khi gim huyt p), nhp tim nhanh, lon nhp tht. - Thn kinh trung ng: mt ng, kch thch, lo u - Tiu ha: bun nn, nn - Nhn m, ban ngoi da. 2.4.1.4. p dng iu tr Naloxon c dng iu tr ng c cp cc opiat v opioid, cai nghin opioid Phi ht sc thn trng khi dng naloxon cho ngi c bnh tim mch, ph n c thai v cho con b. Liu lng; ngi ln: 0,4- 2 mg, tim t nh mch, 2 -3 pht tim nhc li nu cn. Tng liu 10 mg. V thi gian tc dng ca naloxon rt ngn (60- 90 pht) nn cn truyn lin tc naloxon khi bnh nhn ng c opium nng. 2.4.2. Naltrexon i khng vi opioid mnh hn naloxon, thng dng ng ung. Nng ti a trong mu t c sau 1- 2 gi. Thi gian bn thi l 3 gi. Naltrexon c chuyn ha thnh 6- naltrexon (c ho t tnh sinh hc yu hn nhng thi gian bn thi di hn, khong 13 gi). Naltrexon c dng cai nghin opioid (ung 100 mg/ ngy), cai nghin ru (ph i hp vi disulfiram). 2.5. Morphin ni sinh Hai nm sau khi tm ra receptor ca opiat, mt s cng trnh nghin cu cho thy receptor ca morphin cn c i lc rt mnh vi mt s peptid c hiu sn c trong c th ng vt, nhng peptid ny gy ra nhng tc dng ging morphin. Cc morphin n i c chia thnh 3 h: - Enkephalins (Met- enkephalin v leu- enkephalin) - Endorphins - Dynorphins M i loi c tin thn khc nhau v phn b nhng v tr khc nhau trn thn kinh trung ng. Cc morphin n i sinh hot ng nh mt cht dn truyn thn kinh, hoc cht iu bin ca dn truyn hoc l hormon thn kinh. V th, chng tham gia vo cc c ch gim au, cc cm gic thm mun (n ung, tnh dc), cc qu trnh cm xc, tm thn, tr nh.

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tu sng, morphin n i sinh c ch gii phng cht P, l mt decapeptid (10 acid amin) c gii phng ti ngn dy cm gic sng sau tu sng. Cht P c vai tr kim tra ng cm gic truyn vo v kch thch cc nron vn ng ca sng trc gy phn x t v. Cc enkephalin l pentapeptid c tc dng gim au rt ngn v b ging ha nhanh trong c th nh cc enzym: dipeptidyl amino peptidase, aminopeptidase v enkephalinase. Cc endorphin c 4 loi, nhng ch c beta endorphin c tc dng gim au mnh v lu (3- 4 gi) v tng i vng bn. 3. THUC GIM AU KHNG PHI LOI MORPHIN: (xin xem bi thuc h stgim au- chng vim). 4. THUC GIM AU H TR Thuc gim au h tr c tc dng hip ng, lm tng tc dng gim au ca cc opioid v thuc gim au chng vim khng steroid. Cc thuc ny c bit hiu qu i vi au do nguyn nhn thn kinh. 4.1. Thuc chng trm cm: Tc dng gim au khng ph thuc vo tc dng chng trm cm. Thng dng trong cc trng hp au ko di, c lin quan n bnh l thn kinh. Nhm thuc c tc dng tt nht l thuc chng trm cm loi ba vng (xin xem thm bi thuc chng trm cm). 4.2. Thuc chng ng kinh gim au trong bnh thn kinh do i tho ng, au sau zona, au dy thn kinh, d phng cn au na u (migraine) c th dng cc thuc: phenytoin, carbamazepin v valproat (xin xem thm bi thuc cha ng kinh). 5. NGUYN TC S DNG THUC GIM AU 5.1. Chn thuc Thuc gim au ch iu tr triu chng, thuc c th che lp cc du hiu ca bnh trong khi bnh vn tin trin nn phi ht sc cn nhc khi s dng thuc gim au. Khi la chn thuc cn ch n cng v bn cht ca au. T chc Y t Th gii khuyn co nn ung thuc theo bc thang gim au: - Bc 1 (au nh): dng thuc gim au khng phi opioid nh paracetamol, thuc chng vim khng phi steroid. - Bc 2 (au va): phi hp thuc loi opioid yu (codein, oxycodon) vi paracetamol, thuc vim khng steroid hoc thuc gim au h tr. - Bc 3 (au nng): dng thuc gim au loi opioid mnh : morphin, hydromorphon, methadon... phi hp vi thuc chng vim khng steroid. 5.2. ng dng thuc Thng thng nn dng ng ung. Tuy nhin, trong cc cn au nng, cp tnh hoc sau phu thut ln... phi dng ngay cc thuc gim au mnh loi opioid qua ng tim trnh sc v nh hng xu ca au n tin trin ca bnh . CU HI T LNG GI 1. Trnh by cc tc dng ca morphin trn thn kinh trung ng. 2. Trnh by cc tc dng ngoi bin ca morphin. 3. Phn tch mi lin quan gia cu trc ha hc v tc dng dc l ca morphin.

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4. Trnh by cc ch nh v chng ch nh khi s dng morphin. 5. Trnh by cc tc dng khng mong mun v thn trng khi dng morphin. 6. Trnh by triu chng v cch x tr ng c cp morphin. 7. Trnh by triu chng ng c mn v cch cai nghin morphin. 8. Trnh by tc dng, tc dng khng mong mun v p dng iu tr ca pethidin. 9. Trnh by tc dng v p dng iu tr ca loperamid. 10. Trnh by tc dng, tc dng khng mong mun v p dng iu tr ca methadon. 11. Trnh by tc dng, tc dng khng mong mun v p dng iu tr ca pentazoxin. 12. Trnh by tc dng, tc dng khng mong mun v p dng iu tr ca fentanyl.

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Bi 10: THUC H ST - GIM AU - CHNG VIM MC TIU HC TP: Sau khi hc xong bi ny, sinh vin c kh nng: 1. Phn tch c nhng tc dng chnh v c ch tc dng ca thuc chng vim phi steroid (CVKS) 2. Trnh by c c im tc dng v p dng iu tr ca cc thuc: aspirin, indomethacin, diclofenac. 3. Trnh by c c im tc dng v p dng iu tr ca cc thuc: dn xut Oxicam, dn xut acid propionic, paracetamol v thuc c ch COX- 2 4. Nu c 7 nguyn tc khi s dng thuc CVKS. Cc thuc trong nhm ny rt khc nhau v cu trc ha hc, gm cc dn xut ca salicylat, pyrazolon, anilin, indol v mt s thuc khc. Tt c cc thuc, mc khc nhau, u c tc dng h st, gim au, v - tr dn xut anilin - cn c tc dng chng vim, chng thp khp, chng ng vn tiu cu. V vy cn c gi chung l thuc chng vim khng (mang nhn) steroid (CVKS) phn bit vi cc glucocorticoid, mang nhn sterol, c gi l thuc chng vim steroid. 1. TC DNG CHNH V C CH C ch chung ca thuc CVKS: c ch sinh tng hp prostagladin Vane 1971 cho rng c ch tc dng chnh ca cc thuc CVKS l c ch enzym cyclooxygenase, lm gim tng hp cc prostaglandin l nhng cht trung gian ha hc c vai tr quan trng trong vic lm tng v ko di p ng vim m sau tn thng. Khi tn thng, mng t bo gii phng phospholipid mng. Di tc dng ca phospholipase A2 (l enzym b corticoid c ch), cht ny chuyn thnh acid arAChidonic. Sau , mt mt, di tc dng ca lipooxygenase (LOX), acid arAChidonic cho cc leucotrien c tc dng co kh qun; mt khc, di tc dng ca cyclooxygenase, acid arAChidonic cho PGE2 (gy vim, au), prostacyclin (PGI2) v thromboxan A2 (TXA2) tc ng n s lng ng tiu cu. Cc CVKS c ch COX nn c ch c cc phn ng vim (s )
CORTICOID

Phospholipid mng (t bo tn thng) Lipocortin (+) Phospholipase A2 Acid arachidonic LOX Cc leucotrien (co kh qun) PGE2 PGI2 TXA2 (-) COX CVKS (-)

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(vim au)

(lng ng tiu cu...)

Hnh 10.1: V tr tc dng ca CVKS v corticoid trong tng hp PG Tuy nhin, c ch trn cha gii thch c y nhng nhn xt lm sng trong qu trnh s dng CVKS, nh: - Hiu qu v tnh an ton ca cc thuc CVKS khng ging nhau. - Hiu qu c ch tng hp PG v TX ca cc thuc rt thay i. Nhiu thuc c ch mnh tng hp PG hn TX v ngc li. Aspirin c ch mnh v khng h i phc s kt t tiu cu vi liu thp, nhng phi liu rt cao mi c tc dng chng vim. T mi nm gn y, cc nghin cu cho thy c 2 loi COX, c g i l COX- 1 v COX- 2 c chc phn khc nhau v cc thuc chng vim tc dng vi mc khc nhau trn COX- 1 v COX-2 (s ) - COX-1: hay PGG/ H synthetase- 1 c tc dng duy tr cc hot ng sinh l bnh thng ca t bo l mt "enzym cu to". Enzym c mt hu ht cc m, thn, d dy, n i mc mch, tiu cu, t cung, tinh hon ... Tham gia trong qu trnh sn xut cc PG c tc dng bo v, do cn gi l "enzym gi nh" ("house keeping enzyme") : . Thromboxan A2 ca tiu cu . Prostacyclin (PGI2) trong ni mc mch, nim mc d dy . Prostaglandin E2 ti d dy bo v nim mc . Prostaglandin E2 ti thn, m bo chc phn sinh l. - COX- 2: hay PGG/ H synthetase 2 c chc phn thc y qu trnh vim. Thy hu ht cc m vi nng rt thp, cc t bo tham gia vo phn ng vim (bch cu 1 nhn, i thc bo, bao hot dch khp, t bo sn). Trong cc m vim, nng COX- 2 c th tng cao ti 80 ln do cc kch thch vim gy cm ng v hot ha mnh COX- 2. V vy COX- 2 cn c gi l "enzym cm ng" Nh vy, thu c c ch COX- 1 nhiu s gy nhiu tc dng khng Kch thch Kchmong thchmun, thuc c ch COX- 2 mnh s c tc ph . sinh l dng chng vim mnh m t gy tc dng gy vim
Gii phng acid arAChidonic mng t bo CVKS (-) COX- 1 (enzym cu to) Cc tc dng ph COX- 2 (enzym cm ng) Tc dng chng vim (-) CVKS

TXA2 (tiu cu)

PGI1 (ni mc nim mc d dy

PGE2 (thn)

Cc PG (bch cu 1 nhn i thc bo, t bo sn)

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Chc phn bo v t bo v "gi nh"

Thc y qu trnh vim

Hnh 10.2: Vai tr sinh l ca COX- 1 v COX- 2 Ngoi tc dng c ch tng hp PG, cc CVKS cn c th c nhiu c ch khc. Cc CVKS l cc phn t a m, d thm nhp vo mng t bo hoc mng ti th, nht l vo cc bch cu a nhn, nn : . c ch tit cc enzym ca cc th tiu bo . c ch sn xut cc gc t do. . c ch lng ng v kt dnh cc bch cu a nhn trung tnh. . c ch cc chc phn mng ca i thc bo nh c ch NADPH, oxydase, phospholipasse C, protein G v s vn chuyn ca cc anion qua mng. 1.1. Tc dng chng vim Cc CVKS c tc dng trn hu ht cc loi vim khng k n nguyn nhn, theo cc c ch sau: - c ch sinh tng hp prostaglandin (PG) do c ch c h i phc cyclooxygenase (COX), lm gim PG E2 v F1a l nhng trung gian ha hc ca phn ng vim (Vane v cs. 1971). - Lm vng bn mng lysosom (th tiu bo): vim, trong qu trnh thc bo, cc i thc bo lm gii phng cc enzym ca lysosom (hydrolase, aldolase, phosphatase acid, colagenase, elastase...), lm tng thm qu trnh vim. Do lm vng bn mng lysosom, cc CVKS lm ngn cn gii phng cc enzym phn gii, c ch qu trnh vim. - Ngoi ra c th cn c thm mt s c ch khc nh i khng vi cc cht trung gian ho hc ca vim do tranh chp vi c cht ca enzym, c ch di chuyn bch cu, c ch phn ng khng nguyn- khng th. Tuy cc CVKS u c tc dng gim au - chng vim, song li khc nhau gia t l liu chng vim/ liu gim au. T l y ln hn hoc bng 2 vi hu ht cc CVKS, k c aspirin (ngha l liu c tc dng chng vim cn phi gp i liu c tc dng gim au) nhng l i ch gn bng 1 vi indometacin, phenylbutazon v piroxicam. 1.2. Tc dng gim au Ch c tc dng vi cc chng au nh, khu tr. Tc dng tt vi cc chng au do vim (au khp, vim c, vim dy thn kinh, au rng, au sau m). Khc vi morphin, cc thuc ny khng c tc dng vi au n i tng, khng gy ng, khng gy khoan khoi v khng gy nghin. Theo Moncada v Vane (1978), do lm gim tng hp PG F2 a nn cc CVKS lm gim tnh cm th ca cc ngn dy cm gic vi cc cht gy au ca phn ng vim nh bradykinin, histamin, serotinin. i vi mt s chng au sau m, CVKS c th c tc dng gim au mnh hn c morphin v m gy ra vim. Trong au do chn p c hc hoc tc dng trc tip ca cc tc nhn ha hc, k c tim trc tip prostaglandin, cc CVKS c tc dng gim au km hn, cng chng t c ch quan trng ca gim au do CVKS l do c ch tng hp PG. Ngoi ra c th cn nhng c ch khc. 1.3. Tc dng h st

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Vi liu iu tr, CVKS ch lm h nhit trn nhng ngi st do bt k nguyn nhn g, khng c tc dng trn ngi thng. Khi vi khun, c t, nm... (gi chung l cc cht gy st ngoi lai) xm nhp vo c th s kch thch bch cu sn xut cc cht gy st ni ti (cc cytokin, interferon, TNFa...). Cht ny ho t ha prostaglandin synthetase, lm t ng t ng hp PG (c bit l PG E1, E2) t acid arAChidonic ca vng di i, gy st do lm tng qu trnh to nhit (rung c, tng h hp, t ng chuyn ha) v gim qu trnh mt nhit (co mch da). Thuc CVKS do c ch prostaglandin synthetase, lm gim tng hp PG, c tc dng h st do lm tng qu trnh thi nhit (gin mch ngoi bin, ra m hi), lp li thng bng cho trung tm iu nhit vng di i. Cc CVKS khng c ch c st do tim trc tip PG vo vng di i. V khng c tc dng n nguyn nhn gy st nn thuc h st ch c tc dng cha triu chng, sau khi thuc b thi tr, st s tr li. Thuc h st (-) Cht gy st ngoi lai Cht gy st ni ti (+) PG synthetase acid arAChidonic Hnh 10.3. C ch gy st v tc dng ca thuc h st 1.4. Tc dng chng ngng kt tiu cu Trong mng tiu cu c cha nhiu thromboxan synthetase l enzym chuyn endoperoxyd ca PG G2/ H2 thnh thromboxan A2 (ch tn ti 1 pht) c tc dng lm ng vn tiu cu. Nhng n i mc mch cng rt giu prostacyclin synthetase, l enzym t ng hp PG I2 c tc dng i lp vi thromboxan A2. V vy tiu cu chy trong mch bnh thng khng b ng vn. Khi n i mch b tn thng, PGI2 gim; mt khc, khi tiu cu tip xc vi thnh mch b tn thng, ngoi vic gii phng ra thromboxan A2 cn phng ra cc "gi tc" lm dnh cc tiu cu vi nhau v vi thnh mch, dn ti hin tng ngng kt tiu cu. Cc CVKS c ch thromboxan synthetase, lm gim tng hp thromboxan A2 ca tiu cu nn c tc dng chng ngng kt tiu cu (hnh 3.4) Tiu cu khng c kh nng tng hp protein nn khng ti to c cyclooxyganase. V th, mt liu nh ca aspirin (40- 100 mg/ ngy) c th c ch khng hi phc cyclooxyganase sut cuc sng ca tiu cu (8- 11 ngy) Cyclooxygenase (-) Aspirin Thr. synth Tiu cu Thromboxan A2 (lm vn tiu cu) TKTV - co mch - tng chuyn ha Bch cu PG (E1- E2) Vng di i - rung c TKT - tng h hp st

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Acid arAChodonic

PGG2/ H2

Tc dng i khng Prost. Synth ni mc Prostacyclin (PG I2)

Hnh 10.4. C ch c ch ng vn tiu cu 2. CC DN XU T Phn loi ha hc cc thuc CVKS

Loi c ch COX khng chn lc Nhm acid salicylic . Aspirin Nhm pirazolon . Phenylbutazon Nhm indol . Indometacin, sulindac . Etodolac (ring thuc ny li c ch chn lc COX- 2) Nhm acid enolic . Oxicam (piroxicam, meloxicam) Nhm acid propionic . Ibuprofen, naproxen, ketoprofen, fenoprofen Nhm dn xut acid phenylacetic . Diclofenac Nhm dn xut acid heteroarylacetic . Tolmetin, ketorolac Loi c ch chn lc COX- 2 Nhm furanon c nhm th diaryl . Rofecoxib Nhm pyrazol c nhm th diaryl . Celecoxib Nhm acid indol acetic . Etodolac Nhm sulfonanilid . Nimesulid

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2.1. Dn xut acid salicylic 2.1.1. Acid salicylic (acidum salicylicum): Tinh th hnh kim, khng mu, nh, ng nh, khng mi, v chua v hi ngt, kh tan trong nc. Do kch ng mnh nim mc nn khng dng ung. Dng ngoi da, dung dch 10% cha chai chn, ht cm, nm da... 2.1.2. Acid acetylsalicylic (aspirin): Kt tinh hnh kim trng, hi chua, kh tan trong nc, d tan hn trong ru v cc dung dch base. L sn phm acetyl ha ca acid salicylic gim tnh kch ng nn ung c. 2.1.2.1. c im tc dng: - Tc dng h st v gim au trong vng 1 - 4 gi vi liu 500 mg/ln. Khng gy h thn nhit. - Tc dng chng vim: ch c tc dng khi dng liu cao, trn 3g/ngy. Liu thp ch yu l h st v gim au. - Tc dng thi tr acid uric: liu thp (1-2g/ngy) lm gim thi tr acid uric qua nc tiu do lm gim bi xut cht ny ng ln xa. Liu cao (2-5g/ngy) lm i nhiu urat do c ch ti hp thu acid uric ng ln gn. - Tc dng trn tiu cu v ng mu: Aspirin vi liu thp (40-325mg/ngy) c ch mnh cyclooxygenase ca tiu cu, lm gim tng hp thromboxan A2 (cht lm ng vn tiu cu) nn lm gim ng vn tiu cu. Liu cao hn, c ch cyclooxygenase ca thnh mch, lm gim tng hp PG I2 (prostacyclin) l cht chng kt dnh v lng ng tiu cu, gy tc dng ngc li. Nhng tc dng trn tiu cu mnh hn nhiu. Liu cao aspirin cng lm gim tng hp prothrombin, c th l do i khng vi vitamin K. V vy, aspirin c tc dng chng ng mu. - Tc dng trn ng tiu ha: Nim mc d dy - rut sn xut ra PG, c bit l PG E2, c tc dng lm tng to cht nhy v c th l c kch thch phn bo thay th cc t bo b ph hu. Nh vy, vai tr ca PGE l bo v nim mc ng tiu ha. Aspirin v cc thuc chng vim phi steroid ni chung, vi mc khc nhau, c ch cyclooxygenase, lm gim PG, to iu kin cho HCl v pepsin ca dch v gy tn thng cho nim mc sau khi hng ro bo v b suy yu. V vy, khng c dng thuc cho nhng ngi c tin s lot d dy v phi ung thuc sau ba n. 2.1.2.2. Dc ng hc pH ca d dy, cc dn xut salicylic t b ion ha cho nn d khuch tn qua mng, c hp th tng i nhanh vo mu ri b thu phn thnh acid salicylic, khong 5080% gn vi protein huyt tng, b chuyn ha gan, thi gian bn thi khong 6 gi. Thi tr qua nc tiu 50% trong 24 gi di dng t do, glycuro- hp, acid salicylic v acid gentisic. Nu pH ca nc tiu base, thi tr salicylic tng.

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2.1.2.3. c tnh: - Mc du cc dn xut salicylic u t c, d ung, nhng dng lu c th gy h i chng salicyle (salicylisme): bun nn, tai, ic, nhc u, l ln. - c ng: ph, m ay, mn, ph Quincke, hen. - Xut huyt d dy th n (c hng cu trong phn) hoc th nng (lot, nn ra mu). - Nhim c vi liu trn 10g. Do aspirin kch thch trung tm h hp, lm th nhanh v su (nn gy nhim alcali h hp), sau v p lc ring phn ca CO2 gim, m gii phng nhiu acid lactic, a n hu qu nhim acid do chuyn ha (hay gp tr em v c ch iu ha cha n nh). Liu cht i vi ngi ln khong 20g. 2.1.2.4. Liu lng v ch phm: - Ung 1-6g/ngy, chia lm nhiu ln. Dng h st, gim au v chng vim (thp khp cp, thp khp mn, vim a khp, vim thn kinh...) Vin nn aspirin 0,5g (bit dc: Acesal, Aspro, Polopyrin). - Lysin acetyl salicylat (Aspgic): l dng mu i ha tan, m i l tng ng vi 0,5g aspirin. Tim t nh mch hoc tim bp 1-4 l/ngy. - Aspirin pH8: vin nn cha 0,5 g aspirin, c bao bng cht khng vi dch v, nhng tan trong dch rut, on 2 ca t trng, t thuc c hp thu vo mu v b thu phn thnh acid salicylic. Nng ti a trong mu t c sau 7 gi, thi gian bn thi di hn aspirin bnh thng, do gim c s ln ung thuc trong ngy, rt tin li cho cc trng hp iu tr ko di. 2.1.3. Methyl salicylat Dung dch khng mu, mi hc lu, ch dng xoa bp gim au ti ch. Ngm qua da cho nn khi xoa bp, thy metyl salicylat trong nc tiu.

2.2. Dn xut pyrazolon Hin ch cn dng mt cch hn ch phenylbutazon. Cc dn xut khc nh phenazon (antipyrin), aminophenazon (pyramidon), metamizol (analgin), khng cn dng na v c nhiu c tnh vi mu (gim bch cu, suy tu ), vi thn (i albumin, vim ng thn cp, v niu). Ch dng phenylbutazon cho vim cng khp v vim a khp mn tnh tin trin khi cc thuc CVKS khc khng cn tc dng v phi theo di cht ch cc tc dng khng mong mun ca thuc. Liu lng v ch phm: Ngy u ung 200mg chia lm 2 ln ung trong hoc sau ba n, tng dn liu ti 600 mg/ngy. Tu theo tnh trng bnh v sc chu ng ca ngi bnh, c th gi liu trong 4 - 5 ngy, sau gim xung liu duy tr 100 - 200 mg. Ni chung, mt t thuc khng qu 15 ngy, sau ngh 4 - 5 ngy mi dng. Phenylbutazon vin 50 v 100 mg.

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Oxyphenbutazon (Tandery) vin 100 mg. Chngta s b thuc ny trong tng lai gn 2.3. Dn xut indol: 2.3.1. Indometacin

2.3.1.1. c im tc dng - Tc dng gim vim mnh hn phenylbutazon 20 - 80 ln v mnh hn hydrocortioson 2 - 4 ln. i khng r vi PG. Tc dng c trn giai on u v giai on mun (mn tnh) ca vim. - Tc dng gim au lin quan mt thit vi tc dng chng vim (liu chng vim/liu gim au = 1). - C tc dng h st, nhng khng dng cha st n thun v c nhiu c tnh v c thuc h st khc thay th (paracetamol, aspirin). - Sinh kh dng gn bng 100%. Gn protein huy t tng 99%, thm c vo dch khp (bng khong 20% nng huyt tng). 2.3.1.2. c tnh: Xy ra cho khong 20 -50% ngi dng thuc. - C th gy chng mt, nhc u (v cng thc ca indomatacin tng t nh serotonin), ri lon tiu ha, lot d dy. V th khng c dng cho ngi c tin s d dy. 2.3.1.3. Ch nh: - Vim xng khp, h khp, thp khp ct sng, vim nhiu khp mn tnh tin trin, au lng, vim dy thn kinh... - Ch phm v liu lng: Indometacin (Indocid; Indocin): vin nn hoc vin nang 25mg. Thuc n 50 - 100mg. Mi ngy ung 50 - 150 mg chia lm nhiu ln. 2.3.2. Sulindac Sulindac l tin cht (prodrug): bn thn n khng c hot tnh, vo c th c chuyn ha thnh dn cht sulfat c hot tnh sinh hc mnh, c ch cyclooxygenase 500 ln mnh hn sulindac. V cu trc ha hc, sulindac l indometacin c thay methoxy bng fluor v thay Cl bng gc methylsulfinyl (CH3SO-). - Trong thc nghim, tc dng dc l ca sulindac bng 1/2 indometacin; trong thc t lm sng, tc dng chng vim v gim au ca sulindac tng t aspirin. - T l v mc c tnh km indometacin. - Ch phm: Arthrocin, Artribid, Clinoril vin 150 v 200 mg; m i ngy ung 1-2 vin, liu ti a 400mg/ngy, l liu tng ng vi 4g aspirin hoc 125 mg indometacin.

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2.3.3. Etodolac L thuc c tc dng c ch u tin COX- 2, hp thu nhanh qua tiu ha, 99% gn vo protein huyt t ng, c chu k gan- rut. Thi gian bn thi l 7 gi. Liu ung 200- 400 mg 2.4. Dn xut enolic acid: oxicam (piroxicam, meloxicam v tenoxicam) L nhm thuc gim vim mi, c nhiu u im: - Tc dng chng vim mnh v ngoi tc dng c ch COX cn c ch proteoglycanase v collagenase ca m sn, liu iu tr ch bng 1/6 so vi cc thuc th h trc. Tc dng gim au xut hin nhanh, na gi sau khi ung. - Thi gian bn thi di (2-3 ngy) cho php dng liu duy nht trong 24 gi. Gn vo protein huyt t ng ti 99%. V t/2 qu di, d c nguy c tch lu thuc. - t tan trong m so vi cc CVKS khc, cho nn d thm vo t chc bao khp b vim, t thm vo cc m khc v vo thn kinh, gim c nhiu tai bin. - Cc tai bin thng nh v t l thp hn so vi cc CVKS khc, ngay c khi dng thuc ko di ti 6 thng. - Thng ch nh trong cc vim mn v tc dng di. - Ch phm v liu lng: + Piroxicam (Feldene) 10-40 mg/ngy. Vin nang 10 mg,20 mg;ng tim 20 mg/ ml T 2002 do thy tai bin trn tiu ha cao nn nhiu nc b. + Tenoxicam (Tilcotil) 20mg/ngy.Vin nn 20 mg, ng tim 20 mg/ ml. + Meloxicam (Mobic). Vin nn 7,5 mg v 15 mg. Liu bnh thng 7,5 mg/ ngy, ti a 15 mg/ ngy; t/2= 20 gi. Lc u, da vo ktqu th in vitro, meloxicam c coi nh thuc c ch chn lc COX- 2 (1999), nhng trn lm sng, in vivo, tc dng c ch COX- 2 ch mnh hn COX- 1 c 10 ln nn khng cn c xp vo nhm thuc ny na. 2.5. Dn xut acid propionic - Liu thp c tc dng gim au; liu cao hn, chng vim. - So vi aspirin, indometacin v pyrazolon c t tc dng ph hn, nht l trn tiu ha, v vy c dng nhiu trong cc vim khp mn. - Ch phm v liu lng: Ibuprofen: - Tc dng chng vim v gim au tng t aspirin, nhng tc dng ph trn tiu ha th thp hn nhiu, d c dung np hn. - c hp thu nhanh qua ng tiu ha, nng ti a t c trong huyt tng sau 1- 2 gi. Thuc b chuyn ha nhanh v thi tr qua thn, thi gian bn thi l 1,8- 2 gi. - Ch nh chnh trong vim khp dng thp, vim cng khp, iu tr cc chng au nh v va (nhc u, au rng, au do kinh nguyt). - Tc dng khng mong mun: ngoi cc tc dng khng mong mun chung ca nhm thuc CVKS, cn thy nhn m, gim th lc, thay i nhn cm mu sc. Cn ngng dng thuc v khm chuyn khoa mt. - Liu lng v cch dng:

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. Vin nn 100, 150, 200, 300 v 400 mg . Vin nang 200 mg . n trc trng 500 mg Vim khp: thng dng 1,2- 1,8g/ ngy, chia lm 4 ln. C th tng liu nhng khng vt qu 3,2g/ ngy. Sau 1- 2 tun cn gim xung liu thp nht c tc dng (0,6- 1,2g/ ngy). Gim au: ung 400 mg/ ln, cch 4- 6 gi/ ln. Naproxen Vin 250mg. Ung 250mg x 2 ln/ngy. Thi gian bn thi l 14 gi. D dung np nn thng c dng nh ibuprofen 2.6. Nhm dn xut ca acid phenylacetic i din duy nht l diclofenac (Voltaren) - Tc dng c ch COX mnh hn indometain, naproxen v nhiu thuc khc. Ngoi ra c th cn lm gim nng acid arAChidonic t do trong bch cu do ngn cn gii phng hoc thu hi acid bo. - Hp thu nhanh v hon ton qua ng tiu ha, nhng ch 50% vo c tun hon v b chuyn ha trong qu trnh hp thu. T1/2 = 1- 2 h, nhng tch lu dch bao khp nn tc dng vn gi c lu. - Ch nh trong vim khp mn. Cn dng gim au trong vim c, au sau m v au do kinh nguyt. - Tc dng ph t, ch khong 20%, c th lm tng aminotransferase gan gp 3 ln, nhng h i phc c. - Ch phm v liu lng: vin 50- 100 mg ung 100- 150 mg/ ngy. 2.7.Nhm dn xut acid heteroarylacetic - Tolmetin: . Tc dng chng vim, gim au v h st tng t aspirin nhng d dung np hn. Thuc c gi li trong bao hot dch ti 8 gi sau 1 liu duy nht. . Tc dng ph: 25- 40%. . Tc dng chng vim, gim au liu 0,8- 1,6g/ ngy, tng ng vi aspirin 4- 4,5g/ ngy hoc indometacin 100- 150 mg/ ngy. Liu ti a l 2g/ ngy chia lm 3- 4 ln. - Ketorolac: . L thuc c tc dng gim au mnh hn chng vim. Khc opioid, tc dng gim au ca ketorolac khng gy quen thuc v du hiu cai thuc, khng c ch trung tm h hp. C tc dng chng vim ti ch, dng nh mt. . L mt trong s t thuc CVKS c th dng ng tim. . Tc dng ph gp 2 ln placebo, thng l ng g, chng mt, nhc u, chm tiu, nn, au ch tim. Thng dng cho gim au sau m, au cp tnh. Liu ung 5- 30 mg/ ngy; tim bp 30- 60 mg/ ngy; Tim t nh mch 150 30 mg/ ngy, khng dng qu 5 ngy.

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. Ch nh gim au ngn hn, di 5 ngy nh au sau m: tim bp 30- 60 mg; tim t nh mch 15- 30 mg v ung 5- 30 mg. . Khng dng cho au trong sn khoa. Khng dng cho au nh v au mn tnh. 2.8. Thuc CVKS loi c ch chn lc COX- 2 Cc thuc loi ny, c nhng c im sau: - c ch chn lc trn COX -2 nn tc dng chng vim mnh, v c ch COX- 1 yu nn cc tc dng ph v tiu ha, mu, thn, cn hen... gim i rt r rt, ch cn t 0,1- 1%. - Thi gian bn thi di, khong 20 gi cho nn ch cn ung m i ngy 1 ln. - Hp thu d dng qua ng tiu ha, d thm vo cc m v dch bao khp nn c nng cao trong m vim, ch nh tt cho vim xng khp v vim khp dng thp V kt t tiu cu ph thuc duy nht vo COX- 1, nn cc thuc nhm ny khng dng d phng c nh i mu c tim. Vn cn dng Aspirin. Qua thc t s dng, vn thy c tc dng ph do c ch COX- 1 cho nn nhiu tc gi ngh khng dng t c ch "chn lc" m nn thay bng t c ch "u tin" COX- 2 th ng hn. Rofecoxib (Vioxx) c ch COX- 2 mnh hn COX- 1 t i 800 ln. c dng t 1999. Qua nhiu th nghim lm sng dng lin tc trn 18 thng iu tr polip i trng, ung th tuyn tin lit, bnh Alzheimer, thy tai bin tim mch ca Vioxx cao hn placebo nn thng 10/ 2004 Hng sn xut (Merck) t nguyn xin rt khi th trng. Celecoxib (Celebrex) Thuc c ch COX- 2 mnh hn COX- 1 t 100 n 400 ln, c dng t 1998. - Hp thu qua tiu ha, t nng ti a trong huyt tng sau 2- 4 gi. Gn mnh vi protein huyt tng. Phn ln b chuyn ha gan. Thi gian bn thi l 11 gi. - Liu thng dng 100 mg 2 ln/ ngy. trong thp khp c th tng liu ti mg 2 ln/ ngy. Etodolac: (xem 2.3.3) Cc thuc c ch chn lc COX- 2 c khng nh l lm gim r rt tai bin chy mu tiu ha, nhng sau 5 nm s dng thy nguy c tim mch tng v thuc gy mt thng bng gia PGI2 v TXA2, lm gim mnh PGI2, yu t bo v n i mc mch. Hin nay (2005) thuc vn c gim st cht ch khi dng ko di. 2.9. Dn xut para aminophenol : Acetaminophen, paracetamol 2.9.1 c im tc dng Paracetamol c cng v thi gian tc dng tng t nh aspirin v gim au v h st. Khng c tc dng chng vim nn nhiu tc gi khng xp vo nhm thuc CVKS. Thc ra, trn m hnh thc nghim, paracetamol vn tc dng chng vim, nhng phi dng liu cao hn liu gim au, v trong vim c nng cao cc peroxid, lm mt tc dng c ch COX ca paracetamol (Marshall v cng s 1987) v mt khc, paracetamol khng c ch s hot ha bch cu trung tnh nh cc CVKS khc (Abramson v cng s, 1989). Trong thc hnh, paracetamol c dng h st, gim au. Ch nh tt cho nhng ngi khng dng c aspirin (lot tiu ha, ri lon ng mu). 200

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2.9.2. Dc ng hc Hp thu nhanh qua tiu ha, sinh kh dng l 80 - 90%, t/2 = 2 gi, hu nh khng gn vo protein huyt tng. Chuyn ha phn ln gan v mt phn nh thn, cho cc dn xut glucuro v sulfo-hp, thi tr qua thn. 2.9.3. c tnh Vi liu iu tr thng thng, hu nh khng c tc dng ph, khng gy tn thng ng tiu ha, khng gy mt thng bng base -acid, khng gy r i lon ng mu. Tuy nhin, khi dng liu cao (> 10g), sau thi gian tim tng 24 gi, xut hin hoi t t bo gan c th tin trin ti cht sau 5 - 6 ngy. Nguyn nhn l paracetamol b oxy ha gan cho N-acetyl parabenzoquinon-imin. Bnh thng, cht chuyn ha ny b kh c ngay bng lin hp vi glutathion ca gan. Nhng khi dng liu cao, N-acetyl parabenzoquinon-imin qu tha s gn vo protein ca t bo gan v gy ra hoi t t bo. Biu hin bng au h sn phi, gan to, vng da, hn m gan (do tng amoniac), acid mu. V sinh ha, AST, ALT, LDH u tng. Bnh nhn thng cht sau 6-7 ngy. Nu iu tr sm bng N-acetyl-cystein (NAC-, Mucomyst, Mucosol), l cht tin thn ca glutathion, bnh nhn c th qua khi. Sau 36 gi, gan b tn thng, kt qu s km. Sau ng c di 10 gi, dng NAC c hiu qu hn: ung dung dch 5% - 140mg/kg, sau , cch tng 4 gi, ung 70mg/kg 17 liu. NAC cng c tc dng ph: ban , my ay, nn, tiu chy, nhng khng cn ngng thuc. 2.9.4. Ch phm v liu lng - Paracetamol (Efferalgan; Dafalgan): vin 0,5g; gi bt 0,08g; vin n 80, 150, 300 mg. . Ngi ln: 0,5-1,0g 1-3 ln/ngy. Khng c dng qu 4 g/ngy. . Tr em 13-15 tui: 0,5g 1-3 ln/ngy. . Tr em 7-13 tui: 0,25g 1-3 ln/ngy. - Propacetamol clohydrat (Pro- Dafalgan) (th h 1) V paracetamol kh tan trong nc nn tng hp tin cht ca paracetamol tan c trong nc, vo c th di tc dng ca esterase huyt tng s gii phng paracetamol: esterase Propacetamol (2g) huyt tng Diethylglycin + PARACETAMOL (1g)

Trnh by: l thuc bt + dung mi. Pha ngay trc khi dng, khng qu 30 pht. Tim bp su hay tim t nh mch chm trong vng 2 pht. C th truyn tnh mch trong vng 15 pht (pha trong 100 mL NaCl 0,9% hoc glucose 5%). Liu dng 1-2g/ ln, cch 4- 6 gi. Khng dng qu 8g/ ngy. Khng dng cho tr em di 15 tui v ngi suy thn. - Perfalgan (th h 2) L paracetamol c lm tan hon ton trong nc (1g/ 100 mL). Perfalgan 1g c tng ng sinh hc vi propacetamol 2g v c tc dng gim au tng ng vi diclofenac 75 mg tim bp, hoc morphin 10 mg tim bp. - Rt nhiu ch phm khc c cha paracetamol kt hp vi cafein, ephedrin, codein, phenylpropanolamin (PPA)... 3. NHNG VN CHUNG

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3.1.

Dc ng hc chung

- Mi CVKS ang dng u l cc acid yu, c pKa t 2 n 5. - Hp thu d qua tiu ha do t b ion ha d dy. - Gn rt mnh vo protein huyt tng, ch yu l albumin, c thuc ti 99,7% (nhm oxicam, diclofenac), do d y cc thuc khc ra dng t do, lm tng c tnh ca thuc (sulfamid h ng huyt, thuc khng vitamin K...). Cc thuc CVKS d dng thm nhp vo cc m vim. Nng thuc trong bao hot dch bng khong 30- 80% nng huyt tng. Khi dng lu, s vt qu nng huyt tng. Do tc dng vim khp c duy tr. - B ging ha gan (tr acid salicylic), thi qua thn di dng cn hot tnh khi dng v i liu chng vim v liu c. - Cc thuc khc nhau v thi tr, t1/2 huyt tng thay i t 1- 2 gi (aspirin, nhm propionic) n vi ngy (pyrazol, oxicam). - Nhm salicylic dng cho au nh (rng) hoc cc vim cp. Cc CVKS c t1/2 di c dng cho vim mn vi liu 1 ln/ ngy. Da theo thi gian bn thi ca thuc, c th chia cc CVKS lm 3 nhm (bng 3.3): - Cc thuc c thi gian bn thi ngn, di 10 gi, cn ung 3 ln/ ngy, bnh nhn kh tun th. Tuy nhin, c li l khi ngng thuc, tc dng s ht nhanh, nht l khi xy ra tc dng khng mong mun. An ton hn cho ngi cao tui v bnh nhn suy thn. - Cc thuc c thi gian bn thi di, trn 30 gi, ch cn dng 1 ln/ ngy, ngi bnh khng qun. Tuy nhin, d gy tch lu thuc, nht l vi ngi c tui v suy thn, d gy tai bin nng, khi ngng thuc tc dng c hi cn ko di. Phi 7 ln t/2 th thuc mi thi tr ht, nh vy, vi piroxicam c t/2 = 40 gi, phi ch 12 ngy. - Cc thuc c thi gian bn thi trung gian: tng i d dng v t tc dng ph hn.

Bng 10.1: Phn loi thuc theo thi gian bn thi (t/2) Loi thuc Tn thuc Aspirin Diclofenac Ketoprofen Salicylat Ibuprofen Indomethacin Naproxen Sulindac Meloxicam Tenidap Piroxicam Tenoxicam t/2 (h) 0.25 1.1 1.8 2.0- 15 2.1 4.6 14 14 20 20- 30 40- 45 60- 75 S ln dng/ ngy 3- 4 2- 4 2- 4 3- 4 3- 4 3- 4 2 2 1 1 1 1

t/2 ngn

t/2 trung bnh

t/2 di

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Phenylbutazon 3.2. Cc tc dng khng mong mun

68

Thng lin quan n tc dng c ch tng hp PG. - Lot d dy - rut: nim mc d dy rut sn xut PG, c bit l PG E2 c tc dng lm tng cht nhy v c th l c kch thch phn bo thng xuyn thay th cc t bo nim mc b ph hu. Thuc CVKS c ch tng hp PG, to iu kin cho HCl ca dch v gy tn thng cho nim mc sau khi hng ro bo v b suy yu. - Lm ko di thi gian chy mu do c ch ngng kt tiu cu. - Vi thn, PG c vai tr quan trng trong tun hon thn. c ch tng hp PG gy hoi t gan v sau l vim thn k mn, gim chc phn cu thn, d dn n tng huyt p. - Vi ph n c thai: + Trong 3 thng u, CVKS d gy qui thai + Trong 3 thng cui, CVKS d gy cc ri lon ph i, lin quan n vic ng ng ng mch ca bo thai trong t cung. Mt khc, do lm gim PG E v F, CVKS c th ko di thi gian mang thai, lm chm chuyn d v PG E, PG F lm tng co gp t cung, trc khi vi gi, s tng hp cc PG ny tng rt mnh. - Mi CVKS u c kh nng gy cn hen gi (pseudo asthma) v t l nhng ngi hen khng chu thuc l cao v c th l CVKS c ch cyclooxygenase nn lm tng cc cht chuyn ha theo ng lipooxygenase (t ng leucotrien). 3.3. Tng tc thuc Khng dng CVKS vi: - Thuc chng ng mu, nht l vi loi khng vitamin K. - Thuc li niu v h huyt p, v CVKS c ch tng hp c cc PG gy gin mch. - Lithium: CVKS lm gim thi tr lithi qua thn, gy tch lu. - CVKS lm tng tc dng ca phenytoin v sulfamid h ng huyt do y chng ra kh i protein huyt tng, lm tng nng thuc t do trong mu. 3.4. Ch nh 3.4.1. Gim au v h st thng thng: aspirin, paracetamol Gim au sau m: cho thuc trc khi rch dao, loi c t/2 trung bnh hoc di. 3.4.2. Cc bnh thp cp v mn - V t l c tnh tiu ha/hiu qu chng vim ging nhau cho m i loi CVKS, cho nn tiu chun chn thuc cn da trn: + p ng ca tng ngi bnh + S thun tin trong s dng + Tc dng nhanh. - Th d: + Vim a khp dng thp: dn xut propionic, diclofenac (Voltaren). + Vim khp mn ca ngi tr: aspirin

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+ Vim cng khp: indometacin + Thoi ha khp: loi c tc dng gim au vi liu thp v khi tng liu s t c tc dng chng vim: aspirin, dn xut propionic. Hoc mt thuc gim au n thun paracetamol. 3.4.3. Cc ch nh khc Cc thuc c ch chn lc COX- 2 ang c th dng d phng v iu tr bnh Alzheimer, polip i trng, ung th rut kt- trc trng, tuyn tin lit. Tuy nhin, do phi dng di ( 18 thng), thy nguy c tim mch tng. 3.5. Nguyn tc chung khi s dng CVKS - Vic chn thuc tu thuc vo c th. C ngi chu ng c thuc ny nhng khng chu ng c thuc khc. - Ung trong hoc sau ba n trnh kch ng d dy. - Khng ch nh cho bnh nhn c tin s lot d dy. Trong trng hp tht cn thit, phi dng cng vi cc cht bo v nim mc d dy. Song, nhng tai bin tiu ha khng phi ch do tc dng kch thch trc tip ca thuc ln nim mc m cn do tc dng chung ca thuc. CVKS gy lot d dy do c ch tng hp PG E2 , PG I2 nim mc d dy. Cc PG ny c vai tr c ch bi tit HCl, v kch thch bi tit dch nhy cng bicarbonat d dy, v th c tc dng bo v nim mc d dy. Hin tng hp c mt loi tng t PG E1 l Misoprostol (Cytotec), tc 15- deoxy- 16 hydroxy- 16 metyl- PG E1 c tc dng chng lot d dy tng t thuc khng H2. c bit c dng trong nhng ngi phi iu tr ko di bng CVKS. Tc dng ph: tiu chy (30%), au qun bng, xy thai. Liu lng: Vin 200 mg x 4 ln/ ngy. ang nghin cu tng hp thuc tng t PGE2 (Arboprostol, Enprostil, Trimoprostil). - Ch nh thn trng i vi bnh nhn vim thn, suy gan, c c a d ng, cao huyt p. - Khi iu tr ko di, cn kim tra c nh k (2 tun mt ln) cng thc mu, chc phn thn. - Nu dng liu cao tn cng, ch nn ko di 5 - 7 ngy. Nhanh chng tm c liu thp nht c tc dng iu tr trnh c tai bin. - Ch khi dng ph i hp thuc: + Khng dng ph i hp vi cc CVKS vi nhau v lm tng c tnh ca nhau. + Khng dng CVKS cng vi thuc chng ng mu loi khng vitamin K (dicumarol, warfarin), sulfamid h ng huyt, diphenylhydantoin, v CVKS s y cc thuc ny ra kh i ni d tr (protein huyt tng), lm tng c. Nu vn cn phi hp th gim liu cc thuc . + Cc CVKS c th lm gim tc dng mt s thuc do lm tng ging ha hoc i khng ti ni tc dng, nh meprobamat, androgen, li niu furosemid. CU HI T LNG GI

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1. Trnh by c ch tc dng chung ca thuc CVKS- Phn bit thuc c ch COX- 1 v c ch COX- 2. 2. Trnh by c ch tc dng chng vim ca thuc CVKS. 3. Trnh by c ch tc dng gim au ca thuc CVKS. 4. Trnh by c ch tc dng h st ca thuc CVKS. 5. Trnh by c ch chng ngng kt tiu cu ca aspirin. 6. Phn tch so snh c im tc dng v p dng iu tr ca aspirin, dn xut indol (indometacin), dn xut phenylacetic (diclofenac, voltaren). 7. Trnh by c im tc dng v p dng iu tr ca cc thuc CVKS loi c ch chn lc COX- 2. 8. Trnh by tc dng, c ch tc dng, c tnh, v p dng iu tr ca paracetamol. 9. Trnh by cc tc dng khng mong mun v nguyn tc chung khi s dng thuc CVKS.

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Bi 11: THUC CHA GT MC TIU HC TP: Sau khi hc xong bi ny, sinh vin c kh nng: Trnh by c c ch tc dng, ch nh cc thuc colchicin, probenecid, allopurinol. Gt l mt bnh do tng acid uric-mu, trong dch bao khp c nhiu tinh th urat l sn phm chuyn ha cui cng ca purin. Bnh c th nguyn pht do ri lon chuyn ha acid uric di truyn, hoc th pht do bnh thn, do dng cc thuc phong ta thi tr urat hoc do sn xut qu nhiu urat (metabolic overproduction). Acid uric-mu bnh thng l 2-5mg/100ml, trong bnh gt c th tng ti 8,8mg/100ml. iu tr gt nhm gii quyt cn cp tnh v ngn nga s ti nhim, da trn sinh bnh hc ca bnh ny. Cc tinh th urat lc u b thc bo bi cc t bo mng hot dch (synovioucytes). Trong qu trnh thc bo, cc t bo ny gii phng ra cc prostaglandin, cc enzym tiu th v interlenkin-1. Cc cht trung gian ha hc ny li g i cc bch cu ht ti khp v lm nng thm qu trnh vim: s lng bch cu ht, i thc bo tng, lng cht ha hc trung gian gy vim tng. Cc thuc iu tr cn gt cp tnh s c ch cc giai on hot ha bch cu. c hiu nht l colchicin. Ngoi ra cn dng thuc CVKS phenylbutazon, indometacin, loi c ch COX-2, hoc corticoid. iu tr gt mn tnh, dng thuc lm gim acid uric trong c th bng cc thuc lm i ra acid uric nh probenecid, sunfinpyrazol v allopurinol. 1. COLCHICIN Colchicin l alcaloid ca cy colchicum antumnal. Bt v nh hnh, vng nht, khng mi. c dng t th k 18. Tc dng iu tr c hiu cn gt cp tnh, lm gim au v gim vim trong vng 12 24 gi u dng thuc, v th cn c dng lm test chn on. Colchicin khng c tc dng gim au v chng vim khp khc. 1.1. C ch tc dng Trong bnh gt, colchicin khng nh hng n bi xut acid uric thn v khng lm gim acid uric mu. Colchicin gn vo protein ca tiu qun (protein tubulin) trong t bo bnh cu v cc t bo di chuyn khc, v th, ngn cn s trng hp ca nhng protein ny trong vi tiu qun (microtubulin), dn n c ch s di chuyn ca bch cu v gim hot tnh thc bo ca bch cu ht, lm gim gii phng acid lactic v cc enzym gy vim trong qu trnh thc bo. Trong qu trnh tiu ha cc tinh th urat, bch cu ht sn xut glycoprotein, cht ny c th l nguyn nhn gy ra cn gt cp tnh. Colchicin ngn cn sn xut glycoprotein ca bch cu ht nn chng c cn gt. Colchicin cn ngn cn s phn bo ca cc t bo ng-thc vt giai on trung k v do lm gim s hnh thnh cc thoi phn bo. 1.2. c tnh Phn ln lin quan n tc dng c ch s trng hp ca tubulin v c ch phn bo: bun nn, nn, tiu chy, au bng (tn thng t bo biu m nim mc tiu ha), c ch tu xng, rng tc, vim thn kinh, c vi thn...

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1.3. Dc ng hc Hp thu nhanh qua ng ung, t nng ti a trong huyt tng sau 0,5-2 gi. Chuyn ha gan, phn ln thi tr qua phn (c chu k rut - gan), ch 10 - 20% thi qua thn. 1.4. Ch nh - iu tr cn gt cp tnh: tim tnh mch 2 mg ha trong 10 - 20 ml dung dch NaCl 0,9%. Tng liu khng vt qu 4mg. Khng tim nhc li trong vng 7 ngy. Nu khng chu c thuc, c th thay bng indometacin. - D phng: ung 0,5mg m i tun 2 - 4 ln. Vin 0,5 mg, 1 mg. ng tim 2ml = 1mg 2. PROBENECID (BENNEMID) Probenecid l dn xut ca acid benzoic, tan nhiu trong lipid. Bt tinh th trng, khng mi. Acid uric c lc qua cu thn v bi xut qua ng thn, song phn ln li c ti hp thu on gia ca ng ln gn. Probenecid vi liu thp do cnh tranh vi qu trnh thi tr acid uric nn lm lu acid uric trong c th (Demartini v cng s, 1962), nhng vi liu cao li c ch ti hp thu acid uric ng thn nn lm tng thi tr acid qua nc tiu. Probenecid cn c ch c tranh chp qu trnh thi tr ch ng ti ng ln gn ca mt s acid yu nh penicilin, para aminosalicylat, salicylat, clorothiazid, indometacin, sunfinpyrazon, v.v... Probenecid khng c tc dng gim au. Khi cn gim au, c th dng cng vi paracetamol. Khng dng cng vi salicylat, v probenecid s mt tc dng. Dng thuc li niu loi thiazid ko di nh trong iu tr cao huyt p thng lm urat v nhng thuc ny c ch bi xut urat ng thn. Probenecid i khng c tc dng ny m khng nh hng n tc dng li niu ca thuc. Tuy nhin, li c ch tc dng i natri ca furosemid. Probenecid c hp thu nhanh qua rut, vo mu, hn 70% kt hp vi albumin huyt tng, thi tr qua thn phn ln di dng glucuro-hp. Thi gian na thi tr khong 612 gi. Tc dng ph rt t (2-8%): bun nn, nn, mng da, st. Khi lm i nhiu acid uric, c th gy cn s i urat vi cn qun thn (khi cn base ho nc tiu). Liu lng: vin 0,5g. Tun u ung 250mg 2ln/ngy. Tng dn tng tun. Ti a 2g/ngy, ung 4 ln. Ung nhiu nc trnh s i acid uric thn. Dng hng nm. C th dng vi allopurinol, sunfinpyrazon. 3. SUNFINPYRAZON (ANTURANT) Cng thc gn ging phenylbutazon. Gy i ra acid uric mnh do ngn cn ti hp thu ng thn, ging c ch ca probenecid. Hp thu nhanh v hon ton qua ng tiu ho. Gy tai bin mu nh phenylbutazon, ri lon tiu ho khong 10%. Salicylat lm mt tc dng ca sunfinpyrazon do tranh chp vi sunfinpyrazon khi vn chuyn qua ng thn v c khi gn vo protein huyt tng.

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Liu lng: vin 50mg 4ln/ngy, t ng dn ti 400mg hoc 800mg mt ngy. Chia lm 2-4 ln, ung vo ba n trnh kch ng d dy. Ung nhiu nc trong ngy. 4. ALLOPURINOL (ZYLOPRIM) Allopurinol l cht ng phn ca hypoxanthin.

4.1. C ch tc dng Acid uric l sn phm chuyn ho ca purin. Cc purin c chuyn thnh hypoxanthin v xanthin r i b oxyho nh xc tc ca xanthin oxydase thnh acid uric. Allopurinol l cht c ch mnh xanthin oxydase nn lm gim sinh tng hp acid uric, gim nng acid uric mu v nc tiu, lm tng nng trong mu v nc tiu cc cht tin thn hypoxanthin v xanthin d tan hn. Nh vy, allopurinol cn ngn nga c s to si acid uric trong thn. Nh vy, allopurinol cn ngn nga c s to si acid uric trong thn. 4.2. c tnh t c. Phn ng qu mn khong 3% (mn da, st, gim bch cu, gan to, au c). Trong nhng thng u iu tr, c th c cc cn gt cp tnh do s huy ng acid uric t cc m d tr. Khi , cn ph i hp iu tr bng colchicin. 4.3. Dc ng hc Hp thu qua ng ung khong 80%, t nng ti a trong mu sau 30-60 pht. Allopurinol cng b chuyn ho bi xanthin oxydase thnh aloxanthin, vn cn hot tnh, v th tc dng ko di, ch cn ung thuc m i ngy 1 ln. 4.4. Ch nh, liu lng - Gt mn tnh, si urat thn. - Tng acid uric mu th pht do ung th, do iu tr bng cc thuc chng ung th, thuc li tiu loi thiazid... - Tng acid uric mu m khng th dng c probenecid hoc sunfinpyrazon do c phn ng khng chu thuc. Mc tiu ca iu tr l lm gim nng acid uric mu xung 6mg/dl (360 micro M). Liu lng: Allopurinol (Zyloprim) vin 100 - 300 mg. Liu u 100mg, t ng dn ti 300mg/ngy tu theo nng acid uric mu. CU HI T LNG GI

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Phn tch so snh c ch tc dng v ch nh iu tr ca colchicin, probenecid v allopurinol.

Bi 12: THUC AN THN KINH V THUC BNH THN MC TIU HC TP: Sau khi hc xong bi ny, sinh vin c kh nng: 1. Trnh by c 3 c im c bn ca thuc an thn kinh v 6 c im ca thuc bnh thn. 2. Trnh by c c ch tc dng v tc dng dc l, tc dng khng mong mun, p dng lm sng ca thuc an thn kinh: clopromazin, haloperidol. 3. Phn tch c c ch tc dng, tc dng v p dng lm sng ca benzodiazepin. 1. THUC AN THN KINH (thuc an thn ch yu) Cc thuc loi ny c 3 c im c bn : - Gy trng thi th , lnh m, ci thin c cc triu chng ca bnh tm thn phn lit. - C thm tc dng c ch thn kinh thc vt, gy h huyt p, gim thn nhit. - C th gy ra hi chng ngoi b thp (hi chng Parkinson). Khc vi thuc ng, cc thuc loi ny d dng vi liu cao cng khng gy ng, ch c tc dng gy m mng, lm d ng. 1.1. Dn xut phenothiazin v thioxanthen: clopromazin Clorpromazin (Largactil, plegomazin, Aminazin): thuc c bng B. Bt trng xm, rt tan trong nc, ru, cloroform. c tm ra t nm 1952 trong khi nghin cu cc thuc khng histamin tng hp dn xut ca vng phenothiazin. L thuc m u cho lnh vc dc l tm thn. 1.1.1. Tc dng dc l 1.1.1.1. Trn h thn kinh trung ng - Clopromazin gy trng thi c bit th v tm thn vn ng: thuc khng c tc dng gy ng, tr vi liu gn c, nhng n lm gim cc hot ng vn ng v cc s bn tm, u t m vn gi c tng i cc hot ng v tr tu v s cnh gic. Liu rt cao cng khng gy hn m. Ngi dng thuc t ra khng quan tm n mi trng xung quanh, khng biu l xc cm, trong khi phn x tu v phn x khng iu kin vi kch thch au vn gi c. - Thuc lm gim c o gic, thao cung, vt v.

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Do , thuc c tc dng vi bnh tm thn phn lit. - Cloprozamin gy h i chng ngoi b thp, ging bnh Parkinson biu hin bng ng tc cng , tng trng lc. - H thn nhit do c ch trung tm iu nhit h khu no. - Chng nn do c ch trung tm nn sn no tht 4. - c ch trung tm trng lc giao cm iu ha vn mch. - Trn vn ng, liu cao gy trng thi gi nguyn th (catalepsia). 1.1.1.2. Trn h thng thn kinh thc vt Va c tc dng hu ph giao cm va c tc dng phong ta receptor a1 adrenergic ngoi bin. Tc dng hu ph giao cm th hin bng nhn m (ng t gin), to bn, gim tit dch v, gim tit nc bt, m hi. Tc dng ny rt t xy ra vi cc dn xut c nhn piperazin. Tc dng hu a1 - adrenergic tng i c ngha, c th phong ta tc dng tng p ca noradrenalin. V loi piperazin c tc dng an tm thn vi liu thp nn tc dng hu giao cm rt yu. 1.1.1.3. Trn h ni tit - Lm tng tit prolactin, gy chy sa v chng v to n ng. - Lm gim tit FSH v LH, c th gy c ch phng non v mt kinh. 1.1.1.4. C tc dng khng histamin H1, nhng yu. 1.1.2. Tng tc thuc - Clopromazin lm tng tc dng ca thuc ng, thuc m, thuc t, thuc gim au loi morphin, thuc h huyt p (nht l guanethidin, thuc c ch enzym chuyn angiotensin), ru. - Clopromazin i khng tc dng vi cc thuc kch thch thn kinh tm thn, c bit vi amphetamin v cc cht gy o gic. - Gia cc thuc an thn kinh, khng c tc dng hip ng tng mc, nhng v mt iu tr cc triu chng ca bnh tm thn, c th dng ph i hp trong thi gian ngn. 1.1.3. C ch tc dng Sinh l hc ca ho t ng thn kinh trung ng v sinh bnh hc ca ri lon tm thn (bnh tm thn phn lit) cn cha c bit r. Tuy nhin, ngi ta nhn thy rng s cn bng gia h dopaminergic trung ng v h serotoninergic trung ng c vai tr quyt nh n cc triu chng ca bnh tm thn phn lit. H dopaminergic (DA) trung ng Cc thuc cng h DA (amphetamin, cocain, DOPA) u lm tng triu chng bnh. Cc thuc hu h DA, c bit l cc receptor thuc nhm D2 (gm D2, D3, D4) nh thuc an thn kinh u lm gim cc biu hin ca bnh tm thn. H serotoninergic (5HT) trung ng C ti 15 loi receptor 5HT, nhng vi bnh tm thn th receptor 5HT2 (c bit l 5 HT2A) c vai tr quan trng hn c. Trong no, nhn tng hp 5HT nhiu nht (c th l duy nht) l cc nhn Raphe (Raphe nuclei). Cc nhn ny kim sot s tng hp DA

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c thn t bo v s gii phng DA trc xinap ca cc nron h DA. Nhn chung, 5HT c ch gii phng DA. Gi thuyt sinh ha v bnh tm thn phn lit cho rng cc triu chng dng tnh (hoang tng, o gic, kch ng, a nghi, tng t cao) l do tng hot h DA h vin v mt c ch iu ha ngc trung ng. Cn cc triu chc m tnh (cm xc cn mn, quan h km, v cm, t duy tru tng kh khn) l do ri lon chc phn vng trn trc, gim hot h DA no gia - v no do tng hot h 5HT2. Cc thuc an thn kinh c in (clorpromazin, haloperidol) c ch mnh D2 hn 5HT nhiu nn tc dng trn triu chng dng tnh mnh, t tc dng trn triu trng m tnh, mt khc, gy tc dng ph ngoi b thp. Cc thuc an thn mi (c nghin cu nhiu t thp k 80 ca th k 20 tr li y) u c c hai tc dng phong ta D2 v 5HT2A v c ch 5HT2A mnh hn D2 (risperidon) do ci thin c c triu chng m tnh v t gy triu chng ngoi b thp, cn vi triu chng dng tnh th tc dng nh thuc c in. Hin c olanzapin, risperidon... 1.1.4. Dc ng hc - Hp thu tt qua ng tiu ho. Nng cao hn 400mg/ml mu thng l c. - Thuc rt a m, gn nhiu vo protein huyt tng, tp trung no v t chc m, qua nhau thai d dng. Thi gian bn thi 20-40gi. Hiu lc sinh hc ca liu mt ln thng tn ti t nht l 24gi nn ch cn dng liu 1 ln m i ngy. - Chuyn ho ch yu gan qua qu trnh oxy ho, to cc cht chuyn ho hon ton mt hoc ch cn mt phn hot tnh. - Thi tr: ch yu qua nc tiu (dng tan trong nc, khng c hot tnh), phn khc qua mt (c chu k gan- rut) v ra phn. Thuc tn ti lu trong c th, sau khi ngng thuc 6-12 thng vn cn tm thy vt trong cht thi. 1.1.5. Tc dng khng mong mun 1.1.5.1. Loi thng gp, lin quan n tnh cht dc l ca thuc: - Ri lon tm l: chng mt m i, suy ngh chm chp, trng thi trm cm, l ln (nht l ngi c tui). - Tt huyt p khi ng v nhp tim nhanh, nht l khi tim. - Kh ming, nut kh, b i, ri lon iu tit th lc, cn tng nhn p cp, to bn... l nhng du hiu hu ph giao cm. - Ri lon iu tit v sinh dc: c ch phng non, v kinh, chy sa, gim tnh dc, tng cn. - Hi chng ngoi b thp: thay i tu thuc vo thi gian iu tr, vo liu lng, vo thuc phi hp, vo tui, gii... 1.1.5.2. Loi khng ph thuc vo tc dng dc l. - Gim bch cu. - Vng da tc mt, xut hin gia tun th 2 n th 4. Gim dn khi ngng thuc. C th do ph n cc ng dn mt do phn ng qu mn v khng ph thuc vo liu. - Phn ng ngoi da: d ng, mn cm vi nh nng, ng sc t trong tin phng ca mt. - Lon nhp tim: nhp nhanh xoang (iu tr bng propranolol), nh tht phn ly.

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- Hi chng st cao c tnh: st cao, da ti nht, m hi nh nhi, trng thi sc. Phi lm h i sc cp cu: gi thng bng nc v in gii. - Tai bin cht t ngt, thng xut hin sau khi tim. Cha r nguyn nhn.C th lin quan n huyt kh i, vim tc mch. 1.1.6. p dng lm sng Do c nhiu tc dng a dng, clopromazin c dng nhiu khoa: - Khoa tm thn: lon thn kinh, tm thn phn lp, thao cung, hoang tng, o gic. - Khoa sn: sn git (ch thuc qua c rau thai) - Khoa gy m: tin m, gy m h th nhit, h huyt p. - Khoa n i: chng nn, chng au, an thn, chng rung tim. - Khoa da liu: chng nga. - Ung 10- 25 mg/ ln 2- 4 ln/ ngy. Tim bp 25- 50 mg/ ln 2- 3 ln/ ngy. 1.2. Dn xut butyrophenon: Haloperidol Haloperidol (Haldol) l tiu biu cho nhm an thn kinh a nng (polyvalent neuroleptics) hay an thn kinh chng triu chng dng tnh (antiproductive), chng thao cung. V cu trc ho hc, haloperidol gn ging vi acid gamma-amin- butyric (GABA) l cht trung gian ho hc ca cc qu trnh c ch trong thn kinh trung ng. Tc dng an tm thn mnh l do c ch receptor dopaminergic trung ng v cng v vy tc dng khng mong mun, h i chng Parkinson cng r. 1.2.1. Ch nh - Cc trng thi thao cung, hoang t ng - Cc trng thi hong lon tm thn cp v mn, tm thn phn lp, paranoid (hoang tng c h thng). - Chng nn. Nn do dng thuc chng ung th, sau chiu x. 1.2.2. Cn thn trng - Khng dng chung vi thuc cng h dopaminergic (levodopa) v cc receptor ca h dopaminergic b haloperidol phong ta. Nu khi ang iu tr bng haloperidol m c du hiu ngoi b thp th dng thuc hu ph giao cm trung ng. - Dng cng vi thuc h huyt p c th gy tt huyt p khi ng. - Thn trng vi ngi li xe, ng my, v lc u iu tr c th gy ng g. 1.2.3. Tc dng khng mong mun Ging nh vi clopromazin, hay gp ng g, h i chng ngoi b thp, ri lon n i tit. 1.2.4. Liu lng ng 5mg/ml x 1-4 ng/ngy. Tim bp; Vin 5mg x 1-8 vin/ngy. 1.3. Dn xut benzamid: Sulpirid (Dogmatil) 1.3.1. Tc dng Sulpirid l i din cho nhm benzamid, l thuc an tm thn c tc dng lng cc (bipolar):

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- Liu 600mg c tc dng gii c ch chng triu chng m tnh, kch thch receptor sau xinap ca h dopaminergic trung ng. - Liu > 600mg c tc dng chng triu chng dng tnh (antiproductive), chng hoang tng v thuc kch thch receptor trc xinap ca h dopaminergic, lm gim gii phng dopamin. V vy, liu thp l cng v liu cao l hu h dopaminergic (trn cc receptor D4 trung ng). 1.3.2. Ch nh - Liu thp (di 600mg): tnh trng mt ngh lc, lon thn. - Liu cao (liu trn 600mg): cc ri lon tm thn cp tnh: tm thn phn lp, thao cung, o gic. 1.3.3. Tc dng khng mong mun - Ri lon n i tit v chuyn ha: tng tit sa, t ng cn. - Thn kinh: + Lon vn ng: vo c, cng hm, xoay mt (oculogyre). + Hi chng ngoi b thp. + Ng g. - Tim mch: tt huyt p khi ng. 1.3.4. Ch phm v liu lng Dogmatil vin 200mg, ng 2ml = 100mg - Chng suy sp, triu chng m tnh: 1-3 vin/ngy. - Chng triu chng dng tnh: 4-8 vin/ngy. - Trong lon thn cp v mn tnh, tim bp 200 - 800mg mt ngy, trong 2 tun lin. 1.4. Nhm benzisoxasol: Risperidon c im tc dng: i khng vi 5 HT2 vng trn trc ca v no nn c hiu qu iu tr cc triu chng m tnh ca tm thn phn lp. ng thi c tc dng i khng D2 vng no gia - h vin nn c hiu qu iu tr cc triu chng dng tnh. Risperidon gn vo 5HT2A khong 20 ln mnh hn vo D2. Vi liu iu tr (4-6 mg/ngy) rt t gy triu chng ngoi b thp. 2. THUC BNH THN (thuc an thn th yu) C nhiu tn gi: minor tranquillizers, anxiolytics, sedatives... hoc thuc an thn th yu, thuc bnh thn. Nhm thuc quan trng hng u l benzodiazepin. c im chung l c ch c bit trn h thng li hot ha i th h vin v cc nron kt hp ca tu sng. Do : - C tc dng an du (sedative), lm gim cnh gic, lm chm cc hot ng vn ng v lm du s bn chn.

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- C tc dng an thn gii lo (anxiolytic effects): lm gim cc phn ng xc cm thi qu v gim cng thng tm thn. - Ch c tc dng gy ng khi mt ng c lin quan n s lo u, bn chn. - t nh hng n h thn kinh thc vt nh nhm thuc an thn ch yu (loi clopromazin). - Chng co git. - Gin c lm gim trng lc c do tc dng trung ng. Benzodiazepin (BZD): l thuc i din cho nhm ny v rt thng dng. 2.1. Tc dng dc l 2.1.1. Trn thn kinh trung ng c 4 tc dng chnh - An thn, gii lo, gim hung hn. - Lm d ng: gim thi gian tim tng v tng thi gian gic ng nghch thng. Khc vi barbiturat l phn ln BZD khng c tc dng gy m khi dng liu cao. - Chng co git: clonazepam, nitrazepam, lorazepam, diazepam: do tnh cm th khc nhau ca cc vng, cc cu trc thn kinh v s cm th khc nhau ca cc loi vi cc dn xut m tc dng c khc nhau: c dn xut cn lm tng vn ng chut nht, chut cng, kh. Ring flurazepam li gy co git, nhng ch trn mo. - Lm gin c vn. Ngoi ra cn: . Lm suy yu k c c (retrograde amnesia) v lm tr ngi k c mi (anterograde amnesia). . Gy m: mt s t BZD c tc dng gy m nh diazepam, midazolam (tim t nh mch) . Liu cao, c ch trung tm h hp v vn mch. 2.1.2. Tc dng ngoi bin - Gin mch vnh khi tim t nh mch - Vi liu cao, phong ta thn kinh - c. 2.2. C ch tc dng BZD gn trn cc receptor c hiu vi n trn thn kinh trung ng. Bnh thng, khi khng c BZD, cc receptor ca BZD b mt protein n i sinh chim gi, lm cho GABA (trung gian ha hc c tc dng c ch trn thn kinh trung ng) khng gn vo c receptor ca h GABA-ergic, lm cho knh Cl ca nron khp li. Khi c mt BZD, do c i lc mnh hn protein ni sinh, BZD y protein ni sinh v chim li receptor, do GABA mi gn c vo receptor ca n v lm m knh Cl-, Cl- i t ngoi vo trong t bo gy hin tng u cc ha (hnh 12.1). Cc receptor ca BZD c lin quan v gii phu v chc phn vi receptor ca GABA.

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Hnh 12.1: C ch tc dng ca Benzodiazepin (BZD) Cc receptor ca BZD c nhiu trn thn kinh trung ng: v no, vng c nga, th vn, h khu no, hnh no, nhng c bit l h thng li, h vin v c tu sng. BZD tc dng gin tip l lm tng hiu qu ca GABA, tng tn s m knh Cl 2.3. Cc tc dng khng mong mun Khi nng trong mu cao hn liu an thn, t ti liu gy ng, c th gp: u oi, ng tc khng chnh xc, l ln, ming kh ng, gim tr nh. c tnh trn thn kinh t ng theo tui. V tm thn, i khi gy tc dng ngc: c mng, bn chn, lo lng, nhp tim nhanh, v m hi, sng khoi, o gic, hoang tng, mun t t. Quen thuc c th l do c ch tng chuyn ha hoc iu ha gim s lng cc receptor ca BZD trong no. t gy ph thuc v lm dng thuc, nhng sau mt t dng BZD ko di, c th gy mt ng tr li, lo lng, bn chn hoc co git. Mc du vy BZD vn l mt thuc an thn tng i an ton v ang c xu hng thay th dn thuc ng loi barbiturat. Thuc c t/2 cng ngn (triazolam t/2 = 3 gi), cng d gy nghin. 2.4. Dc ng hc Hp thu hu nh hon ton qua tiu ha, t nng ti a trong mu sau 30 pht n 8 gi. Gn vo protein huyt tng t 70% (alprazolam) n 99% (diazepam). Nng trong dch no tu gn tng ng nng dng t do trong mu. Thuc qua c rau thai v sa. c chuyn ho bi nhiu h enzym trong gan, thnh cc cht chuyn ho vn cn tc dng ri li b chuyn ho tip, nhng tc chm hn cho nn tc dng t lin quan n thi gian bn thi. Th d flurazepam c t/2 trong huyt tng l 2-3gi, nhng cht chuyn ho cn tc dng l N-desalkyl flurazepam cn tn ti trn 50 gi. Da theo t/2, cc Bzd c chia lm 4 loi: - Loi tc dng cc ngn, t/2 <3 gi c midazolam,triazolam. - Loi tc dng ngn, t/2 t 3-6 gi c, zolpidem (non-benzodiazepin) v zopiclon. - Loi tc dng trung bnh, t/2 t 6-24 gi c estazolam v temazepam. - Loi tc dng di, t/2 >24 gi c flurazepam, quazepam, diazepam. 2.5. p dng 2.5.1. An thn: liu trung bnh 24gi: Diazepam (Valium): 0,005-0,01g. Ung 2.5.2. Chng co git

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Diazepam (Valium): 0,010-0,020g. Tim bp, tnh mch Clorazepam (Tranxene): 0,010-0,020g. Ung 2.5.3. Gy ng, tin m Triazolam (Halcion): 0,125-0,250g. Ung: Mt ng u gic. Ung Midazolam (Versed): 0,025- 0,050. Tim bp, tnh mch- tin m. 2.5.4. Gin c, gim au do co tht: thp khp, ri lon tiu ho Diazepam (Valium): 0,010-0,020g. Ung, tim bp, tim t nh mch. Tetrazepam (Myolastan): 0,050-0,150g. Ung, tim bp, tim t nh mch. * Nguyn tc chung khi dng thuc: - Liu lng tu thuc tng ngi. - Chia liu trong ngy cho ph hp. - Dng gii hn tng thi gian ngn (1tun-3 thng) trnh ph thuc vo thuc. - Trnh dng cng vi cc thuc c ch thn kinh trung ng, ru, thuc ng, khng histamin. 2.6. Chng ch nh - Suy h hp, nhc c: do tc dng c ch thn kinh v gin c. - Suy gan: do thuc chuyn ho to cc cht c tc dng ko di, c th tng c tnh hoc gy c cho gan b suy. - Nhng ngi li t, lm vic trn cao, ng my chuyn ng. 2.7. Nhm thuc mi Do BZD cn mt s tc dng ph nn ang nghin cu mt nhm thuc an thn mi khng tc dng qua h GABA: buspirone, zolpidem (nhm imidazopiridin). Buspiron i din cho mt nhm thuc an thn mi: - c im dc l: . Lm mt lo u nhng khng gy an du, ng g hoc mt tr nh. . Khng i khng hoc hip ng vi cc thuc an thn hoc barbiturat khc. . Dng liu cao cng khng gy c ch thn kinh trung ng r. . Tc dng mnh trn cc triu chng tm l nh lo u, km tp trung t tng. Cn diazepam li c tc dng lm gin c v chng mt ng tt hn. . Nhc im: khi pht tc dng chm, km tc dng trn cn hong s. - C ch tc dng L cht ng vn vi receptor 5- HT 1A c nhiu h vin, h i hi m, no gia, i th, hnh- cu no, th vn, h khu no v tiu no. C ch cn ang nghin cu, nhng khng tc dng trn knh Cl- qua GABA nh BZD. - Tc dng khng mong mun: Chng mt, mt ng, bun nn, nhc u, au ngc, tai, lo u. Cn iu chnh liu. V l thuc mi, cn theo di thm.

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- ng hc Hp thu nhanh qua ng ung nhng c chuyn ha qua gan ln th nht do hydroxy ha v mt alkyl, tuy nhin li to ra nhiu cht chuyn ha cn hot tnh vo c thn kinh trung ng, c cht c tc dng phong ta c receptor a2. Thi gian bn thi l 2- 4 gi. Liu lng: vin 5- 10 mg (Buspar), dng t liu thp, 3 ln/ ngy. CU HI T LNG GI 1. Phn tch 3 c im c bn ca thuc an thn kinh (thuc an thn ch yu). 2. Phn tch c ch tc dng ca clorpromazin. 3. Trnh by cc p dng lm sng v tc dng khng mong mun ca clopromazin. 4. Trnh by tc dng v c ch tc dng ca benzodiazepin.

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Bi 13: THUC CHA NG KINH

MC TIU HC TP: Sau khi hc xong bi ny, sinh vin c kh nng: 1. Phn loi c thuc iu tr ng kinh theo cn v cc cch tc dng ca thuc cha ng kinh. 2. Trnh by c c ch tc dng, tc dng dc l v p dng iu tr ca cc thuc diphenylhydantoin, phenobarbital, carbamazepin v acid valproic. 3. Trnh by c nguyn tc dng thuc cha ng kinh. 1. I CNG Thuc cha ng kinh l nhng thuc c kh nng loi tr hoc lm gim tn s, mc trm trng ca cc cn ng kinh, hoc cc triu chng tm thn km theo bnh ng kinh, m khng gy ng. Thuc m v thuc ng cng c tc dng chng co git, nhng tc dng ny ch xut hin sau khi ngi bnh ng. Thuc chng ng kinh cng khng cng ngha vi thuc chng co git. 1.1. Phn loi cn ng kinh Cc cn ng kinh lun xut pht t v no v c phn loi thnh: - Cn ng kinh cc b: bt u t 1 trn v no v tu theo vng chc phn m th hin ra triu chng. Th d, v tr tn thng vng v no vn ng, s c triu chng git rung phn c th do vng v no y kim tra. Trong loi ny cn phn ra: . Cn cc b n gin, bnh nhn vn cn thc ko di khong 30-60 giy. . Cn cc b phc hp, c km theo mt thc, ko di khong 30 giy n 2 pht. - Cn ng kinh ton th: ngy t u lan rng ton b 2 bn cu i no. C th gp: . Khng c cn co git: bt cht mt thc khong 30 giy trong lc ang lm vic (ng kinh cn nh - petit mal). . Cn git rung c: co tht bt ng, ngn (khong 30 giy) c th gii hn mt chi, mt vng, hoc ton th. . Cn co cng - git rung ton c th (ng kinh cn ln - grand mal). 1.2. Phn loi thuc iu tr theo cn Loi ng kinh ng kinh cc b . Cc b n gin . Cc b phc hp Carbamazepin, phenytoin, phenobarbital, primidon, valproat Carbamazepin, phenytoin, phenobarbital, primidon, valproat Gabapentin Lamotrigin Gabapentin Lamotrigin Thuc thng thng Thuc mi

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ng kinh ton th . Khng cn co git . Cn git rung . Cn co cnggit rung Clonazepam, ethosuximid, valproat valproat Carbamazepin, phenobarbital, phenytoin, primidon, valproat Lamotrigin Lamotrigin Lamotrigin

1.3. Cch tc dng ca thuc cha ng kinh Cc thuc cha ng kinh c th tc ng theo mt trong ba c ch sau: - Lm tng dn truyn c ch ca h GABA- ergic - Lm gim dn truyn kch thch, thng l h glutamatergic. - Lm thay i s dn truyn ion qua mng nron do tc ng trn knh Na+ ph thuc in th, hoc knh Ca++ typ T. V c ch bnh sinh ca ng kinh cha c hon ton bit r cho nn cc thuc cha ng kinh ch c ch c cc triu chng ca bnh ch khng d phng v iu tr c bnh. Thuc phi c s dng lu di, d c nhiu tc dng khng mong mun. Do cn c gim st nghim ngt. 2. CC THUC CHNH Sau y ch trnh by nhng thuc c trong danh mc thuc thit yu Vit Nam ln th 5 (2005) 2.1. Dn xut hydantoin: Diphenylhydantoin (Phenytoin, Dilantin) Diphenylhydantoin l mt trong nhng thuc c tc dng tt cha m i th ng kinh, tr ng kinh th khng c cn co git. 2.1.1. Tc dng v c ch Phenytoin c tc dng chng cn ng kinh nhng khng gy c ch ton b h thn kinh trung ng. Liu c cn gy kch thch. Tc dng trn cn co git ng kinh cng ging phenobarbital, nhng khng gy an thn v ng. Phenytoin c tc dng n nh mng t bo thn kinh v c tim, lm gim lung Na+ trong hiu th hot ng trong kh cc do cc cht ha hc (c ch knh Na+ cm ng vi in th). 2.1.2. Dc ng hc Phenytoin l acid yu, c pKa = 8,3 tan trong nc km. Hp thu qua ng tiu ha chm v i khi khng hon ton. Nng ti a trong mu khi ung l t 3 - 12 gi. Gn vo protein huyt tng 90%. Nng trong thn kinh trung ng tng ng nng trong huyt tng. Phn ln chuyn ha gan v thi tr qua thn di dng lin hp, ch 5% di dng khng chuyn ha. Thi gian bn thi t 6-24 gi. 2.1.3. Tc dng khng mong mun

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- Da v nim mc: vim li qu sn, mn da, lupus ban . - Mu: thiu mu hng cu to do thiu acid folic (do thuc phong ta s hp thu acid folic ti rut), gim bch cu... - Tiu ha: nn, cn au bng cp. - Thn kinh-tm thn: lin quan n nng thuc trong mu: 20 mg/ml c tc dng iu tr. = 30 mg/ml lm rung git nhn cu. = 40 mg/ml gy mt phi hp ng tc. > 40 mg/ml gy ri lon tm thn. - Xng: ci xng hoc mm xng, c th l do ri lon chuyn ha vitamin D, nht l khi ph i hp vi phenobarbital. 2.1.4. Tng tc thuc Cloramphenicol, dicumarol, isoniazid, cimetidin c th lm tng nng ca phenytoin trong huyt tng do lm gim chuyn ha. Tri li, carbamazepin lm t ng chuyn ha nn lm gim nng phenytoin trong huyt tng. Salicylat, tolbutamid, sulfisoxazol tranh chp vi phenytoin v tr gn vo protein huyt tng. 2.1.5. p dng iu tr Phenytoin (Dihydan, Dilantin): vin nn 30-100mg; ng tim 50mg/ml. Liu u 35mg/kg (300mg/ngy). Theo di nng thuc trong mu, khi t c nng c tc dng, ngh 1 tun. Liu cao 300mg/ngy th khong cch gia cc t iu tr l 2 tun. C th dng liu 1 ln/ngy. Phenytoin tim tnh mch khng vt qu 50mg/pht, pha long trong NaCl 0,9% v thuc c pH base, kch thch. Khng tim bp, gy tn thng t chc. 2.2. Phenobarbital (Gardenal, Luminal) Phenobarbital thuc nhm barbiturat (xem bi thuc ng), l thuc u tin dng iu tr ng kinh (1912). Khc vi barbiturat khc, phenobarbital c tc dng chng cc cn co git ca ng kinh ngay c vi nhng liu cha gy an thn hoc ng. Thuc gii hn c s lan truyn ca cn co git v nng c ngng kch thch gy co git. Phenobarbital v c pentobarbital tc dng trn receptor GABA-A lm tng qu trnh c ch. Ngoi ra cn chn knh Ca++ trc xinap nn lm gim gii phng cc cht dn truyn thn kinh, c bit l glutamat nn lm gim mnh cc qu trnh kch thch trn thn kinh trung ng. V t c v gi r nn tng i c dng rng ri, nhng c nhc im l gy an thn, ng g v c xu hng lm ri lon hnh vi ca tr em nn cn thn trng. Liu lng: ung 0,1 - 0,3 g/ngy (1 - 5 mg/kg). Khng ngng thuc t ngt trnh trng thi ng kinh lin tc. 2.3. Dn xut Iminostilben: Carbamazepin 2.3.1. Tc dng v c ch Tuy trn ng vt thc nghim v ngi, carbamazepin c nhiu im gi ng nh phenytoin, nhng:

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- Tc dng chng cn co git gy ra bi pentylentretazol li mnh hn. - C tc dng iu tr bnh nhn b hng trm cm, k c nhng trng hp lithium khng cn tc dng. - C tc dng chng bi niu do lm gim nng ADH huyt tng. Cc c ch ny u cha r. Cc dn xut iminostilben cng c ch knh Na+ nh phenytoin. 2.3.2. Dc ng hc Carbamazepin c hp thu chm qua ng tiu ha, nng ti a trong mu t c sau 4-8 gi v gi c ti 24 gi. Gn vo protein huyt t ng 75% v phn ph i vo m i m. Nng trong dch no tu tng ng vi dng t do trong huyt tng. B chuyn ha gan, cho 10- 11 epoxid vn cn hot tnh. Di 3% thi qua thn di dng khng i. Thi gian bn thi t 10 n 20 gi. Dng cng vi phenobarbital hoc phenytoin, thi gian bn thi gim cn 9-10 gi. 2.3.3. Tc dng khng mong mun - Thng gp: ng g, chng mt, nhn la, mt ng tc, bun nn, nn. - Ngoi ra, c th gp: ri lon to mu, tn thng nng ngoi da, vim gan mt, suy thn cp, suy tim. V vy, trong qu trnh iu tr cn kim tra cc chc phn trn. - Phn ng d ng. 2.3.4. p dng lm sng - Ch nh: . Cn ng kinh th tm thn vn ng. . Cn co git cng hoc git rung cc b hoc ton thn. . Tc dng gim au c hiu trong vim dy thn kinh tam thoa. - Ch phm: Carbamazepin (Tegretol) vin nn 100-200mg. Liu u 200mg x2 ln/ngy. Tng dn liu ti 600-1200mg. Tr em 20-30mg/kg. Nn chia liu hng ngy lm 3 4 ln gi c nng hng nh trong mu. 2.4. Acid valproic 2.4.1. Tc dng dc l v c ch - Tc dng trn mi loi ng kinh. - Rt t tc dng an thn v tc dng ph. - Cc gi thit hin nay u cho rng valproat c ch knh Na+ nhy cm vi in th (MacDonald, 1988) v lm tng tch lu GABA (Lscher, 1985). Nhng tc dng ging vi tc dng ca phenytoin v carbamazepin. Ngoi ra cn lm gim dng Ca++ qua knh. 2.4.2. Dc ng hc Hp thu nhanh v hon ton qua tiu ha. Nng ti a trong huyt tng t c sau 1-4 gi. Gn vo protein huyt tng 90%. Nng trong dch no tu tng ng trong huyt tng. Hu nh hon ton b chuyn ha gan, trong c mt cht chuyn ha 2propyl-2-pentanoic acid vn cn hot tnh nh cht m. Thi gian bn thi l 15 gi.

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2.4.3. Tc dng khng mong mun - Khong 16% c cc triu chng chn n, bun nn, nn, au vng thng v. - Khi dng liu cao 7-30 mg/kg c th gp vim gan cp, vim tu , an thn, run, hi, gim prothrombin. 2.4.4. p dng lm sng - Ch nh: ng kinh cc loi, c bit l th khng c cn co git. - Ch phm: Acid valproic (Depakin): vin bc ng 250mg; sir 5ml c 250mg hot cht. Liu u 15mg/kg, t ng dn hng tun 5 - 10mg/kg cho ti 60mg/kg. Nng iu tr trong mu t 30 n 100mg/ml. 3. NHNG VN TRONG S DNG THUC 3.1. Nguyn tc dng thuc - Ch dng thuc khi c chn on lm sng chc chn. - Lc u ch dng mt thuc. - Cho liu t thp tng dn, thch ng vi cc cn. - Khng ngng thuc t ngt. - Phi m bo cho bnh nhn ung u hng ngy, khng qun. - Cm ung ru trong qu trnh dng thuc. - Ch i thi hn nh gi hiu qu ca iu tr: . Vi ngy vi ethosuximid, benzodiazepin . Hai ba tun vi phenobarbital, phenytoin . Vi tun vi valproic acid. - Hiu r cc tc dng ph, tc dng khng mong mun ca tng thuc theo di kp thi. - Nu c th, kim tra nng ca thuc trong mu khi cn. 3.2. iu tr ng kinh v thai nghn T l thai nhi c d dng hoc t vong ngi m c ng kinh c iu tr cao hn ngi bnh thng 2 - 3 ln. Cc cn ng kinh cng thng tng ln khi c thai, c th do nng thuc trong huyt tng gim. Khi c thai vn khng c ngng thuc, tuy nhin, tu theo tng trng hp, c th gim liu, nht l trong 3 thng u. Tr mi nhng ngi m iu tr bng phenobarbital, primidon hoc phenytoin c th gp tai bin chy mu do thiu vitamin K, cn b sung d phng trc bng vitamin K. CU HI T LNG GI 1. Phn loi cc thuc iu tr ng kinh theo cn v trnh by cc cch tc dng ca thuc cha ng kinh ni chung.

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2. Trnh by tc dng v p dng iu tr ca dn xut hydantoin (Phenytoin) v phenobarbital trong iu tr ng kinh. 3. Phn tch tc dng iu tr v tc dng khng mong mun ca carbamazepin v acid valproic.

PHN IV HA HC TR LIU Bi 14: THUC KHNG SINH KHNG KHUN MC TIU HC TP: Sau khi hc xong bi ny, sinh vin c kh nng: 1. Pht biu c nh ngha khng sinh, tc dng km khun v dit khun 2. Trnh by c c ch tc dng, p dng iu tr v phn loi ca nhm lactam 3. Nu c c ch tc dng, p dng iu tr v c tnh ca nhm aminoglycosid 4. Trnh by c c ch tc dng, c tnh v p dng iu tr ca khng sinh nhm cloramphenicol, tetracyclin, lincosamid & macrolid, quinolon- 5- nitro- imidazol, dn xut nitrofuran v sulfamid. 5. Trnh by c nhng nguyn tc s dng khng sinh an ton v hp l 6. Phn tch c nhng nguyn nhn gy tht bi trong vic dng khng sinh v cch khc phc 1. I CNG 1.1. nh ngha

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K nguyn hin i ca ha tr liu khng khun c bt u t vic tm ra sulfonamid (Domagk, 1936), "Thi k vng son" ca khng sinh bt u t khi sn xut penicilin dng trong lm sng (1941). Khi , "khng sinh c coi l nhng cht do vi sinh vt tit ra (vi khun, vi nm), c kh nng km hm s pht trin ca vi sinh vt khc". V sau, vi s pht trin ca khoa hc, ngi ta - C th tng hp, bn tng hp cc khng sinh t nhin (cloramphenicol) - Tng hp nhn to cc cht c tnh khng sinh: sulfamid, quinolon - Chit xut t vi sinh vt nhng cht dit c t bo ung th (actinomycin) V th nh ngha khng sinh c thay i: "Khng sinh l nhng cht do vi sinh vt tit ra hoc nhng cht ha hc bn tng hp, tng hp, vi nng rt thp, c kh nng c hiu km hm s pht trin hoc dit c vi khun" 1.2. C ch tc dng ca khng sinh S di y ch r v tr v c ch tc dng chnh ca cc khng sinh trn vi khun:

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Hnh 14.2. Cc khng sinh c ch qu trnh tng hp protei

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1. c ch to cu peptid (Cloramphenicol) 2. Ngn cn chuyn ng chuyn on ca ribosom theo ARNm (Erythromycin) 3. Ngn cn s gn kt ca ARNt vo phc hp ribosom ARNm (Tetracyclin) 4. Lm thay i hnh dng 30S m ha trn ARNm nn c nhm (Streptomycin) Hnh 14.3. V tr tc dng ca khng sinh c ch tng hp protein 1.3. Ph khng khun Do khng sinh c tc dng theo c ch c hiu nn m i khng sinh ch c tc dng trn mt s chng vi khun nht nh, gi l ph khng khun ca khng sinh 1.4. Tc dng trn vi khun Khng sinh c ch s pht trin ca vi khun, gi l khng sinh km khun; khng sinh hu hoi vnh vin c vi khun g i l khng sinh dit khun. Tc dng km khun v dit khun thng ph thuc vo nng Nng dit khun ti thiu (MBC) T l Nng km khun ti thiu (MIC) Khi t l > 4, khng sinh c tc dng km khun. Kh t l gn bng1, khng sinh c xp vo loi dit khun. 1.5. Phn loi Cc khng sinh c phn loi theo cu trc ha hc, t chng c chung mt c ch tc dng v ph khng khun tng t. Mt khc, trong cng mt h khng sinh, tnh cht dc ng hc v s dung np thng khc nhau, v c im v ph khng khun cng khng hon ton ging nhau, v vy cng cn phn bit cc khng sinh trong cng mt h

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Mt s h (hoc nhm) khng sinh chnh: - Nhm b lactam (cc penicilin v cc cephalosporin) - Nhm aminosid hay aminoglycosid - Nhm cloramphenicol - Nhm tetracyclin - Nhm macrolid v lincosamid - Nhm quinolon - Nhm 5- nitro- imidazol - Nhm sulfonamid 2. CC KHNG SINH CHNH 2.1. Nhm b lactam V cu trc u c vng b lactam (H ) V c ch u gn vi transpeptidase (hay PBP: Penicilin Binding Protein), enzym xc tc cho s ni peptidoglycan to vch vi khun. Vch vi khun l b phn rt quan trng m bo s tn ti v pht trin. Thnh phn m bo cho tnh bn vng c hc ca vch l mng li peptidoglycan, gm cc chu i glycan ni cho vi nhau bng chu i peptid. Khong 30 enzym ca vi khun tham gia tng hp peptidoglycan, trong c transpeptidase (hay PBP). Cc b lactam v khng sinh lo i glycopeptid (nh vancomycin) to phc bn vng v i transpeptidase, c ch to vch vi khun, lm ly gii hoc bin dng vi khun. Vch vi khu n gram (+) c mng li peptidoglycan dy t 50- 100 phn t, li ngay b mt t bo nn d b tn cng. Cn vi khun gram (-) vch ch dy 1- 2 phn t nhng li c che ph lp ngoi cng mt v bc lipopolysaccharid nh 1 hng ro khng thm khng sinh, mun c tc dng, khng sinh phi khuch tn c qua ng dn (pores) ca mng ngoi nh amoxicilin, mt s cephalosporin. Do vch t bo ca ng vt a bo c cu trc khc vch vi khun nn khng chu tc ng ca lactam (thuc hu nh khng c). Tuy nhin vng lactam rt d gy d ng. Cc khng sinh b lactam c chia thnh 4 nhm da theo cu trc ha hc - Cc penam: vng A c 5 cnh bo ha, gm cc penicilin v cc cht phong ta lactamase. - Cc cephem: vng A c 6 cnh khng bo ha, gm cc cephalosporin. - Cc penem: vng A c 5 cnh khng bo ha, gm cc imipenem, ertapenem. - Cc monobactam: khng c vng A, l khng sinh c th tng hp nh aztreonam.

Penam (vng A c 5 cnh bo ha)

Cephem (Vng A c 6 cnh, khng bo ha)

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2.1.1.1. Penicilin G L nhm thuc tiu biu, c tm ra u tin. * Ngun gc v c tnh l ha

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Trong sn xut cng nghip, ly t Penicillium notatum, 1 mL mi trng nu i cy cho 300 UI; 1 n v quc t (UI)= 0,6 mg Na benzylpenicilin hay 1.000.000 UI = 0,6g. Penicilin G l dng bt trng, vng bn nhit thng, nhng dung dch nc, phi bo qun lnh v ch vng bn pH 6- 6,5, mt tc dng nhanh pH < 5 v > 7,5 * Ph khng khun - Cu khun Gr (+); lin cu (nht l loi b tan huyt), ph cu v t cu khng sn xut penicilinase. - Cu khun Gr (-): lu cu, mng no cu - Trc khun Gr (+) i kh (than, subtilis, bch cu) v ym kh (clostridium hoi th sinh hi) - Xon khun, c bit l xon khun giang mai (treponema pallidum) * Dc ng hc - Hp thu: b dch v ph hu nn khng ung c. Tim bp, nng ti a t c sau 15- 30 pht, nhng gim nhanh (cn tim 4h/ ln). Tim bp 500.000 UI, pic huyt thanh 10 UI/ mL. - Phn ph i: gn vo protein huyt tng 40- 60%. Kh thm vo xng v no. Khi mng no vim, nng trong dch no tu bng 1/ 10 huyt t ng. Trn ngi bnh thng, t/2 l khong 30 - 60 pht. - Thi tr: ch yu qua thn di dng khng hot tnh 60- 70%, phn cn li vn cn hot tnh. Trong gi u, 60- 90% thi tr qua nc tiu, trong 90% qua bi xut ng thn (mt s acid hu c nh probenecid c ch qu trnh ny, lm chm thi tr penicilin) * c tnh Penicilin rt t c, nhng so vi thuc khc, t l gy d ng kh cao (1- 10%), t phn ng rt nh n t vong do chong phn v. C d ng cho vi m i b lactam v cephalosporin. * Ch phm, liu lng - Penicilin G l bt, pha ra dng ngay. Liu lng tu theo tnh trng nhim khun, t 1 triu n 50 triu UI/ 24h chia 4 ln, tim bp hoc truyn t nh mch (pH dch truyn 6- 7). Tr em trung bnh cho 100.000 UI/ kg/ 24 h - Penicilin c ph G, tc dng ko di: kt hp vi cc mu i t tan v chm hp thu s ko di c tc dng ca penicilin G: . Bipenicilin (natri benzylpenicilinat + procain benzylpenicilinat): m i ngy tim 1 ln, khng dng cho tr em. . Extencilin (benzathin penicilin): tim bp 1 ln, tc dng ko di 3- 4 tun. Dng iu tr lu, giang mai v d phng thp khp cp ti nhim - l 600.000, 1.000.000 v 2.400.000 UI - Penicilin c ph G, ung c Penicilin V (Oracilin, Ospen): khng b dch v ph hy, hp thu t trng, nhng phi dng liu gp i penicilin G mi t c nng huyt thanh tng t. Cch 6h/ ln. 2.1.1.2. Penicilin khng penicilinase: Methicilin L penicilin bn tng hp Ph khng khun v thi gian tc dng tng t penicilin G, nhng cng tc dng th yu hn. Tim bp hoc tnh mch 2- 8 g/ 24h chia lm 4 ln. Khng ung dc Mt s thuc khc vng bn vi dch v, ung c: oxacilin (Bristopen), cloxacilin (Orbenin): ung 2- 8g mt ngy chia lm 4 ln

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Ch nh tt trong nhim t cu sn xut penicilinase (t cu vng) C th gp vim thn k, c ch ty xng liu cao 2.1.1.3. Penicilin c ph rng Ampicilin, amoxicilin L penicilin bn tng hp, amino- benzyl penicilin c mt s c im: - Trn cc khun Gr (+) tc dng nh penicilin G, nhng c thm tc dng trn mt s khun gram (-): E. coli, salmonella, Shigella, proteus, hemophilus influenzae - B penicilinase ph hu - Khng b dch v ph hy, ung c nhng hp thu khng hon ton (khong 40%). Hin c nhiu thuc trong nhm ny c t l hp thu qua ng ung cao (nh amoxicilin ti 90%) nn nhiu nc khng cn dng ampicilin na - Liu lng: Amoxicilin (clamoxyl, Oramox) Ung: 2- 4 g/ ngy. Tr em 50 mg/ kg/ ngy. Chia 4 ln - Ch nh chnh: vim mng no m, thng hn, nhim khun ng mt, tit niu, nhi m khun s sinh. 2.1.1.4. Cc penicilin khng trc khun m xanh: Carboxypenicilin v ureidopenicilin. L nhm khng sinh quan trng c dng iu tr cc nhim khun nng do trc khun gram (-) nh trc khun m xanh, Proteus, Enterobacter, vi khun khng penicilin v ampicilin. Thng l nhim khun mc phi ti bnh vin, nhim khun sau bng, nhi m khun tit niu, vim phi. Cc khng sinh ny u l bn tng hp v vn b penicilinase ph hu. - Carbenicilin, ticarcilin: ung 2- 20g/ ngy. - Ureidopenicilin: . Mezlocilin: 5- 15g/ ngy. Tim bp, truyn tnh mch. . Piperacilin: 4- 18g/ ngy. Tim bp, truyn tnh mch. 2.1.2. Cc cephalosporin c chit xut t nm cephalosporin hoc bn tng hp, u l dn xut ca acid amino- 7cephalosporanic, c mang vng b lactam. Tu theo tc dng khng khun, chia thnh 4 "th h" 2.1.2.1. Cephalosporin th h 1: C ph khng khun gn vi meticilin v penicilin A. Tc dng tt trn cu khun v trc khun gram (+), khng c penicilinase ca t cu. C tc dng trn mt s trc khun gram (-), trong c cc trc khun ng rut nh Salmonella, Shigella. B cephalosporinase (b lactamase) ph hu. Ch nh chnh: sc nhim khun, nhim khun huyt do t cu, nhim khun khng penicilin. Cc ch phm dng theo ng tim (bp hoc tnh mch) c: cefalotin (Kezlin), cefazolin (Kefzol), liu 2- 8g/ ngy Theo ng ung c cefalexin (Keforal), cefaclor (Alfatil), liu 2g/ngy.

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khc phc 2 nhc im: t tc dng trn vi khun gram (-) v vn cn b cephalosporinase ph, cc th h cephalosporin tip theo v ang c nghin cu sn xut. 2.1.2.2. Cephalosporin th h 2: Hot tnh khng khun trn gram (-) tng, nhng cn km th h 3. Khng c cephalosporinase. S dung np thuc cng tt hn. Ch phm tim: cefamandole (Kefandol), cefuroxim (Curoxim) liu 3- 6 g/ ngy. Ch phm ung: cefuroxim acetyl (Zinnat) 250 mg 2 ln/ ngy. 2.1.2.3. Cephalosporin th h 3 Tc dng trn cu khun gram (+) km th h 1, nhng tc dng trn cc khun gram (-), nht l trc khun ng rut, k c chng tit b lactamase th mnh hn nhiu. Cho ti nay, cc thuc nhm ny hu ht u l dng tim: Cefotaxim (Claforan), ceftizoxim (Cefizox), ceftriaxon (Rocephin), liu t 1 n 6g/ngy, chia 3- 4 ln tim. 2.1.2.4. Cephalosporin th h 4. Ph khng khun rng v vng bn vi b lactamase hn th h 3, c bit dng ch nh trong nhim trc khun gram (-) hiu kh khng vi th h 3. Ch phm: cefepim, tim t/ m 2g 2 ln/ ngy. 2.1.3. Cc cht c ch b lactamase (cu trc Penam) L nhng cht c tc dng khng sinh yu, nhng gn khng h i phc vi b lactamase v c i lc vi b lactam, cho nn khi ph i hp vi khng sinh nhm b lactam s lm vng bn v tng cng hot tnh khng khun ca khng sinh ny. Hin c cc ch phm sau: Cht (-) b lactamase Acid clavulinic Khng sinh phi hp Amoxicilin Bit dc - Augmentin: vin nn 250, 500 mg, l 500 mg, 1g tim t nh mch - Timentin Ticarcilin Sulbactam Tazobactam 2.1.4. Cc penem Imipenem Thuc nhm carbapenem, trong cng thc vng A thay S bng C. Ph khng khun rt rng, gm cc khun i kh v k kh: lin cu, t cu (k c chng tit penicilinase), cu khun rut (enterococci), pseudomonas. Ampicilin Piperacilin Unasyn: vin nn 220 mg ng tim 500- 1000 mg Zosyn

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c dng trong nhim khun sinh dc- tit niu, ng h hp di, m mm, xngkhp, nhim khun bnh vin. Khng hp thu qua ng ung. Ch tim t nh mch liu 1- 2g/ ngy. Ertapenem Ph khng khun nh imipenem, nhng mnh hn trn gram (-). Tim bp hoc truyn t nh mch 1g/ ngy. 2.1.5. Monobactam Aztreonam Km tc dng trn khun gram (+) v k kh. Tri li, tc dng mnh trn khun gram (-), tng t cephalosporin th h 3 hoc aminoglycosid. Khng b lactamase. Khng tc dng theo ng ung. Dung np tt, c th dng cho bnh nhn d ng v i penicilin hoc cephalosporin. Tim bp 1- 4 g/ ngy. Trng hp nng, tim tnh mch 2g, cch 6- 8 gi/ ln. 2.1.6. Thuc khc cng c ch tng hp vch vi khun: Vancomycin Khng sinh c ngun gc t Streptococcus orientalis. C ch tc dng: c ch transglycosylase nn ngn cn ko di v t o li peptidoglycan. Vi khun khng to c vch nn b ly gii. Vancomycin l khng sinh dit khun. Tc dng: ch dit khun gram (+): phn ln cc t cu gy bnh, k c t cu tit b lactamase v khng methicilin. Hip ng vi gentamycin v streptomycin trn enterococcus. ng hc: c hp thu rt t qua ng tiu ha nn ch c dng iu tr vim rut kt gi mc cng vi tetracyclin, clindamycin. Tim truyn t nh mch, gn vi protein huyt tng khong 55%, thm vo dch no tu 7- 30% nu c vim mng no, trn 90% thi qua lc cu thn (khi c vim thn phi gim liu). Thi gian bn thi khong 6 h. Ch nh chnh: vim mng trong tim do t cu khng methicilin, cho bnh nhn c d ng penicilin. Liu lng 1g 2 ln/ ngy. Tc dng khng mong mun: ch khong 10% v nh. Thng gp l kch ng vim tnh mch ti ch tim truyn, rt run, st, c vi dy VIII. Nng truyn nn gi t 5- 15 mg/ mL (di 60 mg/ mL) th trnh c tc dng ph. Ch phm: Vancomycin (Vancocin, Vancoled): l bt ng kh pha dch tim truyn 500 mg v 1,0g. 2.2. Nhm aminosid hay aminoglycosid u ly t nm, cu trc ha hc u mang ng (ose) v c chc amin nn c tn aminosid. Mt s l bn tng hp. C 4 c tnh chung cho c nhm: - Hu nh khng hp thu qua ng tiu ha v c PM cao. - Cng mt c ch tc dng - Ph khng khun rng. Dng ch yu chng khun hiu kh gram (-). - c tnh chn lc vi dy thn kinh VIII v vi thn (tng creatinin mu, protein - niu. Thng phc h i) Thuc tiu biu trong nhm ny l streptomycin. Ngoi ra cn: Neomycin, kanamycin, amikacin, gentamycin, tobramycin. 2.2.1. Streptomycin

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2.2.1.1. Ngun gc v c tnh Ly t nm streptomyces griseus (1944). Thng dng di dng mu i d tan, vng bn nhit di 250C v pH = 3- 7. 2.2.1.2. C ch tc dng v ph khng khun Sau khi nhp vo vi khun, streptomycin gn vo tiu phn 30 s ca ribosom, lm vi khun c sai m thng tin ARNm, tng hp protein b gin on. C tc dng dit khun trn cc vi khun phn chia nhanh, ngoi t bo hn l trn vi khun phn chia chm. pH t i u l 7,8 (cho nn cn alcali (kim) ha nc tiu nu iu tr nhim khun tit niu) Ph khng khun rng, gm: - Khun gram (+): t cu, ph cu, lin cu (c tc dng hip ng vi khng sinh nhm b lactam) - Khun gram (-): Salmonella, Shigella, Haemophilus, Brucella. - Xon khun giang mai - L khng sinh hng u chng trc khun lao (BK) Vi khun khng streptomycin: khun k kh, trc khun m xanh v mt s nm bnh. 2.2.1.3. Dc ng hc - Hp thu: ung, b thi tr hon ton theo phn. Tim bp, hp thu chm hn penicilin, nhng gi c lu hn nn ch cn tim m i ngy 1 ln. Gn vo protein huyt tng 3040%. - Phn ph i: do tan nhiu trong nc v b ion ha pH huyt tng, streptomycin kh thm ra ngoi mch. Gn nhiu hn vo thn, c, ph i, gan. Nng trong mu thai nhi bng 1/2 nng huyt tng. t thm vo trong t bo (khng dit c BK trong i thc bo nh isoniazid). Khng qua c hng ro mu no. - Thi tr: khong 85- 90% liu tim b thi tr qua lc cu thn trong 24h. 2.2.1.4. c tnh - Dy VIII rt d b tn thng, nht l khi iu tr ko di v c suy thn. c tnh on tin nh thng nh v ngng thuc s kh i, cn c on c tai c th gy ic vnh vin k c ngng thuc. Dihydrostreptomycin c t l c cho c tai cao hn nn khng cn c dng na. - c vi thn v phn ng qu mn t gp. C th thy vim da do tip xc y t (ng i tim thuc). - C tc dng mm c kiu cura nn c th gy ngng h hp do lit c h hp v dng streptomycin sau phu thut c gy m. Khng dng cho ngi nhc c v ph n c thai. 2.2.1.5. Cch dng: Do c tnh nn ch gii hn ginh cho cc nhim khun sau: - Lao: phi hp vi 1 hoc 2 khng sinh khc (xem bi " thuc chng lao") - Mt s nhim khun tit niu, dch hch, brucellose: ph i hp vi tetracyclin - Nhim khun huyt nng do lin cu: ph i hp vi penicilin G. L sulfat streptomycin 1g. Liu thng thng tim bp 1g/ ngy. Trong iu tr lao, tng liu khng qu 80- 100g.

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2.2.2. Cc aminosid khc - Kanamycin: Tc dng, dc ng hc v c tnh tng t nh streptomycin. Thng dng ph i hp (thuc hng 2) trong iu tr lao. Liu 1g/ ngy (xem bi" thuc chng lao") - Gentamycin: Ph khng khun rt rng. L thuc c chn la cho nhim khun bnh vin do Enterococcus v Pseudomonas aeruginosa. Dng ph i hp vi penicilin trong st gim bch cu v nhim trc khun gram (-) nh vim n i tm mc, nhim khun huyt, vim tai ngoi c tnh. Gentamycin sulfat ng trong ng 160, 80, 40 v 10 mg. Liu hng ngy l 3- 5 mg/ kg, chia 2- 3 ln/ ngy, tim bp. - Amikacin: L thuc c ph khng khun rng nht trong nhm v khng c cc enzym lm mt hot aminoglycosid nn c vai tr c bit trong nhim khun bnh vin gram (-) khng v i gentamycin v tobramycin. Liu lng mt ngy 15 mg/ kg tim bp hoc tnh mch 1 ln, hoc chia lm 2 ln. ng 500 mg. - Neomycin: Thng dng di dng thuc bi iu tr nhim khun da- nim mc trong bng, vt thng, vt lot v cc bnh ngoi da b i nhim. Dng neomycin n c hoc ph i hp v i polymyxin, bacitracin, khng sinh khc hoc corticoid. 2.3. Cloramphenicol v dn xut 2.3.1. Ngun gc v tnh cht l ha Phn lp t nm Streptomyces venezualae (1947) v ngay sau tng hp c . L bt trng, rt ng, t tan trong nc, vng bn nhit thng v pH t 2- 9, v th c th ung c. 2.3.2. C ch tc dng v ph khng khun Cloramphenicol c tc dng km khun, gn vo tiu phn 50s ca ribosom nn ngn cn ARNm gn vo ribosom, ng thi c ch transferase nn acid amin c m ha khng gn c vo polypeptid. Cloramphenicol cng c ch tng hp protein ca ty th t bo ng vt c v (v ribosom ca ty th cng l loi 70s nh vi khun), hng cu ng vt c v c bit nhy cm v i cloramphenicol. Ph khng khun rt rng: phn ln cc vi khun Gram (+) v Gram (-), xon khun, tc dng c hiu trn thng hn v ph thng hn. 2.3.3. Dc ng hc - Hp thu: sau khi ung, nng ti a trong mu t c sau 2 gi, t/ 2 t 1,5- 3 gi, khong 60% gn vo protein huyt tng. - Phn ph i: thm d dng vo cc m, nht l cc hch mc treo, nng t c cao hn trong mu (rt tt cho iu tr thng hn). Thm tt vo dch no tu nht l khi mng no b vim, c th bng nng trong mu. Qua c rau thai. - Chuyn ha: phn ln b mt hot tnh do qu trnh glycuro- hp gan hoc qu trnh kh.

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- Thi tr: ch yu qua thn, 90% di dng chuyn ha. 2.3.4. c tnh Hai c tnh rt nguy him: - Suy ty: . Loi ph thuc vo liu: khi liu cao qu 25 mg/ mL c th thy sau 5- 7 ngy xut hi n thiu mu nng, gim mnh hng cu li, bch cu, hng cu non. Liu ung 0,5g s c pic huyt thanh 6- 10 mg/ mL . Loi khng ph thuc liu, thng do c ng: gim huyt cu ton th do suy tu thc s, t l t vong t 50- 80% v tn xut mc t 1: 150.000 n 1: 6.000 - Hi chng xm (grey baby syndrome) gp nh nhi sau khi dng liu cao theo ng tim: nn, au bng, tm ti, mt nc, ngi mm nhn, try tim mch v cht. l do gan cha trng thnh, thuc khng c kh c bng qu trnh glycuro- hp v thn khng thi tr kp cloramphenicol. - Ngoi ra, bnh nhn thng hn nng, dng ngay liu cao cloramphenicol, vi khu n cht gii phng qu nhiu n i c t c th gy try tim mch v t vong. V vy, duy nht trong trng hp thng hn nng phi dng t liu thp. 2.3.5. Tng tc thuc Cloramphenicol c ch cc enzym chuyn ha thuc gan nn ko di t/2 v lm tng nng huyt tng ca phenytoin, tolbutamid, warfarin... 2.3.6. Ch phm v cch dng V c c tnh nng nn phi cn nhc trc khi dng cloramphenicol. Ch dng cloramphenicol khi khng c thuc tc dng tng ng, km c hn thay th. - Thng hn v nhim salmonella ton thn trc y l ch nh tt ca cloramphenicol. Nay khng dng na v c thay bng cephalosporin th h 3 (ceftriaxon) hoc fluoroquinolon. - Vim mng no do trc khun gram (-) (H. influenzae) l ch nh tt v cloramphenicol d thm qua mng no. Cng c th thay bng cephalosporin th h 3. - Bnh do xon khun Rickettsia: Tetracyclin l ch nh tt nht. Nhng khi tetracyclin c chng ch nh th thay bng cloramphenicol. Liu lng: ung t 25- 50 mg/ kg/ 24h. Chia lm 4- 6 ln. Khng dng cho ngi suy gan nng. - Thiophenicol (thiamphenicol): ch phm tng hp, nhm NO2 trong cloramphenicol c thay bng CH3 - SO2 - . c tnh t hn, d dung np, nhng tc dng cng km hn, v v y liu dng gp 2 ln cloramphenicol. Khng dng cho ngi suy thn nng. 2.4. Nhm tetracyclin 2.4.1. Ngun gc v tnh cht l ha u l khng sinh c 4 vng 6 cnh, ly t Streptomyces aureofaciens (clotetracyclin, 1947), hoc bn tng hp. L bt vng, t tan trong nc, tan trong base hoc acid. 2.4.2. C ch tc dng v ph khng khun Cc tetracyclin u l khng sinh km khun, c ph khng khun rng nht trong cc khng sinh hin c. Cc tetracyclin u c ph tng t, tr minocyclin: mt s chng khng v i tetracyclin khc c th vn cn nhy cm vi minocyclin.

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Tc dng km khun l do gn trn tiu phn 30s ca ribosom vi khun, ngn cn RNAt chuyn acid amin vo v tr A trn phc hp ARNm- riboxom to chui polypeptid. Tc dng trn: . Cu khun gram (+) v gram (-): nhng km penicilin . Trc khun gram (+) i kh v ym kh . Trc khun gram (-), nhng proteus v trc khun m xanh rt t nhy cm . Xon khun (km penicilin), rickettsia, amip, trichomonas... 2.4.3. Ch nh Do ph khng khun rng, tetracyclin c dng ba bi, d gy khng thuc. V vy ch nn dng cho cc bnh gy ra do vi khun trong t bo v tetracyclin rt d thm vo i thc bo. - Nhim rickettsia - Nhim mycoplasma pneumoniae - Nhim chlamidia: bnh Nicolas- Favre, vim phi, ph qun, vim xoang, psittacosis, bnh mt ht. - Bnh ly truyn qua ng tnh dc - Nhim trc khun: brucella, tularemia, bnh t, l, E.coli. - Trng c: do tc dng trn vi khun propionibacteria khu tr trong nang tuyn b v chuy n ha lipid thnh acid bo t do gy kch ng vim. Dng liu thp 250 2ln/ ngy. 2.4.4. Dc ng hc - Cc tetracyclin khc nhau v tnh cht dc ng hc, cc dn xut mi c c im hp thu tt hn, thi tr chm hn v do c th gim c liu dng hoc ung t ln hn. - Hp thu qua tiu ha 60- 70%. D to phc vi st, calci, magnesi v casein trong thc n v gim hp thu. Nng ti a trong mu t c sau 2- 4 gi. - Phn ph i: gn vo protein huyt tng t 30% (oxytetracyclin) n 50% (tetracyclin) hoc trn 90% (doxycyclin). Thm c vo dch no tu, rau thai, sa nhng t. c bit l th m c vo trong t bo nn c tc dng tt trong iu tr cc bnh do brucella. Gn mnh vo h li n i m ca gan, lch, xng, rng. Nng rut cao gp 5- 10 ln nng trong mu. - Thi tr: qua gan (c chu k gan - rut) v thn, phn ln di dng cn hot tnh. Thi gian bn thi l t 8h (tetracyclin) n 20h (doxycyclin) Bng 14.1. Cc tetracyclin thng dng Tn thuc Hp thu theo ng ung (%) 30 60- 70 thanh thi ca thn (mL/ pht) 35 90 65 35 t/2 Phn loi tc dng Tc dng ngn Tc dng

Chlortetracycli n Oxytetracyclin Tetracyclin Demeclocyclin

6- 8h 12h

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Methacyclin Doxycyclin Minocyclin 2.4.5. c tnh

90- 100 -

31 16 10

16- 18h -

Trung bnh Tc dng di

- Ri lon tiu ha: bun nn, nn, tiu chy, do thuc kch ng nim mc, nhng thng l do lon khun - Vng rng tr em: tetracyclin lng ng vo rng trong thi k u ca s vi ha (trong t cung nu ngi m dng thuc sau 5 thng c thai hoc tr em di 8 tui) - c vi gan thn: khi dng liu cao, nht l trn ngi c suy gan, thn, ph n c thai c th gp vng da gy thoi ha m, ur mu cao dn n t vong. - Cc r i lon t gp hn: d ng, xut huyt gim tiu cu, tng p lc n i s tr ang b, nhc u, ph gai mt... V vy, phi thn trng theo di khi s dng v trnh dng: . Cho ph n c mang . Cho tr em di 8 tui 2.4.6. Ch phm, cch dng D sao, tetracyclin vn l khng sinh c ph rng, t gy d ng, t c, c bit l thm c vo trong t bo nn c dnh cho iu tr bnh do brucella, nhim khun ng mt, mihng, ph i. Mt s dn xut chnh: - Tetracyclin: ung 1- 2 g/ ngy, chia 3- 4 ln. Vin 250- 500 mg; dch treo 125 mg/ 5mL - Clotetracyclin (Aureomycin): ung, tim t/m 1- 2 g. - Oxytetracyclin (Terramycin): ung 1- 2 g; tim bp, t/m 200 mg- 1g. - Minocyclin (Mynocin): ung 100 mg 2 ln; tim bp hoc t/m 100 mg. Vin 50- 100 mg; dch treo 50 mg/ 5 mL - Doxycyclin (Vibramycin): ung liu duy nht 100- 200 mg. Vin 50- 100 mg; dch treo 2550 mg/ mL 2.5. Nhm macrolid v lincosamid Hai nhm ny tuy cng thc khc nhau nhng c nhiu im chung v c ch tc dng, ph khng khun v c im s dng lm sng. 2.5.1. Ngun gc v tnh cht Nhm macrolid phn ln u ly t streptomyces, cng thc rt cng knh, i din l erythromycin (1952), ngoi ra cn clarithromycin v azithromycin. Cc lincosamid cng ly t streptomyces, cng thc n gin hn nhiu, i din l lincomycin (1962), clindamycin. Hai nhm ny c c tnh: - Tc dng trn cc chng khng penicilin v tetracyclin, c bit l staphylococus. - Gia chng c khng cho do c ch tng t

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- Thi tr ch yu qua ng mt - t c v dung np tt 2.5.2. C ch tc dngv ph khng khun Gn vo tiu phn 50s ca ribosom vi khun, cn tr to chui a peptid (ngn cn chuyn v ca ARNt) ca vi khun. Ph tc dng tng t penicilin G: cu khun v rickettsia. Hon ton khng tc dng trn trc khun ng rut v pseudomonas. Tc dng km khun mnh, c tc dng dit khun, nhng yu. 2.5.3. Dc ng hc B dch v ph hu mt phn, nu dng dng bo ch thch hp, c th ung c tt. Nng ti a t c trong mu sau 1- 4h v gi khng qu 6 ting nn phi ung 4 ln m i ngy. Gn vo protein huyt tng khong 70% (lincomycin) n 90% (erythromycin), t/2 t 1h 30 n 3 h. Thm mnh vo cc m, c bit l ph i, gan, lch, xng, tuyn tin lit. Nng trong i thc bo v bch cu a nhn gp 10- 25 ln trong huyt tng do c vn chuyn tch cc. Rt t thm qua mng no. Thi tr ch yu qua mt di dng cn hot tnh (nng trong mt gp 5 ln trong huyt tng). 2.5.4. Ch nh L thuc c chn la ch nh cho nhim corynebacteria (bch hu, nhim nm corynebacterium minutissimum- erythrasma); nhim clamidia ng h hp, sinh dc, mt, vim ph i mc phi cng ng; thay th penicilin cho bnh nhn b d ng vi penicilin khi nhim t cu, lin cu hoc ph cu; d phng vim n i tm mc trong phu thut rng ming cho nhng bnh nhn c bnh van tim. 2.5.5. c tnh Ni chung t c v dung np tt ch gp cc r i lon tiu ha nh (bun nn, nn, tiu chy) v d ng ngoi da. Tuy nhin, lincomycin v clindamycin c th gy vim rut kt mc gi, i khi nng, d n n t vong; erythromycin v Tri Acetyl Oleandomycin (TAO) c th gy vim da mt, vng da. 2.5.6. Ch phm, cch dng 2.5.6.1. Nhm macrolid - Erythromycin (Erythromycin, Erythrocin): ung 1- 2g/ ngy, chia lm 4 ln - Spiramycin (Rovamycin): ung 1- 3g/ ngy, truyn chm t/m 1,5 triu UI3 ln/ ngy - Azithromycin: thm rt nhiu vo m (tr dch no tu), t nng cao hn huyt t ng ti 10- 100 ln, sau c gii phng ra t t nn t/2 khong 3 ngy. V th cho php dng liu 1 ln/ ngy v thi gian iu tr ngn. Th d vi vim ph i cng ng, ngy u cho 500 mg ung 1 ln; 3 ngy sau ung 250 mg/ ln/ ngy ch dng trong 4 ngy. Vin nang 250 mg 2.5.6.2. Nhm lincosamid - Lincomycin (Lincocin): ung 2g/ ngy. Chia lm 4 ln. Vin nang 500 mg.

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tim bp, t/m: 0,6- 1,8g/ ngy - Clindamycin (Dalacin): ung 0,6- 1,2g/ ngy, chia lm 4 ln (0,15- 0,3g/ ln) Khng sinh 2 nhm ny thng dng cho nhim cu khun gram (+), nht l trong tai m i hng, vim ph i, nhim khun ng h hp. Nhm lincosamid do thm mnh c vo xng nn cn c ch nh tt cho cc vim xng ty. 2.6. Nhm Quinolon 2.6.1. Ngun gc v tnh cht l ha L khng sinh hon ton tng hp. Loi kinh in c acid nalidixic (1963) l tiu biu. Loi mi, do gn thm fluor vo v tr 6, gi l 6- fluoroquinolon (pefloxacin 1985) c ph khng khun rng hn, ung c. Tt c u l cc acid yu, cn trnh nh sng 2.6.2. C ch tc dng v ph khng khun Cc quinolon u c ch ADN gyrase, l enzym m vng xon ADN, gip cho s sao chp v phin m, v vy ngn cn s tng hp ADN ca vi khun. Ngoi ra cn tc dng c trn ARNm nn c ch tng hp protein vi khun. Cc quinolon u l thuc dit khun. Acid nalidixic (cn g i l quinolon th h 1) ch c ch ADN gyrase nn ch c tc dng dit khun gram (-) ng tit niu v ng tiu ha. Khng tc dng trn trc khun m xanh (Pseudomonas aeruginosa). Cc fluoroquinolon c tc dng ln 2 enzym ch l ADN gyrase v topoisomerase IV ca vi khun (Drlica, 1997) nn ph khng khun rng hn, hot tnh khng khun cng mnh hn t 10- 30 ln. Cc fluoroquinolon th h u, cn gi l quinolon th h 2 (pefloxacin, norfloxacin, ofloxacin, ciprofloxacin... 1987- 1997) c khc nhau tng i v tc ng trn gyrase v topoisomerase IV: trn vi khun gram (-), hiu lc khng gyrase mnh hn; cn trn vi khun gram (+), li c hiu lc khng topoisomerrase IV mnh hn. Cc fluoroquinolon th h mi cn gi l quinolon th h 3 (levofloxacin, trovafloxacin, t 1999) c tc ng cn bng trn c 2 enzym v vy ph khng m rng trn gram (+), nht l cc nhim khun ng h hp, v vi khun kh khng thuc hn v phi t bin 2 ln trn 2 enzym ch. Ph khng khun ca fluoroquinolon g m: E.coli, Salmonella, Shigella, Enterobacter, Neisseria, P.aeruginosa, Enterococci, ph cu, t cu (k c loi khng methicilin). Cc vi khun trong t bo cng b c ch vi nng fluoroquinolon huyt tng nh chlamidia, mycoplasma, brucella, mycobacterium... 2.6.3.Dc ng hc Acid nalidixic d hp thu qua tiu ha v thi tr nhanh qua thn, v vy c dng lm khng sinh ng tit niu, nhng phn ln b chuyn ho gan, ch 1/4 qua thn di dng cn ho t tnh. Cc fluorquinolon c sinh kh dng cao, ti 90% (pefloxacin), hoc trn 95% (gatifloxacin v nhiu thuc khc), t gn vo protein huyt tng (10% vi ofloxacin, 30% vi pefloxacin). Rt d thm vo m v vo trong t bo, k c dch no tu. B chuyn ho gan ch mt phn. Pefloxacin b chuyn ha thnh norfloxacin vn cn hot tnh v chnh n b thi tr qua thn 70%. Thi gian bn thi t 4h (Ciprofloxacin) n 12h (pefloxacin). Nng thuc trong tuyn tin lit, thn, i thc bo, bch cu ht cao hn trong huyt tng. 2.6.4. Ch nh

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- Nhim khun ng tit niu v vim tuyn tin lit, acid nalixilic, norfloxacin, ciprofloxacin, ofloxacin, tc dng ging nhau, tng t nh trimethoprim- sulfamethoxazol - Bnh ly theo ng tnh dc: .Bnh lu: ung liu duy nht ofloxacin hoc ciprofloxacin . Nhuyn h cam: 3 ngy ciprofloxacin . Cc vim nhim vng chu hng: ofloxacin ph i hp vi khng sinh chng vi khun k kh (clindamycin, metronidazol) - Nhim khun ng tiu ha: do E. coli, S.typhi, vim phc mc trn bnh nhn phi lm thm phn nhiu ln. - Vim ng h hp trn v di, vim ph i mc phi ti cng ng, vim xoang: cc fluoroquinolon mi nh levofloxacin, trovafloxacin, gatifloxacin. - Nhim khun xng- khp v m mm: thng do trc khun gram (-) v t cu vng, liu lng phi cao hn cho nhim khun tit niu (500- 750 mg 2 ln/ ngy) v thng ph i ko di (7- 14 ngy, c khi phi ti 4- 6 tun) 2.6.5. c tnh Khong 10%, t nh n nng: bun nn, nn, tiu chy, d ng ngoi da, tng p lc n i s (chng mt, nhc u, l ln, co git, o gic). Trn tr nh, c acid chuyn ha, au v sng khp, au c. Thc nghim trn sc vt cn non thy m sn b hu ho i cho nn khng dng cho tr em di 18 tui, ph n c mang v ang nui con b. Khng dng cho ngi thiu G6PD. 2.6.6. Ch phm v cch dng 2.6.6.1. Loi quinolon kinh in, acid nalidixic (Negram): nhim khun tit niu do trc khun gram (-), tr pseudomonas aeruginosa. Ung 2g/ ngy, chia 2 ln. ng tim t/m ch c dng trong bnh vin khi tht cn thit. 2.6.6.2. Loi fluorquinolon: dng cho cc nhim khun bnh vin do cc chng a khng khng sinh nh vim ph i, nhim khun huyt, vim mng no, mng tim, nhim khun xng cn iu tr ko di. Mt s ch phm ang dng: Pefloxacin (Peflacin) : ung 800 mg/ 24h chia 2 ln Norfloxacin (Noroxin): ung 800 mg/ 24h chia 2 ln Ofloxacin (Oflocet) : ung 400- 800 mg/ 24h chia 2 ln Ciprofloxacin (Ciflox) : ung 0,5- 1,5g/ 24 h chia 2 ln Levofloxacin (Levaquin): ung 500 mg Gatifloxacin (Tequin): ung liu duy nht 400 mg/ 24h Hin nay fluoroquinolon l thuc khng sinh c dng rng ri v: - Ph rng - Hp thu qua tiu ha tt, t nng huyt tng gn vi truyn tnh mch. - Phn ph i rng, c cc m ngoi mch - t/2 di, khng cn dng nhiu ln - D dng nn c th iu tr ngoi tr

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- R hn so vi iu tr bng khng sinh tim truyn khc. - Tng i t tc dng khng mong mun V vy sinh ra lm dng thuc. Nn trnh dng cho cc nhim khun thng thng. Hy ginh cho cc nhim khun nng, kh tr nh: Pseudomonas aeruginosa, t cu vng khng methicilin, E. coli v khun gram (-) khng trimethoprim- sulfamethoxazol. 2.7. Nhm 5- nitro- imidazol 2.7.1. Ngun gc v tnh cht L dn xut tng hp, t tan trong nc, khng ion ha pH sinh l, khuch tn nhanh qua mng sinh hc. Lc u (1960) dng chng n bo (trichomonas, amip) (xem bi "thuc cha amip"), sau (1970) thy c tc dng khng khun k kh. 2.7.2. C ch tc dng v ph khng khun Nitroimidazol c c tnh chn lc trn cc vi khun k kh v c cc t bo trong tnh trng thiu oxy. Trong cc vi khun ny, nhm nitro ca thuc b kh bi cc protein vn chuyn electron c bit ca vi khun, t o ra cc sn phm c, dit c vi khun, lm thay i cu trc ca ADN. Ph khng khun: m i cu khun k kh, trc khun k kh gram (-), trc khun k kh gram (+) to c bo t. Loi trc khun k kh gram (+) khng to c bo t thng khng c thuc (propionibacterium). 2.7.3. Dc ng hc Hp thu nhanh qua tiu ha, t gn vo protein huyt tng, thm c vo m i m, k c mng no, t/2 t 9h (metronidazol) n 14h (ornidazol). Thi tr qua nc tiu phn ln di dng cn hot tnh, lm nc tiu c th b xm mu. 2.7.4. c tnh Bun nn, sn da, ri lon thn kinh, gim bch cu, h huyt p. 2.7.5. Ch phm, cch dng Thng c dng trong vim mng trong tim, apxe no, d phng nhim khun sau phu thut vng bng- h chu... C tc dng hip ng vi khng sinh nhm b lactam v aminosid. Metronidazol (Flagyl), ornidazol (Tiberal): ung 1,5g hoc 30- 40 mg/ kg/ 24h. (Xin xem thm bi "thuc chng amp") 2.8. Sulfamid Nm 1935 Domagk pht hin ra tnh khng khun ca mt phm nhum l sulfamidochrysoidin (Prontosil), t m ra k nguyn ca cc thuc chng nhim khun trc khi c penicilin. 2.8.1. Ngun gc v tnh cht Sulfamid u l cc cht tng hp, dn xut ca Sulfanilamid do thay th nhm - NH2 hoc nhm - SO2NH2. L bt trng, rt t tan trong nc, d tan hn trong huyt thanh v mt. 2.8.2. C ch tc dng v ph khng khun PABA (para amino benzoic acid) l ngun nguyn liu cn thit cho vi khun tng hp acid folic pht trin. Do c cu trc ha hc gn ging vi PABA nn sulfamid tranh chp vi PABA ngn cn qu trnh tng hp acid folic ca vi khun.

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Ngoi ra, sulfamid cn c ch dihydrofolat synthetase, mt enzym tham gia tng hp acid folic (xem s mc 2.9). V vy sulfamid l cht km khun. T bo ng vt c v v vi khun no c th s dng trc tip acid folic t mi trng th u khng chu nh hng ca sulfamid. V mt l thuyt, ph khng khun ca sulfamid rt rng, gm hu ht cc cu khun, trc khun gram (+) v (-). Nhng hin nay, t l khng thuc v khng cho gia cc sulfamid ang rt cao nn hn ch vic s dng sulfamid rt nhiu. Vi khun khng thuc bng cch tng tng hp PABA hoc gim tnh thm vi sulfamid. 2.8.3. Dc ng hc - Cc sulfamid c hp thu nhanh qua d dy v rut (tr loi sulfaguanidin), 70- 80% liu ung vo c mu, gn vi protein huyt tng 40- 80%, nng ti a t c sau 2- 4h. - T mu, sulfamid khuch tn rt d dng vo cc m, vo dch no tu (bng 1/2 hoc tng ng vi nng trong mu), qua rau thai, gy c. - Cc qu trnh chuyn ha ch yu gan ca sulfamid gm: . Acetyl ha, t 10- 50% tu loi. Cc sn phm acetyl ha rt t tan, d gy tai bin khi th i tr qua thn. Cc sulfamid mi c t l acetyl ha thp (6-16%) v sn phm acetyl ha li d tan. . Hp vi acid glucuronic (sulfadimethoxin), rt d tan . Oxy ha Thi tr: ch yu qua thn (lc qua cu thn v bi xut qua ng thn). Dn xut acetyl ha (25- 60% trong nc tiu) khng tan, t o tinh th c th gy i mu hoc v niu. V vy, cn ung nhiu nc (1g/ 0,5 lt). * Phn loi sulfamid: V tc dng ca sulfamid u ging nhau, vic iu tr da vo dc ng hc ca thuc cho nn ngi ta chia cc sulfamid lm 4 loi: - Loi hp thu nhanh, thi tr nhanh: nng ti a trong mu sau ung l 2- 4h. t/2=6-8h, thi tr 95% trong 24h. G m sulfadiazin, sulfisoxazol (Gantrisin), sulfamethoxazol (Gantazol). Dng iu tr nhim khun theo ng mu. - Loi hp thu rt t: dng cha vim rut, vim lot i trng. Gm sufaguanidin (Ganidan), salazosulfapyridin (Salazopyrin). - Loi thi tr chm: duy tr c nng iu tr trong mu lu, t/2 c th ti 7- 9 ngy nn ch cn ung 1 ln ngy. Hin dng sulfadoxin (Fanasil), ph i hp vi pyrimethamin trong Fansidar d phng v iu tr st rt khng cloroquin.

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- Loi dng ti ch: t hoc kh tan trong nc. Dng iu tr cc vt thng ti ch (mt, vt bng) di dng dung dch hoc kem. C sulfacetamid, silver sulfadiazin, mafenid. 2.8.4. c tnh - Tiu ha: bun nn, nn, tiu chy. - Thn: do sulfamid t tan v cc dn xut acetyl ha kt ta trong ng thn gy cn au bng thn, i mu, v niu (iu tr, d phng bng ung nhiu nc v base ha nc tiu). Vim ng k thn do d ng. - Ngoi da: cc biu hin d ng t nh n rt nng nh h i chng Stevens- Johnson, h i chng Lyell. Thng gp vi loi sulfamid chm. - Mu: thiu mu tan mu (do thiu G6PD), gim bch cu, gim tiu cu, mt bch cu ht, suy ty. - Gan: tranh chp vi bilirubin gn vo protein huyt tng, d gy vng da, c. Khng dng cho ph n c thai v tr em mi . Khng dng cho ngi suy gan, suy thn, thiu G6PD, a tng d ng. 2.8.5. Ch phm cch dng Do c nhiu c tnh v c khng sinh thay th, sulfamid ngy cng t dng mt mnh. Thng phi hp sulfamethoxazol vi trimethoprim (xin xem phn sau). Hin cn c ch nh trong cc trng hp sau: - Vim ng tit niu: . Sulfadiazin: vin nn 0,5g . Sulfamethoxazol (Gantanol): vin nn 0,5g Ngy u ung 2g 4 ln; nhng ngy sau 1g 4 ln. Ung t 5- 10 ngy - Nhim khun tiu ha: . Sulfaguanidin (Ganidan): vin nn 0,5g ung 3- 4g/ ngy . Sulfasalazin (Azalin): vin nn 0,5g ung 3- 4 g/ ngy - Dng bi ti ch: . Bc sulfadiazin (Silvaden): 10mg/ g kem bi 2.9. Phi hp sulfamid v trimethoprim 2.9.1. C ch tc dng v ph khng khun S di y cho thy v tr tc dng ca sulfamid v trimethoprim trong qu trnh tng hp acid folic. Hai thuc c ch tranh chp vi 2 enzym ca vi khun 2 khu ca qu trnh tng hp nn c tc dng hip ng mnh hn 20- 100 ln so vi dng sulfamid mt mnh. Dihydrofolat synthetase (-) SUL TMP Dihydrofolat reductase (-)

ADN

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PABA+ dihydropteridin

Acid dihydrofolic

Tng hp Acid purin v tetrahydrofolic pyrimidin ARN

Hnh 14.5. V tr tc dng ca sulfamid v trimethoprim trong qu trnh tng hp acid folic Trimethoprim l mt cht ha hc tng hp c tc dng c ch dihydrofolat reductase ca vi khun 50.000- 100.000 ln mnh hn trn ngi, v c ch trn enzym ca k sinh trng st rt 2000 ln mnh hn ngi. Ph khng khun rng v chng khng li t hn so vi sulfamid. C tc dng dit khun trn mt s chng. Khng tc dng trn Pseudomonas, S.perfringens, xon khun. 2.9.2. Dc ng hc T l l tng cho hip ng tc dng ca nng thuc trong mu ca sulfamethoxazol (SMZ): trimethoprim (TMP) l 20: 1. V TMP hp thu nhanh hn SMZ (pic huyt thanh l 2 v 4h) v t/2 10h, cho nn nu t l SMZ: TMP trong vin thuc l 5: 1 (800 mg sulfamethoxazol + 160 mg trimethoprim), sau khi ung, nng trong mu s t c t l 20: 1(40 mg/ mL huyt tng sulfamethoxazol v 2 mg/ mL trimethoprim). C 2 thuc c hp thu qua ng ung, phn ph i tt vo cc m (dch no tu, mt, tuyn tin lit). Thi tr ch yu qua nc tiu vi nng cn hot tnh. 2.9.3. c tnh v chng ch nh Thuc ph i hp ny c t t c cc c tnh ca sulfamid. Ngoi ra, trn nhng ngi thiu folat, TMP c th gy thiu mu nguyn hng cu khng l, t l b ban cng cao hn. Khng dng cho ph n c thai v tr em mi (nht l non) 2.9.4. Ch phm v cch dng Thuc kt hp c ch nh chnh trong nhim khun tit niu, tai- mi- hng, ng h hp, ng tiu ha (thng hn, t), bnh hoa liu (clamydia) - Phi hp trimethoprim + sulfamethoxazol: . Vin Bactrim, Cotrimoxazol, g m trimethoprim (80 hoc 160 mg) v sulfamethoxazol (400 hoc 800 mg). Liu thng dng l 4- 6 vin (loi 80 mg TMP + 400 mg SMZ), ung trong 10 ngy . Dch treo: trong 5 mL c 400 mg TMP + 200 mg SMZ. Dng cho tr em. . Dch tim truyn: TMP 80 mg + SMZ 400 mg trong ng 5 mL. Ho trong 125 mL dextrose 5% truyn tnh mch trong 60- 90 pht. 3. MT S VN V S DNG KHNG SINH 3.1. Nguyn tc dng khng sinh 1. Ch dng khng sinh cho nhim khun. Khng dng cho nhim virus (c loi ring). Dng cng sm cng tt. 2. Ch nh theo ph tc dng. Nu nhim khun xc nh, dng khng sinh ph hp. 3. Dng liu t c nng v n nh. Khng dng liu tng dn.

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4. Dng thi gian: trn c th nhim khun, vi khun nhiu giai on khc nhau vi khng sinh. Nu sau 2 ngy dng khng sinh, st khng gim, cn thay hoc phi hp khng sinh. Khi iu tr ht st, vn cn cho thm khng sinh 2- 3 ngy na. Ni chung, cc nhim khun cp, cho khng sinh 5- 7 ngy. Cc nhim khun c bit, dng lu hn, nh: vim n i tm mc Osler, nhim khun tit niu (vim b thn): 2- 4 tun; vim tuyn nhip h: 2 thng; nhim khun khp hng: 3- 6 thng; nhim lao: 9 thng... 5. Chn thuc theo dc ng hc (hp thu, phn phi, chuyn ha, thi tr) ph thuc vo ni nhim khun v tnh trng bnh nhn. 6. Cn phi hp vi bin php iu tr khc: khi nhim khun c m, hoi t m, vt l (si) th cho khng sinh phi km theo thng m, phu thut. 3.2. Nhng nguyn nhn tht bi trong vic dng khng sinh 1. Chn khng sinh khng ng ph tc dng 2. Khng sinh khng t c ti ngng tc dng ti nhim khun, do liu lng khng hp l, do dc ng hc khng thch hp, do tng tc thuc lm gim tc dng ca khng sinh 3. Do vi khun khng thuc. Cn thay khng sinh khc hoc phi hp khng sinh. 3.3. Vi khun khng khng sinh 3.3.1. Khng t nhin: vi khun c tnh khng t trc khi tip xc vi khng sinh, nh sn xut b lactamase, cu trc ca thnh vi khun khng thm vi khng sinh. 3.3.2. Khng mc phi: vi khun ang nhy cm vi khng sinh, sau mt thi gian tip xc, tr thnh khng nhy cm na, do: * t bin hoc khng qua nhim sc th. Mi vi khun u c "protein ch" gn vi khng sinh c th ti ribosom, DNA gyrase, RNA polymerase... Do t bin, cc "protein ch" thay i, khng gn khng sinh na. *Khng qua plasmid: c nhiu dng. Thng l sn xut cc enzym lm bt hot khng sinh, hoc gim i lc ca khng sinh vi "protein ch", hoc thay i ng chuyn ha. Vi khun khng khng sinh c th pht trin s khng cho vi khng sinh trong cng h. Qua plasmid c th khng nhiu loi khng sinh mt lc. Ngi ln u nu nhim vi khu n khng khng sinh, mc du cha dng khng sinh bao gi c khng khng sinh ngay. Loi khng mc phi thng l do dng khng sinh khng ng liu hoc lm dng thuc, ang gy mt tr ngi rt ln cho vic iu tr. 3.4. Phi hp khng sinh 3.4.1. Ch nh phi hp khng sinh 1. Nhim 2 hoc nhiu vi khun mt lc 2. Nhim khun nng m nguyn nhn cha r 3. S dng tc dng hip ng lm tng hot tnh khng sinh trong mt s nhim khun c bit: . Vim ni tm mc: penicilin + streptomycin . Trimethoprim + sulfamethoxazol . Khng sinh b lactam + cht c ch lactamase 4. Phng nga xut hin vi khun khng khng sinh.

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Ch ph i hp khng sinh cho mt s t cc trng hp nhim khun trong bnh vin nh cu khun rut, mt s trc khun gram (-) (trc khun m xanh, trc khun mt loi Serratia, Enterobacter, Citrobacter). 3.4.2. Nhc im ca phi hp khng sinh Khi thy thuc khng hiu r v phi hp khng ng s: . D gy khng do s chn la ca vi khun . Tng c tnh ca khng sinh . Hip ng i khng . Gi thnh iu tr cao Ni chung, nn hn ch ph i hp v c khng sinh ph rng 3.4.3. Mt s nhim khun thng gp v cch chn khng sinh. Bng gii thiu mt s cch la chn khng sinh.

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Bng 14.2.La chn khng sinh trong iu tr nhim khun Vi khun Bnh Th nht Oxacillin khun Nafcillin Thuc c chn Th hai Cephalospori nI Vancomycin Th ba Clindamycin Erythromycin Trim+ sulfamethoxazol Ciprofloxacin rifampin Erythromycin Clindamycin

Cu khun p xe Nhim Gr(+) huyt T cu vng Vim n i tm mc Vim phi Vim xngtu Lin cu sinh Vim hng m (nhm A) Vim tai gia, xoang Vim phi Nhim khun huyt Streptococcus Vim n i tm viridans mc Nhim khun huyt Ph cu Vim phi Vim khp Vim xoang Vim tai Cu khun Vim tai Vim xoang Gr(-) Vim phi Moraxella catarrhalis Neisseria meningitis Trckhun Gr(+) Corynebacteriu m diphteriae Corynebacteriu m species, i kh

Penicilin Amoxicilin

Cephalospori nI Vancomycin

Penicilin G Gentamycin Penicilin Amoxicilin Amox+ clavulanat Ampi+ sulbactam TMP + SMZ Pen. GRifampin Erythromycin

Ceptriaxon (III) Cephalospori nI TMP- SMZ Cephalospori n II- III

Vancomycin

Chloramphenicol macrolid Clindamycin Ciprofloxacin Tetracyclin Erythromycin

Vim hng Vim phi Vim thanh ph qun

Ceft. Cefot. Ciprofloxacin minocyclin Clindamycin Cephalosporrin I Rifampin

Vim n i tm mc Nhim khun huyt khun Trc khun Nhim tit niu Gr(-) Escheria coli Proteus Nhim tit niu

Penicilin G + aminoglycosi d Vancomycin TMP- SMZ Ciprofloxacin Ampi+ Aminogl khun Ampi/ Amox

Rifampicin + penicilin G Ampicilin + sullactam Pen + c ch penicilinase Aminoglycos id Cephalospori n Aminoglycos

Aztreonam Nitrofurantoin Doxycycline Ciprofloxacin hoc Ofloxacin

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Pseudomonas aeruginosa

Salmonella

id Nhim khun Pen. ph rng Aminoglycos id Ceftazidim tit niu Ciprofloxacin Aztreonam Pen.ph rng Vim phi Nhim khun Aminoglycos Ceftazidim + Aminogl id huyt Ciprofloxacin Ciprofloxacin Ampicilin Thng hn Ph thng hn Ceftriaxon Nhim khun TMP + SMZ huyt Vim rut cp Vim tai gia Vim xoang Vim phi T Ciprofloxacin TMP + SMZ TMP + SMZ Cefuroxim Amoxicilin + Amox/ Ampi clavulinat Doxycyclin Ciprofloxacin CU HI T LNG GI TMP + SMZ

Imipenem Imipenem + aminogl Aztreonam + aminoglycosid Chloramphenicol

Shigella Hemophilus influeuzae Vibrio cholerae

Amoxicilin Ciprofloxacin Azithromycin Chloramphenicol

1. Trong cc thuc di y, thuc no l khng sinh? Khng sinh dit khun? Khng sinh km khun? Penicilin, Streptomycin, Sulfonamid, Iod, Tetracyclin, Erythromycin, Thuc tm (KMnO4), Quinolon, Phenol. 2. Hy phn loi nhm lactam theo cu trc ha hc v nu c im. 3. Hy phn tch c ch tc dng v tc dng ca Penicilin v Cephalosporin. 4. Trnh by c ch tc dng v p dng iu tr ca aminoglycosid. 5. Trnh by c ch tc dng v p dng iu tr ca: Nhm cloramphenicol Nhm tetracyclin Nhm macrolid Nhm quinolon Thuc phi hp sulfamid- trimethoprim Nhm 5- nitro imidazol.

6. Hy phn bit c tnh ca cc nhm khng sinh lactam, aminoglycosid, cloramphenicol, tetracyclin v quinolon. 7. Trnh by 6 nguyn tc s dng khng sinh an ton v hp l. 8. Phn tch cc nguyn nhn tht bi trong vic dng khng sinh v cch khc phc.

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Bi 15: THUC KHNG VIRUS (NHM KHNG VIRUS SAO CHP NGC)

MC TIU HC TP: Sau khi hc xong bi ny, sinh vin c kh nng: 1. Trnh by c cc giai on pht trin ca virus sao chp ngc v v tr c th tc ng ca thuc. 2. Trnh by c c ch tc dng v c tnh ca zidovudin, nevirapin v indinavir. Virus g m c loi 1 hoc 2 chu i ADN hoc ARN c bc trong mt v protein g i l capsid. Mt s virus c c v lipoprotein, v ging nh capsid, v ny c th cha cc protein khng nguyn. Virus bt buc phi sng k sinh trong t bo vt ch, s sao chp ca chng ph thuc ch yu vo cc qu trnh tng hp ca t bo vt ch. - Loi ADN virus nh poxvirus (gy bnh u ma), herpesvirus (gy thu u, herpes, zona), adenovirus (vim kt mc, vim hng), hepa AND virus (vim gan B) v papillomavirus (ht cm). Sau khi thm nhp c vo nhn t bo vt ch, ADN virus c sao m sm vo ARNm bi ARNm polymerase ca t bo vt ch, ARNm c dch m theo cch thng thng ca t bo vt ch thnh cc protein c hiu ca virus. Ring virus u ma, do c ARN polymerase ring nn c th sao chp ngay trong bo tng ca t bo vt ch. - Loi ARN virus g m rubellavirus (gy bnh si c [German measles], rubeon), rhabdovirus (bnh di), picoARNvirus (bnh bi lit, vim mng no, cm lnh), arenavirus (vim mng no, st Lassa), arbovirus (st vng), orthomyxovirus (cm), paramyxovirus (si, quai b). Vi ARN virus, vic sao chp trong t bo vt ch s da vo hoc l cc enzym trong virion (ht virus) tng hp ARNm cho n, hoc l ARN virus c dng nh chnh ARNm ca n. ARNm c dch m thnh cc protein virus, k c ARN polymerase, enzym chi ph i s tng hp nhiu ARNm virus. Mt nhm ARN virus trong loi ny l retrovirus c cha enzym reverse transcriptase (enzym sao m ngc), t o ADN t ARN virus. Sau , bn sao ADN tch hp vo genom (b gen) ca vt ch (lc c coi nh provirus) v c sao m thnh c ARN genom v ARNm dch m thnh cc protein virus (HIV). Trong nhiu bnh nhim virus, nh im ca s sao chp ca virus l vo ngay trc lc triu chng lm sng xut hin. V vy, hiu qu iu tr lm sng ti u l phi bt u iu tr sm. Cc thuc khng virus cn phi: ngn cn s xm nhp ca virus vo t bo v ph i c hot tnh vi virus trong t bo, ngha l phi c tnh c hiu. Da vo cc bc trong qu trnh sao chp, nhn i ca virus m nghin cu cc thuc khng virus, theo bng 15.1 Thuc khng virus sao chp ngc (Antiretroviral agents): thuc chng HIV. HIV (human immunodeficiency virus) l virus sao chp ngc. ARN tn cng vo cc t bo lympho CD4, i thc bo v t bo thn kinh si nhnh (dendritic cells). Nghin cu vng i ca HIV trong t bo chnh l tm mc tiu tc ng ca thuc.

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Hnh 15.1 di y trnh by cc giai on pht trin ca HIV v mc tiu c th tc ng ca thuc.

Bng 15.1: Cc giai on sao chp ca virus v mc tiu tc ng ca thuc chng virus Giai on sao chp - Bm dnh v xm nhp Bm dnh Xm nhp - Tho v Gii phng genom ca virus - Sao m ca genom virus - By receptor ha tan, khng receptor khng th c ch protein kt hp. - Chn knh ion, cht lm vng bn mng capsid c ch cc enzym ca virus: ADN polymerase, ARN polymerase, reverse transcriptase, helicase, primase hoc integrase. - Interferon, antisense oligonucleotid ribozym. - Dch m ca protein virus Cc protein iu ha (sm) Cc protein cu trc (mun) - Thay i sau dch m - Cc cht c ch protease - Interferon, cc cht c ch protein tp hp - Cc cht c ch protein iu ha Cc nhm thuc

- Tp hp cc thnh phn ca Cht c ch neuraminidase, khng th khng virus. virion - Thot khi t bo vt ch

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Hnh 15.1. Qu trnh pht trin ca HIV trong t bo vt ch 1) Virus gn vo cc receptor CD4 2) Ha mng v thot v ca virus 3) Sao chp ngc t ARN ADN 4) Tch hp ca ADN virus vo ADN vt ch 5) Sao m mun hay s tng hp protein ca virus 6) Lp rp hay t hp li ca virus v ny chi; j: ARN virus; j. ARN v enzym reverse transcriptase.

Qua hnh trn, v l thuyt, c th nghin cu cc thuc tc ng vo cc khu sau: - Ngn cn virus gn vo cc receptor t bo (1) - Ngn cn s ha mng v thot v ca virus (2) - Km hm s sao chp ngc t ARN (3) - Ngn cn s tch hp ca ADN virus vo ADN ca t bo vt ch (4). - Ngn cn s sao m mun hay s tng hp protein ca virus (5) - Km hm s lp rp hay s t hp li ca virus v s ny chi (6). m i giai on trn u c nhng c ch c hiu v nhng enzym c hiu ring cho HIV, v nh vy c th tm ra cc thuc c ch thch hp cho tng giai on. Tuy nhin, do nhiu kh khn, cc nghin cu hin nay phn ln tp trung vo cc loi thuc c ch enzym sao chp ngc (reverse transcriptase- RT), protease v integrase. RT l enzym c tc dng chuyn mch n ARN ca HIV thnh mch kp ADN (giai on 3 trn s ) trc khi xm nhp vo nhim sc th ca t bo vt ch. Thuc c ch RT c 2 loi: - Thuc c ch nucleosid reverse transcriptase (NRTI): tc dng rt sm giai on sao chp ca HIV, ngn cn nhim khun cp tnh ca t bo, rt t tc dng trn t bo nhim HIV. Cc thuc ny u l tin thuc, c cu trc tng t nh mt thnh phn cu to ca ADN nhng phi c enzym bo tng ca t bo vt ch phosphoryl ha mi tr nn c hot tnh l nhm thuc quan trng nht trong cng thc ph i hp thuc iu tr HIV. - Thuc c ch non- nucleosid reverse transcriptase (NNRTI): Thuc c ch enzym sao chp ngc khng phi nucleosid l thuc tng hp c kh nng gn vo cnh v tr tc ng ca RT, lm thay i hnh dng ca v tr ny nn enzym b mt hot tnh. Thuc khng cn qua giai on phosphoryl ha nh NRTI v ch c tc ng trn HIV- 1. Tt c u chuyn ha gan qua Cyt. P450, gy cm ng enzym nn lm tng chuyn ha ca chnh n (phi tng liu khi dng ko di) v mt s thuc dng cng.

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Integrase l enzym c tc dng gm ADN ca provirus vo nhim sc th ca t bo vt ch. Nu c ch c enzym ny s lm HIV khng nhn ln c trong t bo k sinh v s b tiu dit. Hin cn l bc nghin cu phng th nghim. Cc protease l cc enzym tham gia trong qu trnh tng hp nhiu protein cu trc ca li virus v cc enzym ch yu, trong c c RT v chnh bn thn protease. c ch protease th HIV ch l cc virion (ht virus) khng trng thnh v khng gy bnh c. V vy, hng nghin cu ny rt hp dn. Trong vng i ca HIV, cc enzym tc ng nh sau: . Mch n ARN . ADN virus

RT

mch kp ADN nhp vo ADN vt ch ARN mi ca virus

integrase c ch phin m bnh

. ADN ho nhp (provirus)

thng ca t bo vt ch protease

protein ca virus Cc thuc chng HIV ang c dng (bng 15.2) hin cn rt t v nhiu thuc cn ang giai on th lm sng.

Bng 15.2: Cc thuc chng HIV Tn gc c ch nucleosid reverse transcriptase(NRT) Zidovudin Didanosin Stavudin Zalcitabin Lamivudin c ch nonnucleosid reverse transcriptase (NNRT) Nevirapin Efavirenz Viramune Sustiva +++ +++ AZT, Retrovir, Videx EC ddI, Videx D4T, Zerit ddC, Hivid 3 TC, Epivir ++ ++ ++ + ++ Tn thng mi Hiu qu khng HIV

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c ch protease Saquinavir Indinavir Ritonavir Nelfinavir Amprenavir Lopinavir Invirase, Fortovase Crixivan Norvir Viracept Agenerase Kaletra ++ +++ +++ +++ +++ +++

Cc thuc ny phn ln cn ang c nghin cu v nh gi trn lm sng. Di y l mt s thuc i din, hin c Vit Nam. 1. THUC C CH NRT 1.1. Zidovudin (azidothymidin, AZT) Zidovudin l cht tng hp tng t thymidin, lc u chng ung th (Horwitz- 1964), sau thy c tc dng chng virus (Ostertag, 1974) v n 1985 th Mitsuya ln u tin thy c tc dng c ch c HIV-1 in vitro 1.1.1. C ch tc dng Sau khi nhp vo t bo, zidovudin cng phi c phosphoryl ha 3 ln thnh zidovudin 5- triphosphat mi c hot tnh. Trong t bo, dng hot tnh c t/2 3 gi. Zidovudin 5triphosphat c ch tranh chp vi deoxythymidin triphosphat ca RT. Ngoi ra cn tranh chp vi thymidin triphosphat tch hp vo ADN provirus, lm kt thc sm chu i ADN, to ra ADN provirus khng hon chnh. In vitro, zidovudin chng c HIV- 1, HIV- 2 v cc virus hng lympho T (T cell lymphotropic viruses) ca ngi. 1.1.2. Dc ng hc Hp thu nhanh qua tiu ha v phn b vo m i m, nng trong dch no tu bng 60% trong huyt tng. Sinh kh dng khong 65%; t/2 huyt tng l 1,1 gi, nhng dng hot tnh trong t bo c t/2 3 gi. Thi tr 90% qua thn di dng chuyn ha v khng chuyn ha. 1.1.3. Tc dng khng mong mun - c tnh chnh l thiu mu thng xy ra trong 4 tun u (7%), gim bch cu (37%), gim tiu cu. - Cc tc dng khng mong mun khc l nhc u, mt ng, chn n, bun nn, mt m i, au c xy ra trong vi tun u. Dng thuc cha triu chng. - Tc dng ph xut hin chm hn, sau 6- 17 thng l t sc t cc mng, cn co git, h i chng gi ng vim nhiu c. - Cc thuc c ch phn ng glucuronyl transferase gan (phn ng ging ha AZT) nh acetaminophen, aspirin, indometacin, probenecid s lm tng tai bin c tnh v mu ca AZT nn cn trnh dng chung. 1.1.4. Ch nh v liu lng Ung 200 mg, cch 8 gi/ ln; hoc 100 mg 5 ln/ ngy. Dng lin tc. C th ph i hp v i thuc c ch RT khc hoc thuc c ch protease. Ch phm: AZT, Retrovir vin nang 100 mg; l 200 mg/20 mL. 1.2. Didanosin (ddI)

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Didanosin (2', 3' dideoxy inosin- ddI) l cht tng t nucleosid purin, c nghin cu t 1989 v dng iu tr t cui nm 1991. Tc dng c trn HIV- 1 v HIV- 2. 1.2.1. C ch tc dng Sau khi thm nhp vo t bo, di tc dng ca enzym chuyn ha ni bo, didanosin c 3 ln phosphoryl ha thnh dng c hot tnh l dideoxyadenosin triphosphat (dd ATP), tranh chp vi dATP (deoxyadenosin triphosphat) c ch RT ca virus, ng thi ngn cn ko di chu i ADN, ngn cn tng hp ADN provirus. 1.2.2. Dc ng hc Didanosin b ph hu nhanh mi trng acid, v vy m i ch phm ung u cha cht trung ha pH ca dch v. Cn ung lc i. Ung sau ba n, lm gim hp thu ti 50%. Nng nh huyt t ng ca liu ung 300 mg l 1 mg/ mL. Nng trong dch no tu bng 20% nng huyt t ng. Thi gian bn thi l 0,6- 1,5 gi, nhng t/2 trong t bo ca ddATP l 8- 24 gi nn ch cn ung 2 ln/ ngy. Thi tr qua thn. 1.2.3. Tc dng khng mong mun - Vim ty v vim thn kinh ngoi bin thng gp nht, lin quan n liu dng, nht l khi liu > 12,5 mg/ kg. T l thng gp l 6- 28%. - Tiu chy: 17%, gn 2% l trng hp nng - Cc ri lon khc: khong 2% g m bun nn, nn, st, rt run, nhc u, au c, i acid uric... - Mt s ri lon sinh ha- huyt hc gim bch cu, gim tiu cu, thiu mu, tng transaminase. Khng lin quan n liu iu tr. 1.2.4. Ch nh, liu lng Dng cho tr em trn 6 thng tui v ngi ln b nhim HIV khng dung np vi AZT hoc dng AZT 4 thng nhng bnh t thuyn gim. Ngi ln: 200 mg 2 ln/ ngy. Gim liu nu nh cn. Tr em, da theo din tch c th: 0,8- 1,2 m2 : 75 mg 2 ln/ ngy 0,5- 0,7 m2 : 50 mg 2 ln/ ngy Phi ung lc i, trc ba n 1 gi. Nhai nt vin thuc hoc ha vo nc cho tht tan ri ung ngay. Didanosin (Videx) vin nn 25, 50, 100, 150 mg; bt ho tan dng cho tr em: 100, 200 mg. 2. THUC C CH NNRT Nevirapin 2.1. C ch tc dng: Nevirapin khuch tn vo trong t bo, gn vo RT, lm thay i hnh dng v bt hot enzym. Tc ng mnh trn HIV- 1, k c cc virion ngoi t bo. Dc ng hc. D hp thu qua ng tiu ha, thm c qua rau thai v sa. Nng trong dch no tu bng 45% nng huyt tng. Thi gian bn thi l 25- 30 gi. Chuyn ha gan qua cytocrom P450. Tc dng khng mong mun: pht ban, st, nhc u ng g v tng transaminase. Liu lng: Nevirapin (Viramune) vin 200 mg 1- 2 vin/ ngy.

2.2.

2.3. 2.4.

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3. THUC C CH PROTEASE 3.1. Indinavir c ch c hiu HIV- 1 protease Dng kt hp vi mt thuc c ch RT lm chm khng thuc. Ung 800 mg, cch 8 gi ung 1 ln; c hp thu tt, nn ung cch ba n 2 gi. Vin 200, 400 mg. Tc dng khng mong mun: tng bilirubin mu, si thn (nn ung nhiu nc), bun nn, tiu chy, gim tiu cu. Indinavir c ch mnh cytochrom P450 nn c tng tc vi nhiu thuc chuyn ha qua cytochrom ny. 3.2. Ritonavir c ch c hiu HIV- 1 protease Sinh kh dng 60- 80%. Ung liu 600 mg 12 gi/ ln. Tc dng khng mong mun: ri lon tiu ha, t b, t ng transaminase, tng triglycerid mu. Cng c ch mnh cytochrom P450 nh indinavir nn c tng tc vi nhiu thuc. Ritonavir (Norvir): vin nang 100 mg, dung dch ung 80 mg/mL. Nguyn tc s dng thuc chng HIV Sau nhiu nm theo di iu tr, WHO a ra mt s khuyn co sau: - Cc liu php iu tr phi theo hng dn ton quc. Liu php hng u c th l: AZT + 3 TC + Nevirapin AZT + 3 TC + Nelfinavir AZT + 3 TC + Lopinavir/ indinavir/ Saquinavir - S dng 2 thuc khng cn c coi l thch hp. - S tun th c ngha quan trng hn s la chn thuc. - Ph n mang thai v tr nh cng phi c iu tr ph i hp thuc ti u. CU HI T LNG GI 1. Trnh by cc giai on pht trin trong t bo vt ch ca virus sao chp ngc (HIV) v cc v tr c th tc ng ca thuc. 2. So snh c ch tc ng v c tnh ca zidovudin, nevirapin v indinavir. Bi 16: THUC KHNG NM MC TIU HC TP: Sau khi hc xong bi ny, sinh vin c kh nng: 1. Trnh by c c ch tc dng, tc dng v c tnh ca nhm thuc chng nm ton thn: amphotericin B, griseofulvin. 2. Trnh by c c ch tc dng, dc ng hc v c tnh ca 3 thuc trong nhm azol. Thnh cng ca khng sinh chng vi khun v virus dn n s tng ng k t l nhim nm. Nhim nm thng c chia lm 2 loi, nhim nm ton thn v nhim nm

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ngoi da, nim mc. Cc thuc chng nm v th cng c chia lm 2 loi, ton thn v ti ch. Nhng thc ra thuc ton thn cng c tc dng ti ch v ngc li. 1. THUC CHNG NM TON THN 1.1. Amphotericin B 1.1.1. c im: Amphotericin c tm ra t nm 1956 (Gold) l mt trong s 200 cht thuc h khng sinh polyen macrolid, khng tan trong nc, v vy thuc tim dng di dng dch treo. 1.1.2. Tc dng v c ch Tc dng trn cc loi Candida albicans v Cryptococcus neoformans, Blastomyces dermatitidis, Histoplasma capsulatum, Coccidioides immitis, Aspergillus. Amphotericin B gn vo ergosterol ca vch t bo nm, to nn cc ng dn lm r r cc ion v cc phn t nh t trong t bo nm ra ngoi, gy cht t bo. Sterol ca vch t bo nm l ergosterol, cn sterol chnh ca vch vi khun v t bo ngi li l cholesterol, v vy amphotericin B khng c tc dng dit khun v khng c vi ngi. 1.1.3. Dc ng hc Khng hp thu qua ng ung. Gn vo protein huyt tng ti 95%, ch yu vo blipoprotein. Ch dng ng truyn t nh mch, thm nhiu vo cc m gan, lch ph i, thn. Nng trong dch bao khp bng khong 2/3 nng huyt tng, nhng ch 23% vo c dch no tu. Thi gian bn thi khong 15 ngy. Thi tr chm qua thn trong vi ngy. 1.1.4. c tnh - c tnh lin quan n vic truyn thuc: run, st, nn, nhc u, h huyt p. Cn gim tc truyn hoc gim liu. C th lm test bng tim 1mg vo tnh mch. Dng thuc h st, khng histamin hoc corticoid trc khi truyn. - c tnh mun: Tn thng ng thn, tng ur-huyt (80%), toan huyt, tng thi K+, Mg++. Truyn dung dch NaCl 0,9% c th lm gim c tnh cho thn. Ngoi ra c th thy bt thng test chc phn gan, thiu mu do gim sn xut erythropoietin ca thn. 1.1.5. Ch phm v liu lng - Amphoterincin B (Fungizon) tim, truyn t nh mch. L 50 mg bt ng kh pha thnh dch treo trong glucose 5%, truyn 0,5-0,6mg/kg trong 4gi. - Vin nn 100 mg. Ngm (nm ming) hoc ung (nm rut) 1- 4 vin/ ngy. - Kem bi 3%. 1.2. Flucytosin 1.2.1. c im Flucytosin (5-FC) c tm ra nm 1957 trong khi nghin cu cc thuc chng ung th (gn ging 5-FU). Flucytosin d tan trong nc, ph khng nm hp hn amphotericin B v khng c tc dng chng ung th. 1.2.2. Tc dng v c ch Ch c tc dng trn Cryptococcus neoformans v vi loi candida. V c tc dng hip ng vi thuc chng nm khc nn thng c dng ph i hp trnh khng thuc.

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Flucytosin c nhp vo t bo nm nh enzym cytosin permease. Trong t bo, 5-FC c chuyn thnh 5-FU (5 fluorouracil), sau thnh 5 fluorodeoxyuridin monophosphat (F-dUMP) c ch tng hp DNA, v thnh fluorouridin tri phosphat (FUTP) c ch tng hp RNA. T bo ngi v t bo ng vt c v khng chuyn c 5-FC thnh 5-FU, v th 5-FC c tc dng chn lc trn nm. 1.2.3. Dc ng hc Hp thu d dng qua ng tiu ha (>90%), t pic huyt tng sau 1-2gi, t gn vo protein huyt t ng, thm d vo cc dch trong c th, vo dch no tu vi nng bng 65-90% nng huyt tng. Thi qua thn 80% di dng khng chuyn ho. Thi gian bn thi l 3-6gi, ngi suy thn, c th ko di ti 200 gi. 1.2.4. c tnh C kh nng l vi khun rut chuyn ho flucytosin thnh hp cht c, gy c ch tu xng, dn n thiu mu, gim bch cu, gim tiu cu, ri lon chc nng gan (5%) ri lon tiu ho (nn, tiu chy). 1.2.5. Ch phm Ancobon: vim nang 250-500mg. Ung 100-150mg/kg/ngy chia lm 4ln. Dng ph i hp vi amphotericin B (0,3mg/kg/ngy) cha nm Candida. Khng dng dng tim. 1.3. Nhm azol: Imidazol v Triazol 1.3.1. c im Imidazol v triazol u thuc nhm azol chng nm, c cng c ch v cng ph tc dng. Triazol dng ng ton thn chm b chuyn ho v t tc dng trn tng hp sterol ca ngi hn l imidazol. V vy, cc dn xut mi u phn ln l t triazol ch khng phi t imidazol. Vic tm ra azol (1980) l mt bc tin quan trng trong nghin cu thuc chng nm.

X = C: Imidazol: ketoconazol, miconazol, clotrrimazol X = N: Triazol; itraconazol, fluconazol Nhn triazol 1.3.2. Tc dng v c ch Ph tc dng rng, gm: cc loi Candida, Cryptococcus neoformans, Blastomyces dermatitidis, cc bnh nm da. Cc azol c ch enzym cytochrom P450 ca nm nn lm gim tng hp ergosterol ca vch t bo nm, km hm s ln ln v pht trin ca nm. 1.3.3. Dc ng hc, c tnh v p dng Ba thuc thng dng ca nhm azol l:

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1.3.3.1. Ketoconazol (Nizoral) - Ung d hp thu, nhng cn mi trng acid (nu dng cng khng H2 s lm gim hp thu mnh). Gn vo protein huyt tng 84%, vo hng cu 15%, cn 1% dng t do. Thi gian bn thi tng theo liu, ung 800mg th t/2 = 7-8gi. Vo dch no tu bng 1% liu dng. - c tnh: Km fluconazol v itraconazol l c ch c cytocrom P450 ca ng vt c v nn dn n 2 hu qu: . Lm cn tr sinh tng hp hormon thng thn, sinh dc, n ng gy chng v to, gim tnh dc; ph n gy lon kinh nguyt, v sinh. . Lm tng c tnh ca thuc kt hp cng chuy n ho qua P450. Ngoi ra cn gp bun nn, chn n (20%), d ng (4%) tng transferase (5-10%). V th khng dng liu cao. - Ch nhv liu dng: Vin 200mg, kem bi 2%. Candida m o: ung 400mg/ngy 5 ngy Candida thc qun: ung 400mg/ngy 10-14 ngy Histoplasmosis, blastomycosis: 400mg/ngy 6-12 thng. Khng dng khi c thai v ang nui con bng sa m. 1.3.3.2. Itraconazol (Sporanox, Sporal) Ph rng, t c hn ketoconazol v ch c ch cytochrom P450 c hiu ca nm. - Hp thu qua ng ung khong 30%, hp thu ti a ngay sau khi n. Pic huyt tng sau 3-4 gi, t/2 khong 1-1,5 ngy. Gn vo protein huyt t ng ti 99,8%. Gn vo cc m sng (da, mng) vi nng cao hn huyt tng 4ln v gi rt lu t vi tun n vi thng sau ngng iu tr. Nng trong m mm (ph i, thn, gan, lch) cng cao hn huyt tng 2-3 ln. - Ch nh v liu lng: Vin nang 100mg, ung ngay sau ba n. . Candida m o: Ung 1 ngy duy nht 400mg chia 2 ln, hoc 200mg/ngy3 ngy. . Nm da, lang ben: ung 200mg/ngy 7 ngy. . Candida ming: 100mg/ngy 15 ngy. . Nm mng: ung 2 t cch nhau 3 tun. Mi t 7 ngy. Mi ngy ung 400mg chia 2 ln. 1.3.3.3. Fluconazol (Flunaz, Diflucan, Triflucan) C gn thm 2 nguyn t Fluo. - Ung hp thu hon ton, khng chu nh hng ca thc n hay acid dch v. Rt tan trong nc nn c th tim tnh mch. Nng trong huyt tng ca ng ung gn bng ng tim t nh mch. Gn vo protein huyt tng 11-12%, t/2 = 25 gi, khong 90% thi qua thn di dng khng i. Thm vo m i dch ca c th, nng trong dch no tu t 50 - 90% nng huyt tng. - Thuc d dung np. C th gp phn ng d ng.

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- Ch nh v cch dng: Vin nang 50, 100, 150 mg. Liu 100 - 400mg/ngy. L 200 - 400 ml, cha 2mg/ml. Candida nim mc (ming, m o), nm da, nm mng, nm Cryptococcosis (mng no, ph i, da), nhim nm trong AIDS (lm tng sinh kh dng ca Zidovudin khong 20% v lm gim chuyn ha Zidovudin). Thi gian iu tr tu tng loi nm, tng t itraconazol. Khng dng cho ph n c thai hoc ang cho con b. Khng dng cho tr di 16 tui v l thuc mi, cha s liu theo di. 1.4. Griseofulvin 1.4.1. c im Khng sinh ly t nm Penicillium griseofulvum, khng tan trong nc, vng bn vi nhit. 1.4.2. Tc dng v c ch Tc dng trn nm da, biu b, tc, mng: Microsporum, Epidermophyton v Trichophyton. Khng c tc dng trn vi khun. Griseofulvin gn vo protein tiu qun, lm gy thoi phn bo nn km hm s pht trin ca nm. 1.4.3. Dc ng hc Hp thu qua tiu ha thay i theo dng thuc v thc n. Ch phm siu vi tinh th (ultramicrocristalline preparation) c sinh kh dng gp ri loi bt vi tnh th. Thc n c m s d hp thu v thuc khng tan trong nc. t pic sau 4 gi v t/2 = 24 gi. Thuc tch lu trong t bo tin thn ca keratin lm n khng li s xm nhp ca nm, do tc, mng mi m c s khng b bnh. 1.4.4. c tnh Thng nh: nhc u (15%), vim thn kinh, ng g, khng lm c vic kho lo, mt m i, nhn m, ri lon tiu ha... 1.4.5. Ch phm, liu dng Griseofulvin (Fulvicin, Grisactin) vin nang 125-250 mg; vin nn 250-500mg. Liu tr em 10mg/kg; ngi ln 0,5 - 1,0 g. Thi gian iu tr t nht l 1 thng cho bnh nm tc v 6-9 thng cho bnh nm mng. 2. THUC CHNG NM TI CH 2.1. Nystatin Nystatin l khng sinh macrolid, tng t amphotericin B c v cu trc v c ch tc dng, nhng c hn nn ch dng ngoi v khng hp thu qua da hoc m o. Tc dng iu tr cc loi nm Candida nim mng v k da. Nystatin (Mycostatin, Nilstrat), dng pomat, kem bi, thuc bt, dng phun, cha 100.000 n v/g. Bi 2 - 3 ln/ngy 7 ngy. 2.2. Clotrimazol v miconazol

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Thuc nhm azol dng ngoi. Bi ngoi da ch hp thu 0,5%; bi m o, hp thu 10%.

3-

Dng thuc: Kem 1%, thuc ra, dung dch (Lotrimin, Mycelex), vin nn t m o 100 - 500 mg, thuc phun 2%. Nm da: bi 2 ln/ngy. Nm m o: t vin 500mg/ngy; kem 5g/ngy, dng trong 7 - 14 ngy. Nm ming: vin ngm 10mg 5 ln/ngy. CU HI T LNG GI 1. Trnh by c ch tc dng v c tnh ca amphotericin B v griseofulvin. 2. So snh ketoconazol, itraconazol v fluconazol v dc ng hc, c tnh v p dng iu tr.

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Bi 17: THUC CHNG LAO - THUC IU TR PHONG MC TIU HC TP: Sau khi hc xong bi ny, sinh vin c kh nng: 1. Trnh by c 5 thuc chng lao thng dng v cc mt tc dng, c ch tc dng, nhng im chnh v dc ng hc v tc dng khng mong mun. 2. Trnh by c nguyn tc v phc iu tr lao hin nay. 3. Trnh by c tc dng, c ch tc dng, nhng im chnh v dc ng hc v tc dng khng mong mun ca dapson v clofazimin. 4. Nu c 3 nguyn tc v phc iu tr phong hin nay. 1. THUC CHNG LAO Lao l bnh nhim khun ph bin do trc khun lao gy nn v c th cha kh i hon ton. Trc khun lao gy bnh lao phi v cc c quan khc l loi vi khun khng cn, khng acid, sng trong mi trng a kh, pht trin chm (chu k phn chia khong 20 gi). Mng t bo ca trc khun lao c cu to bi 3 lp: phospholipid trong cng, polysACharid lin kt vi peptidoglycan. Cc peptidoglycan c gn vi arabingolactose v acid mycolic lp gia. Acid mycolic lin kt vi cc lipid phc tp nh myosid, peptidoglycolipid, phenolglycolipid ngoi cng. dy, mng v s cha nhiu hay t lipid ca mng t bo nh hng r rt n s khuych tn ca cc thuc chng lao vo trong t bo v sc khng ca vi khun vi cc tc nhn ha hc v l hc t bn ngoi. Trong c th, vi khun lao c th tn ti di 4 dng qun th nhng vng tn thng khc nhau. Cc qun th ny chu s tc ng ca thuc chng lao mc rt khc nhau. - Qun th trong hang lao cn gi l qun th A. Trong hang lao c pH trung tnh, lng oxy di do, vi khun nm ngoi t bo v pht trin nhanh, mnh nn s lng vi khun nhiu, d xut hin t bin khng thuc. Qun th ny b tiu dit nhanh bi rifampicin, INH v streptomycin. - Qun th trong i thc bo cn gi l qun th B. Trong i thc bo pH acid, s lng vi khun t v pht trin chm nhng c kh nng sng st cao nn tn ti dai dng gy nguy c ti pht bnh lao. Pyrazinamid c tc dng tt nht vi qun th ny. Rifampicin c tc dng, INH rt t tc dng cn streptomycin khng c tc dng vi loi qun th ny. - Qun th nm trong b u gi l qun th C. b u l vng rt t oxy, c pH trung tnh, vi khun chuyn ha tng t ngn nn pht trin rt chm, ch c rifampicin c tc dng vi qun th vi khun ny. - Qun th nm trong cc tn thng x, vi ha gi l qun th D. S lng vi khun lao khng ln khng pht trin c g i l trc khun ng. Cc thuc chng lao khng c tc dng trn qun th vi khun ny. Mc tiu quan trng trong iu tr lao l dng cc thuc tiu dit tt c cc qun th, c bit l qun th B, C. Ngoi ra, tu theo th bnh c th dng mt s phng php iu tr thch hp nh phu thut, ct lc, b bt hoc chc ht v.v... Hin nay thuc chng lao c chia thnh 2 nhm:

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Nhm I: L cc thuc chng lao chnh thng dng, c ch s iu tr cao, t tc dng khng mong mun : isoniazid (INH, Rimifon), rifampicin, ethambutol, streptomycin v pyrazinamid. Nhm II: L nhng thuc t dng hn, dng thay th khi vi khun lao khng thuc, c phm vi iu tr hp, c nhiu tc dng khng mong mun: ethionamid, paraaminosalicylic (PAS), cycloserin, amikacin, kanamycin, capreomycin, thiacetazon, fluorquinolon v azithromycin, clarythromycin. 1.1. Cc thuc chng lao thng dng 1.1.1. Isoniazid (Rimifon, INH, H) L dn xut ca acid isonicotinic, va c tc dng km khun, va c tc dng dit khun. Nng c ch ti thiu i vi trc khun lao 0,025 - 0,05 mcg/ml. Khi nng cao trn 500mcg/ml, thuc c tc dng c ch s pht trin ca cc vi khun khc. Thuc c tc dng trn vi khun ang nhn ln c trong v ngoi t bo, k c trong mi trng nui cy. 1.1.1.1. C ch tc dng: Mc d isoniazid c s dng iu tr lao vi thp k v n nay vn c coi l thuc s mt trong iu tr tt c cc th lao nhng c ch tc dng ca thuc vn cn cha c gii thch y . Theo Takayama v cng s (1975), acid mycolic l mt thnh phn quan trng trong cu trc mng ca trc khun lao. Giai on u ca qu trnh tng hp mycolic l s ko di mch ca acid nh desaturase. Vi nng rt thp ca INH, enzym ny b c ch lm ngn cn s ko di mch ca acid mycolic dn dn gim s lng lipid ca mng vi khun, vi khun khng pht trin c. Ngoi ra, mt s tc gi cn cho rng, INH to chelat vi Cu2+ v c ch cnh tranh vi nicotinamid v pyridoxin lm r i lon chuyn ha ca trc khun lao. 1.1.1.2. Dc ng hc Thuc c hp thu nhanh qua ng tiu ha. Sau khi ung 1-2 gi, nng thuc trong mu t ti 3-5mcg/ml. Thc n v cc thuc cha nhm lm gim hp thu thuc. Isoniazid khuch tn nhanh vo cc t bo v cc dch mng ph i, dch c trng v nc no tu, cht b u, nc bt, da, c. Nng thuc trong dch no tu tng ng vi nng trong mu. Thuc c chuyn ha gan nh phn ng acetyl ha, thu phn v lin hp vi glycin. S acetyl ha ca isoniazid thng qua acetyltransferase c tnh di truyn. ngi c hot tnh enzym mnh, thi gian bn thi ca thuc khong 1 gi, nhng ngi c hot tnh enzym yu thi gian bn thi ca thuc khong 3 gi. Thuc c thi tr ch yu qua thn. Sau dng thuc 24 gi, thuc thi tr khong 75 95% di dng chuyn ha. Gn y, mt s tc gi cho rng dng acetyl ha ca INH c kh acetyl trong c th to thnh dng cn hot tnh. 1.1.1.3. Tc dng khng mong mun - D ng thuc, bun nn, nn, chng mt, to bn, kh ming, thoi ho bch cu ht, thiu mu. - Vim dy thn kinh ngoi vi chim 10 - 20%, c bit hay gp bnh nhn dng liu cao, ko di, nghin ru, suy dinh dng v tng glucose mu. Vitamin B6 c th lm hn ch tc dng khng mong mun ny ca isoniazid.

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- Vim dy thn kinh th gic. - Vng da, vim gan v hoi t t bo gan thng hay gp ngi trn 50 tui v nhng ngi c hot tnh acetyltransferase yu. C ch gy tn thng gan ca isoniazid n nay vn cha c gii thch y . C gi thuyt cho rng, acetylhydrazin cht chuyn ha ca isoniazid b chuyn ha qua cytocrom - P450 sinh ra gc t do gy tn thng t bo gan. Mt s thuc gy cm ng cytocrom- P450 nh phenobarbital, rifamycin gy tng tn thng gan ca INH. - Isoniazid c ch s hydroxyl ha ca phenytoin, c th gy ng c phenytoin khi iu tr ph i hp thuc. 1.1.1.4. p dng iu tr - Rimifon: vin nn 50 - 100 - 300 mg; ng tim 2ml cha 50mg hoc 100mg/ml; Siro 10 mg/ml. - Phi hp vi cc thuc chng lao khc iu tr tt c cc th lao. Ngi ln dng 5mg/kg th trng, tr em 10-20mg/kg th trng, ti a 300mg/24 gi. - Thuc c th dng d phng cho nhng ngi c test tuberculin dng tnh hoc bnh nhn sau iu tr tn cng bng cc thuc chng lao. Ngi ln dng 300mg/ 24 gi, tr em 10mg/kg th trng, ti a 300mg/24 gi ko di 3 - 6 thng. Khi iu tr, cn dng km vitamin B6 10- 50mg /24 gi gim bt tc dng khng mong mun ca INH. 1.1.2. Rifampicin (RMP,R) Rifamycin l t ch c mt h khng sinh c cu trc ging nhau c chit xut t Streptomyces mediterranei. Rifampicin l khng sinh bn tng hp t rifamycin B c tc dng dit khun c trong v ngoi t bo, chuyn ha v thi tr chm so vi cc cht cng nhm. 1.1.2.1. Tc dng Thuc khng ch c tc dng dit trc khun lao, phong, m cn dit c cc vi khun gram m, E-coli, trc khun m xanh, Haemophilus influenzae, Nesseria meningitis. Rifampicin dit vi khun c trong v ngoi t bo. Trong mi trng acid, tc dng ca thuc mnh gp 5 ln. 1.1.2.2. C ch tc dng Rifampicin gn vo chu i b ca ARN - polymerase ph thuc ADN ca vi khun lm ngn cn s to thnh chu i ban u trong qu trnh tng hp ca ARN. Thuc khng c ch ARN - polymerase ca ngi v ng vt liu iu tr. Khi dng liu cao gp nhiu ln liu iu tr, thuc c th gy c ch ARN - polymerase ty th t bo ng vt. 1.1.2.3. Dc ng hc Thuc c hp thu tt qua ng tiu ha. Sau khi ung 2 - 4 gi, t c nng ti a trong mu. Acid amino salicylic lm chm hp thu thuc. Trong mu, thuc gn vo protein huyt tng khong 75 - 80%. ng thi tr ch yu ca thuc l qua gan v thn. Ngoi ra, thuc cn thi tr qua nc bt, m, nc mt, lm cho cc dch ny c mu da cam. Thi gian bn thi ca thuc khong 1,5 - 5 gi. Khi chc nng gan gim, thi gian bn thi ca thuc ko di. Ngc li, do t gy cm ng h enzym oxy ha thuc gan, sau iu tr khong 14 ngy thi gian bn thi ca thuc b rt ngn li. Thuc c chu k gan - rut.

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Rifampicin lm tng chuyn ha mt s thuc thng qua tc dng gy cm ng cytocrom - P450 nh: thuc trnh thai, phong ta b- adrenergic, chn knh calci, diazepam, quinidin, digitoxin, prednisolon, sulfonylurea, mt s thuc chng ng mu... 1.1.2.4. Tc dng khng mong mun: Thuc t c tc dng khng mong mun, song c th gp mt s ngi: - Pht ban 0,8%; bun nn, nn (1,5%); St (0,5%); ri lon s to mu. - Vng da, vim gan rt hay gp ngi c tin s bnh gan, nghin ru v cao tui. Tc khng mong mun ny tng ln khi dng ph i hp vi isoniazid. 1.1.2.5. p dng iu tr - Ch phm Rifampicin (Rifampin, Rimactan, Rifadin) vin nang hoc vin nn 300 mg, siro 100mg/Ml, dung dch tim truyn 300- 600 mg/l. 150 -

- Phi hp vi cc thuc chng lao khc iu tr cc th lao, khng dng n c rifampicin trong iu tr lao. Ngoi ra thuc cn c ch nh trong mt s bnh nhim khun do cc vi khun cn nhy cm gy nn. - Liu dng cho ngi ln 1 ln trong 1 ngy 10 - 20mg/kg th trng, ti a 600mg/24 gi. -Khng dng thuc ngi gim chc nng gan v khi iu tr cn theo di chc nng gan thng xuyn. 1.1.3. Ethambutol (EMB, E) 1.1.3.1. Tc dng L thuc tng hp, tan mnh trong nc v vng bn nhit cao, c tc dng km khun lao mnh nht khi ang k nhn ln, khng c tc dng trn cc vi khun khc. 1.1.3.2. C ch tc dng: Theo Takayama v cng s (1979), ethambutol c tc dng km khun l do c ch s nhp acid mycolic vo thnh t bo trc khun lao, lm ri lon s to mng trc khun lao. Ngoi ra, mt s tc gi cn cho rng ethambutol gy ri lon s tng hp acid nhn thng qua c ch cnh tranh vi cc polyamin v to chelat vi Zn2+ v Cu2+. 1.1.3.3. Dc ng hc: Thuc c hp thu tt qua ng tiu ha, sau khi ung 2 - 4 gi, t c nng ti a trong mu. Trong c th, thuc tp trung cao trong cc m cha nhiu Zn2+, Cu2+, c bit l thn, ph i, nc bt, thn kinh th gic, gan, ty v.v... Sau 24 gi, mt na lng thuc ung vo c thi ra ngoi qua thn, 15% di dng chuyn ha. 1.1.3.4. Tc dng khng mong mun: Khi iu tr lao bng ethambutol c th gp mt s tc dng khng mong mun nh: ri lon tiu ha, au u, au bng, au khp, pht ban, st, vim dy thn kinh ngoi vi, nhng nng nht l vim dy thn kinh th gic gy r i lon nhn bit mu sc. Ct ngha cho tn thng th gic, c tc gi cho rng dy thn kinh th gic cha nhiu Zn2+, ethambutol to chelat vi Z2+ gy vim. 1.1.3.5. p dng iu tr: Ethambutol vin nn 100 n 400mg c ph i hp vi cc thuc chng lao iu tr cc th lao, ngi ln ung liu khi u 25mg/kg/ngy trong 2 thng sau gim liu xung 15mg/kg/ngy. Tr em ung 15mg/kg/ngy. Khng dng cho ngi c thai, cho con b, tr em di 5 tui v ngi c vim thn kinh th gic v gim th lc.

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1.1.4. Streptomycin (SM , S). L khng sinh thuc nhm aminoglycosid c tc dng dit khun lao mnh c bit vi khun trong hang lao v mt s vi khun Gram (+) v Gram (-). Nng 10mcg/ml c tc dng dit trc khun lao. c ph i hp vi cc thuc chng lao khc iu tr lao. Tim bp hng ngy ho c cch ngy liu 15mg/kg th trng, ti a khng vt qu 1g/ngy. i vi ngi cao tui, liu dng 500 - 750mg/ngy. Dc ng hc, c ch tc dng, tc dng khng mong mun v chng ch nh ca thuc xin c bi khng sinh nhm aminoglycosid. 1.1.5. Pyrazinamid(Z, PZA) 1.1.5.1. Tc dng: L thuc c ngun gc tng hp, t tan trong nc, tc dng mnh trong mi trng acid c tc dng km khun lao c cu trc tng t nh nicotinamid. Thuc dit trc khun lao trong i thc bo c pH acid v t bo n nhn vi nng 12,5mcg/ml, c bit khi vi khun ang nhn ln. C ch: cha bit d cu trc gn ging acid nicotinic v INH. 1.1.5.2. Dc ng hc: Thuc hp thu nhanh qua ng tiu ho. Ung sau hai gi t c nng ti a trong mu v khuch tn nhanh vo m dch c th. Thuc i qua hng ro mu no tt nn c hiu qu iu tr cao trong lao mng no. Thi gian bn thi ca thuc khong 10 n 16 gi. 1.1.5.3. Tc dng khng mong mun: Thuc c th gy mt s tc dng khng mong mun nh: au bng, chn n, bun nn, nn, st, nhc u, au khp. c bit lu , thuc c th gy tn thng t bo gan, vng da 15% s bnh nhn. Do vy, khi iu tr cn kim tra chc nng gan trc v trong iu tr. Nu c du hiu gim chc nng gan phi ngng thuc. Do cnh tranh vi acid uric h vn chuyn tch cc ti ng thn, pyrazinamid c th gy tng acid uric mu. Pyrazinamid lm gim tc dng h acid uric ca probenecid, aspirin, vitamin C v lm tng tc dng h glucose mu ca cc thuc nhm sulfonylure. 1.1.5.4. p dng iu tr: Vin nn 500mg. Pyrazinamid thng ph i hp vi cc thuc chng lao khc iu tr lao trong 6 thng u, sau thay bng thuc khc. Liu trung bnh ngi ln 1,5-2,0 g/ngy v tr em 35mg/kg/ngy. 1.2. Cc thuc chng lao khc 1.2.1. Ethionamid - L thuc va km khun va dit khun (do c ch tng hp acid mycolic). Ung hp thu t t qua ng tiu ha, sau 3 gi t nng ti a trong mu v thi tr ch yu qua thn di dng chuyn ha. - Thuc c ch nh khi vi khun lao khng vi cc thuc nhm I. Ngoi ra, ethionamid cn c dng ph i hp vi dapson, rifampin iu tr phong vi liu 10mg/kg th trng.

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- Mt s tc dng khng mong mun c th gp nh: chn n, bun nn, nn, i lng, ri lon thn kinh trung ng (au u, co git, mt ng), vim dy thn kinh ngoi vi. Ethionamid c th gy ri lon chc nng gan, cn phi theo di chc nng gan trc v trong khi iu tr. - Thuc c dng vi liu tng dn. Khi u 500mg cch 5 ngy tng 125mg n khi t 15 - 20mg/kg th trng v khng vt qu 1gam/24gi. 1.2.2. Acid paraaminosalicylic (PAS) L thuc km khun lao c c ch tc dng ging sulfonamid, nhng khng c tc dng trn cc vi khun khc. Liu dng: 200- 300mg/kg/ngy, ti a 14 - 16g/ngy. PAS c th gy a lng, nn, au bng. hn ch tc dng khng mong mun, cn ung vo lc no. 1.2.3. Mt s khng sinh khc c tc dng chng lao - Kanamycin v amikacin c nng v c ch ti thiu vi trc khun lao 10 mg/ ml. Liu iu tr lao 1g/ 24 gi. - Capreomycin l 1 peptid vng c tc dng chng lao vi liu 15- 30 mg/ kg/ 24 gi. - Ofloxacin v ciprofloxacin l 2 khng sinh nhm fluorquinolon c nng trong t chc ph i cao hn trong huyt t ng c nng c ch ti thiu trn trc khun lao rt thp t 0,25- 3 mg/ ml. Trong iu tr lao ciprofloxacin ung 1,5g chia 2 ln/ngy; ofloxacin ung 600- 800 mg/ ngy. - Azithromycin v clarythromycin l 2 macrolid mi cng c tc dng trn trc khun lao c ch nh khi trc khun lao khng cc thuc chng lao chnh. - Cycloserin c ch nh iu tr lao vi liu 15- 200 mg/ kg/ ngy. Chi tit xin xem bi Thuc khng sinh. 1.2.4. Thiacetazon (Amithiozon) L thuc km khun. C hot tnh chng lao vi nng c ch ti thiu (MIC) l 1mg/ml. Trong lm sng c th ph i hp vi INH iu tr lao. Liu dng hng ngy 150mg. 1.2.5. Clofazimin Thuc c dng cho nhng bnh nhn c trc khun lao a khng thuc vi liu dng 200mg/24 gi. (Chi tit xin c bi "thuc iu tr phong"). 1.3. S khng thuc ca vi khun lao T l vi khun lao khng thuc ngy cng tng, nguyn nhn ch yu l do dng thuc khng ng phc phi hp, liu lng v thi gian dng thuc hoc cht lng thuc km. S khng thuc c th xp thnh 3 loi: - Khng thuc tin pht: l s khng thuc xy ra bnh nhn cha c dng thuc chng lao ln no. Nguyn nhn l do vi khun lao khng thuc lan truyn t bnh nhn khc sang. - Khng thuc mc phi hay cn gi l khng thuc th pht l s khng thuc sau khi dng cc thuc chng lao t nht mt thng. Nguyn nhn do dng thuc khng ng liu lng v phi hp thuc khng ng gy nn s chn lc vi khun khng thuc.

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- a khng thuc l hin tng vi khun lao khng li t nht 2 loi thuc chng lao trong c khng rifampicin v INH v khng cng vi cc thuc chng lao khc. i ph vi s khng thuc ca vi khun lao, ngn nga s chn lc to ra chng khng thuc v s lan truyn cc chng khng thuc trong cng ng, cn phi p dng ng nguyn tc iu tr lao. 1.4. Nguyn tc dng thuc chng lao v mt s phc iu tr lao 1.4.1. Nguyn tc dng thuc chng lao - gim t l khng thuc v rt ngn thi gian iu tr, cc thuc chng lao lun dng cng mt lc (vo thi gian nht nh trong ngy) t nht 3 loi thuc trong 24 gi v c th phi hp 4-5 thuc trong giai on tn cng 2 - 3 thng u, sau chuyn sang iu tr duy tr. - Cn phi cy vi khun v lm khng sinh chn khng sinh thch hp. - Phi hp thuc theo tnh nng tc dng nhm nng cao hiu qu iu tr v gim tc dng khng mong mun. Thng ph i hp thuc va dit khun trong t bo v ngoi t bo cng vi thuc dit khun th ang pht trin v th bnh. - iu tr lin tc, khng ngt qung, t nht 6 thng v c th ko di 9 - 12 thng. - Tr liu ngn ngy c kim sot trc tip (DOTS =directly observed treatment short course). - Liu php d phng bng INH trong 6 thng cho nhng ngi tip xc vi bnh nhn c kh nng b lao, nhng cha c du hiu nhim khun v ngi c test tuberculin rng trn 10mm v ngi trc kia b lao nhng hin nay th khng hot ng v hin ang dng thuc c ch min dch. - Thng xuyn theo di tc dng khng mong mun ca thuc. - Trong trng hp trc khun lao khng vi cc thuc chng lao chnh thng dng hoc c tc dng khng mong mun m bnh nhn khng th chp nhn c th la chn cc thuc chng lao khc. 1.4.2. Mt s phc iu tr lao hin nay Vit Nam Da trn phc iu tr lao ca t chc Y t Th gii, chng trnh chng lao Quc gia xut mt s phc p dng cho iu tr lao hin nay Vit nam. 1.4.2.1. Ngi bnh cha cha lao bao gi: 2SRHZ / 6HE - iu tr tn cng 2 thng lin tc dng 4 loi thuc S (SM); H (INH); R (RMP); Z (PZA) hng ngy. - iu tr duy tr hng ngy lin tc trong 6 thng vi 2 thuc l H v E (EMB). 1.4.2.2. Ngi bnh c lao ti pht hoc tht bi iu tr: 2SHRZE/1HRZE/5H3 R3 E3 * - iu tr tn cng hng ngy lin tc trong hai thng vi 5 loi thuc SHRZE, mt thng tip theo dng hng ngy 4 loi thuc HRZE. - Sau iu tr duy tr 3 loi thuc H, R, E mt tun dng ba ln cch qung trong 5 thng lin tc. * H: Isoniazid Z: pyrazinamid S: Streptomycin

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R: Rifampicin

E: Ethambutol

S trc ch ci ch thi gian iu tr tnh bng thng; ch s di sau ch ci ch s ngy dng thuc trong 1 tun, nu khng c cc ch s ny th dng thuc hng ngy. 2.THUC IU TR PHONG Bnh phong l bnh nhim khun Mycobacterium leprae. Nu c iu tr sm v ng, bnh phong c th khi, khng li di chng. Hin nay, ba thuc ch yu iu tr phong l: dapson, rifampicin v clofazimin. 2.1. Dapson (DDS) L dn xut 4-4 diamino diphenyl sulfon cu trc gn gi ng para-aminobenzoic acid c tc dng km trc khun phong. Mc d, c tng hp t nhng nm 1940, nhng n nay DDS vn c coi l thuc quan trng nht trong iu tr phong. 2.1.1. Dc ng hc Thuc c hp thu gn hon ton qua ng tiu ha. Ung 100mg, sau 24 gi t c nng trong mu gp 50 - 100 ln nng c ch ti thiu. Trong mu, thuc gn vo protein huyt t ng khong 50% v khuch tn nhanh vo cc t chc: da, c, gan, thn v dch no tu. Dapson c chuyn ha gan nh phn ng acetyl ha t o thnh monoacetyl-DDS khng c tc dng km khun. S chuyn ha ca DDS mang tnh di truyn. Thn v mt l ng thi tr ch yu ca thuc. Do c chu k gan - rut, nn thuc tn ti rt lu trong c th, thi gian bn thi ca thuc khong 28 gi. 2.1.2. Tc dng v c ch tc dng Dapson ch c tc dng km khun phong, khng dit khun. C ch tc dng ging sulfonamid. C ch chi tit xin c bi Thuc khng sinh, phn sulfamid. 2.1.3. Tc dng khng mong mun Dng Dapson c th gp mt s tc dng khng mong mun sau: - Bun nn, nn, au u, pht ban da. - Ri lon tm thn, vim dy thn kinh ngoi vi. - Thiu mu, tan mu, c bit hay gp ngi c thiu ht G6PD. - Methemoglobin - Hi chng sulfon hay Jarish - Herxheimer. Hi chng ny thng xut hin sau khi dng thuc 5-6 tun. Biu hin: st, vng da, hoi t gan, vim da, met-Hb v thiu mu.y l h i chng rt nng, cn phi ngng thuc ngay v h i sc tch cc trnh t vong. 2.1.4. p dng iu tr Do t l trc khun phong khng thuc ngy cng cao, nn t nm 1982 Vit Nam khng dng ring dapson iu tr m thng phi hp vi clofazimin hoc rifampin. Thuc dng vin nn 25mg, 100mg ung khi u liu thp 50mg/24 gi. Nu bnh tin trin khng tt, tng liu ln 100 mg/24 gi v duy tr t nht trong 2 nm. Trong iu tr cn theo di cng thc mu thng xuyn. nhng bnh nhn c d ng vi thuc, suy gim chc nng gan, thiu ht G6PD hoc met-hemoglobinreductase, chng ch nh dng thuc. 2.2. Rifampicin

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L khng sinh khng ch dit khun lao v cc vi khun Gram (+), Gram (-) khc, m cn c kh nng dit trc khun phong mnh. So vi dapson, thuc khuch tn vo m thn kinh km nn khng lm gim c triu chng tn thng thn kinh do trc khun phong gy nn. Thuc c phi hp vi cc thuc iu tr phong khc vi liu 600mg/24 gi. Chi tit v rifampicin xin c bi Thuc khng sinh v bi Thuc chng lao. 2.3. Clofazimin (Lampren) Thuc c tc dng km khun phong v mt s vi khun gy vim lot da (Mycobacterium ulcerans) v gy nn vim ph qun mn tnh (Mycobacterium avium). Ngoi ra, clofazimin cn c tc dng chng vim v ngn chn s pht trin ca cc nt sn trong bnh phong. Theo Morrison v Marley (1976), clofazimin c tc dng km khun l do thuc gn vo ADN ca trc khun lm c ch s nhn i ca ADN. Ung hp thu nhanh v tch ly lu trong cc m. Thn l ng thi tr ch yu ca thuc. Ngoi ra, thuc cn c thi qua m hi. Trong qu trnh dng thuc, c th gp mt s tc dng khng mong mun nh: mt mu da, vim rut, tng bch cu a acid. Vin 100mg - phi hp vi dapson v rifampin iu tr mt s th phong vi liu 50mg/24 gi hoc 100-300mg/24 gi/tun. Khi iu tr, cn theo di chc nng gan v thn. 2.4. Cc thuc iu tr phong khc 2.4.1. Sulfoxon Thuc c cu trc tng t nh dapson, nhng hp thu khng hon ton qua ng tiu ha v thi tr ch yu qua mt v qua phn. C ch tc dng v tc dng khng mong mun ca thuc ging dapson. Thuc c th dng thay dapson iu tr phong vi liu 330mg/24 gi. 2.4.2. Thalidomid L thuc an thn, nhng c tc dng iu tr phong, c bit th phong c. Liu dng 100300mg/24 gi. Do gy qui thai, c bit giai on 24 - 36 tun u ca k thai nghn, nn thuc t c dng. 2.4.3. Ethionamid C tc dng va km khun va dit khun lao v phong c th thay th clofazimin trong nhng trng hp khng clofazimin. Liu dng hng ngy 250 - 375mg. Chi tit xin c thm bi Thuc chng lao. 2.5. Nguyn tc v mt s phc iu tr phong hin nay Nhm tng hiu qu iu tr, rt ngn thi gian dng thuc v hn ch s khng thuc ca trc khun phong t 1982, T chc Y t Th gii khuyn co mt s nguyn tc iu tr phong nh sau: - a ha tr liu, khng dng mt loi thuc iu tr phong v thng dng 3 thuc dapson, rifampicin v clofazimin. - Phi hp ha tr liu vi vt l liu php v th dc liu php trnh tn ph. - Ung thuc ng liu lng, ng phc , thi gian v nh k theo di tc dng trn lm sng, xt nghim vi khun v tc dng khng mong mun.

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- Thi gian iu tr ko di tu thuc vo mc nhim trc khun. 2.5.1. Phc iu tr nhm c nhiu trc khun Daps on 100m g t ung m i ngy Rifampici n 600mg m i thng ung 1 ln c gim st Clofazimin 300mg m i thng ung 1 ln c gim st + 50mg hng ngy t ung Thi gian iu tr t nht 2 nm hoc cho n khi xt nghim tm trc khun m tnh Theo di Sau 1-2-6 thng (tron g5 nm)

Phc iu tr nhm t vi khun Dapson 100mg t ung hng ngy Rifampicin 600mg m i thng ung 1 ln c gim st Thi gian iu tr 6 thng Theo di Sau 1-2-4-6 thng (trong 3 nm)

Phc iu tr nhm bnh nhiu vi khun tr em Rifampici n hng thng c kim tra (ung) 150mg Clofazimin Hng thng c gim st (ung) 100mg Hng tun, hng ngy t ung 100mg (hng tun) 300mg 150200mg 200300mg 150mg (hng tun) 50mg (hng tun) 50-75mg 25-50mg Dapson t ung hng ngy Thi gian iu tr

Cn nng tr

20 kg 2130kg 3150kg

25mg

t nht 2 nm hoc n khi xt nghim m tnh

450mg

2.5.4. Phc iu tr nhm bnh t vi khun tr em Cn nng tr Rifampicin hng thng c gim st (ung) Dapson hng ngy t ung Thi gian iu tr

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20kg 21 30 kg 31 50 kg

150 mg 300mg 450 mg

25mg 25 50 mg 50 70 mg 6 thng

CU HI T LNG GI 1. Trnh by tc dng, c ch tc dng, c im dc ng hc v tc dng khng mong mun ca INH v cc nguyn tc iu tr lao. 2. Trnh by tc dng, c ch tc dng, c im dc ng hc v tc dng khng mong mun ca rifampicin, v phc iu tr lao hin nay. 3. Trnh by tc dng, c ch tc dng, c im dc ng hc v tc dng khng mong mun ca ethambutol v pyrazinamid. 4. Trnh by tc dng, c ch tc dng, c im dc ng hc v tc dng khng mong mun cu streptomycin. 5. Trnh by tc dng, c ch tc dng, c im dc ng hc v tc dng khng mong mun cu dapson. 6. Trnh by tc dng, c ch tc dng, c im dc ng hc v tc dng khng mong mun cu clofazimin. 7. Trnh by nguyn tc v phc iu tr phong hin nay.

Bi 18:

THUC IU TR ST RT

MC TIU HC T P: Sau khi hc xong bi ny, sinh vin c kh nng:

1. Trnh by c tc dng, c ch tc dng ca cc thuc chng st rt. 2. Trnh by c tc dng khng mong mun v p dng iu tr ca cc thuc chng st rt. 3. Gii thch c nguyn nhn khng thuc st rt ca plasmodium falciparum.
1. I CNG

Bnh st rt c Hypocrate m t cch y hn 2000 nm, l bnh truyn nhim, do plasmodium gy ra, plasmodium l mt loi k sinh trng khng nhng gy bnh cho ngi m cho c sc vt. Bn loi k sinh trng st rt gy bnh cho ngi l: P. falciparum, P.vivax, P.malariae v P.ovale. Vit nam, st rt do P.falciparum chim khong 70- 80%, do P.vivax 20- 30%, P.malariae 1- 2% cn P.ovale hu nh khng c. Dch st rt do P.falciparum thng xy ra t ngt, din bin nng, t vong cao nhng thi gian tn ti ca dch ngn.

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Ngi c th nhim bnh st rt theo 3 phng thc: - Do mui truyn: y l phng thc nhim ch yu v quan trng nht. - Do truyn mu. - Truyn qua rau thai. Vic iu tr st rt hin nay cn gp nhiu kh khn v k sinh trng st rt (c bit l P.falciparum) khng li nhiu thuc chng st rt. Hn na, Vit nam c khong 35 triu ngi sng trong vng st rt lu hnh (trong c 15 triu ngi sng trong vng st rt lu hnh nng), nn mun iu tr st rt c hiu qu phi trit tun th phc iu tr ca chng trnh phng chng st rt quc gia.
2. CHU K SINH HC CA K SINH TRNG ST RT

2.1.

Chu k pht trin trong c th ngi (chu k sinh sn v tnh)

2.1.1. Giai on gan Khi mui t ngi, thoa trng ( trong tuyn nc bt mui) chui qua mch mu lu thng trong mu. Sau 30 pht, thoa trng vo gan pht trin trong t bo gan thnh th phn lit (10 - 14 ngy), sau ph v t bo gan v gii phng ra cc mnh trng. Giai on ny gi l giai on tin hng cu. Vi P.falciparum, tt c mnh trng u vo mu v pht trin . Cn P.vivax v P.ovale, ngoi s pht trin tc th ca cc thoa trng thnh th phn lit, cn c s pht trin mun hn ca mt s thoa trng khc. Nhng thoa trng ny khng pht trin ngay thnh th phn lit m to thnh cc th ng. Cc th ng pht trin tng t thnh phn lit, v ra v gii phng nhng mnh trng vo mu gy nn nhng cn ti pht xa (th ngoi hng cu). 2.1.2. Giai on mu Cc mnh trng t gan xm nhp vo hng cu, lc u l th t dng ri pht trin thnh phn lit non, phn lit gi. Th phn lit gi s ph v hng cu gii phng ra nhng mnh trng. Lc ny tng ng vi cn st xy ra trn lm sng. Hu ht cc mnh trng ny quay tr li k sinh trong cc hng cu mi, cn mt s bit ha thnh nhng th hu gii, l nhng giao bo c v giao bo ci. 2.2. Chu k pht trin trong c th mui (chu k sinh sn hu tnh) Giao bo c v ci c mui ht vo d dy s pht trin thnh nhng giao t c v ci, qua sinh sn hu tnh sinh ra thoa trng. Cc thoa trng n tp trung trong tuyn nc bt ca mui l tip tc truyn bnh cho ngi khc.

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Chu k ca k sinh trng st rt v v tr tc dng ca cc thuc iu tr st rt

1a: Thoa trng vo t bo gan 2a,3a: Th phn lit pht trin trong t bo gan 4: Gii phng cc mnh trng 5: Mnh trng vo hng cu 6: Th t dng trong hng cu 7,8: Th phn lit pht trin trong hng cu 9: Ph v hng cu v gii phng cc mnh trng 10,11,12: Pht trin thnh giao bo c v giao bo ci 1b, 2b, 3b: Pht trin ca th ng.
3. CC THUC IU TR ST RT THNG DNG

3.1.

Thuc dit th v tnh trong hng cu L thuc tng hp, dn xut ca 4 amino quinolein

3.1.1. Cloroquin (Aralen, Avloclor, Malarivon, Nivaquin) 3.1.1.1. Tc dng

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Cloroquin c hiu lc cao i vi th v tnh trong hng cu ca c 4 loi k sinh trng st rt, tc dng va phi vi giao bo ca P.vivax, P.malariae v P.ovale. Khng nh hng ti giao bo ca P.falciparum. C ch tc dng: tn ti, k sinh trng st rt "nut" hemoglobin ca hng cu vt ch vo khng bo thc n. , hemoglobin c chuyn thnh heme (ferriprotoporphyrin IX) l sn phm trung gian c c tnh gy ly gii mng. Heme c chuyn thnh sc t hemozoin t c hn nh enzym polymerase. Cloroquin c ch polymerase, lm tch ly heme, gy c vi k sinh trng st rt, lm ly gii k sinh trng. Thuc tp trung trong khng bo thc n ca k sinh trng st rt, lm tng pH v nh hng n qu trnh ging ha hemoglobin, lm gim cc amino acid cn thit cho s tn ti ca k sinh trng. Cloroquin cn c th gn vo chui xon kp DNA c ch DNA v RNA polymerase, cn tr s tng hp nucleoprotein ca k sinh trng st rt. 3.1.1.2. Dc ng hc Cloroquin hp thu nhanh v gn nh hon ton ng tiu ha, sinh kh dng khong 90%. Sau khi ung 3 gi, thuc t c nng ti a trong mu, 50- 65% thuc gn vi protein huyt tng. Khuch tn nhanh vo cc t chc. Thuc tp trung nhiu hng cu, gan, thn, lch v phi. hng cu nhim k sinh trng st rt, nng thuc cao gp 25 ln hng cu bnh thng. Chuyn ha chm gan, cho desethylcloroquin vn dit c plasmodium. Thi tr chm, khong 50- 60% qua nc tiu. Thi gian bn thi 3- 5 ngy, c khi ti 12- 14 ngy. 3.1.1.3. Tc dng khng mong mun Vi liu iu tr, thuc thng dung np tt, t gp cc tc dng khng mong mun: au u, chng mt, bun nn, nn, au bng, a chy, ri lon th gic, pht ban, nga (c bit lng). Ung thuc khi no c th lm gim cc tc dng ny. Khi dng liu cao v ko di thuc c th gy tan mu ( ngi thiu G6PD), gi m thnh lc, nhm ln, co git, nhn m, bnh gic mc, rng tc, bin i sc t ca tc, da xm nu en, h huyt p. 3.1.1.4. p dng iu tr Ch nh: - Cloroquin c dng trong iu tr v phng bnh st rt - Thng dng trong st rt th nh v trung bnh ( nhng vng v k sinh trng cn nhy cm vi thuc) khng dng khi st rt nng hoc c bin chng. iu tr d phng cho nhng ngi i vo vng c st rt lu hnh. - Thuc cn c dng dit amp gan, trong vim a khp dng thp, lupus ban . Chng ch nh:

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- Chng ch nh: bnh vy nn, ri lon chuyn ha porphyrin, tin s ng kinh v bnh tm thn, ph n c thai. - Thn trng: cn khm mt trc khi dng thuc di ngy v theo di trong sut qu trnh iu tr. Ch ti nhng ngi c bnh v gan, thn, c bt thng v thnh gic v th gic, nghin ru, ri lon v mu v thn kinh, thiu ht G6PD. Liu lng: Chng trnh phng chng st rt Vit nam dng vin cloroquin phosphat 250 mg 150 mg cloroquin base - iu tr st rt: ung cloroquin phosphat 3 ngy Ngy u: 10 mg cloroquin base/ kg, chia 2 ln Ngy th 2, 3: 5 mg cloroquin base/ kg - iu tr d phng; 5 mg cloroquin base/ kg/ tun cho c ngi ln v tr em. 3.1.1.5. Tng tc thuc - Cc thuc khng acid hoc kaolin c th lm gim hp thu cloroquin, v vy ch ung cloroquin sau khi dng thuc ny 4 gi - Cimetidin lm gim chuyn ha v thi tr, tng th tch phn b ca Cloroquin - Dng cloroquin kt hp vi proguanil lm tng tai bin lot ming. - Cloroquin lm gim kh nng hp thu ampicilin 3.1.2. Quinin L alcaloid chnh ca cy Quinquina, c dng iu tr st rt hn 300 nm (t 1630) 3.1.2.1. Tc dng Quinin c tc dng nhanh, hiu lc cao i vi th v tnh trong hng cu ca c 4 loi k sinh trng st rt. Thuc dit c giao bo ca P.vivax v P.malariae nhng t hiu lc i vi giao bo ca P.falciparum. C ch tc dng ca quinin tng t nh cloroquin. Ngoi tc dng dit k sinh trng st rt, quinin cn c mt s tc dng khc. - Kch ng ti ch: khi ung thuc kch ng d dy, gy bun nn, nn. Tim di da rt au, c th gy p xe v khun, v vy nn tim bp su. - Tim mch: liu cao quinin gy gin mch, c ch c tim, h huyt p (khi tim tnh mch nhanh). - C trn: lm tng co bp t cung u n trong nhng thng cui ca thi k c thai, t tc dng trn t cung bnh thng hoc mi c thai. 3.1.2.2. Dc ng hc Thuc c hp thu nhanh v hon ton qua rut, sau khi ung 1- 3 gi thuc t c nng ti a trong mu, nng trong huyt tng thng gp 5 ln trong hng cu. Gn vi protein huyt tng khong 80%, qua c rau thai v sa, 7% vo dch no

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ty. 80% thuc c chuyn ha qua gan v thi tr phn ln qua thn. Thi gian bn thi 7- 12 gi trn ngi bnh thng v 8- 21 gi ngi b st rt. 3.1.2.3. Tc dng khng mong mun - Hi chng quinin; thng gp khi nng thuc trong mu trn 7- 10 mg/ mL vi cc biu hin: au u, nn, chng mt, tai, ri lon th gic. Phi ngng thuc khi cc triu chng tin trin nng hn. - c vi mu: thuc c th gy tan mu (hay gp ngi thiu enzym G6PD). Gim bch cu, gim prothrombin, mt bch cu ht... l nhng du hiu t gp hn. - H ng huyt c th gp khi dng quinin vi liu iu tr. - c tnh nghim trng (do qu liu hoc dng lu di): st, phn ng da (nga, pht ban...), ri lon tiu ha, ic, gim th lc (nhn m, ri lon mu sc, nhn i...), tc dng ging quinidin. - Khi dng liu cao quinin c th gy xy thai, d tt bm sinh thai nhi. - Trong mt vi trng hp, khi tim tnh mch quinin c th gy vim tnh mch huyt khi. 3.1.2.4. Ch nh: - iu tr st rt nng do P.falciparum v st rt c tnh, hay dng nhng vng m P.falciparum khng cloroquin. Ung quinin sulfat kt hp vi cc thuc chng st rt khc nh tetracyclin (hoc doxycyclin), fancidar, mefloquin hoc artemisinin. - Quinin cn c ch nh cho ph n c thai (thay th cloroquin khi b khng thuc). V hiu lc km hn cloroquin nn quinin khng dng iu tr t cp do P.vivax, P.malariae v P.ovale; khng dng khi P.falciparum cn nhy cm vi cloroquin. - Phng bnh: v c nhiu c tnh nn quinin t c dng phng bnh. Tuy nhin nhng vng P.falciparum khng cloroquin, khi khng c mefloquin v doxycyclin, c th phng bnh bng quinin. Chng ch nh, thn trng: - Chng ch nh: ngi nhy cm vi thuc, tin s c bnh v tai, mt, tim mch. Khng dng quinin phi hp vi mefloquin bnh nhn thiu G6PD. - Thn trng: bnh nhn suy thn phi gim liu thuc Liu lng: - iu tr st rt do P.falciparum khng cloroquin (th nh v trung bnh): ung quinin sulfat 30 mg/ kg/ ny, chia 3 ln. Mt t iu tr 7 ngy. - iu tr st rt nng v st rt c tnh: tim bp hoc truyn tnh mch quinin hydroclorid. Tim bp: 30 mg/ kg/ ngy, trong 7 ngy Truyn tnh mch: quinin hydroclorid 10 mg/ kg mi 8 gi (vi 10 mL/ kg dch truyn) p dng iu tr

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Theo di n khi bnh nhn tnh, chuyn sang tim bp hoc ung cho liu iu tr. 3.1.2.5. Tng tc thuc - Cc thuc khng acid cha nhm lm chm hp thu quinin - Quinin lm tng nng digoxin trong mu do gim thanh thi ca thuc. - Lm tng tc dng ca warfarin v cc thuc chng ng mu khc khi dng phi hp. - Cimetidin lm chm thi tr quinin, acid ha nc tiu lm tng thi quinin. 3.1.3. Fansidar L thuc phi hp gia sulfadoxin 500 mg v pyrimethamin 25 mg. 3.1.3.1. Tc dng Sulfadoxin thuc nhm sulfamid thi tr rt chm. Thuc c tc dng dit th v tnh trong hng cu ca P.falciparum, tc dng ch yu vi P.vivax, khng nh hng ti giao bo v giai on gan ca P.falciparum v P.vivax. Pyrimethamin l dn xut ca diaminopyrimidin, c tc dng chm i vi th v tnh trong hng cu ca bn loi k sinh trng st rt. Thuc cn c ch cc th hu tnh pht trin trong c th mui nn c tc dng ngn chn s lan truyn st rt trong cng ng. Sulfadoxin v pyrimethamin c ch 2 enzym ca 2 giai on khc nhau trong qu trnh tng hp acid folic ca k sinh trng. V vy, khi phi hp hai thuc ny s c tc dng hip ng tng mc, lm c ch s tng hp acid folic, nn k sinh trng khng tng hp c DNA v RNA. Dihydrofolat Dihydrofolat DNA synthetase reductase (-) sulfadoxin (-) pyrimethamin PABA + dihydropteridin Acid dihydrofolic Acid tetrahydrofolic Tng hp cc purin RNA 3.1.3.2. Dc ng hc Fansidar hp thu tt qua ng tiu ha, sau khi ung 2- 8 gi thuc t c nng ti a trong mu, khong 90% gn vi protein huyt tng. Thi tr ch yu qua nc tiu. Thi gian bn thi l 170 gi i vi sulfadoxin v 80- 110 gi i vi pyrimethamin. 3.1.3.3. Tc dng khng mong mun Khi dng Fansidar c th b d ng vi sulfamid (nga, m ay...), ri lon v mu (tan mu, gim bch cu ht), ri lon tiu ha, ri lon chc nng thn. Dng Fansidar phng bnh (di ngy) c th gy phn ng da nghim trng: hng ban, hi chng Stevens- Johnson, hoi t biu b... 3.1.3.4. p dng iu tr

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Ch nh: - iu tr st rt do P.falciparum khng cloroquin, thng phi hp vi quinin (v tc dng ca fansidar chm) - D phng cho nhng ngi i vo vng st rt lu hnh nng trong thi gian di. Chng ch nh, thn trng - Chng ch nh: d ng vi thuc, ngi b bnh mu, bnh gan, thn nng, ph n c thai. - Thn trng: ph n cho con b, tr em di 2 thng tui, ngi thiu enzym G6PD, c a d ng, hen ph qun. Liu lng: iu tr st rt: ung 25 mg sulfadoxin + 1,25 mg pyrimethamin/ kg D phng st rt: ngi ln: ung 1 vin/ tun hoc 3 vin/ thng 3.1.3.5. Tng tc thuc Sulfadoxin lm tng tc dng ca warfarin v thiopenton, lm gim hp thu digoxin qua ng tiu ha. 3.1.4. Mefloquin (Eloquin, Lariam, Mephaquin) L thuc tng hp, dn xut ca 4- quinolin methanol. Cu trc ha hc c lin quan nhiu vi quinin. 3.1.4.1. Tc dng Mefloquin c tc dng mnh i vi th v tnh trong hng cu ca P.falciparum v P.vivax nhng khng dit c giao bo ca P.falciparum hoc th trong gan ca P. vivax. Mefloquin c hiu qu trn cc k sinh trng a khng vi cc thuc st rt khc nh cloroquin, proguanil, pyrimethamin... Tuy nhin, vng ng Nam cng c chng P.falciparum khng mefloquin. Hin nay cn c nhiu gi thuyt khc nhau v c ch tc dng ca mefloquin. Tc dng khng k sinh trng st rt lin quan nhiu ti kh nng c ch enzym polymerase ca thuc. 3.1.4.2. Dc ng hc Mefloquin c hp thu tt qua ng ung. Nng ti a trong huyt tng (0,21,4 mg/ mL) t c khong 2- 12 gi sau khi ung mefloquin vi liu duy nht 250 mg. Gn mnh vi protein huyt tng (98%). Thuc tp trung nhiu trong hng cu, phi, gan, lympho bo v thn kinh trung ng. Thuc c chuyn ha gan, cht chuyn ha chnh l acid quinolin carboxylic khng cn hot tnh. Thi tr ch yu qua phn, c th c chu k gan - rut. Thi gian bn thi khong 21 ngy (t 13 n 33 ngy). 3.1.4.3. Tc dng khng mong mun Mc v tn sut ca cc phn ng c hi lin quan nhiu vi liu dng. Tc dng khng mong mun ph bin nht l chng mt (20%) v bun nn (15%).

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- liu phng bnh tc dng c hi thng nh v thong qua, bao gm ri lon tiu ha (bun nn, nn, au bng, tiu chy), au u, chng mt, ngoi tm thu. t gp cc triu chng thn kinh tm thn (co git, ng g, lon tm thn), tng bch cu, tng amino- transferase. - Khi dng liu cao (> 1000 mg) khong 1% bnh nhn thy bun nn, nn, au u, chng mt, tai, ri lon th gic, lon tm thn cp...t gp: nga, pht ban, rng tc, au c. 3.1.4.4. p dng iu tr Ch nh: iu tr v d phng st rt do P.falciparum khng cloroquin v a khng thuc Chng ch nh, thn trng - Chng ch nh: Mefloquin khng s dng cho nhng ngi c tin s bnh tm thn, ng kinh, lon nhp tim, ngi nhy cm vi mefloquin hoc cc thuc c cu trc tng t nh cloroquin, quinin, quinidin, Tr em di 3 thng tui, ngi suy gan hoc suy thn nng khng c dng mefloquin - Thn trng: cn thn khi dng cho ngi li xe, vn hnh my mc v nguy c gy chng mt, ri lon thn kinh- tm thn c th xy ra trong khi iu tr v 2- 3 tun sau khi ngng thuc. Trong d phng st rt bng mefloquin, nu xut hin cc ri lon nh lo u, trm cm, kch ng hoc l ln phi ngng thuc v y l tin triu ca nhng tc dng ph nghim trng hn. Khng nn dng cho tr em di 15 kg hoc di 2 tui, ph n c thai trong 3 thng u. Khng dng mefloquin lu qu 1 nm. Nu dng lu, phi nh k kim tra chc nng gan v mt (thuc c th lm gim chc nng gan v gy tn thng mt) Liu lng: - iu tr st rt: ngi ln v tr em; 15 mg/ kg, chia lm 2 ln, cch nhau 6- 8 gi. Liu dng ti a ngi ln l 1000 mg Phng bnh Ngi ln: ung 1 vin mefloquin 250 mg/ tu n, vo mt ngy c nh, bt u dng t trc khi i vo vng c st rt v ko di 4 tun sau khi ra khi vng st rt lu hnh. i vi ngi i vo vng st rt nng trong thi gian ngn: tun u ung 1 vin 250 mg mi ngy, ung lin 3 ngy. Sau mi tun ung 1 vin Tr em: ung tu theo tui. 3.1.4.5. Tng tc thuc

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- Phi ht sc thn trng khi dng mefloquin cho ngi bnh ang dng cc thuc chn beta, chn knh calci, digitalis hoc cc thuc chng trm cm (c th xy ra tng tc bt li) - Dng mefloquin cng vi valproic acid lm gim nng valproat trong huyt thanh. - Phi hp mefloquin vi quinin s lm tng c tnh trn thn kinh (gy co git) v tim mch Mefloquin c th dng cho ngi sau khi tim quinin nhng phi cch 12 gi sau liu cui cng ca quinin trnh c tnh. 3.1.5. Artemisinin v cc dn xut Artemisinin c phn lp t cy Thanh hao hoa vng Artemisia annua L. h Asteraceae. Artemisinin t tan trong nc, ch dng ng ung hoc t trc trng. Cc dn xut nh artesunat tan c trong nc, c th ung hoc tim (bp, tnh mch), artemether v arteether tan trong du, ch dng tim bp. 3.1.5.1. Tc dng Artemisinin v cc dn xut c hiu qu cao trong iu tr st rt. Thuc c tc dng dit th v tnh trong hng cu ca c 4 loi k sinh trng st rt, k c P.falciparum khng cloroquin. Thuc khng c tc dng trn giai on gan, trn thoa trng v giao bo ca plasmodium. Artemisinin l mt sesquiterpen lacton c cu ni endoperoxid, cu ni ny rt quan trng i vi tc dng chng st rt ca thuc. Hin nay, ngi ta cha hon ton hiu r v c ch tc dng ca thuc. Thuc tp trung chn lc vo cc t bo nhim k sinh trng v phn ng vi hemozoin trong k sinh trng. Phn ng ny to ra nhiu gc t do hu c c c th ph hu mng ca k sinh trng. Mt s cng trnh nghin cu cho thy bnh nhn dng artemisinin c thi gian ct st v thi gian sch k sinh trng trong mu nhanh hn dng cloroquin , quinin hoc mefloquin. Song t l ti pht cao. Artemisinin, artemether v arteether c tc dng mnh hn artemisinin. 3.1.5.2. Dc ng hc Artemisinin hp thu nhanh sau khi ung, t nng cao sau 1 gi, phn b vo nhiu t chc: gan, no, phi, mu, thn, c, tim, lch. Artemisinin gn 64% vo protein huyt tng, dihydroartemisinin 43%, artemether 76% v artesunat 59%. Chuyn ha ch yu qua gan, cho 4 cht chuyn ha: deoxyartemisinin v crystal- 7 khng cn hot tnh. 80% liu dng c thi qua phn v nc tiu trong vng 24. Thi gian bn thi khong 4 gi. 3.1.5.3. Tc dng khng mong mun

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Artemisinin v cc dn xut l nhng thuc c c tnh thp, s dng tng i an ton. Cc tc dng khng mong mun thng nh v thong qua nh ri lon tiu ha (bun nn, nn, au bng, tiu chy), nhc u, chng mt, hoa mt, c bit l sau khi ung. Mt vi ngi dng artesunat, artemether c th b c ch nh tim, chm nhp tim. Sau t trc trng, artemisinin c th kch thch gy au rt, au bng v tiu chy. Trn sc vt, thuc gy c ch tu xng v c vi thn kinh trung ng. 3.1.5.4. Ch nh - L thuc st rt c dng nhiu Vit nam, thng dng iu tr st rt th nh v trung bnh do c 4 loi plasmodium. - iu tr st rt nng do P.falciparum a khng thuc hoc st rt c tnh. Thuc c bit hiu qu trong st rt th no. Chng ch nh: Khng c chng ch nh tuyt i cho artemisinin v cc dn xut. Tuy vy, khng nn dng cho ph n c thai 3 thng u tr khi b st rt th no hoc st rt c bin chng vng m P.falciparum khng nhiu thuc. Liu lng: Artemisinin: ngy u ung 20 mg/ kg ngy th 2 n ngy th 5: mi ngy 10 mg/ kg Artesunat: ngy u ung 4 mg/ kg ngy th 2 n ngy th 5 : mi ngy 2 mg/ kg 3.1.5.5. Tng tc thuc p dng iu tr

- Artemisinin hip ng tc dng vi mefloquin hoc tetracyclin trong iu tr st rt . - S phi hp gia artemisinin vi cloroquin v pyrimethamin c tc dng i khng. 3.1.6. Halofantrin (Halfan) Thuc tng hp, dn xut phenanthrenmethanol. 3.1.6.1. Tc dng Halofantrin c hiu lc i vi th v tnh trong hng cu ca P.falciparum. Thuc khng c tc dng trn giai on gan, th thoa trng v giao bo ca k sinh trng st rt C ch tc dng ca halofantrin cn cha r, c th thuc tc ng nh cloroquin, quinin trn ferriprotoporphyrin IX v gy tn hi mng k sinh trng. 3.1.6.2. Dc ng hc Hp thu km qua ng tiu ha, thuc t c nng ti a trong mu sau khi ung 6 gi. M trong thc n lm tng hp thu ca thuc

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Cht chuyn ha chnh l N- debutyl- halofantrin vn c tc dng dit k sinh trng st rt. Thi tr ch yu qua phn. Thi gian bn thi t 10- 90 gi. 3.1.6.3. Tc dng khng mong mun Halofantrin t c, thnh thong bnh nhn c th b bun nn, nn, au bng, tiu chy, nga, ban . Tiu chy thng xy ra ngy th 2, th 3 sau dng thuc v lin quan ti liu dng. nh hng ca thuc trn tim ph thuc vo liu: liu iu tr, c th ko di khong QT v PR, khi dng liu cao halofantrin c th gy lon nhp tht. 3.1.6.4. p dng iu tr Ch nh: iu tr st rt do P.falciparum khng cloroquin v a khng thuc. Chng ch nh, thn trng: halofantrin khng c dng cho ph n c thai, ph n cho con b, ngi c tin s bnh tim mch, ngi dng mefloquin trc 2 - 5 tun. Khng phi hp halofantrin vi nhng thuc c c tnh trn tim mch. Khng s dng halofantrin phng bnh st rt. Liu lng: vin nn 250 mg Ngi ln v tr em > 40 kg: ung 24 mg/ kg/ ngy, chia lm 3 ln, cch nhau 6 gi. 3.1.6.5. Tng tc thuc Phi hp halofantrin vi mefloquin , cloroquin, quinin, thuc chng trm cm loi 3 vng, dn xut phenothiazin, thuc chng lon nhp tim (aminodaron, quinidin, procainamid), Cisaprid, khng histamin (astemizole, terfenadin), thuc li tiu, s lm tng c tnh trn tim. 3.2. Thuc dit giao bo: primaquin L thuc tng hp, dn xut 8 amino- quinolein 3.2.1. Tc dng Thuc c tc dng tt i vi th ngoi hng cu ban u gan ca P.falciparum v cc th ngoi hng cu mun (th ng, th phn lit) ca P.vivax v P.ovale, do trnh c ti pht. Primaquin dit c giao bo ca c 4 loi plasmodium trong mu ngi bnh nn c tc dng chng ly lan. C ch tc dng ca primaquin cha r rng. C th cc cht trung gian ca primaquin (quinolin- quinin) tc ng nh nhng cht oxy ha, gy tan mu v methemoglobin. 3.2.2. Dc ng hc Primaquin hp thu nhanh, sau khi ung 1-2 gi thuc t nng ti a trong mu, phn phi d vo cc t chc. Chuyn ha hon ton gan. Thi tr nhanh qua nc tiu sau 24 gi. Thi gian bn thi 3- 8 gi. Carboxyprimaquin (cht chuyn ha chnh ca primaquin) c nng trong huyt tng cao hn nhiu so vi cht m v c tch ly v thi tr chm (thi gian bn thi 22- 30 gi). 3.2.3. Tc dng khng mong mun

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Vi liu iu tr thuc dung np tt, tuy vy bnh nhn c th b au bng, kh chu vng thng v, au u nu ung primaquin lc i. Vi liu cao hn c th gy bun nn v nn. Him gp cc triu chng nng nh tng huyt p, lon nhp tim, mt bch cu ht. c tnh thng gp i vi primaquin l c ch tu xng, gy thiu mu tan mu (hay gp ngi thiu G6PD) v methemoglobin (hay xy ra ngi thiu NADH bm sinh) 3.2.4. p dng iu tr Ch nh: iu tr st rt do P.vivax v P.ovale, thng dng phi hp vi cc thuc dit th v tnh trong hng cu - iu tr cho cng ng ct ng lan truyn ca k sinh trng st rt, c bit P.falciparum khng cloroquin. Chng ch nh: Khng dng primaquin cho ngi c bnh tu xng, bnh gan, tin s c gim bch cu ht, methemoglobin, ph n c thai, tr em di 3 tui. Trong qu trnh iu tr, phi ngng thuc ngay khi c cc du hiu tan mu hoc methemoglobin. Liu lng: Ung 0,5 mg primaquin base/ kg/ ngy iu tr st rt do P.vivax v P.ovale: ung 5 ngy lin trnh ti pht. Dit giao bo ca P.falciparum: ung 1 ngy 3.2.5. Tng tc thuc Primaquin lm tng thi gian bn thi ca antipyrin khi dng phi hp.
4. K SINH TRNG KHNG THUC

K sinh trng st rt khng thuc l vn ht sc nghim trng. Trong nhng thp k gn y c s gia tng nhanh chng v s lan rng k sinh trng P.falciparum khng li cc thuc st rt hin c, ch yu l s dng cho phng bnh, t iu tr khng ng phc , hoc dng khng liu... 4.1. nh ngha Theo WHO, khng thuc l kh nng mt chng k sinh trng c th sng st v pht trin mc d bnh nhn c iu tr v hp thu mt lng thuc, hoc chnh xc trong mu bnh nhn c nng thuc m trc y vn ngn cn v dit c k sinh trng s rt . S khng nh vy c th l tng i (vi liu lng cao hn m vt ch dung np c vn dit c k sinh trng) hoc khng hon ton (vi liu lng ti a m vt ch dung np c nhng khng tc ng vo k sinh trng). Khng thuc st rt c th c chia lm hai nhm: - khng t nhin: K sinh trng c tnh khng t trc khi tip xc vi thuc, do gen ca k sinh trng bin d t nhin, tnh khng thuc c di truyn qua trung gian

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nhim sc th. K sinh trng c th khng cho nh P.falciparum khng cloroquin cng c th khng vi amodiaquin. - khng mc phi: K sinh trng nhy cm vi thuc, sau mt thi gian tip xc, tr thnh khng nhy cm na, do t bin nhim sc th, tip nhn gen khng t bn ngoi qua plasmid hoc transposon (gen nhy) ca k sinh trng. 4.2. C ch khng thuc Cho n nay cha c mt gii thch hon ton sng t v c ch khng thuc ca k sinh trng st rt, c mt s gi thuyt nh sau: 4.2.1. K sinh trng khng cloroquin - Do FPIX c i lc yu vi cloroquin, nn cloroquin khng to c phc FPIX cloroquin, v vy thuc khng hy c mng v dit k sinh trng. - chng k sinh trng khng cloroquin protein gn heme (hemin-binding-protein), tng s lng v i lc vi FPIX, protein ny s cnh tranh vi cloroquin to phc vi FPIX, lm mt tc dng ca cloroquin. - P.falciparum c th c 2 gen m ha cht vn chuyn a khng thuc MDR (multi drug resistant) l Pfmdr 1 v Pfmdr 2, gen ny lm tng s vn chuyn P-glycoprotein qu mc trn mng v gy tng thi tr cloroquin. Pfmdr 1 c trong chng k sinh trng khng vi mefloquin, halofantrin nhng khng tng trong chng k sinh trng khng cloroquin. 4.2.2. K sinh trng khng fansidar Ging nh c ch vi khun khng bactrim. - K sinh trng tng tng hp PABA, tng sn xut dihydrosynthetase. - Gim tnh thm vi sulfonamid v pyrimethamin.
5. NGUYN T C IU TR ST RT

- iu tr sm: iu tr cng sm cng tt, ngay sau khi cc triu chng bnh xut hin (tr em trong vng 12 gi, ngi ln trong vng 24 gi). - iu tr ng thuc, liu, thi gian (theo ng phc ). Phi m bo bnh nhn ung c v ung liu thuc cn thit. - Theo di cht ch kt qu iu tr c bin php x l kp thi v thch hp.
CU HI T LNG GI

1. Trnh by chu k ca k sinh trng st rt v v tr tc dng ca cc thuc chng st rt. 2. Trnh by tc dng, c ch tc dng, tc dng khng mong mun v p dng iu tr ca Cloroquin. 3. Trnh by tc dng, tc dng khng mong mun v p dng iu tr ca quinin. 4. Trnh by tc dng, c ch tc dng v p dng iu tr ca Fansidar.

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5. Trnh by tc dng, tc dng khng mong mun v p dng iu tr ca Mefloquin. 6. Trnh by tc dng, tc dng khng mong mun v p dng iu tr ca artemisinin. 7. Trnh by tc dng, tc dng khng mong mun v p dng iu tr ca primaquin. 8. Trnh by tc dng, tc dng khng mong mun v p dng iu tr ca halofantrin. 9. Phn tch nguyn nhn khng thuc ca k sinh trng st rt.

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Bi 19:

THUC CHNG GIUN SN

MC TIU HC T P: Sau khi hc xong bi ny, sinh vin c kh nng:

1. Trnh by c c ch tc dng, tc dng khng mong mun ca cc thuc iu tr giun, sn. 2. Trnh by c p dng iu tr ca cc thuc iu tr giun sn thng dng
1. I CNG

L mt nc vng nhit i, kh hu nng m nn Vit nam c t l nhim giun sn kh cao. nc ta, bnh do giun thng trm trng hn do sn. Cc loi giun c t l nhim cao Vit nam l giun a, giun tc, giun kim, giun mc (m) v giun ch. Bnh sn thng do sn l v sn dy gy ra. Cc loi sn l gy bnh cho ngi l sn l gan nh, sn l phi v sn l rut. nc ta bnh sn dy b thng gp hn sn dy ln. Thuc chng giun sn c nhiu loi, c sp xp da theo hnh th chung ca k sinh trng. a s thuc u hiu qu cao, t tc dng khng mong mun v d s dng.
2. THUC CHNG GIUN

2.1.

Mebendazol (Fugacar, Vermox, Mebutar, Nemasole)

L dn xut benzimidazol, t tan trong nc v dung mi hu c. Khng ht m, n nh khng kh. 2.1.1. Tc dng Thuc c hiu qu cao trn cc giai on trng thnh v u trng ca giun a, giun kim, giun tc, giun mc, giun m. Mebendazol cn dit c trng ca giun a v giun tc. Vi liu cao, thuc c tc dng i vi nang sn. C ch tc dng ca mebendazol ging nh cc dn xut benzimidazol khc: thuc lin kt vi cc tiu qun ca k sinh trng, c ch s trng hp tiu qun thnh cc vi tiu qun (l thnh phn thit yu cho s hot ng bnh thng ca t bo k sinh trng), do lm gim hp thu glucose, cn d tr glycogen, gim ATP (ngun cung cp nng lng cho k sinh trng). Cui cng k sinh trng b bt ng v cht. 2.1.2. Dc ng hc Thuc t hp thu qua ng tiu ha, sinh kh dng qua ng ung di 20%. S hp thu s tng ln khi ung mebendazol cng vi thc n c cht bo. Sau khi ung 4 gi, thuc t c nng ti a trong mu. Khong 95% thuc gn vi protein huyt tng. Chuyn ha ch yu gan thnh cc cht hydroxy v amino ha mt hot tnh. Thi tr qua phn, ch mt lng nh (5- 10%) thi qua nc tiu. 2.1.3. Tc dng khng mong mun

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Thuc dung np tt, t tc dng ph. i khi gp ri lon tiu ha (au bng, tiu chy), au u nh. Dng liu cao iu tr nang sn, thuc c th gy c ch tu xng, rng tc, vim gan, vim thn, st v vim da trc vy. V vy, khi dng liu cao, phi theo di u n nng transaminase trong huyt thanh, bch cu v tiu cu. 2.1.4. p dng iu tr 2.1.4.1. Ch nh iu tr nhim mt hoc nhiu loi giun nh giun a, giun kim, giun tc, giun mc, giun m... Khi khng c albendazol, c th dng mebendazol trong bnh nang sn. 2.1.4.2. Chng ch nh Khng dng mebendazol cho nhng ngi mn cm vi thuc, ph n c thai, tr em di 2 tui, suy gan. 2.1.4.3. Liu lng Ngi ln v tr em trn 2 tui dng liu nh nhau - Nhim giun a, giun tc, giun mc, giun m: ung mi ln 100 mg, ngy 2 ln trong 3 ngy lin, hoc c th dng liu duy nht 500 mg. - Nhim giun kim: liu duy nht 100 mg, ung nhc li sau 2 tun v giun kim rt d b ti nhim. - Bnh nang sn: ung 40 mg/ kg/ ngy, trong 1- 6 thng 2.1.5. Tng tc thuc - Cimetidin c ch chuyn ha mebendazol, c th lm tng nng mebendazol trong huyt tng. - Dng ng thi vi phenytoin hoc carbamazepin s lm gim nng mebendazol trong mu. 2.2. Albendazol (Albenza, Eskazole, Zeben, Zentel) Albendazol l mt dn xut benzimidazol carbamat, cu trc ha hc c nhiu lin quan vi mebendazol. 2.2.1. Tc dng Thuc c tc dng tt vi nhiu loi giun nh giun a, giun kim, giun tc, giun mc, giun m, giun ln, giun xon v sn dy. Albendazol c tc dng trn c giai on trng thnh v giai on u trng ca cc lo i giun sn k sinh trong ng tiu ha, dit c trng giun a v giun tc. C ch tc dng tng t nh mebendazol. 2.2.2. Dc ng hc Sau khi ung, albendazol c hp thu rt km (5%). V chuyn ha ln u ti gan rt nhanh nn khng thy albendazol hoc ch thy dng vt trong huyt tng. Albendazol sulfoxid (cht chuyn ha vn cn hot tnh ca albendazol) gn 70% vi

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protein huyt tng, qua c hng ro mu no v c nng trong dch no tu bng 1/3 nng trong huyt tng. Thi tr phn ln qua thn, mt lng nh qua mt. Thi gian bn thi khong 9 gi. 2.2.3. Tc dng khng mong mun Khi iu tr trong thi gian ngn (1- 3 ngy) khong 6% bnh nhn gp mt vi tc dng khng mong mun nh, thong qua nh: au bng, tiu chy, chng mt, mt, mt ng. Dng liu cao, ko di iu tr bnh nang sn hoc bnh u trng sn ln c tn thng no, tc dng c hi thng gp nhiu v nng hn; au u, ri lon tiu ha (nn, bun nn, au bng), rng tc, ban , nga, gim bch cu... 2.2.4. p dng iu tr 2.2.4.1. Ch nh - Nhim mt hoc nhiu loi giun nh giun a, giun kim, giun tc, giun mc, giun m, giun ln. - iu tr bnh nang sn v bnh u trng sn ln c tn thng no. 2.2.4.2. Chng ch nh Ph n c thai, tr em di 2 tui, ngi c bnh gan nng 2.2.4.3. Liu lng

Ngi ln v tr em trn 2 tui dng liu nh nhau. Khng cn phi nhn i hoc dng thuc ty. - Nhim giun a, giun kim, giun tc, giun mc: ung liu duy nht 400 mg. Giun kim thng hay b ti nhim, c th dng nhc li sau 2- 4 tun. - Nhim giun ln, sn dy; mi ngy ung 400 mg, trong 3 ngy - Bnh nang sn: dng 4 t, mi t 28 ngy, mi ngy 10- 15 mg/ kg chia lm 3 ln. Cc t cch nhau 14 ngy. Tuy nhin thi gian iu tr cn tu thuc vo tnh trng bnh v s dung np ca ngi bnh. - Nhim u trng sn ln c tn thng no: mi ngy 15 mg/ kg chia lm 3 ln, trong 28 ngy. 2.2.5. Tng tc thuc Dexamethason, cimetiin, praziquantel lm tng nng albendazol sulfoxid trong mu khi dng phi hp
3. THUC CHNG SN

3.1.

Niclosamid (cestocid, Yomesan, tredemine, niclocide)

L dn xut salicylanilid c clor, bt mu vng nht, khng mi, khng v, khng tan trong nc. 3.1.1. Tc dng

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Thuc c hiu lc cao i vi sn b, sn ln, sn c (Diphyllobothrium latum), sn dy rut (Hymenolepis nana) khng c tc dng trn u trng sn ln. Thuc c tc dng ti ch, khi tip xc vi thuc, u v thn sn b "git" ngay v niclosamid c ch s oxy ha. Thuc cn nh hng n chuyn ha nng lng ca sn do c ch s sn sinh ra adenosin triphosphat (ATP) ty lp th. Niclosamid cng c ch s thu nhp glucose ca sn. Sn khng bm c vo rut, b tng ra ngoi theo phn thnh cc on nh. 3.1.2. Dc ng hc Thuc hu nh khng hp thu qua ng tiu ha. Thm vo thn sn qua tn thng m niclosamid to v sn, sn b dit ngay ti rut ca vt ch. 3.1.3. Tc dng khng mong mun Thuc dung np tt, t gy tc dng khng mong mun. C th gp cc ri lon nh ng tiu ha nh bun nn, nn, au bng, tiu chy. Cc triu chng: au u, hoa mt, ban v nga him gp hn v c th do gii phng cc khng nguyn t k sinh trng b phn hu. 3.1.4. p dng iu tr 3.1.4.1. Ch nh Niclosamid c dng khi b nhim sn b, sn c v sn ln (nn dng praziquantel khi b nhim u trng sn ln) Dng iu tr sn dy rut khi khng c praziquantel 3.1.4.2. Chng ch nh Trng hp nhim sn b, sn c, sn ln: ung liu duy nht vo sau ba n sng, nn nhai k vin thuc. - Ngi ln: - Tr em 11- 34 kg: - Tr em > 34 kg: - Tr em < 11 kg: 2,0 g 1,0 g 1,5 g 0,5 g

Trng hp nhim sn dy rut (Hymenolepis nana): dng trong 7 ngy lin tip - Ngi ln: mi ngy 2g ung 1 ln. - Tr em 11- 34 kg: ngy u ung 1 g, 6 ngy sau mi ngy 0,5 g ung 1 ln - Tr em > 34 kg: ngy u ung 1,5g, 6 ngy sau mi ngy 1g, ung 1 ln Khi b to bn, cn lm sch rut trc khi iu tr. Sau khi dng thuc, nu mun tng sn ra nhanh hn v nguyn con, nn dng thuc ty mui c tc dng mnh nh magnesisulfat (ung 2- 4 gi sau khi dng niclosamid) 3.1.5. Tng tc thuc Ru lm tng kh nng hp thu ca niclosamid qua ng tiu ha, gy c. V vy, khng c dng ru trong khi iu tr. 3.2. Praziquantel (Biltricid, Cysticid, Droncit, Cesol)

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L dn xut isoquinolein- pyrazin tng hp, c ph tc dng rng, thng c la chn iu tr cc bnh sn l, sn dy. 3.2.1. Tc dng Thuc c hiu qu cao i vi giai on trng thnh v u trng ca sn mng, cc loi sn l (sn l gan nh, sn l phi, sn l rut) v sn dy (sn c, sn ch, sn mo, sn b, sn ln) Praziquantel khng dit c trng sn, khng phng c bnh nang sn. C ch tc dng: thuc lm tng tnh thm ca mng t bo sn vi ion calci, lm sn co cng v cui cng lm lit c ca sn. Khi tip xc vi praziquantel, v sn xut hin cc mn nc, sau v tung ra v phn hu. Cui cng sn b cht v b tng ra ngoi. 3.2.2. Dc ng hc Thuc c hp thu nhanh khi ung (ngay c khi ung trong ba n), trn 80% liu dng c hp thu. Sau khi ung 1- 3 gi, thuc t nng ti a trong mu. Gn vi protein huyt tng khong 80%. Nng thuc trong dch no tu bng 1520% nng trong huyt tng. Thi gian bn thi l 1- 1,5 gi. Thi tr ch yu qua nc tiu, di dng chuyn ha (60- 80%). 3.2.3. Tc dng khng mong mun Cc phn ng c hi thng nh, xy ra mt vi gi sau ung thuc v c th ko di ti 1 ngy, hay gp: au u, chng mt, chong vng, bun nn, nn, au bng, nga, m ay, st nh, au c- khp, tng nh enzym gan. Cc du hiu st nh, nga, pht ban i khi i cng vi tng bch cu a acid c th do gii phng protein ngoi lai t sn cht. Cc phn ng c hi thng gp nhng bnh nhn nhim sn nng, mc v tn sut ca phn ng c hi tng theo liu lng thuc dng. 3.2.4. p dng iu tr 3.2.4.1. Ch nh - Nhim cc loi sn mng gy bnh ngi, bnh sn l gan nh, sn l phi, sn l rut, sn dy ln, sn dy b. - Bnh do u trng sn ln (bnh go sn) no 3.2.4.2. Chng ch nh - Bnh go sn trong mt, bnh go sn tu sng - Nn thn trng khi dng praziquantel ngi b suy gan (phi gim liu), ph n c thai, ph n cho con b (ngng cho b trong nhng ngy iu tr v 72 gi sau iu tr v thuc qua c sa m) Khng c li xe, iu khin my mc... trong khi dng thuc v praziquantel gy chng mt, chong vng. 3.2.4.3. Liu lng

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- Nhim sn mng: liu thng dng cho ngi ln v tr em trn 4 tui l 60 mg/ kg, chia lm 3 ln, cch nhau 4- 6 gi trong ngy. - Nhim sn l gan nh, sn l phi, sn l rut: ung 75 mg/ kg, chia lm 3 ln, trong 1- 2 ngy. - Nhim sn dy ln, sn dy b, sn dy ch... dng liu duy nht 10 mg/ kg cho c ngi ln v tr em. i vi bnh u trng sn ln no: ung 50 mg/ kg/ ngy, chia lm 3 ln, trong 14 n 15 ngy (c th n 21 ngy i vi mt s ngi bnh). Praziquantel thng ung ngay sau ba n, nut nguyn vin thuc, khng c nhai (thuc c v kh chu, c th gy bun nn) C th dng phi hp praziquantel vi dexamethason (6- 24 mg/ ngy) hoc prednisolon (30- 60 mg/ ngy) gim tc dng ph trn thn kinh trung ng nhng ngi bnh mc u trng sn ln no. 3.2.5. Tng tc thuc Carbamazepin, phenytoin v corticoid lm gim ng k nng praziquantel trong huyt tng trong khi cimetidin c tc dng ngc li. 3.3. Metrifonat (Bilarcil) L mt phc hp phospho hu c, c dng trong iu tr t 1960, tc dng ch yu vi cc loi sn mng gy tn thng bng quang. 3.3.1. Tc dng Thuc c tc dng dit sn mng gy bnh bng quang c giai on trng thnh v u trng, khng c hiu lc i vi trng sn l do trng vn tn ti trong nc tiu mt vi thng sau khi sn trng thnh b dit. C ch tc dng ca thuc cha hon ton bit r, c th do metrifonat c ch enzym cholinesterase, lm lit tm thi sn trng thnh. Cui cng sn b y t m ri mch bng quang n cc tiu ng mch ca phi, mc li v cht. 3.3.2. Dc ng hc Thuc hp thu nhanh qua ng tiu ha, nng ti a trong mu t c sau khi ung 1- 2 gi. Thi gian bn thi khong 1,5 gi. Metrifonat v dichlorvos (cht chuyn ha cn hot tnh ca metrifonat) c phn phi vo nhiu t chc v thi tr hon ton qua nc tiu trong vng 24- 48 gi. 3.3.3. Tc dng khng mong mun Metrifonat c th gy ra cc triu chng cng h cholinergic nh: bun nn, nn, au bng, tiu chy, co tht ph qun, au u, hoa mt, chng mt, v m hi... Cc du hiu ny c th bt u 30 pht sau khi ung thuc v ko di ti 12 gi. 3.3.4. p dng iu tr 3.3.4.1. Ch nh - Nhim sn mng gy tn thng bng quang. Thuc c gi thnh r nn c th p dng rng ri cho cng ng trong chng trnh iu tr sn mng bng quang.

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- Phng bnh cho tr em nhng vng c t l nhim bnh cao. 3.3.4.2. Chng ch nh Ph n c thai khng c dng metrifonat. Sau giai on tip xc vi cht dit cn trng loi phospho hu c hoc cc thuc c ch cholinesterase khng nn dng metrifonat Trong 48 gi sau khi ung metrifonat khng c dng cc thuc gin c. 3.3.4.3. Liu lng Mi ln ung 7,5- 10 mg/ kg, ngy 3 ln, trong 14 ngy. 3.3.5. Tng tc thuc Metrifonat hip ng vi tc dng gin c ca succinylcholin 3.4. Triclabendazol (Egaten) L dn xut benzimidazol, tn ha hc l 6- chloro- 5- (2, 3- dichlorophenoxy)- 2methylthiobenzimidazol. 3.4.1. Tc dng Triclabendazol c hiu lc cao vi sn l gan ln (Fasciola) v sn l phi (paragonimus). Thuc c a vo danh mc thuc thit yu iu tr sn l gan ln t 1997. C ch tc dng: thuc gn c chn lc vi cc tiu qun ca sn l, ngn cn s trng hp tiu qun thnh cc vi tiu qun, lm gim hp thu glucose v cn d tr glycogen ca sn. 3.4.2. Dc ng hc Thuc c hp thu nhanh qua ng tiu ha. S hp thu s tng ln khi ung triclabendazol sau ba n. Thi tr ch yu qua phn (90%), mt phn qua nc tiu (10%). Thi gian bn thi khong 11 gi. 3.4.3. Tc dng khng mong mun Thuc c th gy mt s tc dng khng mong mun nh v thong qua: au bng vng h sn phi, v m hi, chng mt, nhc u, st nh, ho, bun nn, nn, ni mn, nga. 3.4.4. p dng iu tr 3.4.4.1. Ch nh Triclabendazol c ch nh trong nhim sn l gan ln cp v mn tnh. 3.4.4.2. Chng ch nh Ph n c thai, ph n ang cho con b, bnh nhn qu mn vi thuc; ngi ang vn hnh my mc, tu xe. 3.4.4.3. Liu lng Ngi ln dng liu duy nht 10 mg/ kg, ung sau khi n no.
CU HI T LNG GI

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1. Trnh by tc dng, c ch tc dng, tc dng khng mong mun v p dng iu tr ca mebendazol. 2. Trnh by tc dng, tc dng khng mong mun v p dng iu tr ca albendazol. 3. Trnh by tc dng, tc dng khng mong mun ca niclosamid. 4. Trnh by tc dng, p dng iu tr ca praziquantel. 5. Trnh by tc dng, tc dng khng mong mun v p dng iu tr ca metrifonat.

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BI 20:

THUC CHNG AMP- TRICHOMONAS

MC TIU HC T P: Sau khi hc xong bi ny, sinh vin c kh nng:

1. Trnh by c tc dng, c ch tc dng ca cc thuc chng amp. 2. Trnh by c tc dng khng mong mun v p dng iu tr ca cc thuc chng amp.
1. THUC CHNG AMIP

Amp k sinh ngi c nhiu loi, nhng ch c Entamoeba histolytica l loi duy nht thc s gy bnh cho ngi. Amp c th gy bnh rut (l amp, vim i trng mn tnh do amip) hoc cc m khc (p xe gan, amip phi, no, da...) Ngi nhim E. histolytica l do n phi bo nang. Bo nang nhim vo ngi qua ng tiu ha bng nhiu cch: thc n, nc ung hoc do rui, gin vn chuyn mm bnh ... Cc bnh do amp ch yu l iu tr ni khoa, nu iu tr khng trit , bnh d tr thnh mn tnh. Th bo nang (th kn) l th bo v v pht tn amp nn rt nguy him v d lan truyn bnh (bo nang c thi ra theo phn v c th sng nhiu ngy trong nc). Amp th bo nang khi gp iu kin thun li s chuyn sang th hot ng 1.1. Thuc dit amip m Cc thuc ny rt c hiu qu i vi cc th n hng cu ca amp. 1.1.1. Emetin hydroclorid L alcaloid ca cy Ipeca. V c nhiu c tnh nn hin nay rt t dng 1.1.2. Dehydroemetin (Dametin, Mebadin) L dn xut tng hp ca emetin, c tc dng dc l tng t nhng t c hn emetin. 1.1.2.1. Tc dng Thuc c tc dng dit amp trong cc m, t c tc dng trn amip rut. Dehydroemetin c tc dng dit amp trc tip do cn tr s chuyn dch phn t ARN thng tin dc theo ribosom nn c ch khng phc hi s tng hp protein ca amp. 1.1.2.2. Dc ng hc Thuc hp thu km qua ng tiu ha. Sau khi tim bp dehydroemetin c phn b vo nhiu m, tch lu gan, phi, lch v thn. Dehydroemetin thi tr qua nc tiu nhanh hn emetin nn t tch lu hn v do t c hn emetin. 1.1.2.3. Tc dng khng mong mun

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Tc dng khng mong mun ca thuc cng tng t nh khi dng emetin nhng nh v t gp hn. - Cc phn ng ti ch: ti vng tim thng b au, d to thnh p xe v trng. C th gp ban kiu eczema. - Tc dng trn thn kinh c: thng gp mt mi v au c, c bit chn tay v c. Cc triu chng ny ph thuc vo liu dng v l du hiu bo trc c tnh trn tim. - Tc dng trn tim: h huyt p, au vng trc tim, nhp tim nhanh v lon nhp l nhng biu hin thng gp khi b tn thng tim. Nhng thay i trn in tim (sng T dt hoc o ngc, ko di khong Q- T) l cc du hiu n sm hn. - Tc dng trn h tiu ha: bun nn, nn, au bng, tiu chy Cn c th gp cc triu chng: nga, run, d cm. 1.1.2.4. Ch nh - L amp nng - p xe gan do amp Ch nn dng dehydroemetin khi khng c cc thuc khc an ton hn hoc b chng ch nh Chng ch nh Ph n c thai khng c dng dehydroemetin v thuc c vi thai nhi. Ht sc thn trng khi dng thuc bnh nhn c bnh tim, thn, thn kinh c, th trng chung qu yu hoc tr em. Khi dng dehydroemetin, ngi bnh phi lun lun c thy thuc theo di. Phi ngng luyn tp cng thng trong 4- 5 tun sau khi iu tr. Liu lng - Ngi ln: 1 mg/ kg/ ngy, khng dng qu 60 mg/ ngy. Cn gim liu ngi cao tui v ngi b bnh nng (c th gim ti 50%). t iu tr 4- 6 ngy. - Tr em: 1mg/ kg/ ngy, khng dng qu 5 ngy. Thuc nn dng qua ng tim bp su, khng tim tnh mch v d gy c cho tim, khng dng ng ung v kch ng gy nn. Cc t iu tr phi cch nhau t nht 6 tun. Trong iu tr l do amp, dng thm tetracyclin gim nguy c bi nhim. Khi iu tr p xe gan do amp phi ung thm cloroquin ng thi hoc ngay sau . Sau iu tr tt c cc bnh nhn nn ung thm diloxanid loi tr amip cn sng st kt trng, phng ti pht. 1.1.3. Metronidazol (Elyzol, Flagyl, Klion, Trichazol) L mt dn xut 5- nitro- imidazol, c ph hot tnh rng, t tan trong nc, khng ion ha pH sinh l, khuch tn rt nhanh qua mng sinh hc. 1.1.3.1. Tc dng p dng iu tr

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Metronidazol c hiu qu cao trong iu tr nhim amp ngoi rut (p xe gan, amp no, phi- lch) v amp thnh rut. Thuc c tc dng dit amp th hot ng nhng t nh hng n th kn. Thuc cn c dng iu tr trichomonas ng niu- sinh dc, bnh do Giardia lamblia v cc vi khun k kh bt buc. C ch tc dng: trong cc vi khun k kh v ng vt nguyn sinh (n bo), nhm 5- nitro ca thuc b kh thnh cc cht trung gian c vi t bo. Cc cht ny lin kt vi cu trc xon ca phn t DNA, lm v cc si DNA v cui cng lm t bo cht. Qu trnh kh nhm 5- nitro ca thuc c s tham gia "tch cc" ca ferredoxin- mt protein xc tc c nhiu trong cc vi khun v n bo nhy cm vi thuc. Mt s nghin cu cho thy, cc chng khng metronidazol c cha t ferredoxin. 1.1.3.2. Dc ng hc Metronidazol hp thu nhanh v hon ton qua ng tiu ha. Sau khi ung 1- 3 gi, thuc t nng ti a trong mu (6- 40 mg/ mL). Metronidazol gn rt t vo protein huyt tng (10- 20%) v c th tch phn phi ln (Vd 0,6- 0,8 lt/ kg) nn thuc khuch tn tt vo cc m v dch c th, c nng cao trong nc bt, dch no tu, sa m... Thi gian bn thi l 7,5 gi. Trn 90% liu ung c thi tr qua thn trong 24 gi, ch yu l cc cht chuyn ha hydroxy (30- 40%) v dng acid (10- 22%). 10% metronidazol thi nguyn vn qua nc tiu, 14% qua phn. 1.1.3.3. Tc dng khng mong mun Phn ng c hi thng ph thuc vo liu dng. Vi liu iu tr n bo, cc tc dng khng mong mun ca thuc thng nh, c phc hi v gp 4- 5% bnh nhn c iu tr. Hay gp cc ri lon ng tiu ha: bun nn, chn n, kh ming, li c v kim loi, au vng thng v v cc triu chng trn h thn kinh trung ng: au u, chng mt, bun ng. C th gp tiu chy, vim ming, phng rp da, pht ban, nga, d cm. Khi dng liu cao, ko di, thuc c th gy cn ng kinh, ri lon tm thn, vim a dy thn kinh ngoi bin, vim ty. Nc tiu c mu nu xm do cht chuyn ha ca thuc 1.1.3.4. p dng iu tr Ch nh - L amp cp rut - p xe gan do amp, amp trong cc m - Nhim trichomonas vaginalis: cn iu tr cho c v v chng. - Bnh do Giardia Lamblia - Nhim khun k kh; vim mng trong tim, nhim khun ton thn, p xe no, vim mng no c m, vim lot li cp, vim quanh thn rng...

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Chng ch nh Khng nn dng Metronidazol cho ph n c thai (c bit trong 3 thng u), ph n cho con b, ngi c tin s qu mn vi thuc. Cn thn trng khi dng thuc bnh nhn c tin s ri lon th tng mu, bnh h thng thn kinh trung ng. Phi gim liu ngi b suy gan nng. Liu lng Metronidazol c th ung di dng vin nn (250 mg, 500 mg) hoc dung dch treo metronidazol benzoat. Trng hp bnh nhn khng ung c, c th truyn tnh mch (dung dch 5 mg/ mL), tc truyn 5 mL/ pht. - iu tr l a mp cp: c th dng n c hoc tt hn nn phi hp vi iodoquinol hoc vi diloxanid furoat. Liu thng dng cho ngi ln l 750 mg, ngy ung 3 ln trong 5- 10 ngy, ung sau ba n. - p xe gan do amp: ngi ln ung 500- 750 mg/ ln, ngy 3 ln trong 5- 10 ngy. i vi tr em liu thng dng l 30- 40 mg/ kg/ 24 gi, chia lm 3 ln, ung lin 510 ngy. - Bnh do Giardia: . Ngi ln: ung 250 mg, ngy 3 ln, trong 5- 7 ngy hoc ung 1 ln 2g/ ngy, trong 3 ngy. . Tr em: ung 15 mg/ kg/ ngy, chia lm 3 ln, trong 5- 10 ngy. Tinidazol (Fasigyne): vin nn 500 mg. L dn xut th ca imidazol (C8H13N3O4). Tc dng v c ch tc dng tng t metronidazol, ch khc nhau v dc ng hc: hp thu nhanh v hon ton qua ng tiu ha, nng ti a trong mu t c sau 2gi, t/2 = 12- 14 gi, gn vo protein huyt tng 8- 12%, thm vo mi m, thi tr ch yu qua thn, phn nh qua phn (t l 5: 1). Liu lng: liu duy nht 2g. Hoc iu tr cc nhim khun k kh dng ngy u 2g; ngy sau 1g (hoc 500 mg 2 ln) trong 5- 6 ngy. 1.1.3.5. Tng tc thuc Metronidazol lm tng tc dng chng ng mu ca cc thuc khng vitamin K, c th gy chy mu nu dng ng thi metronidazol vi warfarin. Phenobarbital v cc thuc gy cm ng microsom gan lm tng chuyn ha metronidazol nn metronidazol thi tr nhanh hn. Metronidazol c tc dng kiu disulfiram (cai ru)v vy, khng nn ung ru trong thi gian dng thuc trnh tc dng c trn thn kinh: au u, bun nn, nn, chng mt, ri lon tm thn, l ln... 1.2. Thuc dit amp trong lng rut (dit amp do tip xc) Thuc tp trung trong lng rut v c tc dng vi th minuta (sng hoi sinh trong lng rut) v bo nang (th kn). 1.2.1. Diloxanid (Furamid)

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Diloxanid Furoat l dn xut dicloro acetamid c tc dng ch yu vi amp trong lng rut. 1.2.1.1. Tc dng Thuc c tc dng dit trc tip amp trong lng rut nn c dng iu tr cc bnh amp rut. Diloxanid c hiu lc cao i vi bo nang amp. Khng c tc dng i vi amp trong cc t chc. C ch tc dng ca thuc cha c sng t. Diloxanid c cu trc gn ging cloramphenicol (u l dn xut dicloro acetamid) nn thuc c th c ch s tng hp protein ca vi sinh vt. 1.2.1.2. Dc ng hc Nhng nghin cu trn ng vt cho thy diloxanid hp thu rt chm nn nng thuc trong rut kh cao. Ti rut thuc (Diloxanid furoat) b thu phn thnh diloxanid v acid furoic. Lng thuc hp thu c thi tr trn 50% qua thn di dng glucuronid trong 6 gi u tin. Di 10% liu dng thi tr qua phn. 1.2.1.3. Tc dng khng mong mun Thuc dung np tt ngay c khi dng liu cao. Diloxanid t gy cc phn ng c hi nghim trng. Hay gp cc ri lon trn ng tiu ha: chng bng (87%), chn n (3%), nn (6%), tiu chy (2%), co cng bng (2%). t gp cc triu chng trn h thn kinh trung ng: nhc u, ng lm, chng mt, hoa mt, nhn i, d cm... 1.2.1.4. Ch nh Diloxanid c la chn iu tr amp th bo nang (khng c triu chng lm sng nhng vng khng c dch bnh lu hnh). Thuc cn c phi hp vi metronidazol dit amp th hot ng trong lng rut. Chng ch nh Khng nn dng thuc cho ph n c thai (3 thng u) v tr em di 2 tui. Liu lng Diloxanid ch dng theo ng ung - iu tr cho ngui bnh mang kn amp khng triu chng: . Ngi ln: mi ln ung 500 mg, ngy ung 3 ln trong 10 ngy. Nu cn, iu tr c th ko di n 20 ngy. . Tr em: 20 mg/ kg/ ngy, chia lm 3 ln, ung lin 10 ngy. - iu tr l amp cp: cn iu tr bng metronidazol trc, sau tip theo bng diloxanid furoat liu nh trn. p dng iu tr

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1.2.2. Iodoquinol (Yodoxin, Moebequin) 1.2.2.1. Tc dng Iodoquinol (diiodohydroxyquin) l mt dn xut halogen ca hydroxyquinolein c tc dng dit amp trong lng rut nhng khng nh hng n amp thnh rut v trong cc t chc. C ch tc dng ca thuc cha c r rng. 1.2.2.2. Dc ng hc Thuc hp thu rt km qua ng tiu ha (90% thuc khng c hp thu). Phn thuc vo c vng tun hon c thi gian bn thi khong 11- 14 gi v thi tr qua nc tiu di dng glucuronid. 1.2.2.3. Tc dng khng mong mun Khi dng liu cao v ko di, iodoquinol c th gy nhng phn ng c hi trn h thn kinh trung ng. Thuc d gy phn ng c hi tr em hn ngi ln. Vi liu iu tr, iodoquinol c th gy mt s tc dng khng mong mun nh v thong qua nh: bun nn, nn, tiu chy (thng ht sau vi ngy), chn n, vim d dy, kh chu vng bng, au u, ban , nga... 1.2.2.4. Ch nh Phi hp iu tr cc trng hp nhim amp rut (th nh v trung bnh) Chng ch inh Khng nn dng thuc cho nhng ngi c bnh tuyn gip, d ng vi iod, ph n c thai, tr em di 2 tui. Liu lng Ung 650 mg/ ln, ngy 3 ln, trong 10- 20 ngy. Nn ung thuc sau ba n.
2. THUC DIT TRICHOMONAS

p dng iu tr

Trichomonas k sinh ngi c 3 loi: Trichomonas hominis (Trichomonas intestinalis) Trichomonas bucalis (Trichomonas tenax) Trichomonas vaginalis Trichomonas vaginalis k sinh ch yu m o, trong nc tit m o, cc np nhn ca da b phn sinh dc ngi. Khi k sinh m o, Trichomonas chuyn pH t acid sang base, nn to iu kin cho vi khun trong m o sinh sn, gy vim m o cp v mn tnh. Thuc dit T.vaginalis gm c cc dn xut ca 5- nitroimidazol nh metronidazol (Flagyl), tinidazol (Fasigyn), ornidazol (Tibral, Secnidazol, Flagentyl), nimorazol... (xin xem bi khng sinh) Trong iu tr bnh do Trichomonas cn m bo cc nguyn tc sau:

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- V sinh b phn sinh dc thng xuyn l rt cn thit v tng cng v sinh s gi m mc vim nhim ca b phn sinh dc - iu tr cho c v v chng (v y l mt bnh ly truyn t v sang chng v ngc li) - Trong thi gian ang iu tr khng c giao hp bnh khi truyn t v sang chng hoc ngc li. - Phi phi hp dit Trichomonas vi dit vi khun v nm men (Candida albicans) v thuc khng dit trc khun Dderlein (l vt ch bnh thng v cn ca m o), khng tc ng vi candida albicans. V vy, nn dng km acid boric trong iu tr Trichomonas chng s pht trin ca nm men v phi hp vi khng sinh dit vi khun. Liu lng: ung 1 liu duy nht 2 g hoc dng 7 ngy, mi ngy 3 ln, mi ln 250 mg.
CU HI T LNG GI

1. Trnh by tc dng, c ch tc dng, tc dng khng mong mun ca dehydroemetin. 2. Trnh by p dng iu tr ca dehydroemetin. 3. Trnh by tc dng, c ch tc dng, tc dng khng mong mun ca metronidazol. 4. Trnh by ch nh, chng ch nh v cch dng metronidazol. 5. Trnh by tc dng, tc dng khng mong mun v p dng iu tr ca diloxanid. 6. Trnh by tc dng, tc dng khng mong mun v p dng iu tr ca iodoquinol.

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Bi 21:

THUC ST KHUN - THUC TY U

MC TIU HC T P: Sau khi hc xong bi ny, sinh vin c kh nng:

1. Pht biu c nh ngha thuc st khun, cht ty u. Tiu chun ca mt thuc st khun l tng. 2. Trnh by c c ch tc dng ca cc thuc st khun thng thng

3. Nu c tc dng, tc dng ngoi (hoc c tnh) v p dng trn lm sng


ca cc thuc st khun thng thng
1. I CNG

1.1. nh ngha - Thuc st khun, thuc kh trng (antiseptics) l thuc c tc dng c ch s pht trin ca vi khun c in vitro v in vivo khi bi trn b mt ca m sng (living tissue) trong nhng iu kin thch hp. - Thuc ty u, cht ty u (disinfectants) l thuc c tc dng dit khun trn dng c, c, mi trng. 1.2. c im - Khc vi khng sinh hoc cc ha tr liu dng ng ton thn, cc thuc ny t hoc khng c c tnh c hiu. - Tc dng khng khun ph thuc nhiu vo nng , nhit v thi gian tip xc: nng rt thp c th kch thch s pht trin ca vi khun, nng cao hn c th c ch v nng rt cao c th dit khun. - lm v khun, c th dng cc phng php khc: + Nhit + Dung dch khng chu nhit, c th lc qua mng c l d = 0,22 micron, hoc chiu tia cc tm c bc sng 254nm vi liu khong 200.000 microwatt-sec/cm2, hoc chiu tia d, hoc tit trng lnh (cho qua kh ethylen oxyd hoc ngm trong dung dch glutaraldelhyd, ru formaldehyd) 1.3. Cc thuc st khun l tng cn t c cc tiu chun sau - Tc dng nng long - Khng c vi m hoc lm hng dng c - n nh - Khng lm mt mu hoc khng nhum mu - Khng mi - Tc dng nhanh ngay c khi c mt protein l, dch d vim - R

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Hin cha c cht no t c! 1.4. Phn loi theo c ch tc dng - Oxy ha: H2O2, phc hp c clo, KMnO4 - Alkyl ho: Ethylenoxyd, Formaldehyd, Glutaraldehyd - Lm bin cht protein: cn, phc hp phenol, iod, kim loi nng - Cht din hot: cc phc hp amino bc 4 - Ion ho cation: cht nhum - Cht gy tn thng mng: clorhexidin 1.5. Nguyn tc dng thuc st khun 1.5.1. da lnh - Ra sch cht nhn - Bi thuc st khun 1.5.2. Trn vt thng - o pH ch cn bi. Xc nh vi khun (nu cn) - Lm sch vt thng - Ra bng nc dit khun - Bi thuc tu theo pH vt thng
2. CC THUC ST KHUN THNG THNG

2.1. Cn Thng dng cn ethylic (C2H5OH) v isopropyl (isopropanol) [CH3CH(OH)CH3] 60 - 70%. Tc dng gim khi cn <60% v >90%. C ch: gy bin cht protein Tc dng: dit khun, nm bnh, siu vi. Khng tc dng trn bo t. Dng ring hoc phi hp vi tc nhn dit khun khc. nng thp cn c th c s dng nh cc c cht cho mt s vi khun, nhng nng cao cc phn ng kh hydro s b c ch. 2.2. Nhm halogen 2.2.1. Iod - C ch: Iod lm kt ta protein v oxy ha cc enzim ch yu theo nhiu c ch: phn ng vi cc nhm NH, SH, phenol, cc carbon ca cc acid bo khng bo ho, lm ngn cn to mng vi khun. - Iod c tc dng dit khun nhanh trn nhiu vi khun, virus v nm bnh. Dung dch 1: 20.000 c tc dng dit khun trong 1 pht, dit bo t trong 15 pht v tng i t c vi m. - Ch phm v cch dng: Iod c dng nh thuc st khun v ty u.

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+ Cn iod: c iod 2% + kali iodid 2,4% ( lm iod d tan) + cn 44-50%. Nhc im l hi kch ng da, st v nhum mu da. + Povidon - iod, l cht dn iod (iodophore), ch to bng cch to phc iod vi polyvinyl pyrolidon. Iod s c gii phng t t. Hin c dng nhiu v vng bn hn cn iod nhit mi trng, t kch ng m, t n mn kim loi. Tuy nhin gi thnh t. Vi vt thng m, do c vi nguyn bo si (fibroblast) nn c th lm chm lnh. Ch phm: - Betadin - Povidin 2.2.2. Clo - Tc dng v c ch: clo nguyn t phn ng vi nc to thnh acid hypoclor (HOCl). C ch dit khun cn cha r. + C th HOCl gii phng oxy mi sinh ra oxy ha cc thnh phn ch yu ca nguyn sinh cht:
2HOCl

= H2O + Cl2 + O

+ Hoc, Cl kt hp vi protein ca mng t bo to thnh phc hp N - Clo lm gin on chuyn ha mng t bo. + Hoc, oxy ha nhm - gH ca mt s enzym lm bt hot khng hi phc. Tc dng pH trung tnh hoc acid nh (ti u l 5) nng 0,25 ppm (phn triu) Clo c tc dng dit khun trn nhiu chng, tr vi khun lao c sc khng 500 ln mnh hn. Clo khng cn c dng nh mt thuc st khun v c tc dng kch ng v b mt hot tnh bi cc cht hu c do chng d kt hp vi cc cht hu c. Tuy nhin, n cn c dng nhiu lm thuc ty u v kh trng nc v r. - Cc ch phm: . Cloramin: l cc dn xut Cl - N ca sulfonamid, dn xut guanidin, phc hp N d vng, cha 25 - 29% Clo. Tc dng ko di, t kch ng m, nhng yu. Thng dng Cloramin T (Na-p-toluen sulfon cloramid), dung dch 1-2% ra vt thng. . Halazon (acid p-dicloro sulfamidobenzoic): vin 4mg st khun cho 1 lt nc, ung c sau 30 pht.
3. CC CHT OXY HA

Thng dng peroxyd hydro (H2O2, nc oxy gi), thuc tm (KMnO4). Do c tc dng oxy ha, to gc t do, nn cc thuc ny lm tn hi mng vi khun, ADN v mt s thnh phn ch yu khc ca t bo. Nc oxy gi 3- 6% c tc dng dit khun v virus, nng cao hn (10- 25%) dit c bo t. Khi tip xc vi m s gii phng oxy phn t. Khng thm vo m nn ch dng sc ming v ra cc vt thng, cc b phn gi. Catalase lm bt hot thuc.

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Nc oxy gi c vi nguyn bo si nn c th lm chm lin so vt thng. Khng c dng H2O2 di p lc ra cc vt thng su c rch nt v c th to hi di da. - Thuc tm: vi nng 1:10.000, c tc dng dit nhiu loi vi khun trong 1 gi. Nng cao hn d kch ng da. Thng dng ra cc vt thng ngoi da c r nc.
4. CC KIM LOI NNG

Mi kim loi nng u c tc dng dit khun. Thng dng l Hg, Ag. 4.1. Thu ngn - Tc dng v c ch: ion Hg++ lm kt ta protein v c ch cc enzym mang gc SH. V vy cc vi khun b c ch bi Hg, c th hot ng tr li khi tip xc vi cc phc hp c nhm SH. Thu ngn hu c c tc dng km khun v yu hn cn, km c hn Hg v c. - Ch phm: Thuc (mercurochrom) dung dch 2%, ch dng bi ngoi da. Khng nn bi din rng vng mt da. Khng c ung, c th gy c cho ng thn. Dng thn trng tr s sinh. 4.2. Bc - Tc dng v c ch: Bc ion kt ta protein v ngn cn cc hot ng chuyn ha c bn ca t bo vi khun. Cc dung dch mui bc v c c tc dng st khun. - Cc ch phm: . Bc nitrat dung dch 1% dng nh mt cho tr mi , chng c bnh lu cu gy vim mt. Hin ang thay th bng pomat khng sinh. . Bc - Sulfadiazin 1% di dng kem bi cha bng, lm gii phng t t c bc v sulfadiazin, c tc dng dit khun tt v lm gim au. Bi din rng v ko di, i khi c th gy gim bch cu. . Cc ch phm bc di dng keo (collargol, protargol, argyrol) c tc dng km khun tt, t gy thng tn cho m. Ch phm cha 20% bc dng st khun nim mc. Thuc b hu bi nh sng nn phi trong l mu. Mi ch phm bc dng lu gy chng nhim bc (argyrism).
5. X PHNG

X phng l cht din hot loi anion, thng l cc mui Na hoc K ca mt s acid bo. V NaOH v KOH l cc base mnh trong khi phn ln acid bo li l cc acid yu, v vy cc x phng khi tan trong nc u l cc base mnh (pH 8.0 10.0), d kch ng da (pH ca da = 5,5 - 6,5). Mt s x phng c sn xut vi pH = 7. Cc x phng loi b trn b mt da cc cht bn, cc cht xut tit, biu m trc vy v mi vi khun cha trong . lm tng tc dng st khun ca x phng,

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mt s cht dit khun c cho thm vo nh hexaclorophan, phenol, carbanilid, l nhng cht s trnh by di.
6. CC HP CHT CHA PHENOL

Phenol c Lister dng u tin t nm 1867 tit khun. Do lm bin cht protein v kch ng da nn c, ch dng ty u. Ngy nay dng cc cht thay th. 6.1. Hexaclorophen L cht km khun mnh. X phng v cht ty u cha 3% hexaclorophen c tc dng km khun mnh v lu bn v gi li lp sng ca da. Nhng dng nhiu ln c th b nhim c, nht l tr nh. 6.2. Carbanilid v Salicylanilid Hin dng thay th hexaclorophen trong x phng st khun. Dng thng xuyn x phng ny c th lm gim mi ca c th do ngn nga c s phn hu ca vi khun vi cc cht hu c cho trong m hi. Cc loi x phng ny c th gy d ng hoc mn cm vi nh sng. 6.3. Clohexidin L dn xut ca biguanid, c tc dng lm ph v mng bo tng ca vi khun, c bit l chng gram (+). Dng trong x phng st khun, nc sc ming. Dung dch 4% dng ra vt thng. Thuc c th c gi li lu da nn tc dng km khun ko di. Tuy nhin t c vi ngi v khng kch ng v khng hp thu qua da v nim mc lnh.
CU HI T LNG GI

1. Pht biu nh ngha v thuc khng sinh, thuc st khun v thuc ty u. 2. K c tiu chun ca mt thuc st khun l tng v nguyn tc dng thuc st khun 3. Trnh by c ch tc dng v phn tch u nhc im ca cc thuc st khun: cn, iod, clo. 4. Trnh by c ch tc dng, p dng v phn tch u nhc im ca H2O2, KMnO4, Ag, x phng.

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PHN V THUC TC DNG TRN C QUAN V TRN MU


Bi 22:

THUC TR TIM

MC TIU HC T P: Sau khi hc xong bi ny, sinh vin c kh nng:

1. Nu c mi lin quan gia cu trc ha hc v dc ng hc ca thuc loi glycosid 2. Phn tch c c ch tc dng v c tnh ca digitalis 3. Phn bit c ch nh v chng ch nh ca digitalis v strophantus

4. Trnh by c c ch tc dng v p dng iu tr ca hai nhm thuc tr tim


do lm tng AMPv Thuc tr tim l nhng thuc c tc dng lm tng lc co bp ca c tim, dng trong cc trng hp suy tim. Cc thuc c chia lm 2 nhm: - Thuc loi glycosid c ch nh trong suy tim mn. - Thuc khng phi glycosid dng trong suy tim cp tnh.
1. THUC LOI GLYCOSID ( GLYCOSID TR TIM): DIGITALIS

Cc thuc loi ny u c 3 c im chung: - Tt c u c ngun gc t thc vt: cc loi Digitalis, Strophantus - Cu trc ho hc gn ging nhau: u c nhn steroid ni vi vng lacton khng bo ha C17, gi l aglycon hoc genin, c tc dng chng suy tim. V tr C3 ni vi mt hoc nhiu phn t ng(ose), khng c tc dng dc l nhng nh hng n dc ng hc ca thuc. - Hin ch cn digoxin v digitoxin c dng lm sng. Digitoxin khc digoxin l khng c OH C12 v th t tan trong nc hn. - Cc thuc tc dng trn tim theo cng mt c ch.

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Digoxin

1.1. Dc ng hc 1.1.1. Hp thu Glycosid khng ion ho, c khuch tn th ng qua ng tiu ha (d dy, t trng, rut non): thuc cng tan trong lipid, cng d khuch tn. Cc nhm OH ca genin l nhng cc a nc, lm hn ch tan trong lipid ca thuc: - Digitoxin ch c mt nhm OH t do C14, nn d tan trong lipid, c hp thu hon ton khi ung. - Uabain c 5 nhm OH t do, khng hp thu qua ng tiu ho, nn phi tim tnh mch. Hin khng cn c dng na. - Digoxin c 2 nhm OH t do, hp thu qua ng tiu ha tt hn uabain, nhng khng hon ton nh digitoxin. 1.1.2. Phn phi Thuc cng d tan trong lipid, cng d gn vo protein huyt tng, song khng vng bn v d dng c gii phng ra dng t do. Glycosid gn vo nhiu t chc, c bit l tim, gan, phi, thn, v nhng c quan ny c ti mu nhiu; vi c tim, thuc gn vng bn theo kiu lin kt cng ho tr. Kali- mu cao, glycosid t gn vo tim v ngc li khi kali- mu gim, glycosid gn nhiu vo tim, d gy c. Digitalis c th qua c hng ro rau thai. 1.1.3. Chuyn ho Digitoxin chuyn ho hon ton gan, digoxin 5%, cn uabain khng chuyn ho. Nhng phn ng chuyn ho quan trng ca digitoxin v digoxin l: - Thu phn, mt dn phn ng, cui cng cho gennin - Hydroxyl ho genin v tr 5-6 bi micrsm gan - Epime ho: chuyn -OH v tr 3 t bta sang alpha - Lin hp vi cc acid glucuronic v sulfuric. 1.1.4. Thi tr Digitoxin v digoxin thi tr qua thn v qua gan, nhng ni , mt phn thuc c ti hp thu, nn lm tng tch ly trong c th. Uabain khng b chuyn ho, thi tr qua thn di dng cn hot tnh. Bng 22.1: So snh chuyn ha ca ba glycosid Digitoxin Digoxin Uabain

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Digitoxin Ngun gc S OH gn vo sterol Tan trong m Hp thu qua tiu ha Gn vo protein huyt tng Thi gian c tc dng sau (t/m) Phn hu gan Thi tr T l mt hot tnh trong ngy Thi gian tc dng Thi gian bn thi Lu li trong c th Trnh by D.purpurea 1 +++ 100:100 90:100 2h (khng dng) +++ Chm 7:100 2-3 ngy 110 gi 2-4 tun - Dung dch ru 1:1000 1ml = 50 git = 1mg vin 0,1mg = 5git 1.2. Tc dng ca digitalis 1.2.1. Tc dng trn tim

Digoxin D.laineuse 2 + 80:100 50:100 20 pht + Nhanh 18-20:100 12-24 gi 33 gi 1 tun Vin 0,25mg ng 0,5mgt/m

Uabain Strophanth us 5 0 0 0 5 pht 0 Rt nhanh 40:100 12 gi 6 gi 1-2 ngy ng 0,25mg - t/m

y l tc dng ch yu: digitalis lm tm thu ngn v mnh, tm trng di ra, nhp tim chm li. Nh , tim c ngh nhiu hn, mu t nh vo tht thi k tm trng c nhiu hn, cung lng tim tng v nhu cu oxy gim. Do bnh nhn kh th v nhp h hp tr li bnh thng. Digitalis cn lm gim dn truyn ni ti v tng tnh tr ca c tim nn nu tim b lon nhp, thuc c th lm u nhp tr li. C ch tc dng: Cc glycosid tr tim u c ch cc ATPase mng, l enzym cung cp nng lng cho bm Na+ - K+ ca mi t bo. Bm ny c vai tr quan trng trong kh cc mng t bo, do y 3 ion Na+ ra trao i vi 2 ion K+ vo trong t bo. Tc dng ca glycosid ph thuc vo tnh nhy cm ca ATPase ca tng m. Trn

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ngi, c tim nhy cm nht, v vy: vi liu iu tr, glycosid c tc dng trc ht l trn tim. Khi ATPase b c ch, nng Na+ trong t bo tng s nh hng n mt h thng khc, h thng trao i Na+ - Ca++. Bnh thng, h thng ny sau mi hiu th hot ng s y 1 ion Ca++ v nhp 4 ion Na+ vo t bo. Di tc dng ca glycosid, nng Na+ trong t bo s tng cn tr s trao i ny v lm nng Ca++ trong t bo tng cao, gy tng lc co bp ca c tim, v ion Ca++ c vai tr hot ha myosin ATPase cung cp nng lng cho s co c (cc si actin trt trn si myosin). (Hnh 22.1)

Hnh 22.1. Tc dng ca digitalis trn cc lung ion (-) c ch

Sau c tim ATPase ca cc t bo nhn cm p lc ca cung ng mch ch v xoang ng mch cnh cng rt nhy cm vi glycosid. Khi ATPase b c ch, tn s phng xung tc gim p hng tm tng, kch thch trung tm ph giao cm v lm gim trng lc giao cm s lm tim p chm li v lm gim dn truyn nh - tht. 1.2.2. Cc tc dng khc - Trn thn: digitalis lm tng thi nc v mui nn lm gim ph do suy tim. C ch ca tc dng ny l: mt mt, digitalis lm tng cung lng tim, nn nc qua cu thn cng tng; mt khc, thuc c ch ATPase mng t bo ng thn lm gim ti hp thu natri v nc. - Trn c trn: vi liu c, ATPase ca bm Na+ - K+ b c ch, nng Ca++ trong t bo thnh rut tng lm tng co bp c trn d dy, rut (nn, i lng), co tht kh qun v t cung (c th gy xy thai). - Trn m thn kinh: digitalis kch thch trc tip trung tm nn sn no tht 4 v do phn x t xoang cnh, quai ng mch ch. 1.3. Nhim c

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Cc du hiu nhim c digitalis rt a dng. Khi iu tr, cn ch pht hin cc du hiu, triu chng sau: - Tm thn: m sng, kh chu, mt mi, l ln, chong vng. - Th gic: nhn m, c qung sng. - Tiu ha: chn n, bun nn, nn, au bng. - H hp: th nhanh. - Tim mch: nhp xoang chm, lon nhp ngoi tm thu nh, tht; ri lon dn truyn nh- tht; nghn nh- tht cc loi; rung tht. Digitalis l thuc b tch lu trong c th, phm vi nng huyt tng c tc dng iu tr li hp, v vy trong lm sng, tuy dng liu iu tr vn c th gp nhim c do nhiu yu t tng tc nh: ri lon in gii (h K+ mu, h Mg++ mu, tng Ca++ mu); nhim kim chuyn ha; suy gan, suy thn lm gim chuyn ha v thi tr thuc. Trong gim st iu tr, cn o nng ca thuc trong huyt tng hiu chnh liu. 1.4. p dng lm sng - Ch nh: + Gin tm tht. + Nhp nhanh v lon. + Suy tim do tn thng van. - Chng ch nh: + Nhp chm. + Nhp nhanh tm tht, rung tht. + Vim c tim cp (bch hu, thng hn...) + Nghn nh tht. + Khng dng cng vi cc thuc sau, c th gy cht t ngt hoc tng c ca digitalis: calci (nht l khi tim tnh mch), quinidin, thuc kch thch adrenergic, reserpin. 1.5. Ch phm v liu lng - Digitoxin: Nng iu tr trong huyt tng l 10- 25 ng/ mL, nng c l > 35 ng/ mL Liu iu tr: 0,05- 0,2 mg/ ngy. Ch phm: vin nn 0,05 v 0,1 mg - Digoxin: Nng iu tr trong huyt tng l 0,5- 1,5 ng/ mL, nng c l 0,2ng/ mL. Liu iu tr: 0,125- 0,5 mg/ ngy

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Ch phm: vin nn 0,125- 0,25- 0,5 mg ng tim 0,1- 0,25 mg/ mL 1.6. iu tr ng c Ng c do tch lu thuc hoc ung qu liu, v digitalis gn rt cht vo c tim, cho nn khi ng c phi dng thuc c ch gn tip tc digitalis vo tim (kali), thi tr calci l cht hip ng tc dng vi digitalis trn c tim (EDTA) v cc thuc cha triu chng lon nhp tim (diphenylhydantoin, thuc phong to bta vv...) - KCl ung 20-80mEq/L/ngy; hoc 40-60mEq/L chuyn tnh mch trong 2-3gi u. Truyn tnh mch th d kim tra v khi cn c th ngng ngay. Tuyt i khng dng khi suy thn. - Diphenylhydantoin: lm tng ngng kch thch ca tim, i khng vi tc dng in tim ca digital. Tim tnh mch 125-250mg trong 1-3pht. Tc dng nhanh v gi c 4-6 gi. C th truyn lidocain 2mg/ pht. Nu c nhp chm, thm atropin 0,5-1,0mg tim tnh mch. - EDTA (acid etylen diamino tetraacetic) c tc dng gp calci ra khi c th. Dng khi kali v diphenylhydantoin khng c ch nh. Truyn tnh mch 3,0g pha trong 200ml glucose 5%. - Min dch tr liu khng digoxin (antidigoxin immuno therapy). Hin c thuc gii c c hiu cho digoxin v digitoxin di dng khng th, l cc phn on Fab tinh khit t khng huyt thanh khng digoxin (antidigoxin antisera) ca cu (DIGIBIND). Pha trong dung dch nc mui, truyn tnh mch trong 30- 60 pht. Liu lng tnh theo nng hoc tng lng digoxin c trong c th. Ch phm: Digibind l bt ng kh cha 38 mg Fab v 75 mg sorbitol. Mi l gn c khong 0,5 mg digoxin hoc digitalin. 1.7. Strophanthus Ht cy Strophanthus c glycosid l strophantin (genin l strophantidin). Trong lm sng, c dng nhiu l G. strophantin (tc uabain) ly Strophanthus gratus, v K. strophantin ly Strophanthus kombe. Tc dng ca strophantin xut hin nhanh, 5- 10 pht sau khi tim tnh mch, tc dng ti a sau khong 1 gi v thi tr nhanh. Thuc t tc dng trn dn truyn ni ti c tim, c th dng khi nhp chm. Ch nh trong suy tim l khi digitalin t ra khng hiu lc, v trong cp cu (v tc dng nhanh). Nhc im l tim bp khng c tc dng v ung th b thu phn nhanh. Mi ngy tim tnh mch 0,25 mg- 1 mg. v thuc thi nhanh, nn c th tim hng ngy nu dng liu 0,25 mg. Strophantin cng c th gy nn, a chy v rung tm tht (c bng A). Hin ang c thay th bng cc thuc cng 1 giao cm.
2. THUC TR TIM KHNG PHI DIGITALIS: Thuc lm tng AMPv

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Thuc loi ny c dng cho suy tim cp tnh v t cp tnh ca suy tim mn, biu hin bng cn kh th nng, ph ngoi bin hoc ph phi. Vic iu tr trc tin l phi lm gim gnh nng cho tim bng thuc gin mch, thuc li niu (xin xem phn tng ng); sau l dng thuc lm tng sc co bp ca c tim. Cc thuc loi ny u l thuc tim v bnh nhn thng phi nm vin. Thuc tng co bp tim loi digitalis, khng c dng trong shock v c nhiu tc dng ph, cng d xy ra khi c tng catecholamin ni sinh (stress), thiu oxy, acid huyt. Thng xy ra lon nhp. Hin a dng loi lm tng AMPv mng t bo c tim, tc dng lm m knh calci nn lm tng co bp tim: ATP (+) Cc protein kinase Tc dng sinh l 5 AMP (+) 3- 5- AMPv (+) Phosphodiesterase (-) Xantin Amrinon Enoximon Adnylcyclase (+) cng 1, 2

Thuc kch thch adenylcyclase, enzym tng hp AMPv, v c ch phosphodiesterase, enzym ging ho AMPv, u c tc dng lm tng AMPv (s ). Cc thuc ny lm tng bin co bp ca c tim, tc co bp nhanh v thi gian co ngn li, c tc dng tt trong iu tr suy tim cp, sc. Cc glycosid tim cng lm tng bin co bp ca c tim, nhng tc co bp ch tng va phi v thi gian co bp li ko di (hnh 22.2), c tc dng ci thin c tnh trng suy tim mn

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Tc dng qua trung gian AMPc tim

Tc dng ca glycosid

Hnh 22.2. Chu k co bp ca tim b suy () v di nh hng ca thuc (----------)

2.1. Cc thuc cng b adrenergic (Xin xem thm mc ny bi Thuc tc dng trn h adrenergic) 2.1.1. Isoprenalin - Tc dng dc l: + Cng b1: tc dng ln c 4 tnh cht ca tim, lm tim p mnh, p nhanh, tng tnh dn truyn v tnh chu kch thch. Do lm tim p nhanh, lm tng nhu cu oxy ca c tim. Lu lng tim tng, huyt p ti a tng. + Cng b2: lm gin kh qun, gin mch (gim sc cn ngoi bin, gim hu gnh). Huyt p ti thiu gim. Lu lng tim tng v gin mch l 2 tc dng quan trng lm ci thin c s ti mu, c bit l cho vng tng ni chu nh hng nhiu ca shock. Ngoi tc dng tim mch, isoprenalin cn lm tng ng huyt, tng hu lipid v do sinh nng lng. - Tc dng khng mong mun v c tnh: + H huyt p, lon nhp, au vng trc tim, nhi mu c tim. Cn theo di bng in tim. Khng dng cng thuc m nh cyclopropan, fluothan, lm tng c tnh vi tim. - Ch nh chnh: + Shock c h huyt p, cn tr mu ti cc mch do co mch ngoi bin v thiu nng tim, th hin bng tng p lc tnh mch trung tm. + Ngng tim, kt hp vi xoa bp tim ngoi lng ngc. - Ch phm: + Isoprenalin clohydrat (Isuprel) + Isoprenalin sulfat (Aleudrine) ng 1ml = 0,2mg. Truyn tnh mch 2-6 ng trong 250- 500ml huyt thanh ngt ng trng, khng c base. Khi ngng tim tim 2 ng vo tim. 2.1.2. Dobutamin Tc dng chn lc ch trn b1 receptor. - c im tc dng trn h tim - mch:

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+ Trn tim: lm tng co bp c tim, c bit l vi liu lm tng bin nh isoprenalin th dobutamin ch lm tng nhp tim rt t, do ch lm tng t nhu cu s dng oxy ca c tim, tuy lm tng c lu lng ca tim. + Lm gim nh sc cn ngoi vi v p lc mao mch phi. - Ch nh: + Shock - tim, nht l sau m tim vi tun hon ngoi c th. + Cc suy tim nng, khng b tr, khng p ng vi cc cch iu tr khc. - Ch phm: + Dobutrex l 20ml = 250mg Pha trong dung dch glucose hoc mui ng trng, khng c base, truyn tnh mch vi tc 2- 15 mg/ kg/ pht, tu tnh trng bnh v t/2 = 2- 3pht. Khi xut hin nhp tim nhanh v lon nhp, cn gim liu. 2.2. Dopamin Dopamin l cht tin thn ca noradrenalin v l cht dn truyn thn kinh ca h dopaminergic. Trn tim mch, tc dng ph thuc vo liu (xin xem Thuc cng h adrenergic). Tuy nhin, ngay c vi liu trung bnh (2- 5 mg/ kg/ pht- liu kch thch 1), dopamin lm nhp tim nhanh nn d gy thiu mu c tim, nht l trn bnh nhn c bnh mch vnh. Cn cn nhc khi ch nh. 2.3. Cc thuc phong ta phosphodiesterase Nhm thuc mi phong ta phosphodiesterase c u im hn nhm thuc c in (nhm xantin) l: - Tc dng ch yu trn isoenzym F typ III ca phosphodiesterase c nhiu mng t bo c tim. - Khng kch thch thn kinh trung ng. 2.3.1. Dn xut bipyridin: amrinon (Inocor) v milrinon (Primacor) - Lm tng co bp c tim, tng lu lng tim - Lm gin mch nn lm gim tin gnh v hu gnh - Tc dng ph: t. C th gp st, nhc u, ri lon tiu ho, gim v gic v khu gic. Gim tiu cu, ngng thuc s khi, him gp vi milrinon - Ch dng thuc cho bnh nhn nm vin - Cch dng: + Amrinon (Inocor) ng 20mL c 100mg amrinon lactat pha trong dung dch mui ng trng dng ngay trong ngy. Tim tnh mch liu tn cng 0,5 mg/kg, sau truyn vi tc 2-20 mg/kg/pht; t/2 = 2-3gi. + Milrinon (Primacor) 5mg/mL. ng tim tnh mch. Khong 10 ln mnh hn amrinon. Liu tn cng 50mg/kg tim tnh mch, sau truyn vi tc 0,25 1,0mg /kg/ pht; t/2 = 30-60pht. ang l thuc c la chn v c ch c hiu PDE III.

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2.3.2. Dn xut benzimidazol L cc dn xut c ch PDE III ang c nghin cu: - Pimobendan: ngoi c ch c ch PDE III cn c c ch lm mn cm cc yu t co tht ca c tim vi Ca++ ni bo. 2.3.3. Vesnarinon: l quinolinon tc dng theo ng ung lm tng lc co bp tim mch v gin mch theo nhiu c ch: c ch PDE III, tng nhp Ca++, ko di in th hot ng, lm chm nhp tim. Tuy nhin phm vi an ton hp, nhiu nc khng dng na. 2.4. Cc thuc khc 2.4.1. Spartein Alcaloid chit xut t hoa cy Kim tc (Spartium junceum L.), thng dng spartein sulfat. Lm tim p mnh u, v chm li. Ch nh: - e da try tim mch do chn thng nhim c. - nh trng ngc, nhi vng tim (khng phi hi chng ng mch vnh). - Tr tim gia hai t dng digitalis hay strophanthus. - C th phi hp vi morphin, scopolamin trong tin m; spartein cn c ch bi tit catecholamin. Nn dng, nu gy m bng cloroform. - Thc : lm t cung co bp mnh v u. Liu lng: ung hay tim di da 0,05g/ ln, 1-3 ln/ ngy. 2.4.2. Long no Lm nhp tim p mnh, u, kch thch h hp, gy tit m hi v h nhit (rt t). Ch nh: - Try tim mch. - Nhim khun, nhim c. Liu lng: - Dung dch du 10%: tim di da 2- 5 mL. - Long no tan trong nc (natri camphosulfonat): dung dch 10%. Tim di da 110 mL. Hai thuc trn ngy cng t dng v tc dng khng mnh. 2.4.3. Amino- 2- methyl- 6 heptaminol- 6 Lm tng cung lng ng mch vnh, cung lng tim, li niu, tng huyt p. t c. Thng dng cng digitalis cha suy tim. c ch nh trong try tim mch, bin chng tim trong phu thut, vim c tim cp, nhim khun, nhi mu c tim. Ung mi ngy 0,3- 0,5g. Tim bp, tnh mch: 0,05- 0,1g (dung dch 5%).

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CU HI T LNG GI

1. Phn tch v sao c s khc bit v dc ng hc gia digitoxin, digoxin v uabain. 2. Phn tch c ch tc dng trn tim ca digitalin, t gii thch tc dng v c tnh ca thuc. 3. So snh cc thng s dc ng hc ca digitoxin v digoxin, t suy ra cch dng trong lm sng. 4. Cc du hiu nhim c digitalis v cch iu tr. 5. So snh ch nh v chng ch nh ca thuc tr tim digitalis v khng phi digitalis. 6. So snh c ch tc dng v tc dng ca dobutamin v dopamin trn tim mch. Bi 23:

THUC IU TR CN AU THT NGC

MC TIU HC T P: Sau khi hc xong bi ny, sinh vin c kh nng:

1. Nu c cc yu cu mt thuc cha cn au tht ngc 2. Phn bit c thuc loi nitrit v thuc chn knh calci v mt c ch v p dng iu tr Nguyn nhn ca cn au tht ngc l do c tim b thiu oxy t ngt v mt thng bng gia s tng nhu cu oxy ca c tim v s cung cp khng oxy ca mch vnh. C tim ch chim 0,5% trng lng c th, nhng khi ngh ngi cng lu gi 5% lu lng tim. C tim ly 80- 90% oxy ca dng mu qua c tim. Khi c gng, khi xc ng hoc dng catecholamin, tim phi lm vic tng, nhu cu oxy ch c tho mn bng tng lng mu cung cp cho tim. T lu, chng cn au tht ngc, vn dng thuc lm gin mch vnh. Tuy nhin, nhiu thuc ngoi tc dng lm gin mch vnh, li ng thi lm gin mch ton thn, v vy mt khi lng mu ng l cn cung cp cho tim th li chy ra cc vng khc. Mt khc, p lc tnh mch gim, i hi tim phi lm vic nhiu hn, v v vy li cng tng s dng oxy ca tim. Khi mt phn mch vnh b tc, vng di ch tc b thiu mu, chuyn ho lm vo tnh trng k kh, lm tng to thnh acid lactic, adenosin, kali l nhng cht gy gin mch mnh ti ch. Nu cho thuc gin mch, s cung cp mu s tng ln vng lnh, khng c li g cho vng b thiu mu, tri li, s ti mu cho vng b thiu mu li cn b gim i. Hin tng ny c gi l ly trm ca mch vnh (vol coronarien). Trong cn au tht ngc m nguyn nhn l do thiu mu t ngt ca c tim th vic cn trc ht l lm gim nhu cu oxy ca c tim, v hn na l loi tr tt c nhng tc ng i hi tim phi lm vic nhiu ln v chuyn ho tng ln. V vy, cc thuc chng cn au tht ngc tt cn t c nhng yu cu sau:

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- Tng cung cp oxy, ti mu cho c tim. - Gim s dng oxy bng cch gim cng nng tim (tnh trng co bp ca c tim, nhp tim). - Lm gim cn au. Tuy nhin cn thy rng v tr ca vng thiu mu c tim khng hon ton c lin quan n s c mt hoc mc ca cm gic au, ngha l c th thiu mu c tim m khng c au. Cc thuc iu tr c chia thnh hai loi: - Loi chng cn: cc nitrat v nitrit - Loi iu tr cng c lm gim cng nng tim v gim s dng oxy: thuc phong to recptor b adrenergic, thuc chn knh calci (c c tc dng gin mch)
1. LOI CHNG CN: NITRAT V NITRIT

Cc nitrat hu c l cc este polyol ca acid nitric, cn cc nitrit hu c l cc este ca acid nit. Este nitrat (C-O-NO2) v este nitrit (C-O-NO) c c trng bi chui C -O-N, trong khi cc hp cht nitro l C-NO2. Nh vy, nitroglycerin l tn gi khng ng ca glyceryl trinitrat v khng phi l hp cht nitro, nhng do dng quen v qu ph bin nn khng sa c! Cc thuc nhm ny hoc l dung dch bay hi (amylnitrit), hoc l dung dch bay hi nh (nitroglycerin), hoc l th rn (isosorbid dinitrat). Tt c cc hot cht trong nhm ny u gii phng nitric oxid (NO) ti m ch c trn thnh mch Cc loi thng dng lm sng l: Tn chung v bit dc Amyl nitrit Cu trc ha hc H3 C CHCH2CH2ONO H3 C Nitroglycerin (glyceryl trinitrat Nitrostat, Nitrobid
H2 C HC H2 C O O O NO2 NO2 NO2

Liu lng v ng dng Ht: 0,18- 0,3 ml

Vin: 0,15- 0,16 mg, ngm Phun: 0,14 mg/ nht bp Vin gii phng chm: 2,5- 9 mg Dn: 2,5- 15 mg/ ngy

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Isosorbid dinitrat (Isorrdil, sorbitrat)


O O2N O

H 2C HC CH C CH2 O NO2

Vin ngm: 2,5- 10 mg Vin nhai: 5- 10 mg Vin ung: 10- 40 mg Vin gii phng chm: 40- 80 mg Vin ngm: 5- 10 mg Vin ung: 10 mg

Erythrityl tetranitrat (cardilat)

H2C -O - NO2 HC -O - NO2 HC -O - NO2 H2C -O - NO2

1.1. Tc dng dc l v c ch Nitrat lm gin mi loi c trn do bt k nguyn nhn gy tng trng lc no. Khng tc dng trc tip trn c tim v c vn. Trn mch, nitrat lm gin mch da v mt (gy mt) lm gin mch ton thn. Tnh mch gim, lm gim dng mu chy v tim (gim tin gnh). ng mch gin, lm gim sc cn ngoi bin (gim hu gnh). Mc d nhp tim c th nhanh mt cht do phn x gin mch, nhng th tch tm thu gim, cng nng tim gim nn vn gim s dng oxy ca c tim. Mt khc, s phn b mu cho c tim cng thay i, c li cho vng di ni tm mc. Trn c trn khc, nitrat lm gin ph qun, ng tiu ho, ng mt, ng tit niu sinh dc. C ch lm gin c trn: Cc nitrit, nitrat v hp cht nitroso gii phng nitric oxyd (NO) trong t bo c trn di tc dng ca h enzim cha hon ton bit r. NO c gii phng ra s hot ha guanylyl cyclase v lm tng tng hp GMPv, dn n kh phosphoryl chui nh ca myosin, gy gin c trn (hnh 23.1). Myosin chui nh (myosin light chain) phosphoryl ha (Myosin - LC - PO4) th gy co c. Nitrat NO Guanylyl cyclase Guanylyl cyclase hot ha GTP GMPv T bo ni mc mch

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Myosin- LC- PO4 Co c

Myosin LC Gin c

Hnh 23.1: c ch gy gin c trn ca nitrat

Tc dng gin c ca nitrat ging tc dng ca yu t gin c ca t bo ni m (EDRF: Endothelium- derived relaxing factor). T bo ni m mch mu tit EDRF, chnh n l NO hoc l tin cht ca NO (nitrosothiol). EDRF thm t ni m mch vo t bo c trn thnh mch v hot ha guanylyl cyclase ti . Cc cht ni sinh gy gin mch c th cng do thng qua c ch gii phng EDRF (hnh 23.2) nh con ng chung cui cng.

Hnh 23.2. Tc dng gin c thng qua EDRF

Vng gin mch ph thuc vo sinh kh dng v chuyn ho khc nhau ca thuc. Nitroglycerin cn c cystein mi chuyn thnh nitrosothiol. V vy, dng lu tc dng s gim (quen thuc), cn dng ngt qung hi phc cystein. Nitroprussiat trong qu trnh chuyn ha khng cn cystein nn khng c hin tng quen thuc. 1.2. Dc ng hc Cc nitrat hu c chu nh hng rt mnh ca enzim gan glutathion - organic nitrat reductase, thuc b kh nitrat tng bc v mt hot tnh. Nitroglycerin t di li, t nng ti a sau 4 pht, t/2 = 1-3 pht. Cht chuyn ho dinitrat c hot tnh gin mch km 10 ln v t/2 khong 40 pht.

255 | P a g e

Isosorbid dinitrat t di li c pic huyt tng sau 6 pht v t/2 = 45 pht. Cc cht chuyn ho ban u l isosorbid - 2 - mononitrat v isosorbid - 5 - mononitrat vn cn tc dng v c t/2 l t 2 5 gi. 1.3. c tnh c tnh cp tnh lin quan n tc dng gin mch: tt huyt p th ng, nhp tim nhanh, au nhi u. Cc ch phm nitrat vn c th dng cho ngi c tng nhn p, tuy nhin khng dng c cho ngi c tng p lc ni s. 1.4. Cc ch phm v liu lng Bng di y ghi cc ch phm ca nitrat v nitrit dng trong iu tr cn au tht ngc.

Thuc

Liu lng

Thi gian tc dng

Loi tc dng ngn Nitroglycerin, t di li Isosorbid dinitrat, di li Amyl nitrit, ngi 0,15- 1,2 mg 2,5- 5,0 mg 0,18- 0,3 mL 10- 30 pht 10- 60 pht 3- 5 pht Loi tc dng di Nitroglycerin, ung tc dng chm Nitroglycerin, thuc m 2% Nitroglycerin, gii phng chm, ung Nitroglycerin, gii phng chm qua da. Isosorbid dinitrat, ung Isosorbid dinitrat, nhai Isosorbid dinitrat, ung 6,5- 13 mg mi 6- 8 gi 2,5- 5 mg mi 4- 8 gi 2 mg mi 4 gi 10- 25 mg(1 ming cao)/24 gi 10- 60 mg mi 4- 6 gi 5- 10 mg mi 2- 4 gi 20 mg mi 12 gi 6- 8 gi 3- 6 gi 3- 6 gi 8- 10 gi 4- 6 gi 3 gi 6- 10 gi

2. LOI IU TR CNG C

2.1. Thuc phong to b adrenergic Lm gim cng nng tim do lm chm nhp tim. i khng vi tng nhp tim do gng sc. Lm tng th tch tm tht v ko di thi k tm thu. Tuy vy, tc dng

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chnh vn l tit kim s dng oxy cho c tim. Mt khc, thuc lm h huyt p trn ngi tng huyt p. Khng dng cho ngi c suy tht tri, v c th gy try tim mch t ngt. Khng nn ngng thuc t ngt v c th gy hin tng bt li lm nhi mu c tim, t t. - Ch phm: cc thuc thng dng l timolol, metoprolol atenolol v propranolol. Xin xem mc ny trong bi thuc tc dng trn h thn kinh thc vt. 2.2. Thuc chn knh calci Trong hiu th hot ng ca tim, Ca2+ c vai tr trong giai on 2 (giai on cao nguyn) v c bit l trong kh cc ca nt dn nhp (pacemaker), nt xoang v nt nh tht. Calci vo t bo theo knh chm. Trong c tim, Ca2+ gn vo troponin, lm mt hiu qu c ch ca troponin trn b co tht, do actin v myosin c th tng tc vi nhau gy ra co c tim. V th, cc thuc chn knh calci lm gim lc co bp ca c tim (xim xem thm mc ny trong bi Thuc cha tng huyt p), lm chm nhp tim v gim dn truyn nh tht. 2.2.1. C ch tc dng chng cn au tht ngc - Cc thuc chn knh calci do lm gim lc co bp ca c tim nn lm gim nhu cu oxy ca c tim (c ch chnh). - Trn thnh mch, cc thuc lm gin mao ng mch, lm gim sc cn ngoi bin, gim huyt p v gim p lc trong tm tht, gim nhu cu oxy. - i khng vi co tht mch vnh. Tc dng tt trong iu tr cc cn au tht ngc cha n nh. Tc dng phn phi li mu trong c tim, c li cho vng di ni mc, l vng rt nhy cm vi thiu mu. 2.2.2. Ch nh - D phng cc cn co tht mch vnh - Cn au tht ngc do co tht mch vnh (Prinzmetal) l ch nh tt nht. - Cn au tht ngc do co tht ngc khng n nh: tc dng tng t vi thuc chn b. C th dng phi hp vi cc dn xut nitro 2.2.3. Tc dng khng mong mun Cc tc dng khng mong mun thng lin quan n tc dng gin mch nh nhc u, cn bc ho, tt huyt p th ng, thu. Nng hn l cc du hiu c ch trn tim: tim nhp chm, nh tht phn ly, suy tim sung huyt, ngng tim. 2.2.4. Cc thuc Bng 23.1: So snh tc dng trn tim ca mt s thuc

Tn thuc

Gin mch vnh

c ch co bp tim

c ch tnh t ng (nt

c ch s dn truyn nh

257 | P a g e

xoang) Nifedipin Nicardipin Nimodipin Diltiazem Verapamil 5 5 5 3 4 1 0 1 2 4 1 1 1 5 5

tht 0 0 0 4 5

Ghi ch: Thang im cho t 0 (khng tc dng) n 5 (tc dng mnh nht).

Qua bng trn cho thy nifedipin v cc thuc cng nhm (xem Thuc cha tng huyt p) lm gin mch vnh mnh, t nh hng n hot ng ca c tim. Verapamil c ch hot ng ca c tim mnh nht, dng tt cho iu tr lon nhp tim. Bng 23.2: Dc ng hc v liu lng mt s thuc thng dng

Tn thuc

Sinh kh dng (%) 45- 70

Khi pht tc dng

t/2 (h)

Liu lng (ung)

Nifedipin

5- 20 pht (ngm, ung)

20- 40 mg, cch 8gi/ ln

Nicardipin Amlodipin Diltiazem Verapamil

35 65- 90 40- 65 20- 35 20 pht ung -

2- 3 3050 3- 4 > 30 pht 6 30 pht (ung) 30- 80 mg, cch 6gi/ ln 80-160 mg, cch 8gi/ ln 20- 40mg, cch 8gi/ ln 5- 10 mg/ ln/ ngy

3. THUC KHC

Cc hng nghin cu thuc mi ang pht trin v cn ang trong bc th nghim:

258 | P a g e

- Yu t pht trin ni mc mch (VEGF: vascular endothelial growth factor) nhm pht trin cc mch bng h cho vng thiu mu. - Tremetazidin (Vastarel): duy tr chuyn ho nng lng cc t bo b thiu oxy hoc thiu mu do trimetazidin ngn nga s gim st mc ATP trong t bo, v vy m bo c chc phn ca cc bm ion qua mng t bo, duy tr c tnh hng nh ni mi. Dng iu tr di ngy. Vastarel vin nn 20mg. Mi ln ung 1 vin vo ba n, mi ngy ung 2-3 ln.
CU HI T LNG GI

1. Trnh by c ch bnh sinh ca cn au tht ngc v nhng yu cu ca 1 thuc cha cn au tht ngc tt. 2. Trnh by c ch tc dng ca thuc loi nitrit. 3. Phn tch dc ng hc v cch dng ca loi nitrit tc dng ngn v nitrit tc dng di. Cho th d tng loi. 4. Phn tch c ch thuc chn knh calci la chn thuc cho tim mch

259 | P a g e

Bi 24:

THUC IU TR TNG HUYT P

MC TIU HC T P: Sau khi hc xong bi ny, sinh vin c kh nng:

1. Phn loi c cc thuc h huyt p 2. Trnh by c c ch tc dng v p dng iu tr ca cc thuc chn knh calci: nifedipin v verapamil. 3. Trnh by c c ch tc dng v p dng iu tr ca nhm thuc c ch enzym chuyn dng angiotesin.
1. HUYT P V BNH TNG HUYT P

1.1.

Huyt p

Huyt p T iu ho Huyt p = cung lng tim Tn s sc cn mch ngoi vi d lng mch

Th tch tm thu Tng HA tin gnh

co tht cng g/c stress

Ph i thnh mch

V mu tng Tng nhp Na+ Thn gi Na+

Renin angiotensin

Vai tr ca thn trong kim tra th tch tun hon: Khi p lc ti mu cho thn b gim, s c s phn phi li mu trong thn, km theo lm gim p lc mao mch thn v hot tnh giao cm (thng qua receptor b) dn n sn xut renin t tng sn xut angiotensin, gy ra: - Co mch - Kch thch sn xut aldosteron lm gi Na+ v nc Tng huyt p thng c chia thnh hai loi:

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- Tng huyt p th pht: khi huyt p tng ch l mt triu chng ca nhng tn thng mt c quan nh: thn, ni tit, tim mch, no... iu tr nguyn nhn, huyt p s tr li bnh thng. - Tng huyt p nguyn pht: khi nguyn nhn cha r, lc c gi l bnh tng huyt p. C ch bnh sinh ca tng huyt p rt phc tp. Huyt p ph thuc vo lu lng ca tim v sc cn ngoi vi. Hai yu t ny li ph thuc vo hng lot cc yu t khc, nh hot ng ca h thn kinh trung ng v thn kinh thc vt, ca v v tu thng thn, ca hormon chng bi niu (ADH), ca h renin - angiotensin aldosteron, ca tnh trng c tim, tnh trng thnh mao mch, khi lng mu, thng bng mui v th dch v.v... Mt yu t quan trng trong tng huyt p l lng cc ng mch nh v mao mch thu hp li. Phn ln khng tm c nguyn nhn tin pht ca tng huyt p, v vy phi dng thuc tc ng ln tt c cc khu ca c ch iu ha huyt p lm gin mch, gim lu lng tim dn n h huyt p (xem hnh). Tt c u l thuc cha triu chng v nhiu thuc c trnh by trong cc phn c lin quan (xem bng b). Bng 24.1: Phn loi cc thuc h huyt p theo v tr hoc c ch tc dng

1. Thuc li niu: lm gim th tch tun hon Nhm thiazid Thuc li niu quai Tc dng trung ng: methyldopa, clonidin Thuc lit hch: trimethaphan Thuc phong to nron: guanethidin, reserpin Thuc chn : propranolol, metoprolol Thuc hu a: prazosin, phenoxybenzamin Gin ng mch hydralazin, minoxidil, diazoxid Gin ng mch v tnh mch: nitroprussid Nifedipin, felodipin, nicardipin, amlodipin. 5. Thuc c ch enzym chuyn angiotensin Captopril, enalapril, ramipril. 6. Thuc i khng ti receptor angiotesin II Losartan, Irbesartan

2. Thuc hu giao cm

3. Thuc gin mch trc tip

4. Thuc chn knh calci

261 | P a g e

2. THUC CHN KNH CALCI

2.1. Khi nim v knh calci Nng Ca ngoi t bo 10.000 ln hn trong t bo (10-3 M so vi 10-7 M) v khi ngh mng t bo hu nh khng thm vi Ca, ng thi c bm Ca cng vi s trao i Na+ - Ca++ y Ca++ ra khi t bo. Ca vo t bo bng 3 ng (knh): 2.1.1. Knh hot ng theo in p (voltage operated chanel-VOC hoc cn gi l POC: potential operated channel): hot ng theo c ch tt c hoc khng c g (hoc hon ton m hoc hon ton khp kn) gy ra do s kh cc mng (t 90mV ln -40mV). Thuc h knh loi ny cn c c knh Na+, K+. Tu vo s dn (conductance) v s cm th (sensitive) vi in th, knh VOC cn c chia thnh 4 loi knh: - Knh L (long acting): c nhiu trong c tim v c trn thnh mch - Knh T (transient): c trong cc tuyn tit - Knh N (neuron): c trong cc nron - Knh P (purkinje): c trong purkinje tiu no v nron. Knh T, N v P t cm thu vi thuc chn knh Ca. 2.1.2. Knh hot ng theo receptor (receptor operated channel-ROC): p ng vi cc cht ch vn. 2.1.3. Knh d : Tri vi 2 knh trn, knh ny lun c m cho qua lung Ca nh, nhng lin tc. Ca t bo hoc vo li bo tng v t li bo tng ra, lm cho nng Ca trong bo tng t 10-7 M (nng gin c) tng ln 10-5M (nng co c), s kt hp c vi calci protein (troponin/calmodulin-CaM) v gy ra nhiu tc dng sinh l. 2.2. Vai tr sinh l ca Ca trn tim mch
10-3 M Ca++ VOC S.R Dn truyn nh tht Tnh t ng tim Prot. Co bp Proteinkinase enzyme Ch.ha Ca++ 10-7M 10-5M Troponin Calmodulin nhp bo/ xut bo gii phng TGHH

Co bp tim

co c trn thnh mch

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VOC: knh hot ng theo in p SR: li bo tng Hnh 24.1: Vai tr ca Ca++ sau khi qua knh

Trn c tim, Ca++ gn vo troponin, lm mt tc dng c ch ca troponin trn chc nng co bp, do cc si actin c th tng tc vi myosin, gy co c tim. Trn c trn thnh mch, khi calci ni bo tng s to phc vi calmodulin, phc hp ny s hot ha cc protein-kinase (phosphoryl ha myosin kinase chui nh), thc y s tng tc gia actin v myosin, gy co c trn thnh mch (Hnh 24.1) Sau khi tc ng, nng Ca2+ ni bo s gim do Ca2+ c bm li vo ti li ni bo hoc y ra khi t bo do bm v do trao i vi Na+. S trao i Na+/Ca2+ c th thc hin c hai chiu: Na+ vo Ca2+ ra, hoc Na+ ra Ca2+ vo. Trong iu kin sinh l bnh thng Na+ vo v Ca2+ ra, ngha l s trao i ny c vai tr chnh trong vic gi nng Ca2+ thp trong t bo. Khi c tr Na+ trong t bo (th d digitalis phong ta bm Na+) th hot ng theo chiu ngc li: Ca2+ vo t bo trao i vi Na+ i ra, gy tc dng tng co bp tim. Khc vi knh Na+, knh calci chu nh hng rt mnh ca cc yu t ngoi lai (trung gian ha hc, hormon) v cc yu t ni ti (pH, ATP). Ni chung, cc knh Ca ch hot ng khi trc c phosphoryl ha. S phosphoryl ha ph thuc vo hot tnh ca adenylcyclase. 2.2. Cc thuc chn knh calci Fleckenstein (1964) ln u tin a ra khi nim chn knh calci khi m t tc dng ca verapamil trn t bo c tim, l thuc c tng hp phng theo cng thc cu to ca papaverin. Cc thuc thuc nhm ny gn c hiu trn knh v phong ta knh, tuy cu trc ha hc rt khc nhau. 2.2.1. Phn loi Theo cu trc ha hc v c im iu tr, c 3 nhm thng thng. Sau li chia thnh th h: th h 1 l thuc chn knh Ca mng t bo v mng ti li ni bo; th h 2 tc dng nh th h 1 nhng chn lc trn t bo c trn thnh mch hoc tim hn. Tc dng ko di. Bng 24.2: Cc thuc chn knh calci Nhm ha hc Dihydropyridin Benzothiazepin Phenyl alkyl amin Tc dng c hiu ng mch > tim ng mch = tim Tim > ng mch Th h 1 Nifedipin Diltiazem Verapamil Th h 2 Felodipin Nicardipin Nimodipin Amlodipin Clentiazem Gallopamid Anipamil

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Thuc c tc dng trn ng mch mnh hn trn tim do lm gin mch nhanh v mnh, d gy h huyt p nhanh, dn n phn x lm tng nhp tim, khng li, nht l trn c tim b thiu mu. Verapamil do c tc dng c ch trn tim mch hn trn ng mch nn thng c ch nh trong lon nhp tim (xin xem thm bi Thuc cha lon nhp tim). 2.2.2. Dc ng hc Cc thuc chn knh calci tc dng theo ng ung v chu s chuyn ha qua gan ln th 1, v vy ngi ta nghin cu thay i cc nhm chc trong cng thc cu to, lm cho thuc chm b chuyn ha, chm b thi tr hoc n nh hn, c tnh chn lc hn. Do to ra cc thuc th h 2, 3. Bng 24.3: Dc ng hc mt s thuc chn knh calci
Thuc Hp thu (un g) 4570% Khi pht tc dng t/2 (gi ) 4 Phn phi

Nifedipin

- tm: < 1 pht - Ngm, ung 5- 20 pht

- Gn protein huyt tng90% - B chuyn ha, thi qua thn

Nicardipi n

35%

ung: 20 pht

2- 4

- Gn protein huyt tng 95% - B chuyn ha, thi qua gan

Felodipin

1520%

ung: 2- 5 h

1116

- Gn protein huyt tng > 99% - B chuyn ha nhanh gan

Nimodipi n Nisoldipi n Amlodipi n Bepridil

13% < 10% 6590% 60%

cha c ti liu -

1- 2 2- 6

- B chuyn ha nhiu - Lm gin mch no mnh - B chuyn ha nhiu - Lm gin mch vnh mnh

3050 24-

- Gn protein huyt tng >90% - B chuyn ha nhiu - Gn protein huyt tng

Ung: 1 h

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40 Diltiaze m 4065% - Tim t nh mch < 3 pht - Ung:>30 pht - Tim t nh mch: < 1,5pht - Ung: 30 pht 3- 4

> 99% - B chuyn ha nhiu - Gn protein huyt tng 70-80% - B chuyn ha, thi qua phn

Verapam il

2035%

- Gn protein huyt tng 90% - Thi qua thn 70% - Thi qua rut 15%

2.2.3. C ch tc dng Cc thuc chn knh Ca gn ch yu vo knh L, l knh c nhiu t bo c tim v c trn thnh mch. Nifedipin v cc thuc nhm dihydropyridin (DHP) gn vo mt v tr mt trong knh, trong khi verapamil v diltiazem gn vo tr tr khc. Knh L c nhiu di n v a2, b, g v d. DHP gn ch yu vo a. Ngoi ra, DHP c th cn c ch nucleotid phosphodiesterase vng nn lm tng nucleotid vng, gy gin c trn: thuc cng phong ta knh hot ng theo receptor, nhng mc km hn. Knh T v N rt km nhy cm vi thuc nn nron v cc tuyn tit t chu nh hng ca cc thuc ny. 2.2.4. Cc tc dng trn c quan 2.2.4.1. Trn c trn Lm gin cc loi c trn: kh- ph qun, tiu ha, t cung, nhng c bit l thnh mch (mao ng mch nhy cm hn mao tnh mch). 2.2.4.2. Trn c tim Hot ng ca tim ph thuc nhiu vo dng Ca (xem in sinh l ca tim). Thuc chn knh Ca lm gim to xung tc, gim dn truyn v gim co bp c tim, v th lm gim nhu cu oxy trn bnh nhn c co tht mch vnh. Mc tc dng gia cc thuc c khc nhau. 2.2.4.3. Mch no Nimodipin c i lc cao vi mch no, v vy c dng cho bnh nhn c tai bin mch no (chy mu di mng nhn gy co mch do chn p; t qu c vim tc mch). Nhng cn cha r kt qu iu tr l do gin mch no hay l do lm gim nhu cu oxy ca nron. 2.2.5. Tc dng khng mong mun v c tnh - Tc dng nh, khng cn ngng iu tr: cn nng bng, nhc u, chng mt (do phn x gin mch, tng nhp tim nn dng cng vi thuc chn b giao cm), bun nn, to.

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- Tc dng nng hn, lin quan n tc dng iu tr do c ch qu mnh knh Ca: tim p chm, nghn nh tht, suy tim xung huyt, ngng tim. Him gp. 2.2.6. p dng lm sng trong iu tr THA - Do lm gim lc co bp c tim, gim nhu cu oxy ca c tim, gim trng lc v sc cn mch ngoi bin nn cc thuc ny c dng iu tr THA. Cho ti nay, cc thuc chn knh calci c coi l thuc iu tr THA an ton v c hiu qu. Verpamil, nifedipin, nicardipin v diltiazem u c hiu qu h p nh nhau. Tuy nhin, do c s khc nhau v hiu qu huyt ng hc nn vic chn la iu tr c khc nhau: Nifedipin c tc dng chn lc nht trn mch v tc dng c ch tim li yu nht. Phn x giao cm hi lm tng nhp tim v lm tng hiu sut tim. Verapamin c tc dng trn tim mnh nht, lm gim nhp tim v gim hiu sut tim. Diltiazem c tc dng trung gian - Ngn cn co tht mch vnh khu tr, c ch chnh ca cn au tht ngc - Verapamil, diltiazem lm gim dn truyn nh tht, c ch nh trong nhp tim nhanh trn tht do ti nhp (xin xem bi Thuc chng lon nhp tim). 2.2.7. Ch phm Amlodipin: vin nn 2,5- 5- 10 mg Diltiazem: vin nn 30- 60- 90- 120 mg Vin nang gii phng chm: 60- 90- 120- 180 mg Thuc tim 5 mg/ mL Felodipin (Plendil): vin gii phng chm 2,5- 5- 10 mg Nifedipin (Adalat): vin nang 10- 20 mg Vin gii phng chm 30- 60- 90 mg Nimodipin (Nimotop): vin nang 30 mg Verapamil: vin nn 40- 80- 120 mg Vin gii phng chm 120- 180- 200 mg Thuc tim 5 mg/ 2mL
3. THUC C CH ENZYM CHUYN ANGIOTENSIN (ECA)

Enzym chuyn angiotensin (ECA) hay bradykinase II l mt peptidase c tc dng: - Chuyn angiotensin I (decapeptid khng c hot tnh) thnh angiotensin II (octapepetid c hot tnh) l cht c tc dng co mch v chng thi tr Na+ qua thn. - Lm mt hot tnh ca bradykinin, l cht gy gin mch v tng thi Na+ qua thn. Sau khi c hnh thnh, angiotensin II s tc ng trn cc receptor ring, hin c bit l AT1, AT2, AT3, AT4, trong ch c AT1 l c bit r nht (s ).

266 | P a g e

Hnh 24.2: Tc dng ca ECA v thuc c ch ECA

Cc receptor AT1 c nhiu mch mu, no, tim, thn, tuyn thng thn. Vai tr sinh l: co mch, tng gi Na+, c ch tit renin, tng gii phng aldosteron, kch thch giao cm, tng co bp c tim v ph i tht tri. Cc receptor AT2 c nhiu tuyn thng thn, tim, no, c t cung, m bo thai. Vai tr sinh l: c ch s tng trng t bo, bit ha t bo, sa cha m, kch hot prostaglandin, bradykinin v NO thn. 3.1. C ch v c im tc dng Cc thuc do c ch ECA nn lm angiotensin I khng chuyn thnh angiotensin II c hot tnh v ngn cn ging ha bradykin, kt qu l lm gin mch, tng thi Na+ v h huyt p. Trong iu tr tng huyt p, cc thuc ny c cc c im sau: - Lm gim sc cn ngoi bin nhng khng lm tng nhp tim do c ch trng lc giao cm v tng trng lc ph giao cm. - Khng gy tt huyt p th ng, dng c cho mi la tui. - Tc dng h huyt p t t, m du, ko di. - Lm gim c huyt p tm thu v tm trng. - Lm gim thiu mu c tim do tng cung cp mu cho mch vnh. - Lm chm dy tht tri, gim hu qu ca tng huyt p. - Trn thn kinh trung ng: khng gy trm cm, khng gy ri lon gic ng v khng gy suy gim tnh dc. 3.2. Ch nh - Thuc c tc dng iu tr tt cho mi loi tng huyt p: . Trn ngi c tui, h huyt p khng nh hng n tun hon no v khng nh hng n phn x p lc. . Trn ngi c i tho ng: khng nh hng n chuyn ha glucid, lipid. Mt khc, insulin lm K+ vo t bo, gy h K+ mu; thuc c ch ECA lm gim aldosteron nn gi li K+.

267 | P a g e

. Trn ngi c bnh thn, do angiotensin II gim, lm lu lng mu qua thn tng nn lm gim bi tit - Suy tim sung huyt sau nhi mu c tim. 3.3. Tc dng khng mong mun - H huyt p mnh c th xy ra khi dng liu u trn nhng bnh nhn c th tch mu thp do ang s dng thuc li niu, ch n gim mui hoc mt nc qua tiu ha. - Suy thn cp nht l trn bnh nhn c hp mch thn. - Tng Kali mu khi c suy thn hoc i tho ng. - Ho khan v ph mch l do bradykinin khng b ging ha, prostaglandin tch lu phi gy ho (nhiu khi lm bnh nhn phi b thuc). - Khng dng cho ph n c thai 3 - 6 thng cui v thuc c th gy h huyt p, v niu, suy thn cho thai, hoc gy qui thai, thai cht. 3.4. Phn loi v dc ng hc 3.4.1. Thuc c ch ECA

Captopril Thuc Cc thng s Sinh kh dng % Gn protein huyt tng % t/2 (h) Khi pht tc dng (h) Thi gian tc dng (h) Liu ung 24h (mg) 70 30 2 0,25 4- 8 75- 300

Enalap ril

Perindop ril

Beneze pril

Lisinop ril

40 50 11 2- 4 24 5- 20

70 9- 18 9 1- 2 24 2- 8

17 95 11 0,5 24 5- 20

25 3- 10 12 1- 2 24 5- 20

Enalapril, perindopril, benezepril u l tin thuc, vo c th phi c gan chuyn ha mi c tc dng. 3.4.2. Thuc c ch ti receptor ca angiotensin II Do vic chuyn angiotensin I thnh II cn c s tham gia ca cc enzym khc (nh chymase) khng chu tc ng ca thuc c ch ECA nn s to thnh angiotensin II vn cn. Mt khc, do thuc c ch ECA ngn cn s ging ha ca bradykinin

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nn bradykinin phi tng, kch ng gy cn ho khan rt kh tr. V vy kch thch vic nghin cu cc thuc c ch angiotensin II ngay ti receptor ca n: thuc c ch AT1. Cc thuc ny cn ang c nghin cu, nh gi trn cc th nghim lm sng. V nguyn tc, do c tc dng chn lc trn AT1 nn trnh c tc dng ph ca bradykinin (ho, ph mch). Bng 24.4: Mt s c im dc ng hc ca cc thuc c ch AT1

Losartan Thuc Cc thng s i lc gn vo AT1 Sinh kh dng t/2 (h) Thi tr Liu ung (mg/ 24 h) + 33 2 (6- 9)* Thn v gan 50- 100

Valsartan

Irbesartan

Telmisartan

+++ 25 9 Gan 70%; thn 30% 80- 320

++++ 70 11- 15 Gan 80%, thn 20% 150- 300

+++ 43 24 Gan 40- 80

* t/2 ca loscartan l 2 gi, nhng ca cht chuyn ha cn hot tnh l 6-9 gi.
4. CC THUC H HUYT P KHC

4.1. Clonidin (2,6 diclorophenyl - amino - 2 imidazolin - catapres) L thuc kch thch receptor a2 ca h giao cm trung ng nn lm gim trng lc giao cm ngoi bin. 4.1.1. Tc dng - Lm h huyt p do: . Lm gim cng nng tim, gim nhp tim . Lm gim sc cn ngoi bin, nht l khi trng lc giao cm tng. . Lm gim sc cn mch thn, duy tr dng mu ti thn. . Nh methyl dopa, clonidin rt t khi gy tt huyt p th ng. - Cc tc dng khng lin quan n h huyt p: . An thn (do hu giao cm trung ng?) khong 50% trng hp. . Kh ming do c ch trung ng: khong 50% trng hp. . Gim au do gim hot tnh nron sng sau tu sng. Nhng tc dng ny l do thuc gn vo receptor imidazolin c trong thn kinh trung ng. 4.1.2. Dc ng hc

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Thuc tan nhiu trong m, vo thn kinh trung ng nhanh. Ung hp thu tt, sinh kh dng ti 100%, t c pic huyt tng sau 1-3gi, t/2 khong 12gi. Thi tr qua thn 50% di dng nguyn cht. 4.1.3. Ch nh - Tng huyt p - Tin m: do c tc dng an thn, gim au nn lm gim c lng thuc m v tng n nh huyt ng. - Cai nghin: ma tu, ru, thuc l. 4.1.4. c tnh - Kh ming, an thn: l tc dng trung ng, lin quan n liu dng. - Ngng thuc sau dng lu v liu cao (>1mg/ngy) c th gp cn tng huyt p kch pht do tng trng lc giao cm: bun nn, tim nhp nhanh, nhc u, v m hi. Cn gim liu dn v dng thuc thay th. iu tr nn tng huyt p ny bng dng li clonidin v dng cc thuc chn a, chn b giao cm. 4.1.5. Ch phm v liu lng Clonidin (Catapres) Vin nn: 0,1 - 0,2 - 0,3mg Ung 0,2 -1,2 mg/ngy, chia lm 2 ln Cao dn: Gii phng 0,1 - 0,2 - 0,3mg/24gi. C tc dng 7 ngy cho 1 ln dn. C th c phn ng ti ch dn. 4.2. Natri nitroprussid L thuc gin mch mnh dng theo ng tim iu tr cp cu cn tng huyt p v suy tim nng. Lm gin c ng mch v tnh mch. C ch: hot ho guanyl cyclase do tc dng kch thch trc tip hoc thng qua gii phng NO, dn n lm tng GMPv, gy gin c trn.

Nitroprussid l mt phc hp ca st, cc nhm cyanid v phn nitroso. c tnh nng nht lin quan n s tch lu cyanid; ngoi ra cn gp nhim acid, lon nhp, tt huyt p. Hydroxocobalamin (vitamin B12) kt hp vi cyanid to cyanocobalamin khng c, do c dng gii c nitroprussid.

CN CN 2Na NC Fe CN ON CN

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Natrinitroprussid c ch nh trong cn tng huyt p, suy tim sung huyt (do lm gim c tin gnh v hu gnh) v lm gim nhu cu oxy ca c tim sau nhi mu c tim. Trong ngoi khoa cn dng lm h huyt p c kim tra khi gy m lm gim chy mu do phu thut. Nitroprussid (Nipride): l 50mg. Khi dng pha trong dextrose 5% - 250 - 1000 ml, truyn tnh mch 0,5 mg/kg/pht, c th tng ti 10 mg/kg/pht. Chai thuc phi bc trong giy mu, trnh nh sng. Kim tra huyt p thng xuyn.
5. CHIN THUT IU TR TNG HUYT P V CN

V THA v cn mang tnh cht rt a dng nn vic iu tr cng cn c th ha va c hiu qu, va c th dung np c. 5.1. Ai cn c iu tr - Mi ngi khi c HA 140- 90 mmHg - Khi c tn thng c quan ch hoc c i tho ng, mc du HA cn gii hn trn (130-139/85-89 mmHg). Mc tiu iu tr l a HA v chun < 140/99mmHg, nhng khng n gin, M ch 27% bnh nhn THA t c ch tiu ny. 5.2. Cch iu tr 5.2.1. Phng php khng dng thuc - n gim mui, gim ru, gim cn (bo)... - Th dc u, nh nhng 5.2.2. Thuc Cn c th ha, vi th cn iu tr th - Lc u dng li niu, chn b, chn knh calci v thm ch c cc thuc khc (chn a1 c ch ECA). iu cn tu thuc vo bnh km theo: thuc c ch ECA khi c i tho ng; chn b khi c bnh mch vnh; chn knh Ca (loi dihydropyrindin) khi c THA tm thu ring bit ngi cao tui. Lc u nn chn mt loi thuc. - Khi mt thuc khng cho kt qu mong mun: Khng nn tng liu v s c tc dng ph: thuc li niu (ri lon chuyn ha), chn b (tc dng trung ng, chm nhp tim), chn knh Ca (ph, nh trng ngc, nhc u, nng mt), chn a1 (h HA th ng). Thay thuc khc Phi hp thuc c c ch khc nhau Mt thuc h HA c th gy phn ng b tr, lm gim tc dng ca chnh n. Dng thuc phi hp ngn chn phn ng b tr. Th d thuc li niu lm thi Na, gy tng renin (dng thm thuc c ch ECA); thuc chn knh Ca gy tng nhp tim phn x (dng chn b ). Hin c vin thuc phi hp sn. Tin dng nhng khng hay v khng c th ha c.

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Trong nhng nm gn y, vic iu tr THA tr nn n gin hn trc rt nhiu nh c nhiu loi thuc hiu qu. Vn l phi c th ha trong iu tr mi bnh nhn c th tm c cho mnh mt thuc thch hp va c hiu qu, va dung np tt. 5.3. Tiu chun thuc h huyt p l tng - C tc dng h huyt p tt . H HA t t, m du, ko di . Gim c s ti a v s ti thiu . Gim c ngi tr v ngi cao tui . Lm mt nh tng huyt p trong ngy - Khng lm mch nhanh do khng lm tng cng c tim v tng nhu cu oxy. - Khng lm mch chm, trnh c nghn nh - tht - Khng lm gim sc co bp ca c tim, nht l tht tri - Dng c cho nhiu i tng: suy thn, tiu ng, tng lipid mu - Khi ngng thuc, khng c nguy c "phn hi".
CU HI T LNG GI

1. Phn loi cc thuc iu tr tng huyt p theo c ch tc dng ca thuc 2. Trnh by c ch tc dng v phn loi cc thuc chn knh calci. 3. Trnh by cc tc dng iu tr v tc dng khng mong mun ca thuc chn knh calci. 4. Trnh by c ch tc dng ca thuc c ch enzym chuyn angiotensin (ECA). 5. Nu c im tc dng v ch nh iu tr ca ECA. 6. So snh u- nhc im ca thuc chn knh calci v ECA trong iu tr tng huyt p.

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Bi 25:

THUC LI NIU

MC TIU HC T P: Sau khi hc xong bi ny, sinh vin c kh nng:

1. Trnh by c c ch tc dng v p dng iu tr ca 4 nhm thuc li niu: nhm thuc c ch enzym carbonic anhydrase, nhm thiazid, nhm thuc li niu quai v nhm lu kali mu. 2. Nu c cc tai bin ri lon v ion khi dng cc thuc li niu ko di 3. Trnh by c c ch tc dng v p dng iu tr ca thuc li niu thm thu
1. I CNG

Tt c cc cht lm tng khi lng nc tiu u c coi l c tc dng li niu (ung nc nhiu lm i nhiu). Song nu ch nh vy th khng gii quyt c ph, l tnh trng ng Na+ dch ngoi t bo. Cho nn thuc li niu phi l thuc lm tng thi tr Na+, km theo l thi tr nc ly t dch ngoi t bo. Trn ngi khng c ph, thuc li niu vn c tc dng. l c s s dng n trong iu tr cao huyt p: lm gim Na+ ca thnh mch s lm tng tc dng ca thuc h p v gim tc dng ca cc hormon gy co mch (nh vasopressin). Ngoi tc dng c ch chn lc ti hp thu Na+, cc thuc li niu cn c nh hng trc tip hoc gin tip n s bi xut ca mt s in gii hoc cc cht khc: K+, Cl, HCO3-, acid uric... v gy ra cc ri lon khi dng ko di. hiu r c ch v cc tc dng khng mong mun ca thuc li niu, cn nhc li qu trnh vn chuyn ca mt s ion khi qua thn. 1.1. Vn chuyn ca Na+ - ng ln gn, khong 70- 80% Na+ c ti hp thu cng vi cc cht hu c ha tan (ng, acid amin), vi cc anion (acetat, phosphat, citrat, Cl-), vi bicarbonat di nh hng ca carbonic anhydrase. - on ln ca quai Henle, Na+ tip tc c ti hp thu khong 15- 20%, theo c ch cng vn chuyn 1 Na+, 1 K+ v 2 Cl-. - ng ln xa, ti hp thu Na+ (0- 10%) ph thuc vo bi xut K+ v H+: . Trao i Na+ v K+ di nh hng ca aldosteron, hormon lm tng ti hp thu Na+ v tng thi K+ . Trao i gia Na+ v H+ ph thuc vo trng thi thng bng acid- base. Trong nhim acid, c s tng thi tr H+ nn lm tng ti hp thu Na+: c 1 ion H+ thi tr vo lng ng thn th 1 ion Na+ c ti hp thu. Trong nhim base c hin tng ngc li. Kt qu cui cng l sau khi lc qua cu thn (25.000 mEq/ 24h), Na+ c ti hp thu ti 98- 99%, ch thi tr 20- 400 mEq/ 24h.

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1.2. Vn chuyn K+ K+ qua cu thn c ti hp thu hon ton ng ln gn. S c mt ca K+ trong nc tiu l do c bi xut ng ln xa bng cc qu trnh sau: - nh hng ca aldosteron: thi K+ v ti hp thu Na+ - nh hng ca trng thi thng bng acid- base: H+ v K+ l 2 ion c thi tr tranh chp ng ln xa. Trong nhim acid, khi tng thi tr H+ trao i vi ti hp thu Na+ th s gim bi xut K+. Trong nhim base th ngc li, ion H+ c to ra phn ln l do enzym carbonic anhydrase (CA). ng ln xa, CA ng vai tr ch yu trong acid ha nc tiu. 1.3. Bicarbonat ng ln gn, 4/5 bicarbonat lc qua cu thn c ti hp thu do nh hng ca enzym CA (hnh 25.1). Phn cn li hu nh s b ti hp thu nt ng ln xa (pH ca nc tiu l acid nn khng cha bicarbonat). 1.4. Vn chuyn nc - ng ln gn, nc c ti hp thu th ng theo cc cht in gii. Nc tiu trong lng ng ng trng. - nhnh xung ca quai Henle, nc c ti hp thu n thun, khng km theo in gii, nc tiu ngy cng u trng.

Hnh 25.1. Ti hp thu bicarbonat ng ln gn

- nhnh ln ca quai Henle, nc khng thm qua c, trong khi Na+ li c ti hp thu, nn nc tiu dn dn tr thnh nhc trng. V vy, phn cui ca nhnh ln v phn u ca ng ln xa c gi l on pha long.

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Hnh 25.2. Vn chuyn nc v in gii n v thn = : Nc tiu ng trng + : u trng - : Nhc trng

- Trong ng gp, tnh thm vi nc c thay i ph thuc vo ADH, hormon chng bi niu ca thu sau tuyn yn. Vi s c mt ca ADH, ng gp thm nc mnh, nc c ti hp thu khng km theo ion, nc tiu c c c dn v tr thnh u trng. Khi khng c ADH th ng gp khng thm nc, nc tiu t ng ln xa n vn gi trng thi nhc trng trong ng gp (H.29). Nh vy, cu thn lc 130 ml/ pht v bi xut nc tiu l 1 ml/ pht (1440 ml/ 24h). Ngha l trn 99% nc tiu lc qua cu thn c ti hp thu. R rng l mun c tc dng li niu nhanh khng phi l lm tng sc lc ca cu thn m l cn c ch qu trnh ti hp thu ca ng thn.
2. CC THUC LI NIU

Mi thuc li niu thng tc dng mt v tr nht nh ca ng thn, lm thay i thnh phn ion ca nc tiu trong lng ng thn. S thay i s gin tip hoc trc tip gy ra cc phn ng trong s vn chuyn cc ion v nc cc phn khc, v s l nguyn nhn ca cc ri lon in gii, thng bng acid- base ca thuc. tin theo di lm sng khi dng thuc li niu ko di, ta chia thnh 2 nhm ln: - Thuc li niu lm gim K+ mu (tng thi tr K+) - Thuc li niu gi K+ mu (gim thi tr K+) - Ngoi ra, c loi thuc li niu thm thu, khng gy ri lon ion. 2.1. Thuc li niu lm gim K+ mu Cc thuc ny do tc dng lm tng thi Na+ on trn ca ng ln nn on cui ca ng ln c phn ng tng thi K+ gi Na+, gy cc ri lon gim K+ mu v lm tng c tnh ca thuc dng cng (nh loi digitalis). 2.1.1. Thuc phong to carbonic anhydrase (CA)

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Cn gi l sulfamid li niu. Tt c u c nhm sulfonamid (-SO2NH2) trong cng thc, nhng khng c tc dng km vi khun. 2.1.1.1. Tc dng v c ch ng ln gn, trong t bo ng thn, CA c tc dng lm gii phng ion H+ vo lng ng thn theo phn ng sau: CA H2O + CO2 H2CO3 HCO3- + H+

H+ c gii phng vo lng ng thn s trao i vi Na+ c ti hp thu (hnh 1). Khi enzym CA b phong ta, lng ion H+ bi xut b gim nn Na+ khng c ti hp thu, thi tr ra nc tiu di dng bicarbonat, ko theo nc nn li niu. Mt khc, do s bi xut tranh chp gia H+ v K+, khi thiu H+, K+ s b tng thi tr. Tm li, thuc lm tng thi tr Na+, K+ v bicarbonat (c th lm thi tr ti 45% lng HCO3- qua thn), do lm gim K+ mu v gy nhim acid chuyn ha. Tnh trng nhim acid ny ch b tr sau 3- 7 ngy v sau l nguyn nhn t gii hn hiu qu ca thuc: dng thuc lin tc, tc dng b gim nhanh. Do qu trnh b tr, nng Cl- huyt tng tng (do tng ti hp thu NaCl) Ngoi ra mt (cun m) v thn kinh trung ng cng c enzym CA. Thuc c ch enzym lm gim tit thu dch ca mt, gim sn xut dch no ty v gy toan chuyn ha trn thn kinh trung ng. 2.1.1.2. Ch nh - V c nhiu thuc li niu tt hn nn thuc ny khng cn c dng vi mc ch li niu. Ch nh ca thuc lin quan n tc dng thi tr bicarbonat v tc dng ngoi thn. - iu tr tng nhn p (glcm gc m) do thuc lm gim tit dch nhn cu. - iu tr chng ng kinh: ngoi tc dng lm gim to thnh dch no tu, thuc cn c tc dng chng co git. Trong no, cc qu trnh oxy ha xy ra rt nhanh cho nn CO2 cng c sinh ra nhanh. Thuc phong to enzym CA bo tng, lm tch lu H2CO3 gy nhim acid t bo nn lm thay i chc phn t bo thn kinh. 2.1.1.3. Chng ch nh - Bnh tim phi mn tnh, hoc cc bnh phi mn tnh c suy h hp v tng CO2 mu, v cc thuc phong to CA ngn cn ti hp thu bicarbonat cn thit nh l cht m trung ha trng thi qu tha CO2 trong m. - X gan v suy gan, v thuc gy acid mu, d lm xut hin hn m gan. 2.1.1.4. Tai bin - Gy acid huyt do lm gim d tr base, khi tc dng ca thuc cng b gim i nu dng thuc nhiu liu lin nhau, cho nn cn dng ngt qung.

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- Gim K+ mu, gy mt mi, hoc d xy ra nhim c khi ang iu tr bng digitalis. 2.1.1.5. Ch phm

Vin 0,25 g. Mi ngy ung 1 vin. Trong bnh tng nhn p, c th ung 4- 6 vin mt ngy. Hp thu nhanh qua ng tiu ha, gn vi protein huyt tng 92%. Thi gian bn hy ngn, khng b chuyn ha. Thi tr hon ton qua nc tiu trong 24 gi. 2.1.2. Nhm thiazid (benzothiadiazid) Trong phn t c 2 nhm sulfonamid (-SO2NH2), 1 t do v 1 nm trong d vng. 2.1.2.1. Tc dng v c ch Tc dng c ch CA km acetazolamid (Diamox), nhng tc dng li niu li nhanh hn v vy cn c nhng tc dng khc m c ch cn cha hon ton bit r. L thuc tc dng trc tip trn thn, tim vo 1 thn th gy li niu ch cho thn (tuy nhin cha tm thy receptor hay enzym c hiu). Thiazid c ch ti hp thu Na+ v km theo l c Cl- (v tr ng vn chuyn) on pha long (phn cui ca nhnh ln quai Henle v phn u ca ng ln xa), thi tr Na+ v Cl- vi s lng gn ngang nhau nn cn gi l thuc li niu thi tr mui (saluretics). Khong 5- 10% Na+ lc qua cu thn b thi tr nn thuc loi thuc c tc dng li niu trung bnh. Thuc c tc dng c mi trng acid v base. - Lm tng thi tr K+, theo 2 c ch: mt phn do thuc c ch enzym CA, lm gim bi tit ion H+ nn tng thi K+ (c ch thi tr tranh chp ng ln xa); mt phn do c ch ti hp thu Na+ lm m Na+ tng cao ng ln xa, gy phn ng b tr bi xut K+ ko Na+ li. - Khng lm tng thi tr bicarbonat nn khng gy acid mu. - Lm gim bi tit acid uric qua ng thn nn c th lm nng thm bnh gut. Cc thiazid c thi tr qua h thi tr acid hu c ca ng thn nn tranh chp mt phn vi thi tr acid uric qua h ny. - Dng lu, lm gim calci niu do lm tng ti hp thu Ca++ ng ln gn v c xa nn c th dng d phng si thn. Tuy nhin, him khi gp tng calci mu do thiazid v c th c cc c ch b tr khc. - Lm h huyt p trn nhng bnh nhn b tng huyt p v ngoi tc dng lm tng thi tr mui, cc thuc cn c ch ti ch tc dng ca thuc co mch trn thnh mch, nh vasopressin, noradrenalin. Mt khc, do lng Na+ ca m thnh mch gim nn dch gian bo ca thnh mch cng gim, lm lng mch rng ra, do sc cn ngoi vi gim xung (huyt p ti thiu h). 2.1.2.2. Ch nh

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- Ph cc loi: tim, gan, thn, c th gy thiu mu thai v teo thai, khng dng cho ph v tng huyt p khi c thai. C th dng cho ph tim, gan, thn ngi c thai. - Tng huyt p: dng ring hoc dng cng vi cc thuc h p khc, v c tc dng hip ng. - Tng calci niu khng r nguyn nhn d dn n si niu. 2.1.2.3. Chng ch nh hoc dng thn trng - Trng thi gim kali- mu trn bnh nhn b x gan (v d lm xut hin hn m gan), trn bnh nhn ang iu tr bng digital (s lm tng c tnh ca digital). Khc phc bng ung KCl 1- 3 g mt ngy. - Bnh gut: do thiazid lm tng acid uric mu - Suy thn, suy gan, khng dung np sulfamid (gy bnh no do gan). 2.1.2.4. Tai bin Khi dng lu, thuc c th gy cc tai bin sau: - Ri lon in gii: h Na+ v K+ mu (theo c ch trnh by trn), gy mt mi, chn n, nhc u, bun nn, chut rt. - Tng acid uric mu gy ra cc cn au ca bnh gut. iu tr bng probenecid. - Lm nng thm i ng ty. C ch cha r. Mt s tc gi thy thiazid c ch gii phng insulin v lm tng bi tit catecholamin u dn ti tng ng huyt. - Lm tng cholesterol v LDL mu khong 5- 15%. Tuy nhin khi dng ko di th c 2 mc li tr v bnh thng. - Mt s biu hin d ng hoc khng chu thuc. 2.1.2.5. Tng tc thuc - Cc thiazid lm gim tc dng ca cc thuc chng ng mu, thuc lm tng thi tr uric iu tr gut, cc sulfonylure v insulin. - Cc thiazid lm tng tc dng ca thuc t, diazoxid, glycosid tr tim, lithi, thuc li niu quai v vitamin D. - Tc dng li niu ca thiazid b gim khi dng cng vi thuc chng vim phi steroid. Amphotericin B v corticoid lm tng nguy c h kali mu ca thiazid. 2.1.2.6. Ch phm: mt s thuc thng dng Chc halogen C6 v nhm sulfamid C7 rt cn cho tc dng li niu ca c nhm. Thay nhm -SO2 NH2 C7 bng Cl, c diazoxid c tc dng ngc vi chlorothiazid, gi Na+, nhng c tc dng gin mch, h huyt p. Hydrochlorothiazid do bo ha ng ni 3- 4, c tc dng thi tr Na+ mnh gp 10 chlorothiazid.

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Bng 25.1: Mt s ch phm


Tn thuc X ng ni 3- 4
Ni kp Bo ha Bo ha Bo ha Bo ha H H H -CH2Cl -CH2-S- CH2 CF3

Mc Thi gian tc thi tr mui dng


8- 12h 8- 12h 8- 12h 12- 24h 30h 1 10 10 200 500

Liu lng

Chlorothiazid Hydrochlorothiazid (hypothiazid) Hydroflumethiazid Methylchlothiazid Polythiazid

Cl Cl CF3 Cl Cl

H H H CH3 CH3

0,5- 2,0g 0,025- 0,1 0,025- 0,1 0,005- 0,01 0,002- 0,004

Hin nay c thm mt s ch phm mi: - Chronexan (Xipamid). Vin 20 mg D hp thu qua tiu ha. nh huyt tng 45 pht- 2 gi sau khi ung liu duy nht. T1/2: 6- 8h. Gn vo protein huyt tng 95%. Thi 90% qua thn, ch yu l dng khng i. Ung liu duy nht bui sng 10- 40 mg - Hygroton (Chlorthalidone). Vin 25 mg Hp thu chm. T1/2 l 50 gi.Thi 1/2 qua thn di dng khng i. Qua c sa. Ung 1 ln vo bui sng, 1- 2 vin - Fludex (Indapamid) vin 2,5 mg, Natrilix vin 1,5 mg. c im: . Gin mch (thay i dng ion, c bit l Ca) . Kch thch tng hp PGE2 v PGI2 (gin mch v chng vn tiu cu) . Khng nh hng n chuyn ha ng v lipid ng hc: t c nh huyt tng sau 1- 2h. Gn 75% vo protein huyt tng, T1/2 = 14- 24h 2.1.3. Thuc li niu tc dng mnh hay thuc li niu "quai" ("loop diuretics") l nhm thuc c tc dng rt mnh so vi cc thuc li niu bit v v tr tc dng l on phnh to ca nhnh ln quai Henle. on ny c qu trnh ti hp thu ti 35% lng Na+ v Cl- ca nc tiu ban u. Thuc tiu biu l furosemid v acid ethacrynic. 2. 1.3.1. Tc dng v c ch - c ch c ch cng vn chuyn (cotransport mechanism) ca 1Na+, 1K+ v 2 Cl- on phnh to ca nhnh ln quai Henle. V vy lm tng thi tr Na+, Cl- (gn ngang nhau) v K+ (t hn thiazid). - Furosemid v bumetanid cn c c tc dng c ch carbonic anhydrase do trong cng thc cng c gc sulfonamid. Nhng tc dng ny ch rt yu.

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- Tuy c lm tng thi tr ion H+, nhng pH nc tiu t thay i v tc dng c ch carbonic anhydrase b tr li. - Cc thuc nhm ny lm tng thi tr Ca++ v c Mg++, tri vi tc dng ca thiazid, v vy c th dng iu tr tng calci mu triu chng. V Ca++ cn c ti hp thu ng ln nn thng ch thy h Mg++ mu khi dng lu. Kt qu l cc thuc li niu "quai" c th lm thi tr ti 30% s lng nc tiu lc qua cu thn, vt qu s lng nc ti hp thu ca quai Henle, cho nn c th cn c mt s c ch ph c ch ti hp thu ng ln gn. Hin l thuc c tc dng li niu mnh nht. 2.1.3.2. Ch nh - Nh nhm thiazid - V c tc dng nhanh nn cn c dng trong cp cu: cn ph nng, ph phi cp, cn tng huyt p, tng calci huyt cp tnh. 2.1.3.3. Tai bin - Do thi tr qu nhanh nc v in gii nn c th gy mt mi, chut rt, tin hn m gan, h huyt p. - Ging nhm thiazid, c th gp tng acid uric mu, tng ng mu. - Dng lu, do tng thi tr Cl-, K+ v H+ nn c th gy nhim base gim Cl-, hoc nhim base gim K+. - Do lm tng thi tr Mg++ v Ca++ nn c th gy h Mg++ mu (d gy lon nhp tim) v h Ca++ mu (him khi dn n ttani) - Nhng biu hin khc c th gp: ri lon tiu ha (c khi l chy mu), gim s lng hng bch cu, ri lon chc phn gan thn, sn da, t b. - Duy nht vi nhm ny l c tnh vi dy VIII, c th gy ic tai do ri lon ion trong ni dch hoc do c ng. V vy khng nn dng cng vi khng sinh nhm aminosid. 2.1.3.4. Ch phm v liu lng * Ethacrynic acid (Edecrin): trong cng thc c cha ceton khng bo ha cho nn d phn ng vi nhm sulfydril ca cc enzym vn chuyn ion ca ng thn. - Vin 25 hoc 50 mg. Ung 50- 200 mg/ ngy - ng bt Edecrin natri 50 mg. Tim tnh mch 50 mg hoc 0,5mg/kg cn nng. Khng tim bp hoc di da v thuc kch thch ti ch gy au. Hp thu nhanh qua ng tiu ha. Gn nhiu vi protein huyt tng, t/2 di 1 gi. Thi tr qua thn 40% di dng khng chuyn ha. * Furosemid (Lasix, Lasilix, Trofurit) L dn xut ca acid anthranilic, c cha gc sulfonamid trong cng thc. - Vin 20, 40 v 80 mg. Ung 20- 80 mg/ ngy - ng 2 ml = 20 mg. Tim bp hoc tnh mch: 1- 2 ng

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Trong ph phi cp, sau liu u 60- 90 pht c th tim nhc li. Tc dng li niu xut hin nhanh, 3- 5 pht sau khi tim tnh mch, 20 pht sau khi ung. Ht tc dng sau 4- 6h. Thuc d hp thu qua tiu ha, mt phn gn vi protein huyt tng. Ch yu nm ngoi t bo v t tan trong m. Thi tr phn ln di dng khng chuyn ha. * Bumetanid (Bumex): L dn xut ca acid 3- aminobenzoic, trong cng thc cng cha nhm sulfonamid. Mnh hn furosemid 40 ln. - Vin 0,5- 1,0 v 2,0 mg. Ung 0,5- 2,0 mg - ng 0,5- 1,0 mg. Tim bp hoc tnh mch 0,5- 1,0 mg. 2.2. Thuc li niu gi kali- mu (gim thi tr K+) Cc thuc li niu thuc cc nhm trn khi dng lu u gy gim kali- huyt. Cc thuc thuc nhm ny tc dng phn cui ng ln xa, do c ch ti hp thu Na+ bng c ch trao i vi bi xut K+, v th lm gim bi xut K+. ng thi thuc lm tng thi tr bicarbonat, gim bi xut H+ cho nn nc tiu nhim base. Cc thuc ny hu nh khng dng mt mnh v tc dng thi Na+ yu v tai bin tng kali- mu thng bt li. Dng phi hp vi cc thuc li niu lm gim kali- mu s gi c tc dng thi tr Na+ v khc phc c ri lon h K+ mu. C nhiu bit dc phi hp. 2.2.1. Thuc i lp vi aldosteron Spironolacton (Aldacton): cng thc gn ging vi aldosteron, tranh chp vi aldosteron ti receptor ng ln xa, nn cn gi l thuc khng aldosteron. Tc dng thi tr Na+ ca thuc ph thuc vo s lng aldosteron bi tit v b c ch. Tc dng xut hin chm sau 12- 24 gi. - Vin 25 mg. Ung mi ngy 2- 4 vin - Dng lu c th gy tc dng ph ging hormon: nam gy chng v to, n gy chng rm lng v lon kinh nguyt. 2.2.2. Thuc khng i lp vi aldosteron Triamteren (Teriam). Cn gi l khng aldosteron gi (pseudo- anti- aldosterone). Cng thc hon ton khng ging vi aldosteron nn khng c tc dng tranh chp vi aldosteron. Lm tng thi Na+, Cl- do lm gim tnh thm ca ng ln xa vi Na+. Lm gim bi xut K+ v H+. Tc dng c khi c mt cng nh khi khng c mt aldosteron (ng vt ct b thng thn). Spironolacton lm tng tc dng ca triamteren cho nn 2 thuc tc dng trn 2 receptor khc nhau. Tc dng ti a t c sau khi ung 2 gi v ch gi c tc dng trong 10 gi. - Nang 100 mg. Ung 1- 2 nang/ ngy - C th gy bun nn, nn, chut rt, ng g.

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Amilorid (Modamid): tc dng thi Na+, lu K+ mnh hn triamteren. Ngoi c ch tc dng theo kiu triamteren, amilorid cn tc dng trn c ng ln gn. Nng ti a trong mu t c 4 gi sau khi ung, thi gian bn hu khong 6 gi, tc dng ko di 24 gi. - Vin 5 mg. Ung mi ngy 1 vin. Khng vt qu 20 mg/ ngy 2.3. Thuc li niu thm thu Thuc li niu thm thu dng ch mt s cht ha tan c cc tnh cht sau: - c lc t do qua cu thn - c hp thu c gii hn khi qua ng thn - Hu nh khng c hot tnh dc l Nhng cht ny c dng vi s lng tng i ln lm thay i mt cch c ngha nng osmol trong huyt tng hay trong nc lc cu thn, hoc dch ng thn. Hin ch c mannitol l c dng nhiu hn c. 2.3.1. Ch nh Do khng lm tng thi tr Na+ nn khng dng c trong cc chng ph. Thng dng phng nga i t sau m, sau chn thng, tng p lc trong s, hoc lm tng li niu trong cc trng hp nhim c thi tr cht c. 2.3.2. Chng ch nh - Mt nc trong t bo - Suy tim 2.3.3. Ch phm Mannitol dung dch 10- 20% ng trong l 250- 500 v 1000 ml dng truyn nh git tnh mch. Mannitol thi tr qua cu thn v ch khong 10% c ti p thu ng ln, do lm tng p lc thm thu trong ng ln, c ch ti hp thu nc, gy li niu.
CU HI T LNG GI

1. Trnh by c ch tc dng v p dng iu tr ca thuc c ch enzym carbonic anhydrase (CA). 2. Trnh by c ch tc dng v tc dng ca nhm thiazid. 3. Phn tch v so snh ri lon in gii ca thuc c ch CA v thiazid. 4. Trnh by c ch tc dng v tai bin ca thuc li niu quai. 5. So snh tc dng v c ch ca 2 nhm thuc li niu gi kali- mu. 6. Trnh by c ch tc dng v p dng iu tr ca mannitol.

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Bi 26:

CC CHT IN GII CHNH V CC DCH TRUYN

MC TIU HC T P: Sau khi hc xong bi ny, sinh vin c kh nng:

1. Phn bit c cc du hiu tha v thiu Na+, K+, Ca++ 2. Trnh by c cc thuc iu chnh ri lon (tha hoc thiu) cc ion trn. 3. Phn tch c s khc nhau gia dch b ion v dch thay th huyt tng. 4. Trnh by c vai tr ca cc dch dinh dng.
1. CC CHT IN GII CHNH

1.1. Natri 1.1.1. Vai tr sinh l - Gi vai tr sng cn: duy tr nng v th tch dch ngoi t bo. Na+ l ion ch yu ngoi t bo, v vy ri lon Na+ bao gi cng km theo ri lon nc. - Gi tnh kch thch v dn truyn thn kinh - c do duy tr hiu th hot ng gia trong v ngoi t bo. - Duy tr thng bng base acid iu ha Na trong c th do hormon v thng thn aldosteron (ti hp thu Na+ v thi K+, H+ qua ng thn) v hormon vasopressin (hay ADH, hormon chng bi niu) ca tuyn hu yn. Natri mu bnh thng l 137- 147 mEq/L 1.1.2. Thiu Na (gim natri- mu; hyponatremia) Khi Na- mu < 137 mEq/L 1.1.2.1. Nguyn nhn - Nhp nhiu nc, tng tit ADH - Mt nhiu Na+: do m hi, do dng thuc li niu thi Na (nh loi thiazid), do thiu aldosteron. 1.1.2.2. Lm sng - Na+ gim, lm gim p lc thm thu ca huyt tng, nc t ngoi t bo s i vo trong t bo. c bit l khi t bo thn kinh b "trng", s gy cc triu chng thn kinh nh: kch thch, mi mt, lo s, run tay, tng phn x co tht cc c, hn m. Khi Na+ mu t 120- 125 mEq/L: cha c du hiu thn kinh 115- 120 mEq/L: bun nn, u oi, nhc u < 115 mEq/L + Nguyn nhn: : co git, hn m - Mt Na+ c th i km theo mt dch, lm gim th tch dch ngoi t bo

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. Tiu ha: tiu chy, nn, c ng thng ht dch . Thn: dng li niu, suy thng thn . Da: bng, dn lu vt thng + Lm sng: gim th tch mu, gim p lc tnh mch trung tm, gim p lc ng mch phi v huyt p trung bnh - Na+ mu gim , nhng th tch dch ngoi t bo vn bnh thng hoc tng. + Nguyn nhn . Hi chng tng ADH, gi nc . Ph do suy tim, s gan, thn h . Truyn tnh mch qu nhiu dung dch nhc trng + Lm sng: ngc vi cc du hiu trn: th tch mu tng, tng p lc tnh mch trung tm, tng p lc ng mch phi v huyt p trung bnh. 1.1.2.3. iu tr -Bo v bnh nhn khi nguy c trc tip: nng ngay Na+ ln trn 120 mEq/L, sau dn dn a v bnh thng v cho thng bng vi dch ngoi t bo (xem 1.3.4.) - Ch iu chnh in gii khc: K+, HCO3- (khi tiu chy nhiu). - Ch dng dung dch mui u trng (3-5%) khi Na+ di 115 mEq/L v rt thn trng v c th lm tng th tch trong mch. - Nu Na+ mu gim m dch ngoi t bo tng th dng "li niu quai" nh furosemid (Lasix 0,2 - 0,3g/ ngy), v lm mt nc nhiu hn mt mui. Khng dng loi thiazid v lm mt mui nhiu hn mt nc. 1.1.3. Tha natri (tng natri- mu, hypernatremia) Khi Na+ mu > 147 mEq/L do mt nc hoc do nhp nhiu Na+ 1.1.3.1. Nguyn nhn - Mt nc qua da, qua phi, bnh i nht, dng li niu thm thu, tng ng huyt. - Nhp nhiu mui: truyn dung dch mui u trng, NaHCO3, tng aldosteron, n nhiu mui. 1.1.3.2. Lm sng Tng p lc thm thu, tng trng lc ca dch ngoi t bo, nc trong t bo ra ngoi t bo, gy kht, mt mi, nhc c, hn m, gim p ng vi ADH. nh gi tnh trng tng hoc gim khi lng dch ngoi t bo bng o p lc tnh mch trung ng v p lc ng mch phi. 1.1.3.3. iu tr Ph thuc vo nguyn nhn - Nu do mt nc: cho ung v truyn nc vo tnh mch

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- iu chnh tng natri mu cn t t, khong 2 ngy trnh mt lng nc ln vo no, gy ph no. Cn theo di cc du hiu ph no: tng huyt p, gim nhp tim, lon cm gic. 1.1.3.4. Tnh lng nc v mui iu chnh * Thiu nc (trong Na+ mu cao): Th d Na+ mu hin c l 160 mEq/L ([Na]1), mun lm gim xung 150 mEq/L ([Na]2) bng pha long, cn bao nhiu nc (TNC2)? Gi s ngi bnh nng 50 kg, tng lng nc ca c th (TNC) chim 60%, l 30 lt. Cng thc tnh l: TNC1 [Na]1 = TNC2 [Na]2 30 160 = x 150 30 160 x= = 32 L 150 S nc cn thm l 32L - 30 = 2 L * Thiu Na+ Th d: Na+ mu l 120 mEq/L, cn bao nhiu Na+ nng ln 130 mEq/L? Nh vy, mi lt cn 130 mEq - 120 mEq = 10 mEq. Vi th d trn, tng lng nc trong c th (TNC) cho c dch trong v ngoi t bo l 30 lt, cn 10 30 = 300 mEq Na+. Pmg ha tr Phn t lng mEq phn t lng Pmg = Ha tr

Ta bit:

mEq =

Nh vy, lng Na+ tng ng vi 300 mEq l: 300 23 Pmg = = 6900 mg 1

T tnh ra lng dung dch cn truyn tu theo vic ch nh dng nc mui ng trng (0,9%) hoc u trng. C th tnh ring cho dung dch ngoi t bo. Nc chim 60% trong lng c th. Nc trong t bo chim 2/3 v ngoi t bo l 1/3. 1.2. Kali 1.2.1. Vai tr sinh l K+ l ion ch yu trong t bo, c vai tr: - m bo hiu th mng, tnh chu kch thch ca thn kinh- c

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- Trn c tim, K+ lm gim lc co bp, gim tnh chu kch thch v gim dn truyn. Tc dng i khng vi Ca++ v glycosid, tim. - Tham gia vo iu ha acid- base y l qu trnh phc tp v K+ tham gia vo: + C ch trao i ion qua mng t bo + Chc phn thi tr qua thn; lin quan vi thi tr H+ * Thng bng ion qua mng t bo: Nng trong t bo ca K+ v H+ ln hn ngoi t bo - Khi H+ thay i l nguyn pht: . Nu nng H+ ngoi t bo tng (acid mu) th H+ s i vo t bo, v gi thng bng ion, K+ s ra khi t bo, gy tng K+ mu: acid huyt tng kali (hyperkaliemic acidosis). . Ngc li, nu H+ dch ngoi t bo gim (base mu) th H+ trong t bo s i ra. V gi thng bng ion, K+ s i t ngoi vo trong t bo, gy gim kali mu: base mu gim kali (hypokaliemic alkalosis). pH huyt tng thay i 0,1 th K+ thay i 0,6 mEq/L - Khi K+ thay i l nguyn pht th lm H+ thay i theo: nu K+ i t trong ra ngoi t bo th H+ v Na+ s i vo gi thng bng ion, kt qu l ngoi t bo th base v trong t bo th acid (trng hp mt nhiu K+). * Chc phn iu ha ca thn: Khi K+ tng cp tnh trong mu, thn tng thi K+, gim thi H+, nc tiu base v mu cng acid. Kali mu bnh thng l 3,5- 5,0 mEq/L 1.2.2. Thiu kali (gim kali- mu- hypokaliemia) Khi K+ mu < 3,5 mEq/L 1.2.2.1. Nguyn nhn - Gim kali ton b c th: hi chng cng aldosteron, dng thuc li niu thi K+ (loi thiazid), mt K+qua ng tiu ha (nn nhiu, tiu chy, dn lu), mt K+ qua thm phn. - K+ nhp t ngoi t bo vo trong t bo: do dng insulin hoc tng insulin ni sinh, base mu, thi k phc hi t chc sau bng, sau chn thng. Trong t bo tp trung mt s lng ln cc cht hu c khng khuch tn qua mng (cc protein). mi trng pH ca dch th, cc nhm chc ca cc hp cht hu c ny u tch in m nn gi l anion c nh ca t bo. m bo trung ha in, t bo phi gi li mt s lng tng ng cation, l K+ (chnh) v cc cation khc. T , h qu l: . Khi anion c nh tng (tng ng ha, sau n, tng insulin) th K+ s i vo t bo. . Khi anion c nh gim (d ha, i, sc, tng cortisol) th K+ s ra khi t bo.

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- Stress: do c tng tit aldosteron v adrenalin t thng thn. Adrenalin lm tng nhp K+ vo t bo. 1.2.2.2. Lm sng - Lit gc chi, sau l u chi. S thy c chc, gim phn x gn xng, cm gic cn bnh thng, sau l chut rt v d cm (thm c ri lon Na v Ca) - Chng bng, lit rut, to, b i - Tim: mch rng, nhy, tng nh. in tim: ST h dn, T c bin gim dn, ng in ri m, QT di. 1.2.2.3. iu tr - Cc ch phm: . Dung dch KCl: cha 20 mEq/ 15 mL (hoc 1 tha canh) . Vin bao cha 4- 8 mEq. . ng tim: 1 mL cha 1 mEq (dung dch 7,5%) hoc 1 mL cha 2 mEq (dung dch 15%); ng ng 10- 20 mL- 30mL. Khi dng pha long trong huyt thanh ngt ng trng. - Liu lng: . D phng gim K- mu (khi dng li niu lu): 50 mEq/ ngy (tng ng 4,0g KCl), chia liu nhiu ln. . Liu truyn ti a 10- 20 mEq/ h ; 50- 100 mEq/ ngy Dung dch truyn tnh mch cha 30- 40 mEq/L. Dung dch m c qu gy huyt khi v hoi t nu tim chch tnh mch. - Tai bin khi dng qu liu: . Du hiu in tm : T rng v nhn, P dt, PR di, phc hp QRS rng. . X tr: truyn dung dch NaHCO3, hoc dung dch huyt thanh ngt c thm 10 n v insulin cho 100 g glucose (xem phn iu tr tng kali mu) 1.2.3. Tha kali (tng kali mu; hyperkaliemia) Khi kali mu > 5 mEq/L 1.2.3.1. Nguyn nhn - Ung hoc truyn qu tha kali - Tn thng nng m (t bo v, kali c gii phng) - Acid huyt cp tnh (i khi acid huyt mn tnh) - Bnh Addison - Kch thch cp tnh receptor a giao cm - Dng li niu lu kali khng ng liu lng - ng huyt tng 1.2.3.2. Lm sng

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- n v cm. D cm u chi, li, mi. - Lon vn mch: da lnh, m, ti. Nhc c, t b nht l chi di - Trn in tim: nu kali tng va phi (5- 7 mEq/L huyt tng), dn truyn trong c tim b gim nh: sng T tng cao hoc ko di, PR di, P mt. - Nu kali tng cao hn (8-9 mEq/L huyt tng) s c ch mnh hn trn nt dn nhp v s dn truyn trong ton b c tim: QRS di, c th mt tm thu (asystole), i khi trc l nhp tht nhanh hoc rung tht. 1.2.3.3. iu tr - Nha trao i cation: natri polystyren sulfonat (Kayexalate) l nha trao i Na+- K+, c i lc vi K+ mnh hn nhiu so vi Na+. rut, c bit l rut gi, n gii phng Na+ v gn K+ ri b thi tr theo phn. Kayexalat khng c hp thu khi ung v khng b tc dng ca dch tiu ha. Ngoi K+, n cn gn c c ion ha tr 2 l Mg++ v Ca++, nn c th gy gim Mg v Camu. Thng gy to, nn dng cng vi sorbitol (vin 5 mg, 1- 2 vin/ ngy, c tc dng nhun trng). . Ung 15 g 1- 4 ln/ ngy . Cn kim tra K+, Mg++, Ca++, mu. . Khng dng khi K+ < 5 mEq/L v cn nh rng 1g nha gii phng 1 mEq Na+. - Glucose v insulin: insulin lm K+ nhp vo t bo, v glucose chng h ng huyt do insulin gy ra. Insulin 10- 15 n v Huyt thanh ngt u trng 5-%- 250- 500 mL Tc dng h K+ trong 6h. - Natri bicarbonat: lm K+ nhp vo t bo, tc dng tm thi trong 1- 2h. Tim truyn tnh mch dung dch 1,4% (c 166,6 mEq HCO3- v 166,6 mEq Na+ trong 1000 mL), hoc dung dch 4,2% (c 500 mEq HCO3-, 500 mEq Na/ lt). - Calci gluconat: khng c tc dng trn nng K+ nhng chng li tc dng c ca K+ trn tim. ng 10 mL cha 4,5 mEq Ca++. Tim tnh mch (trong khi CaCl2 cha 13,6 mEq). - Thm phn: dng nha trao i ion c th thi qu nhiu K+. Thm phn an ton hn, c th dng cho c ngi suy thn. 1.3. Calci 1.3.1. Vai tr sinh l - To xng, rng di dng calci phosphat - Co c, dn truyn thn kinh, bi xut ca cc tuyn tit - ng mu - Tnh thm ca mng t bo

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dch ngoi t bo c 1- 2% tng lng Ca. Trong mu, Ca di 3 dng: 50% di dng ion Ca++, gn 50% kt hp vi protein huyt tng, ch yu l albumin v ch cn rt t di dng phc hp vi phosphat, citrat, carbonat. Ch calci di dng ion mi c vai tr sinh l quan trng. iu ho calci do hormon cn gip trng (PTH) v calcitonin. Calci- mu bnhthng l 4,3- 5,3 mEq/L 1.3.2. Thiu calci (gim calci- mu; hypocalcemia) Khi calci- mu < 4,3 mEq/L 1.3.2.1. Nguyn nhn - Gim dng ion ha; base mu, dng nhiu citrat hoc mu long - Mt Ca qua dch th: dng "li niu quai" loi furosemid - Gim hp thu qua rut: ch n thiu Ca, thiu vitamin D, tiu chy mn, ct d dy. - Suy cn gip trng. - Tng phospho mu (hyperphosphatemia), gim magnesi mu . P v Ca c tc dng qua li: P- mu tng khi Ca- mu gim v ngc li. l c ch bo v sinh l quan trng v nu c 2 cng tng s dn ti kt ta calci phosphat vo cc m. Khi P tng th Ca gim v lm gim sn xut dng hot ng ca vitamin D v lm gim huy ng calci phosphat t xng. . Mg gim, th Ca mu cng gim v lm gim tit v gim tc dng ca PTH. - Vim ty cp cng lm gim calci mu v c th l lm lng ng Ca vo m m hoi t, gim tit PTH, gim albumin- huyt v tng sn xut calcitonin ca tuyn gip. 1.3.2.2. Lm sng T, nga cc ngn, tng phn x, chut rt, tetani vi cc du hiu Trousseau (+), Chvostek (+), co git do ngng kch thch ca thn kinh b gim. Nu mn tnh, gy xp xng, gy xng, du hiu gim calci nng: co tht thanh qun, kh th, ting th rt (stridor) 1.3.2.3. iu tr - Tim tnh mch: . Calci gluconat: ng 10 mL dung dch 10% cha 4,5 mEq Ca . Calci clorid: ng 10 mL, dung dch 10% cha 13,6 mEq Ca Tim chm 1mL/ pht phng ngt tim v tt huyt p do gin mch nhanh. - Ung: . Calci lactat, calci carbonat, calci gluconat: di dng gi bt . Vitamin D: Ergocalciferol (D2): calcitriol 1,25 (OH)2 D3 Khng dng cng vi fluor v phosphat v to phc khng tan, khng hp thu c.

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1.3.3. Tha calci (tng calci-mu, hypercalcemia) Khi calci- mu > 5,3 mEq/L 1.3.3.1. Nguyn nhn - Ch n nhiu Ca - Hp thu nhiu Ca: tha vitamin D, cng ph gip trng. - Tng gii phng ca t xng: ung th cn gip trng, bnh Paget (tng tit PTH) - Gim thi tr Ca qua thn; thn suy, dng li niu loi thiazid lu. - Tng Ca++ dng ion v acid huyt. 1.3.3.2. Triu chng Suy nhc, chn nn, bun nn, nn, i nhiu, m mng, l ln, t b, thay i nhn cch, hn m. in tim: ST v QT ngn, PR di. 1.3.3.3. iu tr iu tr nguyn nhn: cn gip trng, ch n Khi calci mu > 7 mEq/L phi iu tr tch cc: - Ung hoc tim tnh mch thanh huyt mn 0,45% hoc 0,9%, c th ti hng lt/ ngy vi iu kin chc phn thn bnh thng: th tch mu tng, pha long c Ca, thn tng thi Na+ (gim ti hp thu), ng thi tng thi Ca. C th cho ung thm 23 lt/ ngy. "Li niu quai" furosemid lm tng thi Ca v d phng c tha nc do dng huyt thanh mn: 40- 60 mg cch 6 h ung 1 ln. Khng dng li niu loi thiazid v gim thi Ca. Phosphat tim tnh mch dng cha cc cn cp tnh. Tim tnh mch Na phosphat hoc K phosphat lm gim nhanh ion Ca++ v to Ca phosphat. Nhng khi Ca phosphat > 75 mg/ dl th gy lng ng Ca vo cc m. Khng dng qu 1,5g/ ngy v khng qu 2 ngy. - Ch n t Ca v dng cortison: steroid tranh chp vi vitamin D receptor ca rut, lm gim hp thu Ca qua tiu ha v tng thi qua thn. Cn dng liu cao: Prednison 1mg/ kg/ ngy. Tc dng h calci mu xut hin chm, sau 1- 2 tun dng thuc. Ngng thuc khi c du hiu nhim c. Mt s thuc lm gim tiu xng: - Mithracin (Plicamycin) l khng sinh gy c t bo, tc dng c ch trc tip cc hu ct bo (osteoclastes), lm gim huy ng Ca t xng ra mu v gim ti hp thu Ca ti ng thn. Ch dng trong tng Ca- mu do ung th nng khng vi cc cch iu tr khc, v mithracin c nhiu tc dng ph, c bit l gim tiu cu, bch cu, gim prothrombin, gy chy mu c th dn n cht. ng trong l ng kh 2500 mg

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Truyn tnh mch 25 mg/ kg/ ngy. Pha trong 500 mL huyt thanh ngt ng trng. Cch 2-3 ngy, truyn li tu thuc vo Ca - mu. - Cc diphosphonat: l thuc tng hp ca cc pyrophosphat v c c tc dng c ch tiu xng ca cc hu ct bo. Th d: Didronel (etidronat disodic): ch nh chnh trong bnh Paget hoc cc di cn ung th vo xng, gy tiu xng. Dng liu duy nht, ung 2 gi trc ba n v i liu 5 mg/ kg/ ngy, trong thi gian 6 thng. Khng dng cho ngi suy thn. Dng qu liu gy h Ca- mu (iu tr bng calci- gluconat tim tnh mch) Vin 200 mg - Calcitonin: l hormon ca t bo C tuyn gip trng, lm h calci mu do: . c ch hu ct bo (ngc vi PTH, kch thch) lm gimtiu xng . Tng thi Ca v P qua thn do c ch ti hp thu Cc ch phm sn xut t ng vt (Staporos, Calcitar t ln, Calsyn, Miacalcic t c hi salmon) hoc tng p (Cibacalcin). Calcitonin ca c hi mnh hn ca ngi v ln 10- 40 ln v tc dng lu hn 10 ln. Liu lng: 4- 8 n v quc t/ kg/ ngy chia lm 4 ln tim di da, tim bp hoc tim chm vo tnh mch. Tc dng xut hin nhanh
2. CC DCH THAY TH HUYT T NG

Khi th tch huyt tng b gim do mt nc v mui n thun (tiu chy, nn nhiu) th ch cn truyn nc v in gii l . Nhng nu do mt nhiu mu hoc huyt tng nh trong sc xut huyt, bng nng, th phi truyn mu, huyt tng hoc cc dch thay th c p lc keo cao. Cc sn phm thin nhin (mu, huyt tng ca ngi) l tt nht, nhng t v c nhiu nguy c (phn ng min dch, lan truyn vim gan siu vi khun B hoc C, lan truyn AIDS). V vy, cc dch thay th huyt tng c nghin cu v s dng. Cc dch ny cn phi c by tnh cht sau: - Tn ti trong tun hon lu, ngha l c p lc keo tng t vi huyt tng, c trng lng phn t tng ong vi albumin huyt tng ( 40.000). - Khng c tc dng dc l khc. - Khng c tc dng khng nguyn, khng c ch nhit t. - Khng c tng tc hoc phn ng cho vi nhm mu. - Gi n nh lu khi bo qun hoc thay i ca nhit mi trng. - D kh khun - nht thch hp vi s tim truyn. Di y l mt s dch truyn t tiu chun hin ang c dng: 2.1. Gelatin bin cht

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c sn xut t colagen ca xng, thu phn cho ti khi t c cc phn t protein c trng lng phn t khong 3.000. C nhiu dng: - Plasmion: cha 30g gelatin lng trong 1 lt, c thm thnh phn cc ion Na+, K+, Mg++ v Cl- tng t nh huyt tng, khng c Ca++. Cht m l lactat. ng trong l 500 mL. - Plasmagel: cha 30g gelatin lng trong 1 lt dung dch mui ng trng, thm 27 mEq Ca++ (cho nn khng c dng cho bnh nhn ang c iu tr bng digitalis). Khng c cht m. ng trong l 500 mL. - Plasmagel khng mui, c ng (Plasmagel dsod glucos): cha 25 g gelatin trong 1 lt dung dch glucose ng trng, khng c mui, Ca++ v cht m (trnh b tha mui). ng trong l 500 mL. + u im ca gelatin lng l d bo qun, khng cn xc nh nhm mu trc khi truyn. + Nhc im: . Khng gi c lu trong c th, khong 75% b thi tr qua nc tiu trong 24h. . Vn cn phn ng khng nguyn: d ng biu hin da, him gp phn ng tim mch. . C ri lon ng mu: gim protrombin, fibrinogen, tiu cu, ko di thi gian chy mu. . Gy protein- niu gi. Nu dng Plasmagel, ch c th lm tng calci huyt. . Phi hm nng trc khi dng v rt qunh khi gp lnh. 2.2. polyvinyl- pyrrolidone (PVP) l cht tng hp, c trng lng phn t khong 40.000. ng trong l 500 mL (Subtosan) - u im: tng i d bo qun. - Nhc im: cn phn ng khng nguyn, gy protein niu gi v nht l b gi lu trong h lin vng ni mc. 2.3. Dextran L cht trng phn c trng lng phn t rt cao, c to ra t glucose di tc ng ca vi khun Leuconostoc mesenteroides. Phn hai loi: 2.3.1. Loi c trong lng phn t cao Khong 80.000. ng trong l 250 v 500 mL. Thi tr qua chuyn ha. - u im: d bo qun, gi khng t lm. - Nhc im: . To phc hp fibrinogen- dextran, gn vo hng cu, lm tng dnh tiu cu, v vy c th gy ri lon ng mu. Rt t c, nhng c th gy phn ng qu mn ngay t ln truyn u tin v mn cm vi dextran t nhin gp trong mt s thc n.

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2.3.2. Loi c trng lng phn t thp. Khong 40.000. ng trong l 250 v 500 mL (Rheomacrodex). Thi tr bng chuyn ha v qua thn. - u im: lm d dng tun hon ca hng cu trong mao mch. - Nhc im: gi thnh cn cao v gy ri lon ng mu. Ch l sau khi truyn, c th lm sai lc vic xc nh nhm mu v glucose mu. 2.4. Dung dch in gii C 5 loi hay dng Loi dung dch Na+ NaCl 0,9% Ringer Ringer lactat NaCl 10% NaCl 20% 154 147 130 1.709 3,419 4 4 Nng (mmol/ L) K+ Cl154 156 112 1.709 3,419
ASTT: p sut thm thu

ASTT Lactat mOsm/L 308

pH 5.7 5.1

Ca2+ 5 1,82

309 28 280 3.418 6.836

1g NaCl = 17 mmol Na= 400 mg Na.

2.4.1. Dung dch ng trng: 2.4.1.1. Dung dch nc mui sinh l (NaCl 0,9%) - u: R, ph bin. - Nhc: d gy toan mu do lng Cl- cao. Truyn nhiu v nhanh d gy nc ngoi bo v ph phi cp. 2.4.1.2. Ringer lactat (dung dch Hartman) - Vo c th, lactat chuyn thnh bicarbonat (do gan) v kim ha mu (chnh c toan nh). - C thm K+ v Ca2+. - Truyn 1 lt s tng c 200- 300 mL th tch tun hon, v vy cn truyn 1 lng gp 3 ln th tch b mt. Nhng khng c gi lu trong mu nn cn truyn lin tc. Ch truyn khi th tch tun hon mt 1 lt. Tng lng truyn khng qu 3- 4 lt/ 24h. 2.4.2. Dung dch u trng - Cc loi dung dch: NaCl 1,2- 1,8- 3,6- 7,2- 10 v 20%. Trn th trng c sn loi 10- 20%, ng 10- 20 mL. Khi dng, pha vi glucose 5% t nng mong mun. - c im: . ASTT qu cao, d gy ph. . Lm gim kt tp tiu cu, tng nguy c chy mu.

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. Lm gin mch ni tng: thn, tim. Tng co bp tim. . Lm gim ph no, gim tng p lc ni s tt hn so vi dung dch keo.
3. CC DCH CUNG CP GLUCID, ACID AMIN V LIPID

Dng cung cp nng lng khi khng dinh dng c qua ng tiu ha. Trong sc, nhu cu nng lng c cung cp giai on u ch yu bng glucid v c hp thu trc tip, sau l cc acid amin, v trong giai on hi phc l lipid. 3.1. Cc glucid d hp thu 3.1.1. Glucose (dextrose) - Dung dch ng trng 50g/ 1000 mL (5%) - Dung dch u trng 100g; 150g v 300g/ 1000 mL. ng trong l 500- 1000 mL, 100g glucose cung cp 400 kilo calo. Ngoi ra cn dng iu tr v d phng cc trng hp mt nc nhiu hn mt mui. Truyn chm vo tnh mch. Cc dung dch u trng d lm vim tc tnh mch ti ni truyn v gy hoi t nu truyn ra ngoi tnh mch. Glucose huyt tng ph thuc khng nhng vo nng dung dch tim truyn m cn vo tc truyn v kh nng chuyn ha ca ngi bnh. Khi nui dng bng dch truyn, cn phn phi liu u trong ngy v gim liu dn, trnh ngng t ngt d gy h ng huyt. C th b tr thm bng insulin v kali tu thuc vo ng- niu, aceton- niu, kali- mu. 3.1.2. Sorbitol Sorbitol l hexa- alcol khng c chc kh, trong c th, b phn hu nhanh thnh fructose di tc dng ca sorbitol deshydrogenase gan. Dung dch ng trng 50g/ 1000 mL Dung dch u trng 100g/ 1000mL.

ng trong l 500- 1000 mL. Tc dng v ch nh ging nh glucose, 100g sorbitl cung cp 400 Kcal. Dung dch u trng c th gy ri lon thn kinh hoc l do tng p lc thm thu, hoc l do tc dng c trc tip trn thn kinh. 3.2. Cc acid amin L dung dch c cha cc acid amin cn thit nh leucin, isoleucin, lysin, methionin, arginin di dng L d hp thu. Truyn chm tnh mch (khng vt qu 50 git/ pht). Khng dng trong giai on u ca sc. Thn trng khi c suy gan, suy thn nng, suy tun hon nng v dung dch cha nhiu m v u trng. C th gy ra hoc lm nng thm phn ng phn v. Tc dng khng mong mun: nim toan chuyn ha do qu liu acid amin, tng N mu ngi suy thn, mn cm, d ng, a niu do tng p lc thm thu. Cc ch phm: Alvesin 40, Amigreen- TPN, Proteolysat, Moriamin.

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Phi tuyt i v khun khi tim truyn v khng c trn bt k mt thuc g vo dung dch truyn. L thuc dng tim truyn 100- 250- 500- 1000mL. 3.3. Lipid L dung dch cung cp nng lng v cc acid bo cn thit cho c th, khng gy u trng huyt tng. Cc phn ng khng mong mun sm c th gp l st, bun nn, nn, h ng huyt, m phi, gim tiu cu. Cc phn ng mun: gan to, vng da, do mt, lch to, gim tiu cu, gim bch cu, tng tm thi cc test chc phn gan. Ch phm: Intralipid, Lipofundin, Lipovenoes 10% PLR (du u tng- soja). Dch nh tng 10% ng trong l 100 v 500 mL, cung cp 1100 Kcal/ lit. Dch nh tng 20% ng trong l 100- 250 v 500 mL, cung cp 2000 Kcal/ lt

Liu lng: tng lng lipid cho ngi ln trong 24 gi l 2- 3g/ kg thn trng; cho tr em l 0,5- 4g/ kg. Trong 10 pht u truyn 10 git/ pht; trong 20 pht sau l 20 git/ pht, sau t ti 40 git/ pht. Khi m l phi dng ht trong 1 ln.
CU HI T LNG GI

1. Trnh by vai tr sinh l ca Na+, cc ri lon do thiu Na+ v cch iu tr 2. Trnh by vai tr sinh l ca Na+, cc ri lon do tha Na+ v cch iu tr. 3. Trnh by vai tr sinh l ca K+, cc ri lon do thiu K+ v cch iu tr. 4. Trnh by vai tr sinh l ca K+, cc ri lon do tha K+ v cch iu tr 5. Trnh by vai tr sinh l ca Ca++, cc ri lon do thiu Ca++ v cch iu tr. 6. Trnh by vai tr sinh l ca Ca++, cc ri lon do tha Ca++ v cch iu tr. 7. Nu v phn tch 7 tnh cht cn c ca 1 dch thay th huyt tng. Cho th d. 8. Nu cc ch nh v cch dng ca dch truyn cung cp glucid. 9. Nu cc ch nh v cch dng ca dch truyn cung cp cc acid amin. 10. Nu cc ch nh v cch dng ca dch truyn cung cp lipid.

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Bi 27:

THUC IU CHNH RI LON TIU HA

MC TIU HC T P: Sau khi hc xong bi ny, sinh vin c kh nng:

1. Trnh by c c ch tc dng, tc dng khng mong mun v p dng iu tr ca nhm hydroxyd, magnesi hydroxyd, thuc khng histamin H2, thuc c ch H+/ K+- ATPase v cc mui bismuth. 2. Phn tch c v tr, c ch tc dng v ch nh ca cc thuc gy nn v chng nn 3. Nu c c ch tc dng, tc dng v p dng iu tr ca cc thuc iu ha chc nng vn ng ca ng tiu ha v thuc chng co tht c trn ng tiu ha. 4. Trnh by c phn loi, c ch tc dng, p dng iu tr ca cc thuc nhun trng v thuc ty thng dng. 5. Trnh by c tc dng v p dng iu tr ca cc thuc chng tiu chy: dung dch ung b nc v in gii; cc cht hp ph, bao ph nim mc rut; thuc lm gim nhu ng rut; cc vi khun v nm. 6. Phn bit c tc dng ca thuc li mt v thuc thng mt, p dng lm sng.
1. THUC IU TR VIM LOT D DY- T TRNG

1.1 i cng Lot d dy- t trng l bnh l ng tiu ha ph bin, hu qu ca s mt cn bng gia cc yu t gy lot (acid clohydric, pepsin, xon khun Helicobacter pylori) v cc yu t bo v ti ch nim mc d dy (cht nhy, bicarbonat, prostaglandin). Xon khun H.pylori ng vai tr quan trng trong nguy c gy lot: khong 95% ngi lot t trng v 70- 80% ngi lot d dy c vi khun ny. Chng gy vim d dy mn v lm tng bi tit acid. Dit tr c H.pylori s lm lot lin nhanh v gim r rt t l ti pht. Mc tiu ca iu tr lot d dy- t trng l: - Chng cc yu t gy lot: . Cc thuc khng acid: trung ha acid trong lng d dy (magnesi hydroxyd, nhm hydroxyd...) . Cc thuc lm gim bi tit acid v pepsin: thuc khng histamin H2 v thuc c ch bm proton. . Thuc dit H.pylori: cc khng sinh, bismuth. - Tng cng yu t bo v: sucralfat, bismuth, misoprostol. Vic iu ha bi tit HCl ca t bo thnh d dy l do histamin, acetylcholin v gastrin thng qua H+/ K+- ATPase (bm proton).

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Prostaglandin c vai tr quan trng trong c ch iu ha ngc: PGE2 c ch adenylcyclase lm gim AMPv, i khng vi tc dng ca histamin v c ch gii phng gastrin. PGI2 kch thch t bo biu m ca nim mc d dy, lm tng tit cht nhy, bicarbonat bo v nim mc. Cc thuc chng vim khng steroid c ch tng hp prostaglandin, c th gy lot v chy mu ng tiu ha.

Hnh 27.1. C ch iu ha sinh l v dc l ca bi tit dch v v cc v tr tc dng ca thuc

Hnh 27.2. Vai tr trung ha acid ca NaHCO3 ti lp nhy nim mc d dy

1.2. Thuc khng acid 1.2.1. Tnh cht chung

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Cc thuc khng acid l nhng thuc c tc dng trung ho acid trong dch v, nng pH ca d dy ln gn 4, to iu kin thun li cho ti to nim mc. Khi pH d dy tng, hot tnh ca pepsin s gim (pepsin b bt hot trong dung dch pH ln hn 4). Cc thuc khng acid c tc dng nhanh nhng ngn, ch l thuc iu tr triu chng, ct cn au. Khi d dy rng, cc thuc khng acid thot khi d dy sau 30 pht, khi c thc n th khong 2 gi. Thuc khng acid thng dng nht l cc ch phm cha nhm v magnesi, c tc dng khng acid ti ch, hu nh khng hp thu vo mu nn t gy tc dng ton thn. Thuc khng acid cha magnesi c tc dng nhun trng, ngc li thuc cha nhm c th gy to bn. V vy, cc ch phm khng acid cha c hai mui magnesi v nhm c th lm gim tc dng khng mong mun trn rut ca hai thuc ny. Nu chc nng thn bnh thng, rt t nguy c tch lu magnesi v nhm. Natribicarbonat c tc dng trung ha acid dch v mnh, nhng hin nay hu nh khng dng lm thuc khng acid na v hp thu c vo mu, gy nhiu tc dng khng mong mun ton thn v c hin tng tit acid hi ng (tng tit acid sau khi ngng thuc). Dng thuc khng acid tt nht l sau ba n 1- 3 gi v trc khi i ng, 3- 4 ln (hoc nhiu hn) trong mt ngy. Cc ch phm dng lng c hiu qu hn dng rn nhng thi gian tc dng ngn hn. Do lm tng pH d dy, cc thuc khng acid lm nh hng n s hp thu ca nhiu thuc khc, phi dng cc thuc ny cch xa thuc khng acid t nht 2 gi. Mt s ch phm phi hp thuc khng acid vi simeticon (cht chng si bt) lm gim s y hI hoc lm nh triu chng nc. 1.2.2. Magnesi hydroxyd - Mg(OH)2 1.2.2.1. Tc dng v c ch d dy, magnesi hydroxyd phn ng nhanh vi acid clohydric: Mg(OH)2 + 2HCl MgCl2 + 2H2O

Xung rut non, Mg2+ tc ng vi cc ion phosphat (PO43-) v carbonat (CO32-) to thnh mui rt t tan hoc khng tan, do trnh c s hp thu base, trnh c base mu ngay c khi dng lu. C th dng cc mui khc ca magnesi nh magnesi carbonat, magnesi trisilicat. 1.2.2.2 Ch nh - Tng tit acid (au, y bng, kh tiu, nng, chua) ngi c lot hoc khng c lot d dy- t trng. - Tro ngc d dy- thc qun. 1.2.2.3. Chng ch nh Mn cm vi thuc, suy thn nng, tr nh (c bit tr mt nc v suy thn). 1.2.2.4. Tc dng khng mong mun

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Ming ng cht, bun nn, nn, cng bng, a chy, tng magnesi mu (gp ngi suy thn hoc dng liu cao, ko di). 1.2.2.5. Tng tc thuc - Cc thuc gim hp thu khi dng cng thuc khng acid: tetracyclin, digoxin, indomethacin, cc mui st, isoniazid, benzodiazepin, ranitidin - Cc thuc tng tc dng do gim thi tr khi dng cng thuc khng acid: amphetamin, quinidin. 1.2.2.6. Liu lng, cch dng Ngi ln: mi ln ung 300- 600 mg, ti a ti 1g, ngy 3- 4 ln. Nhai k vin thuc trc khi nut. 1.2.3. Nhm hydroxyd- Al(OH)3 1.2.3.1. Tc dng v c ch d dy, nhm hydroxyd phn ng vi acid clohydric:
ch m

Al(OH)3 + 3HCl

AlCl3 + 3H2O

Nhm hydroxyd c tc dng trung ha acid yu nn khng gy phn ng tng tit acid hi ng. rut, nhm kt hp vi phosphat t thc n, to phosphat nhm khng tan, hu nh khng hp thu, thi tr theo phn, khng gy base mu. V phosphat b thi tr, c th phi huy ng phosphat t xng ra, d gy chng nhuyn xng. V vy, cn n ch nhiu phosphat v protein. 1.2.3.2. Ch nh: nh magnesi hydroxyd (mc 1.2.2.2) Tng phosphat mu (t dng) 1.2.3.3. Chng ch nh: nh magnesi hydroxyd. (mc 1.2.2.3) Gim phosphat mu. Ri lon chuyn ha porphyrin. 1.2.3.4. Tc dng khng mong mun Cht ming, bun nn, cng bng, to bn, phn trng, gim phosphat mu. Nguy c nhuyn xng khi ch n t phosphat hoc iu tr lu di. Tng nhm trong mu gy bnh no, sa st tr tu, thiu mu hng cu nh. 1.2.3.5. Tng tc thuc: ging nh magnesi hydroxyd (mc 1.2.2.5) 1.2.3.6. Liu lng, cch dng Ngi ln: dng vin nhai mi ln 0,5- 1,0g, dng hn dch ung mi ln 320- 640 mg, ngy 4 ln. Tr em: 6- 12 tui: dng hn dch ung mi ln 320 mg, ngy 3 ln. * Ch phm phi hp magnesi hydroxyd v nhm hydroxyd - Dng hn dch cha magnesi hydroxyd 195 mg v nhm hydroxyd 220mg trong 5mL. Ngi ln ung mi ln 10- 20 mL

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- Dng vin: cha magnesi hydroxyd 400 mg v nhm hydroxyd 400 mg. Ngi ln mi ln nhai 1- 2 vin, ti a 6 ln mt ngy. * Ch phm phi hp thuc khng acid v simeticon: dng vin hoc dng hn dch (cha magnesi hydroxyd 195 mg, nhm hydroxyd 220 mg v simeticon 25 mg trong 5 ml. Ngi ln ung mi ln 5- 10 mL, ngy 4 ln).
1.3. Thuc lm gim bi tit acid clohydric v pepsin ca d dy

1.3.1. Thuc khng histamin H2 1.3.1.1. c im chung C ch tc dng Do cng thc gn ging vi histamin, cc thuc khng histamin H2 tranh chp vi histamin ti receptor H2 v khng c tc dng trn receptor H1. Tuy receptor H2 c nhiu m nh thnh mch, kh qun, tim, nhng thuc khng histamin H2 tc dng ch yu ti cc receptor H2 d dy. Thuc khng histamin H2 ngn cn bi tit dch v do bt k nguyn nhn no lm tng tit histamin ti d dy (cng ph giao cm, thc n, gastrin, bi tit c s). Tc dng ca thuc khng histamin H2 ph thuc vo liu lng, thuc lm gim tit c s lng v nng HCl trong dch v Ch nh - Lot d dy- t trng lnh tnh, k c lot do dng thuc chng vim khng steroid. - Bnh tro ngc d dy- thc qun. - Hi chng tng tit acid dch v (Hi chng Zollinger- Ellison) - Lm gim tit acid dch v trong mt s trng hp lot ng tiu ha khc c lin quan n tng tit dch v nh lot ming ni d dy- rut - Lm gim cc triu chng ri lon tiu ha (nng rt, kh tiu, chua) do tha acid dch v. - Lm gim nguy c ht phi acid dch v khi gy m hoc khi sinh (Hi chng Mendelson). Chng ch nh v thn trng - Chng ch nh: qu mn vi thuc - Thn trng: trc khi dng thuc khng histamin H2, phi loi tr kh nng ung th d dy, c bit ngi t trung nin tr ln v thuc c th che lp cc triu chng, lm chm chn on ung th. C nhy cm cho gia cc thuc trong nhm khng histamin H2. Dng thn trng, gim liu v/ hoc ko di khong cch gia cc ln dng thuc ngi suy thn. Thn trng ngi suy gan, ph n c thai v cho con b (ngng thuc hoc ngng cho con b). Tc dng khng mong mun

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a chy v cc ri lon tiu ha khc, tng enzym gan, au u, chng mt, pht ban. Him gp vim ty cp, chm nhp tim, nghn nh tht, ln ln, trm cm, o gic (c bit ngi gi), ri lon v mu, phn ng qu mn. Chng v to n ng v thiu nng tnh dc gp ngi dng cimetidin nhiu hn cc thuc khng histamin H2 khc. Tng tc thuc - Do pH d dy tng khi dng thuc khng histamin H2 nn lm gim hp thu ca mt s thuc nh penicilin V, ketoconazol, itraconazol - Cimetidin c ch cytochrom P450 gan nn lm tng tc dng v c tnh ca nhiu thuc nh warfarin, phenytoin, theophylin, propranolol, benzodiazepin Ranitidin c tng tc ny nhng mc thp hn nhiu (km 2- 4 ln). Famotidin v nizatidin khng gy tng tc kiu ny. Mt s thng s dc ng hc ca thuc khng histamin H2 Tn thuc Sinh kh dng (%) Gn protein huyt tng (%) 20 15 15- 20 35 Th tch phn b Vd (L/ kg) 2 2- 3 3 1- 2 t/2 (gi) Qua rau thai Qua sa

Cimetidin Ranitidin Famotidin Nizatidin

60- 70 50 40- 45 > 70

1 1,3 1,2 1,3

+ + ? ?

+ + + +

1.3.1.2. Cc thuc Cimetidin Hp thu nhanh khi ung. Ung 200 mg cimetidin c tc dng nng pH v gim au trong 1,5 gi. Liu 400 mg trc khi i ng gi c pH ca d dy > 3,5 sut c m. Vi liu 1,0g/ 24 gi, t l ln so l 60% sau 4 tun v 80% sau 8 tun. Liu dng iu tr lot d dy- t trng ngi ln: ung mi ln 400 mg, ngy 2 ln (vo ba n sng v trc khi i ng) hoc 800 mg trc khi i ng. Thi gian dng t nht 4 tun i vi lot t trng v 6 tun i vi lot d dy. Liu duy tr: 400 mg trc khi i ng Khi lot nng hoc ngi bnh nn nhiu, tim bp hoc tnh mch chm (t nht trong 5 pht) mi ln 200 mg, cch 4- 6 gi mt ln. Gim liu ngi suy thn. Liu dng tr em: tr trn 1 tui mi ngy ung 25- 30 mg/ kg, chia lm nhiu ln. Tr di 1 tui mi ngy ung 20 mg/ kg, chia lm nhiu ln.

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Cimetidin gy nhiu tc dng khng mong mun, c nhiu tng tc thuc hn cc thuc khng histamin H2 khc. V vy, trong trng hp cn phi hp nhiu thuc, khng nn chn cimetidin. Ranitidin Tc dng mnh hn cimetidin 4- 10 ln, nhng t gy tc dng khng mong mun v t tng tc thuc hn cimetidin. Liu dng: ung mi ln 150 mg, ngy 2 ln (vo bui sng v bui ti) hoc 300 mg vo bui ti trong 4- 8 tun. Liu duy tr: 150 mg vo bui ti. Tim bp hoc tnh mch chm (t nht trong 2 pht, phi pha long 50 mg trong 20 mL): mi ln 50 mg, cch 6- 8 gi/ ln. Famotidin Tc dng mnh hn cimetidin 30 ln. Liu dng: ung mi ngy 40 mg trc khi i ng trong 4- 8 tun. Liu duy tr: 20 mg trc khi i ng. Tim tnh mch chm hoc truyn tnh mch (pha trong natri clorid 0,9%) mi ln 20 mg, cch 12 gi mt ln cho n khi dng c ng ung. Nizatidin Tc dng v liu lng tng t ranitidin, nhng t tc dng khng mong mun hn cc thuc khng histamin H2 khc. 1.3.2. Thuc c ch H+/ K+- ATPase (bm proton) 1.3.2.1. c im chung C ch tc dng Cc thuc c ch bm proton l nhng tin thuc, khng c hot tnh pH trung tnh. t bo thnh d dy (pH acid), chng c chuyn thnh cc cht c hot tnh, gn vo bm proton, c ch c hiu v khng hi phc bm ny. Do , cc thuc c ch bm proton lm gim bi tit acid do bt k nguyn nhn g v l con ng chung cui cng ca s bi tit acid. Thuc rt t nh hng n khi lng dch v, s bi tit pepsin v yu t ni ti ca d dy. Dng mt liu, bi tit acid d dy b c ch trong khong 24 gi (so snh vi thuc khng histamin H2 ti a ch 12 gi). Bi tit acid ch tr li sau khi enzym mi c tng hp.. T l lin so c th t 95% sau 8 tun. Ch nh - Lot d dy- t trng lnh tnh. Phng v iu tr cc trng hp lot do dng thuc chng vim khng steroid. - Bnh tro ngc d dy- thc qun khi c triu chng nng hoc bin chng. - Hi chng Zollinger- Ellison (k c trng hp khng vi cc thuc khc). - D phng ht phi acid khi gy m. Chng ch nh v thn trng

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- Chng ch nh: qu mn vi thuc - Thn trng: suy gan, ph n c thai hoc cho con b. Phi loi tr kh nng ung th d dy trc khi dng thuc c ch bm proton. Tc dng khng mong mun Ni chung thuc dung np tt. C th gp kh ming, ri lon tiu ha, tng enzym gan, au u, chng mt, ri lon th gic, thay i v mu, vim thn, lit dng, phn ng d ng. Do lm gim acid trong d dy, nn lm tng nguy c nhim khun ng tiu ha, c th gy ung th d dy. Tng tc thuc - Do pH d dy tng nn lm gim hp thu mt s thuc nh ketoconazol, itraconazol - Omeprazol c ch cytochrom P450 gan nn lm tng tc dng v c tnh ca diazepam, phenytoin, warfarin, nifedipin Lansoprazol t nh hng n cytochrom P450, trong khi pantoprazol khng nh hng n enzym ny. - Clarithromycin c ch chuyn ha ca omeprazol, lm tng nng omeprazol trong mu ln gp hai ln. 1.3.2.2. Cc thuc Omeprazol Lot d dy- t trng: ung mi ngy mt ln 20 mg trong 4 tun nu lot t trng, trong 8 tun nu lot d dy. Trng hp bnh nng hoc ti pht c th tng liu ti 40 mg mt ngy (ung hoc tim tnh mch). D phng ti pht: 10- 20 mg/ ngy - Hi chng Zollinger- Ellison: liu khi u 60 mg/ ngy. Sau iu chnh liu trong khong 20- 120 mg/ ngy tu p ng lm sng. Esomeprazol L ng phn ca omeprazol. Mi ngy ung 20- 40 mg trong 4- 8 tun Pantoprazol Ung mi ngy mt ln 40 mg vo bui sng trong 2- 4 tun nu lot t trng hoc 48 tun nu lot d dy. Trng hp bnh nng c th tim tnh mch chm hoc truyn tnh mch mi ngy mt ln 40 mg n khi ngi bnh c th ung li c. Lansoprazol - Lot d dy: mi ngy ung 30 mg vo bui sng trong 8 tun. - Lot t trng: mi ngy ung 30 mg vo bui sng trong 4 tun. - Liu duy tr: 15 mg/ ngy. Rabeprazol

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Mi ngy ung 20 mg vo bui sng trong 4- 8 tun nu lot t trng hoc 6- 12 tun nu lot d dy. Lu : cc thuc c ch bm proton b ph hu trong mi trng acid nn phi dng di dng vin bao tan trong rut. Khi ung phi nut nguyn c vin vi nc (khng nhai, nghin) v ung cch xa ba n (trc khi n sng, trc khi i ng ti).
1.4. Cc thuc khc

1.4.1. Cc mui bismuth c dng di dng keo subcitrat (trikalium dicitrato), subsalicylat Cc mui bismuth c tc dng: - Bo v t bo nim mc d dy do lm tng tit dch nhy v bicarbonat, c ch hot tnh ca pepsin. - Bao ph chn lc ln y lot, to chelat vi protein, lm thnh hng ro bo v lot chng li s tn cng ca acid v pepsin. - Dit Helicobacter pylori. Khi dng ring, cc mui bismuth ch dit c H.pylori khong 20% ngi bnh, nhng khi phi hp vi khng sinh v thuc c ch bm proton, c th ti 95% ngi bnh tit tr c H.pylori. V th bismuth c coi l thnh phn quan trng trong cng thc phi hp thuc. Bismuth dng keo t hp thu qua ng ung (ch khong 1%) nn t gy c vi liu thng thng. Nu dng liu cao hoc dng ko di c th gy bnh no. Chng ch nh: qu mn vi thuc, suy thn nng, ph n c thai. Tc dng khng mong mun: bun nn, nn, en ming, en li, en phn (thn trng ngi c tin s chy mu ng tiu ha, v d nhm vi i tin phn en). Ch phm: Bismuth subcitrat vin nn 120 mg Ung mi ln 1 vin, ngy 4 ln vo 30 pht trc cc ba n v 2 gi sau ba n ti, hoc mi ln ung 2 vin, ngy 2 ln vo 30 pht trc ba n sng v ti. iu tr trong 4- 8 tun. Khng dng iu tr duy tr, nhng c th iu tr nhc li sau 1 thng. * Ch phm phi hp ranitidin v mui bismuth: ranitidin bismuth citrat d dy ranitidin bismuth citrat c phn ly thnh ranitidin v bismuth, do c c hai tc dng ca hp cht bismuth v ca ranitidin. Ung mi ln 400 mg, ngy 2 ln trong 4- 8 tun nu lot t trng hoc 8 tun nu lot d dy lnh tnh. Khng dng iu tr duy tr. 1.4.2. Sucralfat Sucralfat l phc hp ca nhm hydroxyd v sulfat sucrose. Ging nh bismuth, sucralfat t hp thu, ch yu c tc dng ti ch. Thuc gn vi protein xut tit ti lot, bao ph vt lot, bo v lot khi b tn cng bi acid dch v, pepsin v acid mt. Ngoi ra, sucralfat cn kch thch sn xut prostaglandin (E2, I1,) ti ch, nng pH dch v, hp ph cc mui mt.

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Thn trng khi dng ngi suy thn (trnh dng khi suy thn nng) do nguy c tng nng nhm trong mu, ph n c thai v cho con b. t gy tc dng khng mong mun, ch yu l cc ri lon tiu ha. Ung mi ngy 4,0g, chia lm 2- 4 ln vo 1 gi trc cc ba n v trc khi i ng, trong 4- 8 tun. Sucralfat lm gim hp thu ca nhiu thuc, v vy phi ung cc thuc ny trc sucralfat 2 gi. 1.4.3. Misoprostol L prostaglandin E1 tng hp, c tc dng kch thch c ch bo v nim mc d dy v gim bi tit acid, lm tng lin vt lot d dy- t trng hoc d phng lot d dy do dng thuc chng vim khng steroid. Do hp thu c vo mu nn gy nhiu tc dng khng mong mun: bun nn, y bng, kh tiu, au qun bng, tiu chy, chy mu m o bt thng, gy sy thai, pht ban, chng mt, h huyt p. Chng ch nh dng misoprostol ph n c thai (hoc d nh c thai) v cho con b. Thn trng: bnh mch no, bnh tim mch v nguy c h huyt p. Liu dng: - Lot d dy- t trng: mi ngy 800 mg chia lm 2- 4 ln vo ba n v trc khi i ng, trong 4- 8 tun. - D phng lot d dy- t trng do dng thuc chng vim khng steroid: mi ln ung 200 mg, ngy 2- 4 ln cng vi thuc chng vim khng steroid. 1.5. Khng sinh dit Helicobacter pylori Nu xc nh c s c mt ca H- pylori trong lot d dy t trng (bng test pht hin), phi dng cc phc dit H.pylori vt lot lin nhanh v trnh ti pht. Phc ph bin nht, t hiu qu cao, n gin, sn c v chi ph hp l l phc dng 3 thuc trong 1 tun (one- week triple- therapy) gm mt thuc c ch bm proton v 2 khng sinh: amoxicilin vi clarithromycin hoc metronidazol. Phc ny dit tr c H.pylori trong hn 90% trng hp. Gii thiu mt s phc dng 3 thuc trong 1 tun dit tr H.pylori: Thuc c ch bi tit acid Esomeprazol mi ln 20 mg, ngy 2 ln Lansoprazol Amoxicilin Khng sinh Clarithromycin Metronidazol Mi ln 1 g, ngy Mi ln 500 mg, 2 ln ngy 2 ln Mi ln 500 mg, Mi ln 400 mg, ngy 2 ln ngy 2 ln Mi ln 1 g, ngy Mi ln 500 mg, 2 ln ngy 2 ln

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mi ln 30 mg, ngy 2 ln

Mi ln 1 g, ngy 2 ln

Mi ln 400 mg, ngy 2 ln Mi ln 500 mg, Mi ln 400 mg, ngy 2 ln ngy 2 ln

Omeprazol mi ln 20 mg, ngy 2 ln

Mi ln 1 g, ngy Mi ln 500 mg, 2 ln ngy 2 ln Mi ln 500 mg, ngy 3 ln Mi ln 400 mg, ngy 3 ln Mi ln 500 mg, Mi ln 400 mg, ngy 2 ln ngy 2 ln

Pantoprazol mi ln 40 mg, ngy 2 ln Rabeprazol mi ln 20 mg, ngy 2 ln Ranitidin bismuth citrat

Mi ln 1 g, ngy Mi ln 500 mg, 2 ln ngy 2 ln Mi ln 500 mg, Mi ln 400 mg, ngy 2 ln ngy 2 ln Mi ln 1 g, ngy Mi ln 500 mg, 2 ln ngy 2 ln Mi ln 500 mg, Mi ln 400 mg, ngy 2 ln ngy 2 ln Mi ln 1 g, ngy Mi ln 500 mg, 2 ln ngy 2 ln Mi ln 400 mg, ngy 2 ln Mi ln 500 mg, Mi ln 400 mg, ngy 2 ln ngy 2 ln

mi ln 400 mg, ngy 2 ln Mi ln 1 g, ngy 2 ln

Nu lot ti pht nhiu ln, lot to, c nhiu lot hoc cc trng hp lot khng p ng vi phc 3 thuc, dng phc 4 thuc trong 2 tun gm thuc c ch bm proton, mui bismuth v 2 khng sinh. Cng c th phi hp tinidazol hoc tetracyclin vi cc khng sinh khc v thuc c ch bi tit acid dit tr H. pylori.
2. THUC IU CHNH CHC NNG VN NG V BI TIT CA NG TIU HA

ng tiu ha c chc nng vn ng hp thu cc cht dinh dng, in gii, nc v bi tit cc cht cn b. Khi ri lon cc chc nng ny s sinh ra cc triu chng bun nn, nn, chng bng, kh tiu, to bn, tiu chy Ngoi vic cha triu chng, thy thuc cn tm nguyn nhn iu tr. 2.1. Thuc kch thch v iu chnh vn ng ng tiu ha 2.1.1. Thuc gy nn Nn l mt phn x phc hp, bao gm co tht hang- mn v, m tm v, co tht c honh v c bng, kt qu l cc cht cha trong d dy b tng ra ngoi qua ng

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ming. Trung tm nn nm hnh no, chu s chi phi ca cc trung tm cao hn l m o v vng nhn cm ha hc sn no tht 4 (area postrema) hay trigger zone (Hnh 27.3)
Hyoscin Khng histamin Khng serotonin (5-HT3) Phenothiazin Butyrophenon Metoclopramid Domperidon Khng histamin

(-) (+)
Tin nh (tai) (ACh, H1)

(-) (+)

(-) (+)

(-)
Vng nhn cm ha hc (sn no tht 4) (D2)

Vn ng

Trung tm nn (hnh no) (ACh, H1, 5- HT3)

(+)

Kch thch nn khc

Hng tm Metoclopramid Khng 5- HT3 Gim nhy cm

(+)

Ly tm Dy thn kinh X, giao cm, c honh v cc dy thn kinh khc

(-)

Receptor hng, mn v, rut v ng mt

Metoclopramid Domperidon Tng tc lm rng d dy v tng trng lc thc qun

(-)

M tm v ng mn v co c bng

NN

Hnh 27.3: V tr, c ch tc dng ca nn v thuc chng nn

C 3 loi thuc gy nn: 2.1.1.1. Thuc gy nn trung ng: L thuc kch thch vng nhn cm ha hc trigger: apomorphin, ng 5 mg tim di da. Tr em dng liu 1/20- 1/10 mg/ kg. 2.1.1.2. Thuc gy nn ngoi bin L thuc c tc dng kch thch cc ngn dy thn kinh li, hu v dy ph v ti nim mc d dy. - ng sulfat 0,3 g/ 100mL nc, c th ung thm sau 10- 20 pht. - Km sulfat 0,6- 2 g/ 200 mL nc. 2.1.1.3. Thuc gy nn c c ch hn hp

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Ipeca hoc ipecacuanha: bt vng sm ng trong nang 1- 2g, hoc ru thuc 5- 20 mL, hoc siro 15 mL, c th dng nhc li tng 15 pht cho n khi nn. Thuc gy nn c ch nh trong cc ng c cp tnh qua ng tiu ha, nhng trong thc hnh thng ra d dy s tt hn. Khng dng thuc gy nn cho ngi hn m hoc nhim c cht n da. 2.1.2. Thuc lm tng nhu ng rut 2.1.2.1. Thuc nhun trng L thuc lm tng nhu ng ch yu rut gi, y nhanh cc cht cha trong rut gi ra ngoi. Ch dng thuc nhun trng khi chc chn b to bn, trnh lm dng thuc v c th gy hu qu h kali mu v mt trng lc i trng. Him khi cn iu tr to bn ko di, tr mt s ngi cao tui. C th phng to bn bng ch n cn bng, nc v cht x, vn ng hp l. Theo c ch tc dng, thuc nhun trng c chia thnh 5 nhm chnh. Mt s thuc nhun trng c c ch tc dng hn hp. - Thuc nhun trng lm tng khi lng phn: methylcellulose. - Thuc nhun trng kch thch: kch thch trc tip c trn thnh rut lm tng nhu ng rut, c th gy co cng bng: bisacodyl, glycerin, nhm anthraquinon, cc thuc cng ph giao cm, docusat natri - Cht lm mm phn: paraphin lng, du arachis. - Thuc nhun trng thm thu, c tc dng gi li dch trong lng rut: mui magnesi, lactulose, sorbitol, macrogol, glycerin - Dung dch lm sch rut dng trc khi phu thut i trng, soi i trng hoc chun b chiu chp X - quang i trng, khng dng iu tr to bn. Bisacodyl - Bisacodyl lm tng nhu ng rut do kch thch m ri thn kinh trong thnh rut, ng thi lm tng tch ly ion v dch trong lng i trng. - Ch nh: . To bn do cc nguyn nhn khc nhau. . Lm sch rut trc khi phu thut. . Chun b chp X- quang i trng. - Chng ch nh: Tc rut, vim rut tha, chy mu trc trng, vim d dy- rut. - Tc dng khng mong mun: Thng gp au bng, bun nn. t gp kch ng trc trng khi t thuc. Dng di ngy lm gim trng lc i trng v h kali mu. - Liu dng: . To bn: ung 5- 10 mg vo bui ti hoc t trc trng vin n 10 mg vo bui sng .

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Tr em di 10 tui ung 5 mg vo bui ti hoc t trc trng vin n 5 mg vo bui sng. . Chun b chp X- quang i trng hoc phu thut: ngi ln ung mi ln 10 mg lc i ng, trong 2 ngy lin trc khi chp chiu hoc phu thut. Tr em dng na liu ngi ln. Lu : dng vin bao bisacodyl phn r rut, do khng c nhai hoc nghin vin thuc. Khng dng thuc qu 7 ngy, tr khi c hng dn ca thy thuc. Magnesi sulfat L thuc nhun trng thm thu. Do t c hp thu, magnesi sulfat lm tng p lc thm thu trong lng rut, gi nc, lm tng th tch lng rut, gy kch thch tng nhu ng rut. Ung magnesi sulfat liu thp (5g) c tc dng thng mt v nhun trng, liu cao (15- 30g) c tc dng ty. Tim tnh mch magnesi sulfat c tc dng chng co git trong sn khoa. Chng ch nh: cc bnh cp ng tiu ha. Thn trng: suy thn, suy gan, ngi cao tui, suy nhc. Liu dng nhun trng: ngi ln v tr em trn 12 tui: 10g; 6- 11 tui: 5g; 2- 5 tui: 2,5g. Pha thuc trong cc nc y (t nht trong 240 ml) ung trc ba n sng. Thuc tc dng trong 2- 4 gi. 2.1.2.2. Thuc ty L thuc tc dng c rut non v rut gi, dng tng mi cht cha trong rut ra ngoi (cht c, giun sn) nn thng ch dng 1 ln. Thuc ty mui L cc mui t c hp thu, lm tng p lc thm thu, gi nc, lm tng th tch lng rut. Thng dng megnesi sulfat, natri sulfat ung 15- 30g vi nhiu nc. Thuc ty du Thng dng du thu du (ricin) c cha triglycerid ca acid ricinoleic. Di tc dng ca lipase ty tng, triglycerid b thu phn, gii phng acid ricinoleic. Acid ny c tc dng kch thch nim mc rut non lm tng nhu ng rut v tng xut tit. Mt khc, khi acid ricinoleic chuyn thnh natri ricinoleat, th cht ny khng b hp thu, c tc dng nh thuc ty mui. Liu lng ung 15- 30g. Du ricin c th lm d dng hp thu mt s thuc qua rut, gy ng c: v d khi dng cng vi mt s thuc chng giun sn. Khi iu tr ng c thuc cp tnh, thng dng thuc ty mui, khng dng thuc ty du. 2.1.3. Thuc iu ho chc nng vn ng ng tiu ha

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Cc thuc loi ny c tc dng phc hi li nhu ng ng tiu ha b , dng iu tr chng y bng, kh tiu khng do lot. 2.1.3.1. Thuc khng dopamin ngoi bin Domperidon Domperidon l thuc i khng vi dopamin ch ngoi bin v khng qua c hng ro mu no. V vy c tc dng: - Chng nn trung ng: c ch cc receptor dopamin vng nhn cm ha hc sn no tht IV (nm ngoi hng ro mu- no). - Lm tng tc y cc cht cha trong d dy xung rut do lm gin vng y d dy, tng co hang v, lm gin rng mn v sau ba n. - Tng trng lc c tht thc qun, chng tro ngc d dy- thc qun. - Tng bin v tn s ca nhu ng t trng, iu ho nhu ng ng tiu ha. Ch nh: iu tr triu chng bun nn v nn cp, c bit ngi bnh ang iu tr bng thuc c t bo; chng bng, kh tiu sau ba n do thc n chm xung rut. Chng ch nh: chy mu ng tiu ha, tc rut c hc, nn sau khi m, tr em di 1 tui. Tc dng khng mong mun: nhc u, tng prolactin mu (chy sa, ri lon kinh nguyt, au tc v) Liu dng: ung 10- 60 mg/ ngy, trc ba n 15- 30 pht. Khng dng thng xuyn hoc di ngy. Metoclopramid Khc vi domperidon, metoclopramid phong b receptor ca dopamin, i khng vi tc dng ca dopamin c trung ng v ngoi bin do thuc d dng qua c hng ro mu no. ngoi bin, metoclopramid c tc dng tng t nh domperidon. Do c tc dng c trn trung ng, metoclopramid c tc dng an thn v c th gy phn ng lon trng lc c cp tnh (co tht c xng v c mt, cc cn vn nhn), thng xy ra ngi bnh l n tr hoc ngi rt gi. Ch nh: chng nn, chng tro ngc d dy- thc qun, y bng kh tiu, chun b chp X- quang d dy hoc t ng thng vo rut non. Chng ch nh: ng kinh, chy mu ng tiu ha, tc rut c hc hoc thng rut. Tc dng khng mong mun: a chy, bun ng, phn ng ngoi thp (lon trng lc c cp), mt mi, yu c. Liu dng: ung 5- 10mg/ ln, ngy 3 ln. C th dng ng tim (bp, tnh mch) hoc truyn tnh mch nu bnh nng. 2.1.3.2. Thuc cng ph giao cm ng tiu ha: Cisaprid. Cisaprid kch thch gii phng ACh u tn cng ca m ri thn kinh tng, khng kch thch trc tip receptor M hoc phong to ChE nn tc dng ch khu tr rut,

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tng. Khc vi metoclopramid, cisaprid kch thch vn ng tt c cc phn ca ng tiu ha, k c thc qun v rut gi. Tc dng: tng nhu ng thc qun, tng p lc qua tm v. Tng nhu ng d dy- t trng nn lm nhanh rng d dy. Tng chuyn vn ca d dy- rut non- rut gi. Ch nh: Tro ngc d dy- thc qun. Chm tiu. To bn mn tnh. Liu dng: ung mi ln 5- 20mg, ngy 2- 4 ln, trc ba n 30 pht. 2.1.3.3. Thuc tc dng trn h enkephalinergic ti rut Cc receptor ca h enkephalinergic ti rut c tc dng iu ha nhu ng: tc dng kch thch trn c gim vn ng v tc dng chng co tht trn c tng vn ng Trimebutin Kch thch receptor enkephalinergic rut khi c ri lon. Ch nh: hi chng kch thch rut/ lit rut sau m. Ri lon chc nng tiu ha: au bng, chm tiu, tiu chy/ to bn. Liu dng: ung mi ln 100- 200 mg, ngy 3 ln. Racecadotril Cht c ch enkephalinase c hi phc ti rut, lm gim tit dch rut v in gii ca nim mc rut khi b vim hoc c t vi khun kch thch. Khng c tc dng trn rut bnh thng v khng nh hng n nhu ng rut nn dng trong tiu chy cp. Liu dng: ung mi ln 100 mg, ngy 3 ln trc cc ba n. Khng dng cho tr em di 15 tui 2.2. Thuc chng co tht v lm gim nhu ng ng tiu ha 2.2.1. Thuc chng nn Cc thuc chng nn c ch nh trong cc chng nn do c thai, sau m, nhim khun, nhim c (do nhim acid, do ur mu cao), say tu xe v do tc dng ph ca thuc, nht l cc thuc chng ung th. 2.2.1.1. Gy t ngn dy cm gic d dy: kh CO2, natri citrat, procain 2.2.1.2. Thuc c ch ph giao cm: atropin, scopolamin, benzatropin 2.2.1.3. Thuc khng histamin H1: diphenhydramin, hydroxyzin, cinnarizin, cyclizin, promethazin. Ngoi khng H1, cc thuc ny cn c tc dng khng M cholinergic v an thn kinh (xin xem bi Histamin v thuc khng histamin H1) 2.2.1.4. Thuc khng receptor D2 (h dopaminergic) Thuc c tc dng c ch receptor dopamin vng nhn cm ha hc sn no tht IV. Ngoi ra, thuc cn c ch cc receptor D2 ngoi bin ng tiu ha. - Loi phenothiazin: clopromazin, perphenazin. - Loi butyrophenon: haloperidol, droperidol - Domperidon, metoclopramid.

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2.2.1.5. Thuc khng serotonin Phng v iu tr bun nn, nn do ha tr liu ung th, do chiu x hoc sau phu thut. Cc thuc: - Ondansetron: ung hoc tim tnh mch 8- 32 mg/ ngy. - Granisetron: ung hoc tim tnh mch 1- 3 mg/ ngy. - Dolasetron mesilat: ung hoc tim tnh mch 12,5- 200 mg/ ngy. 2.2.1.6. Cc thuc khc - Benzodiazepin: lorazepam, alprazolam - Corticoid: dexamethason, metylprednisolon. C ch cha hon ton bit r, c mt phn tc dng c ch trung tm nn. 2.2.2. Thuc chng co tht c trn ng tiu ha Do c tc dng chng co tht c trn theo cc c ch khc nhau, cc thuc ny c dng iu tr triu chng cc cn au do co tht ng tiu ha, ng mt v c ng sinh dc, tit niu. 2.2.2.1. Thuc hu ph giao cm Atropin sulfat: Hu ph giao cm c trung ng v ngoi bin (xin xem bi Thuc tc dng trn h thn kinh thc vt) Hyoscin N- butylbromid V mang amin bc 4 nn khng vo c thn kinh trung ng, ch c tc dng hu ph giao cm ngoi bin. Tc dng khng mong mun: kh ming, mch nhanh, b i, to bn, ri lon iu tit mt. Chng ch nh: glcm gc ng, ph i tuyn tin lit, nhc c, tc lit rut, hp mn v, ri lon chuyn ha porphyrin. Liu dng: mi ln ung 10- 20 mg, ngy 3- 4 ln. 2.2.2.2. Thuc chng co tht c trn trc tip Papaverin hydroclorid Papaverin l mt alcaloid trong nha kh ca qu cy thuc phin, khng c tc dng gim au, gy ng ging morphin. Tc dng ch yu ca papaverin l lm gin c trn ng tiu ha, ng mt v ng tit niu. Chng ch nh: qu mn vi thuc, bloc nh- tht hon ton, mang thai (c th gy c cho thai). Tc dng khng mong mun: bng mt, nhp tim nhanh, chng mt, nhc u, ng g, ri lon tiu ha, vim gan. Liu dng: ung hoc tim (bp, tnh mch) mi ln 30- 100mg, ngy 2- 3 ln.

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Alverin citrat L thuc chng co tht, tc dng trc tip ln c trn ng tiu ha v t cung. So vi papaverin, tc dng mnh hn 3 ln nhng c tnh km 3 ln. Chng ch nh: tc nghn rut hoc lit rut, mt trng lc rut kt. Tc dng khng mong mun: bun nn, au u, chng mt, phn ng d ng. Liu dng: mi ln ung 60- 120 mg, ngy 1-3 ln. Cc thuc khc: mebeverin, dicycloverin, phloroglucinol, drotaverin. 2.3. Thuc chng tiu chy Trong iu tr tiu chy, ngoi vic iu tr nguyn nhn, vn u tin trong mi trng hp l nh gi v x l ng nhng ri lon nc v in gii. Cc thuc lm gim triu chng (hp ph, bao ph nim mc, gim tit dch, gim nhu ng rut) c th dng trong mt s trng hp tiu chy ngi ln, nhng khng nn dng tr em v chng khng lm gim c s mt dch v in gii, m cn c th gy ra nhiu tc dng c hi. 2.3.1. Thuc ung b nc v in gii (ORS, Oresol) 2.3.1.1. Thnh phn v c ch tc dng - Thnh phn mt gi bt (ORS ca Unicef) Natri clorid: 3,5g; Kali clorid: 1,5g; Natribicarbonat: 2,5g; Glucose: 20,0g. Nc ha tan: 1gi/ 1 lt. - C ch tc dng: s hp thu ca natri v nc rut c tng cng bi glucose (hoc carbohydrat khc). Glucose hp thu tch cc rut ko theo hp thu natri (h thng ng vn chuyn glucose- natri rut non). B kali trong tiu chy cp c bit quan trng tr em, v tr mt kali trong phn cao hn ngi ln. Bicarbonat (hoc citrat) c tc dng khc phc tnh trng nhim toan chuyn ha trong tiu chy. 2.3.1.2. Ch nh: phng v iu tr mt nc v in gii mc nh v va. 2.3.1.3. Chng ch nh: Gim niu hoc v niu do gim chc nng thn. Mt nc nng (phi truyn tnh mch dung dch Ringer lactat). Nn nhiu v ko di, tc rut, lit rut. 2.3.1.4. Tc dng khng mong mun: Nn nh, tng natri mu, suy tim do b nc qu mc. 2.3.1.5. Liu dng: - Mt nc nh: ung 50 ml/ kg trong 4- 6 gi u.

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- Mt ncva: ung 100 ml/ kg trong 4- 6 gi u. Sau iu chnh theo mc kht v p ng vi iu tr. Cn tip tc cho tr b m hoc n ung bnh thng. C th cho ung nc trng gia cc ln ung ORS trnh tng natri mu. 2.3.2. Cc cht hp ph, bao ph nim mc rut Do c trng lng phn t cao, cu trc phin mng, tnh cht do dai nn cc cht ny c kh nng gn vi protein ca nim mc ng tiu ha, to thnh mt lp mng bao ph, bo v nim mc. - Atapulgit: ngoi tc dng to mng bo v nim mc rut, thuc cn hp ph cc c t ca vi khun, cc kh trong rut, c tc dng cm mu ti ch . Liu dng: gi bt 3g atapulgit hot ha, ung 2- 3 gi/ ngy. Khng dng trong iu tr tiu chy cp tr em. - Smecta: gi bt 3g, 2- 3 gi/ ngy, ung xa ba n. 2.3.3. Cc cht lm gim tit dch, gim nhu ng rut Loperamid Tc dng: loperamid l opiat tng hp nhng c rt t tc dng trn thn kinh trung ng. Loperamid lm gim nhu ng rut, ko di thi gian vn chuyn qua rut, gim tit dch ng tiu ha, tng vn chuyn nc v cht in gii t lng rut vo mu, tng trng lc c tht hu mn. Ch nh: iu tr triu chng tiu chy cp khng c bin chng hoc tiu chy mn ngi ln. Chng ch nh: mn cm vi thuc, khi cn trnh c ch nhu ng rut, vim i trng nng, tn thng gan, hi chng l, trng bng. Tc dng khng mong mun: bun nn, to bn, au bng, trng bng, chng mt, nhc u, d ng. Liu dng: - Ngi ln: lc u ung 4 mg, sau mi l n i lng ung 2 mg cho ti khi ngng tiu chy. Liu ti a: 16 mg/ ngy. Khng dng qu 5 ngy trong tiu chy cp. - Tr em: khng dng thng qui trong tiu chy cp. Ch dng cho tr em trn 6 tui khi tht cn thit. Mi ln ung 2 mg, ngy 2- 3 ln tu theo tui. Ngng thuc nu thy khng c kt qu sau 48 gi. 2.3.4. Vi khun v nm 2.3.4.1. Lactobacillus acidophilus Vi khun sn xut acid lactic v 2 cht dit khun: lactocidin v acidophillin. C kh nng tng hp vitamin nhm B. Bnh thng, cc vi khun cng sinh trong lng rut c s cn bng gia vi khun hu saccharose v cc vi khun hu protein. Mt s cht tn cng vo vi khun hu saccharose nh ru, stress, nhim khun, khng sinh gy ra s mt cn bng, lm tng vi khun hu protein, dn n ri lon tiu ha (tiu chy, to bn, trng bng)

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Lactobacillus acidophilus c tc dng lp li thng bng vi khun cng sinh trong rut, kch thch vi khun hu saccharose pht trin, kch thch min dch khng c hiu ca nim mc rut (tng tng hp IgA) v dit khun. Ch nh: cc tiu chy do lon khun rut Ch phm: Antibio: gi bt 1g cha 100 triu vi khun sng. Ngi ln ung mi ln 1gi, ngy 3 ln. Tr em ung mi ngy 1- 2 gi. 2.3.4.2. Saccharomyces boulardii L nm men c tc dng tng hp vitamin nhm B, km khun, dit Candida albicans, kch thch min dch khng c hiu. Ch nh: d phng v iu tr tiu chy do dng khng sinh, tiu chy cp. V nm men l cc t bo sng nn khng c trn vo nc hay thc n nng (trn 500C), qu lnh hoc c ru. Khng dng cng vi cc thuc chng nm. Ch phm: Ultra- levure, vin nang cha Saccharomyces boulardii ng kh 56,5mg. Mi ln ung 1 vin, ngy 4 ln. 2.4. Thuc li mt v thuc thng mt 2.4.1. Thuc li mt Phn bit hai loi: - Thuc li mt nc (secretin, thuc cng ph giao cm) lm tng bi tit nc v in gii ca t bo biu m ng mt, gy tng tit mt long. - Thuc li mt thc th kch thch t bo gan tng bi tit mt ging nh mt sinh l. Tu theo ngun gc, c: 2.4.1.1. Thuc li mt c ngun gc ng vt l mui mt, cc acid mt, hoc mt ton phn loi b sc t v cholesterol Ch phm: Bilifluine, vin nang 0,1g, ung 2 vin trc mi ba n tra v ti. 2.4.1.2. Thuc li mt c ngun gc thc vt: ngh, actiso, boldo. Thng dng ch phm phi hp nhiu cy thuc 2.4.1.3. Thuc li mt tng hp - Cyclovalon: vin bao ng 50 mg, ung 6- 12 vin/ ngy - Anthol trithion: dng thuc ht c 0,0125g/ ht. Mi ngy ung 3- 6 ht. Ch nh chung ca cc thuc li mt - iu tr triu chng cc ri lon tiu ha: trng bng, y hi, hi, bun nn - iu tr ph tr chng to bn Chng ch nh: tc mt v suy gan nng 2.4.2. Thuc thng mt L nhng thuc gy co tht ti mt, ng thi lm gin c trn Oddi. Mt hon ton thot khi ti mt.

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V mt sinh l, tc dng ny ph thuc vo cholecystokinin pancreatozinin (CCKPZ) do t trng tit ra khi lipid v peptid t d dy trn xung. Hu nh cc thuc c tc dng thng mt l do lm bi tit CCK- PZ. Ch nh: cc ri lon tiu ha nh y bng, chm tiu, hi, bun nn Chng ch nh: si ng mt, c tin s amip. Cc thuc: Sorbitol gi bt 5g. Mi ln pha 1 gi trong nc, ung trc ba n. Magnesi sulfat: ung 2- 5g
CU HI T LNG GI

1. Trnh by c ch tc dng, tc dng khng mong mun v p dng iu tr ca thuc khng acid magnesi hydroxyd v nhm hydroxyd. 2. Trnh by c ch tc dng, tc dng khng mong mun v p dng iu tr ca thuc khng histamin H2 v thuc c ch H+/ K+- ATPase. 3. Trnh by tc dng, tc dng khng mong mun v p dng iu tr ca cc mui bismuth. 4. V s phn tch v tr, c ch tc dng v nu ch nh iu tr ca cc thuc gy nn v chng nn. 5. Trnh by v phn loi v c ch tc dng ca cc thuc nhun trng v thuc ty thng dng. 6. Trnh by tc dng, tc dng khng mong mun v p dng iu tr ca bisacodyl v magnesi sulfat. 7. Nu cc nhm thuc iu ha chc nng vn ng ng tiu ha. Mi nhm k tn 1- 2 thuc i din. 8. Trnh by c ch tc dng, tc dng, tc dng khng mong mun v p dng iu tr ca domperidon v metoclopramid. 9. Trnh by c ch tc dng, tc dng, tc dng khng mong mun v p dng iu tr ca hyoscin N- butylbromid, papaverin v alverin citrat. 10. Trnh by tc dng, p dng iu tr ca ORS. 11. Trnh by tc dng, p dng iu tr ca cc thuc chng tiu chy: atapulgit, loperamid, vi khun lactobacillus acidophilus, nm saccharomyces boulardii. 12. Phn bit tc dng ca thuc li mt v thuc thng mt, p dng iu tr ca cc thuc ny. Bi 28:

THUC IU CHNH RI LON H HP

MC TIU HC T P: Sau khi hc xong bi ny, sinh vin c kh nng:

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1. Phn bit c c ch tc dng ca thuc lm long m, thuc cha ho, thuc cha hen, thuc dng trong hi sc h hp. 2. Trnh by c tc dng, tc dng khng mong mun v p dng iu tr ca: N- acetylcystein, bromhexin Codein, dextromethorphan Thuc cng 2 adrenergic, thuc hu ph giao cm (ipratropium), theophylin. Glucocorticoid (trong iu tr hen)

- Cafein v nikethamid
3. Nu c cch s dng thuc trong iu tr hen.
1. THUC LM THAY I BI TIT DCH KH - PH QUN

Dch kh- ph qun c bi tit: - T cc t bo nim mc: cc t bo hnh i tit dch nhy (do c nhiu mucoprotein v mucopolysaccharid) v cc t bo thanh dch tit dch lng, qunh thp. - T cc tuyn tit di nim mc: l tuyn hn hp tit nc hoc dch nhy. Acetylcholin v cc thuc cng ph giao cm lm tng bi tit dch kh- ph qun. Dch kh- ph qun l cht lm du t nhin ca nim mc ng h hp. Dch nhy c tc dng bm dnh cc ht bi, vi khun, sau nh h thng lng mao y chng ra ngoi. 1.1. Thuc lm gim tit dch Thuc hu ph giao cm hoc thuc khng histamin H1. Thc t t dng v c th lm cht tit c qunh, kh tng ra ngoi, d gy xp ph nang. 1.2. Thuc lm long m 1.2.1. Thuc lm tng dch tit L thuc lm tng bi tit dch ng h hp, bo v nim mc chng li cc tc nhn kch thch v khi lm tan c nhng tc nhn s cho php loi tr chng d dng. C 2 c ch tc dng: 1.2.1.1. Kch thch cc receptor t nim mc d dy gy phn x ph giao cm lm tng bi tit dch ng h hp, nhng liu c tc dng thng lm au d dy v c th gy nn. Mt s thuc thng dng l: - Natri iodid v kali iodid: ung 1- 2g/ ngy. Dng ko di lm tch lu iod. Khng dng cho ph n c thai, tr em, ngi b bu gip. - Natri benzoat: ung 1- 4 g/ ngy. Dng ko di lm tch lu Na+. - Amoni acetat: 0,5- 1g/ ngy. Khng dng ngi suy gan hoc suy thn - Ipeca hoc ipecacuanha, hot cht l emetin. Dng liu thp (ti a 1,4 mg alcaloid) trong trng hp ho c m. Liu cao gy nn. 1.2.1.2. Kch thch trc tip cc t bo xut tit

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Thng dng cc tinh du bay hi nh terpin, gaicol, eucallyptol. Nhng tinh du ny cn c tc dng st khun. Khng dng gaicol cho tr em di 30 thng tui. 1.2.2. Thuc lm tiu cht nhy Cc thuc ny lm thay i cu trc, dn n gim nht ca cht nhy, v vy cc nt nhy c th d dng di chuyn ra khi ng h hp nh h thng lng chuyn hoc s khc m. Nhng thuc c nhm thiol t do (nh acetylcystein) c tc dng ct t cc cu ni disulfit S S ca cc si mucopolysaccharid nn lm lng dch tit ca nim mc ph qun. Cc thuc lm tiu cht nhy c th lm ph v hng ro cht nhy bo v d dy, phi thn trng nhng ngi c tin s lot d dy- t trng. 1.2.2.1. N- acetylcystein Dng lm thuc tiu cht nhy trong bnh nhy nht, cc bnh l h hp c m nhy qunh nh trong vim ph qun cp hoc mn. Cn dng lm thuc gii c khi dng qu liu paracetamol. Khng dng ngi c tin s hen (nguy c phn ng co tht ph qun) Tc dng khng mong mun: bun nn, nn, bun ng, nhc u, phn ng d ng. Khng dng ng thi vi cc thuc chng ho hoc cc thuc lm gim bi tit dch ph qun. Liu dng: Ung mi ln 200 mg, ngy 3 ln. Kh dung 3- 5 mL dng dch 20%, 3- 4 ln/ ngy. Nh trc tip vo kh qun 1- 2 mL dung dch 10- 20%, mi gi 1 ln. Do tc dng nhanh, i khi c th lm trn dch trong kh qun nu ngi bnh khng c kh nng ho tng ra ngoi kp thi. C th ht m long bng my ht. 1.2.2.2. Bromhexin (Bisolvon) Dng iu tr nhng ri lon h hp i km vi ho c m. Khi iu tr nhim khun ng h hp, bromhexin lm tng s xm nhp ca mt s khng sinh vo dch bi tit ph qun, tng p ng vi khng sinh. Thn trng ngi c tin s lot d dy- t trng, bnh hen, suy gan hoc suy thn nng. Tc dng khng mong mun: ri lon tiu ha, tng nh enzym gan, chng mt, nhc u, pht ban da. Kh dung bromhexin i khi gy ho hoc co tht ph qun nhng ngi nhy cm. Liu dng: ung mi ln 8- 16 mg, ngy 3 ln. C th dng ng kh dung, tim bp su hoc tim tnh mch chm. 1.2.2.3. Cc thuc khc: Carbocistein, mucothiol, mecystein
2. THUC CHA HO

Ho l c ch t v sinh l quan trng tng ra ngoi cc d vt phn trn ca ng h hp c th gy tc ng th. Ho cng c th l triu chng ca mt s ri lon

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trong c th (hen, tro ngc d dy- thc qun), m khi iu tr nhng bnh ny s gim ho, nhng nhiu khi cng cn iu tr triu chng. Ch dng thuc gim ho trong trng hp ho khng c m (ho khi cm cm, ho do kch ng, d ng), ho nhiu lm ngi bnh mt mi, mt ng. Khng dng thuc lm gim ho trong trng hp ho c m (trong bnh vim ph qun mn, gin ph qun) v ho c coi nh c ch bo v c li, lm sch ng th. Cc thuc gim ho c chia lm 2 loi: 2.1. Thuc gim ho ngoi bin Lm gim nhy cm ca cc receptor gy phn x ho ng h hp - Thuc lm du ho do c tc dng bo v, bao ph cc receptor cm gic hng, hu: glycerol, mt ong, cc siro ng ma - Thuc gy t cc ngn dy thn kinh gy phn x ho: benzonatat, bc h (menthol), lidocain, bupivacain. 2.2. Thuc gim ho trung ng Cc thuc ny c ch trc tip, lm nng cao ngng kch thch ca trung tm ho hnh tu, ng thi c tc dng an thn, c ch nh trung tm h hp. 2.2.1. Alcaloid ca thuc phin v cc dn xut 2.2.1.1. Codein Codein (methylmorphin) l alcaloid ca thuc phin. Trong c th, khong 10% codein b kh methyl thnh morphin. So vi morphin, codein c hp thu tt hn khi ung, t gy to bn hoc co tht ng mt, t gy c ch h hp v t gy nghin hn nhng tc dng gim au cng km hn. Codein c tc dng gim ho do c ch trc tip trung tm ho, nhng lm kh v tng qunh ca dch tit ph qun. Dng codein trong trng hp ho khan gy kh chu, mt ng v trong cc chng au nh v va. Chng ch nh: mn cm vi thuc, tr em di 1 tui, bnh gan, suy h hp, ph n c thai. Liu dng iu tr ho khan: ung mi ln 10- 20 mg, ngy 3 4 ln. 2.2.1.2. Pholcodin Tc dng gim ho mnh hn codein 1,6 ln, t gy tc dng khng mong mun hn. Liu dng: 5- 15 mg/ ngy 2.2.1.3. Thuc gim ho khng gy nghin * Dextromethorphan: L cht tng hp, ng phn D ca morphin nhng khng tc dng ln cc receptor ca morphin nn khng gy nghin, khng c tc dng gim au v rt t tc dng an

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thn. Do c ch trung tm ho, dextromethorphan c tc dng chng ho tng t codein, nhng t gy tc dng ph hn. Dextromethorphan ch nh tt trong trng hp ho khan, mn tnh. Chng ch nh: qu mn vi thuc, tr em di 2 tui, ang iu tr bng thuc c ch monoaminoxydase (MAO). Thn trng: ngi c nguy c hoc ang suy gim h hp, tin s b hen, d ng. Liu dng: ung mi ln 10- 20 mg, 4 gi/ ln hoc mi ln 30 mg, 6- 8 gi/ ln, ti a 120 mg/ ngy. * Noscapin: Tc dng, cch dng, tc dng khng mong mun v thn trng tng t nh dextromethorphan. Khng dng cho ph n c kh nng mang thai (v nguy c gy t bin) Liu dng: mi ln 15- 30 mg, ngy 3 ln. 2.2.2. Thuc gim ho khng histamin Mt s thuc c tc dng khng histamin H1 trung ng v ngoi bin (khng H1 th h 1) ng thi c tc dng chng ho, khng cholinergic, khng serotonin v an thn. Ch nh: cc chng ho khan do d ng, do kch thch, nht l v ban m. Tc dng an thn ca thuc l iu bt li khi dng thuc ban ngy, nhng c th thun li khi ho ban m. Cc thuc: - Alimemazin: ngi ln ung 5- 40mg/ ngy, chia nhiu ln. Tr em: 0,5- 1 mg/ kg/ ngy, chia nhiu ln. - Diphenhydramin: mi ln ung 25 mg, 4- 6 gi/ ln.
3. THUC CHA HEN PH QUN

3.1. i cng Hen ph qun l hi chng vim mn tnh ng h hp, c gia tng tnh phn ng ca ph qun vi cc tc nhn gy kch thch, gy nn tnh trng co tht, ph n, tng xut tit ph qun, lm tc nghn ng th. Hen ph qun c th do d ng (bi, phn hoa, lng v, thc phm) hoc khng do d ng (nhim khun, ri lon ni tit, gng sc, dng thuc chng vim khng steroid) ngi hen do d ng, khi tip xc vi d nguyn, rt nhiu cht trung gian ha hc c gii phng t dng bo (t bo mastocyt), gy nhiu tc dng ph qun v cc ni khc trong c th.

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Gii phng t ht

Gii phng t mng


hng pht

Sn xut cytokin
Tng hp ARNm v protein mi, sau hng gi Cc Interleukin (IL) IL 1 IL 4 IL 6 TNF IL 3 IL 5 IL8

Gii phng ngay Histamin Protease Heparin

Chuyn ha lipid, sau Cc prostaglandin (PGD2) Cc leucotrien(LTC4,D4) cu(PAF)

Yu t hoi t u (TNF) Yu t hot ha tiu

Hnh 28.1. Cc cht trung gian ha hc c gii phng khi dng bo trong phn ng d ng

Nu pht hin c d nguyn gy bnh, c th iu tr bng phng php gim mn cm c hiu. iu tr khng c hiu bnh hen, theo c ch bnh sinh, c hai nhm thuc c dng: - Cc thuc lm gin ph qun: thuc cng 2 adrenergic, thuc hu ph giao cm, theophylin. - Cc thuc chng vim: corticoid, cromolyn natri. Thuc khng leucotrien (montelukast, zafirlukast) lm gim tc dng co tht ph qun v gy vim ca LTD4. 3.2. Thuc lm gin ph qun 3.2.1. Thuc cng 2 adrenergic 3.2.1.1. C ch tc dng C trn ng h hp c nhiu receptor 2, khi b kch thch s gy gin c trn kh ph qun do lm tng AMPv trong t bo. Khi dng di dng kh dung, cc thuc cng 2 c ch gii phng histamin v leucotrien khi dng bo phi, lm tng chc phn ca h thng lng mao, gi m

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tnh thm ca mao mch phi v c ch phospholipase A2, tng kh nng chng vim ca corticoid kh dung. 3.2.1.2. Phn loi Cc thuc cng 2 adrenergic c chia lm 2 loi: - Loi c tc dng ngn (short acting 2 agonist: SABA): salbutamol, terbutalin, fenoterol ch yu dng ct cn hen; Dng di dng ht, tc dng sau 2- 3 pht, ko di 3- 5 gi. - Loi c tc dng di (long acting 2 agonist: LABA): salmeterol, formoterol gn vo receptor 2 mnh hn salbutamol, tc dng ko di khong 12 gi, dng phi hp vi corticoid d phng di hn v kim sot hen. 3.2.1.3. Tc dng khng mong mun v thn trng - Tc dng khng mong mun thng gp: nh trng ngc, nhp tim nhanh, run nh (c bit u ngn tay). Him gp: nhc u, mt ng, gin mch ngoi bin, lon nhp tim, h kali mu, tng glucose v acid bo t do trong mu, phn ng qu mn. Dng ng kh dung c th gy co tht ph qun. Dng nhiu ln s c hin tng quen thuc nhanh do s lng receptor 2 ca ph qun gim dn (c ch iu ha gim), bnh nhn c xu hng phi tng liu. - Thn trng: cng tuyn gip, bnh tim mch, tng huyt p, lon nhp tim, i tho ng, ang iu tr bng MAOI. 3.2.1.4. Cc thuc - Salbutamol Ch nh: hen, tc nghn ng h hp hi phc c, chng non. Liu dng: . Cn hen cp: ht nh liu mi ln 100- 200 mg (1- 2 xt), ti a 3- 4 ln/ ngy. Hoc: tim bp hoc tim di da mi ln 500 mg, nhc li sau mi 4 gi nu cn. . Cn hen cp nghim trng: dung dch kh dung 2,5 5 mg, ti a 4 ln/ ngy hoc tim tnh mch chm 250 mg, dng nhc li nu cn. . phng cn hen do gng sc: ht 100- 200 mg (1- 2 xt) truc khi vn ng 15- 30 pht, hoc ung 2- 4 mg trc khi vn ng 2 gi. Dng ng kh dung, nng thuc trong mu ch bng 1/10- 1/50 so vi liu ung. - Terbutalin Ch nh: ging nh salbutamol Liu dng: cn hen cp: ht 250- 500 mg (1- 2 ln xt), ti a 3- 4 ln/ ngy, hoc tim di da, tim bp hoc tnh mch chm 250- 500 mg, ti a 4 ln/ ngy. Bambuterol l tin thuc ca terbutalin, mi ngy ung mt ln 10- 20 mg trc khi i ng - Salmeterol

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Ch nh: iu tr d phng di hn bnh hen, tc nghn ng h hp phc hi c (k c hen ban m v phng co tht ph qun do gng sc) ngi phi iu tr bng thuc gin ph qun thng xuyn, bnh phi tc nghn mn tnh. Liu dng: . Bnh hen: mi ln ht 50- 100 mg (2- 4 xt), 2 ln/ ngy. Tr em trn 4 tui: mi ln ht 50 mg (2 xt), 2 ln/ ngy. . Bnh phi tc nghn mn tnh: mi ln ht 50 mg (2 xt), 2 ln/ ngy. 3.2.2. Thuc hu ph giao cm Ipratropium bromid (Atrovent) l dn xut amin bc 4, dng ng ht. Khi kh dung, ch khong 1% thuc c hp thu, 90% b nut vo ng tiu ha, khng c hp thu, thi theo phn nn t gy tc dng khng mong mun ton thn. Tc dng gin ph qun ca ipratropium trn ngi bnh hen thng chm v khng mnh bng thuc cng 2 tc dng ngn (SABA), nn thng ch c phi hp s dng khi cc thuc SABA khng mnh hoc c tc dng ph nng. Phi hp ipratropium vi SABA lm gin ph qun mnh hn, cho php gim liu SABA nn hn ch c tc dng ph ca SABA. Kh dung ipratropium c tc dng ti a sau 30- 60 pht, thi gian tc dng ko di 3- 6 gi. Ipratropium cng c tc dng tt trong iu tr bnh phi tc nghn mn tnh. Thn trng: tng nhn p, ph i tuyn tin lit v tc nghn dng chy ra t bng quang, c thai v cho con b. Tc dng khng mong mun: kh ming, bun nn, to bn, au u. Liu dng: ht nh liu: mi ln 20- 40 mg (1- 2 xt), 3-4 ln/ ngy. Berodual (ipratropium bromid + fenoterol): mi ln xt c 20 mg ipratropium v 50 m g fenoterol. Liu thng thng 1- 2 xt/ ln, ngy 3 ln. Oxitropium c tc dng tng t nh ipratropium. 3.2.3. Theophylin v dn xut Theophylin l base xanthin (cng vi cafein v theobromin) c nhiu trong ch, c ph, ca cao. 3.2.3.1. C ch tc dng v tc dng dc l Do c ch phosphodiesterase- enzym ging ha AMPv, theophylin lm tng AMPv trong t bo nn tc dng tng t thuc cng adrenergic. - Trn h hp: lm gin ph qun, ng thi kch thch trung tm h hp hnh no, lm tng bin v tn s h hp. - Trn tim mch: lm tng bin , tn s v lu lng tim, tng s dng oxy ca c tim v tng lu lng mch vnh. - Trn thn kinh trung ng: tc dng kch thch thn kinh trung ng km cafein, lm d dng cho cc hot ng ca v no, gy mt ng c th do tc dng ln h thng li kch thch. - Lm gin c trn ng mt v niu qun.

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- Tc dng li niu km theobromin. Theophylin c chuyn ha qua gan. Nng trong huyt tng, thi gian bn thi ca theophylin thay i ng k trong mt s tnh trng sinh l v bnh l (tng trong suy tim, x gan, nhim virus, ngi cao tui) hoc do tng tc thuc, trong khi gii hn an ton gia liu iu tr v liu c ca theophylin kh hp. Tc dng gin ph qun ca theophylin khng mnh bng cc thuc kch thch 2, trong khi nguy c xut hin cc tc dng khng mong mun kh cao, v vy theophylin khng c la chn u tin trong ct cn hen. Hin nay, theophylin ung gii phng nhanh t c dng trong iu tr hen, ch yu dng theophylin gii phng chm, duy tr nng thuc trong mu trong 12 gi iu tr d phng v kim sot hen v m. Trong cn hen nng, theophylin c dng phi hp vi cc thuc cng 2 hoc corticoid lm tng tc dng gin ph qun, nhng li c th lm tng tc dng khng mong mun ca thuc cng 2 (h kali mu). Theophylin c th dng ng tim l aminophylin, hn hp ca theophylin v ethylendiamin, tan trong nc gp 20 ln so vi theophylin n c. Trong iu tr cn hen nng, tim tnh mch aminophylin rt chm (t nht trong 20 pht). 3.2.3.2. Chng ch nh v thn trng Chng ch nh: qu mn vi thuc, lot d dy- t trng tin trin, ri lon chuyn ha porphyrin, ng kinh khng kim sot c. Thn trng: bnh tim, tng huyt p, cng gip, tin s lot d dy- t trng, suy gan, ng kinh, c thai v cho con b, ngi cao tui, ang b st, dng cng cc thuc c ch enzym chuyn ha thuc gan. 3.2.3.3. Tc dng khng mong mun: thng gp nhp tim nhanh, tnh trng kch thch, bn chn, bun nn, nn. t gp: kch ng ng tiu ha, au u, chng mt, mt ng, run, co git, lon nhp tim, h huyt p, phn ng d ng. 3.2.3.4. Liu dng: Vin theophylin gii phng chm (Theostat, Nuelin SA): mi ln ung 200- 400 mg, cch 12 gi ung 1 ln. Hen ban m: ung mt ln duy nht vo bui ti vi liu bng tng liu dng trong mt ngy. . Aminophylin: ung mi ln 100- 300 mg, ngy 3- 4 ln, sau ba n. Tim tnh mch chm t nht trong 20 pht liu 5 mg/ kg. 3.3. Thuc chng vim 3.3.1. Glucocorticoid (GC) Glucocorticoid c hiu qu rt tt trong iu tr hen, do thuc c tc dng chng vim, lm gim ph n, gim bi tit dch nhy vo lng ph qun v lm gim cc phn ng d ng. Glucocorticoid phc hi p ng ca cc receptor 2 vi cc thuc cng 2 adrenergic (xin xem thm bi Hormon v thng thn). - Dng di dng ht c tc dng tt, iu tr d phng hen khi ngi bnh phi dng thuc cng 2 nhiu hn 3 ln/ tun, t gy tc dng khng mong mun ton

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thn. Bt buc phi dng thuc u n t li ch ti a v lm gim nguy c tng nng ca hen. Tc dng khng mong mun ti ch thng gp khi dng GC ht l nhim n m Candida ming hng, khn ting v ho. Dng liu cao ko di c th gy c ch thng thn, gim mt khong xng, tng nhn p. Cc GC dng ng ht: beclometason dipropionat, budesonid v fluticason propionat. (ba thuc ny c tc dng tng ng nhau), ciclesonid, mometason furoat. * Beclometason dipropionat (Becotide): kh dung nh liu mi ln 100- 400 mg, 2 ln/ ngy, sau iu chnh theo p ng ca ngi bnh. * Budesonid (Pulmicort): ht mi ln 200 mg, 2 ln/ ngy. Ch phm phi hp: Symbicort cha formoterol v budesonid vi cc hm lng formoterol/ budesonid mi ln xt l 4,5mg/ 80 mg; 4,5mg/ 160 mg; 9mg/ 320mg. Ngi ln v tr em trn 12 tui: mi ln 1- 2 xt, ngy 2 ln. iu tr duy tr: 1 ln xt/ ngy. * Fluticason propionat: ht nh liu mi ln 100- 250 mg, 2 ln/ ngy. tr em 4- 16 tui: mi ln 50- 100 mg, 2 ln/ ngy Ch phm phi hp: Seretide cha salmeterol v fluticason propionat vi cc hm lng salmeterol / fluticason propionat mi ln xt l 25 mg/ 50 mg; 25 mg/ 125 mg; 25 mg/ 250 mg Ngi ln v tr em trn 12 tui: mi ln 2 xt, ngy 2 ln. Dng ch phm c hm lng thuc ph hp vi mc nng ca bnh hen. * Ciclesonid: ngi ln xt mi ngy mt ln 160 mg. * Mometason furoat: ngi ln ht 200- 400 mg vo bui ti hoc chia lm 2 ln trong ngy. - Dng ton thn: iu tr cn hen cp nng hoc kim sot hen mn tnh nng. . Hen nng cp tnh: ngi ln ung prednisolon 40- 50 mg/ ngy, t nht trong 5 ngy (tr em 1- 2 mg/ kg/ ngy, trong 3 ngy), sau iu chnh liu theo p ng ca ngi bnh, hoc tim tnh mch hydrocortison 400 mg/ ngy, chia lm 4 ln. . Hen mn tnh nng khng p ng y vi cc thuc chng hen khc, ht GC liu cao phi hp vi ung GC mi ngy mt ln vo bui sng. Tm liu thp nht kim sot c triu chng 3.3.2. Cromolyn natri - Tc dng: c ch dng bo ca phi gii phng cc cht trung gian ha hc do p ng vi cc kch thch hoc do tng tc khng nguyn- khng th IgE. c ch tc dng hot ha ca cc peptid ha hng ng trn bch cu trung tnh, a acid hoc n nhn.

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Cromolyn natri ch c tc dng phng cn, ngn nga p ng hen vi cc kch thch do d ng hoc khng do d ng, c dng iu tr di hn sm trong hen, khng c tc dng iu tr cn hen cp. Tr em p ng vi thuc tt hn ngi ln. Nhn chung tc dng d phng hen ca cromolyn natri km hiu qu hn so vi GC ng ht. - Cromolyn natri dng theo ng ht, t c hp thu nn t gy c tnh ton thn. - Tc dng khng mong mun: ho, co tht nh ph qun, nhc u, bun ng, ri lon tiu ha, phn ng qu mn. - Liu dng: ht mi ln 10 mg (2 xt, ngy 4 ln cch u nhau). Phng cn hen do gng sc, kh lnh, tc nhn mi trng: ht 10 mg (2 xt) ngay trc khi tip xc vi cc yu t gy cn. 3.3.3. Thuc khng leucotrien Thuc khng leucotrien ngn cn tc dng ca cc cysteinyl leucotrien ng h hp. Chng c tc dng khi dng ring hoc khi phi hp vi GC ht (tc dng hip ng cng) - Ch nh: iu tr d phng hen nng Phi hp vi thuc cng b2 v GC ng ht iu tr hen mn tnh

- Tc dng khng mong mun: ri lon tiu ha, kh ming, kht, au u, chng mt, ri lon gic ng, au khp, au c, ph, phn ng nhy cm. C th gp hi chng Churg- Strauss (c tin s hen, thng vim mi, vim xoang, vim mch v tng bch cu a eosin). - Cc thuc: . Montelukast: Ngi ln: nhai hoc ung 10 mg trc khi i ng. Tr em 6 thng 5 tui: 4 mg/ ngy, 6- 14 tui: 5 mg/ ngy Thn trng khi dng ngi mang thai v cho con b . Zafirlukast: ung mi ln 20 mg, ngy 2 ln. Khng dng cho tr em di 12 tui, suy gan, cho con b. Thn trng khi dng ngi cao tui, ngi mang thai, suy then. 3.4. S dng thuc trong iu tr hen 3.4.1. ng dng thuc Cc thuc iu tr hen c th dng bng cc ng khc nhau: + ng ht: thuc c a trc tip vo ng h hp nn t nng cao ti , liu ht thng thp hn liu ung, gim c tc dng khng mong mun ton thn . . Ht nh liu l phng php thun tin v c hiu qu khi s dng thuc iu tr hen mc nh v trung bnh. iu rt quan trng l phi hng dn ngi bnh tht cn thn v cch s dng ng dng c ht nh liu t kt qu ti u.

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. Bung ht (spacing devices) to ra mt khoang gia dng c ht v ming, dng tt hn ngi gi, tr em, nhng ngi kh s dng dng c ht nh liu ng cch, hoc dng khi ht corticoid liu cao gim lng ng thuc ming v hng, d gy nhim nm Candida. Dn ngi bnh phi sc ming sau khi ht thuc. . Dung dch kh dung thng dng trong cn hen nng cp tnh, dng cng vi oxygen trong bnh vin. - ng ung: khi khng th dng bng ng ht hoc ng ht km hiu qu. Dng ng ung gy nhiu tc dng khng mong mun ton thn hn ng ht. - ng tim: cc thuc cng 2, corticoid hoc aminophylin ch dng ng tim trong cp cu cn hen nng, cp tnh, khi ng kh dung khng hoc khng ph hp. 3.4.2. X tr hen - Ct cn hen: ht thuc cng 2 tc dng ngn (SABA) c hiu qu nht. - iu tr duy tr, kim sot di hn hen: phi hp corticoid ht v thuc cng 2 tc dng di (LABA) ht c hiu qu nht. Nu hen vn cha kim sot c, cn nhc phi hp thm vi ung mt trong cc thuc sau: theophylin gii phng chm, thuc cng 2 gii phng chm, thuc khng leucotrien hoc corticoid. Xem xt li iu tr sau mi 3 thng iu chnh ch iu tr cho ph hp. - Cn hen nng cp tnh: th oxy, kh dung dung dch SABA, corticoid (ung, tim tnh mch). - D phng cn co tht ph qun khi gng sc, do kh lnh hoc do tc nhn mi trng: ht cromolyn natri hoc SABA (ht, ung).
4.THUC IU TR BNH PHI T C NGHN MN TNH

Bnh phi tc nghn mn tnh l tnh trng bnh c trng bi ri lon thng kh tc nghn khng c kh nng phc hi hon ton. S hn ch thng kh thng tin trin t t v lin quan n phn ng vim bt thng ca phi do cc phn t hoc kh c hi. Cc yu t nguy c ca bnh phi tc nghn mn tnh: ht thuc l, khi bi do nhim mi trng, nhim khun ng h hp v yu t di truyn (thiu a1 antitrypsin). c im ca bnh phi tc nghn mn tnh l tnh trng vim nhim thng xuyn ton b ng dn kh v nhu m phi, dn n x ha ng th v ph hu ph nang. V vy, iu tr bnh phi tc nghn mn tnh, trc ht phi loi b cc yu t nguy c. Cc thuc iu tr bnh bao gm: 4.1. Thuc gin ph qun: iu tr triu chng ca bnh - Ht thuc cng b 2 tc dng ngn (salbutamol, terbutalin, fenoterol) hoc thuc khng cholinergic tc dng ngn (ipratropium) khi cn thit.

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- Nu bnh tin trin nng: phi hp thuc cng b 2, thuc khng cholinergic v/ hoc theophylin. - Tiotropium l thuc khng cholinergic tc dng ko di dng iu tr duy tr trong bnh phi tc nghn mn tnh, khng dng trong co tht ph qun cp. - Ht mi ngy mt ln 18 mg. Khng dng cho ngi di 18 tui. 4.2. Glucocorticoid: Phi hp LABA v GC dng ht iu tr bnh phi tc nghn mn tnh mc trung bnh v nng. Ngng phi hp nu khng thy ch li sau 4 tun. Nu bnh tin trin nng hn: dng thuc gin ph qun (dung dch kh dung) v th oxy, ung GC trong thi gian ngn. 4.3. Cc thuc khc - Tim vaccin cm mi nm mt ln, vaccin phng ph cu. - Dng khng sinh khi c nhim khun. - Thuc lm long m (acetyl cystein, carbocistein) trong t cp c ho khc m dnh qunh. - iu tr tng cng a1 antitrypsin. 5. THUC KCH THCH H HP Ngoi cafein l thuc tc dng u tin trn v no, cc thuc khc u c tc dng ch yu trn hnh no. Vi liu iu tr, trn ngi bnh thng khng c tc dng r rng. Vi liu cao, cc thuc u gy co git, lc u l co git cng, ri ngay sau chuyn sang co git rung. C ch ca tc dng co git cha c hon ton bit r, nhng ni chung l lm gim ngng kch thch ca thn kinh trung ng. Trn trung tm h hp, cc thuc u c tc dng kch thch, i lp vi tc dng ca barbiturat. 5.1. Cafein v cc alcaloid dn xut ca xanthin Ly l ch, ht c ph, ht cla, cacao, hoc c th tng hp t acid uric. C 3 cht c dng trong iu tr l cafein, theophylin v theobromin, trong cng thc u c nhn purin. 5.1.1. Tc dng - Trn v no, cafein c tc dng r rt lm mt cm gic mt nhc, bun ng, lm tng qu trnh hng phn, tng cng nhn cm ca cc gic quan, lm kin n nhanh, tr tu minh mn. Nu dng thuc lin tc v ko di th sau giai on hng phn thng tip theo giai on c ch, mt mi. - Trn h thng tim mch: theophylin tc dng mnh hn cafein. Kch thch trc tip trn c tim lm tim p nhanh, mnh, tng lu lng tim v lu lng mch vnh. Trn c th nguyn vn, do cn c tc dng kch thch trung tm dy thn kinh X nn c tc dng ngc li. V vy, tc dng ca cafein trn tim l phc tp, tu theo liu: liu nh lm tim p chm, liu cao lm tim p nhanh. Liu iu tr t lm thay i huyt p.

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- Trn h hp: kch thch trung tm h hp hnh no, lm gin ph qun v gin mch phi do tc dng trc tip trn c trn. Tc dng cng r khi trung tm h hp b c ch bi thuc m, thuc ng hay morphin. - Trn c quan: lm gin mch thn v li niu. Lm tng tit dch v c s, tng tnh acid ca dch v do trc tip kch thch nim mc d dy v kch thch qua trung tm ph giao cm. 5.1.2. C ch tc dng - Gii phng catecholamin - Huy ng calci v c ch s thu hi calci vo ti li ni bo. - c ch phosphodiesterase, lm vng bn v tng AMPc. Catecholamin cng lm tng AMPc nhng l do kch thch adenylcyclase, tng tng hp AMPv t ATP. V vy, gii thch c nhiu tc dng ging nhau gia catecholamin v cafein trn tim mch, ph qun, mt s chuyn ha nh tng ng huyt, tng hu lipid (xin xem trong bi Thuc tc dng trn h thn kinh thc vt). Catecholamin (+) Adenylcyclase ATP AMPv Xanthin (-) Phosphodiesterase AMP

Tng ng huyt 5.1.3. p dng iu tr

Tim mch

Tng hu lipid Qu trnh hng phn ca thn kinh trung ng b gim, hen, suy tim (khng dng trong trng hp vim c tim), phi hp vi thuc h st ( i khng vi tc dng c ch tim ca cc thuc ny). Liu lng: - ng tim cafein natri benzoat 0,07g/ mL, tim di da hoc tim bp 1- 2 ng/ ngy. - Theophylin mi ln ung 200 mg, ngy 2 ln. 5.2. Nikethamid L thuc tng hp, lm nhp th nhanh v su do kch thch qua phn x xoang cnh, nhng tc dng chnh l kch thch trc tip cc trung tm hnh no. Khng c tc dng trc tip trn tim v mch mu. Ch nh trong cc trng hp suy tim mch v h hp. Tim di da, bp tht hoc tnh mch chm, mi ln 1 ng 1mL (dung dch 25%), mi ngy 3 ng. Ung dung dch 25% mi ln X- XX git, ngy 2- 3 ln. 5.3. Bemegrid

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Cng thc ha hc gn ging barbiturat, nhng c tc dng i khng vi barbiturat. Bemegrid kch thch trc tip cc trung tm h hp v tun hon hnh no, lm tng nhp tim, tng huyt p, tng bin h hp. Liu cao cng gy cc cn co git, nhng phm vi an ton rng hn, d s dng hn, nn c xu hng c s dng trong iu tr mt s bnh tm thn bng cc cn co git. Ngoi tc dng trn thn kinh trung ng, bemegrid cn kch thch cc si thn kinh vn ng, lm d dng s vn chuyn xung tc thn kinh qua cc nron, nn cn c dng iu tr mt s chng vim dy thn kinh, au tht lng hng Liu lng: nhim c barbiturat c th tim hng gam vo tnh mch lm nhiu ln tu theo tnh trng nhim c. Tim bp 25- 50 mg iu tr vim dy thn kinh. 5.4. Doxapran hydroclorid - Ch nh: dng trong trng hp suy h hp cp, suy gim h hp sau m - Chng ch nh: tng huyt p nng, tnh trng hen, bnh mch vnh, nhim c do tuyn gip, ng kinh, tc nghn c hc ng h hp. - Tc dng khng mong mun: chng mt, tot m hi, tng huyt p v nhp tim. Tc dng khng mong mun trong giai on sau m bao gm: co cng c cc b, tng hot ng, ln ln, o gic, ho, kh th, co tht thanh qun, co tht ph qun, nhp nhanh xoang, nhp tim chm, ngoi tm thu, bun nn, nn, tit nc bt. - Liu dng: . Suy gim h hp sau m: tim tnh mch (t nht trong 30 giy) 1- 1,5 mg/ kg, nhc li nu cn thit sau 1 gi hoc truyn tnh mch 2- 3 mg/ pht. iu chnh liu theo p ng ca ngi bnh. . Suy h hp cp: truyn tnh mch 1,5- 4 mg/ pht, iu chnh theo p ng ca ngi bnh. Dng cng vi oxygen v phi theo di thng xuyn p sut kh trong mu v pH mu. Khng dng cho tr em.
CU HI T LNG GI

1. Phn bit c c ch tc dng ca hai nhm thuc lm long m. 2. Trnh by tc dng, tc dng khng mong mun v p dng iu tr ca Nacetylcystein v bromhexin. 3. Trnh by c ch tc dng ca cc nhm thuc cha ho. 4. Trnh by tc dng, tc dng khng mong mun v p dng iu tr ca cc thuc cha ho: codein, dextromethorphan. 5. Trnh by tc dng, tc dng khng mong mun v p dng iu tr ca thuc cng 2 adrenergic (salbutamol, salmeterol), ipratropium v theophylin.

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6. Trnh by tc dng, tc dng khng mong mun v p dng iu tr ca glucocorticoid trong iu tr hen. 7. Nu cch s dng thuc trong iu tr hen. 8. Trnh by nguyn tc iu tr bnh phi tc nghn mn tnh. 9. Trnh by c ch tc dng, tc dng v ch nh iu tr ca cafein, nikethamid, doxapram.

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Bi 29:

THUC IU TR THIU MU

MC TIU HC T P: Sau khi hc xong bi ny, sinh vin c kh nng:

1. Trnh by c vai tr sinh l, dc ng hc v ch nh ca st. 2. Phn tch c ngun gc, vai tr sinh l, ch nh ca vitamin B12, acid folic, erythropoitin, v nguyn tc iu tr thiu mu.

1. I CNG

1.1. nh ngha thiu mu Thiu mu l tnh trng gim s lng hng cu hoc huyt sc t hoc hematocrit di mc bnh thng so vi ngi cng tui, cng gii kho mnh. - i vi nam gii c coi l thiu mu khi: s lng hng cu di 4 triu hoc hemoglobin di 12 g/ 100 mL hoc hematocrit di 36%. - i vi n gii c coi l thiu mu khi: s lng hng cu di 3,5 triu hoc hemoglobin di 10 g/ 100 mL hoc hematocrit di 30%. 1.2. Nguyn nhn thiu mu Thiu mu do rt nhiu nguyn nhn c th : do chn thng, sau phu thut, do giun mc, tc, rong kinh, tr, lot d dy- t trng, do tan mu ngi c bt thng v hemoglobin, thiu G6PD, bnh t min, do thuc hoc ha cht, st rt hoc do tu xng km hot ng hoc khng hot ng hoc do thiu ht cc thnh phn tng hp hemoglobin, sn xut hng cu. Da vo ch s nhim sc v kch thc hng cu thiu mu c xp thnh 3 loi: . Thiu mu nhc sc: hng cu nh v ch s nhim sc < 1 . Thiu mu ng sc: hng cu bnh thng v ch s nhim sc = 1 . Thiu mu u sc: hng cu to v ch s nhim sc > 1
2. NGUYN T C IU TR THIU MU

Trong qu trnh iu tr thiu mu phi kt hp iu tr nguyn nhn vi dng thuc hoc vi iu tr triu chng v bi dng c th. - Trng hp mt mu cp vi khi lng ln: cn phi truyn mu ngay. Trong khi ch i mu phi truyn nc mui sinh l hoc Ringer lactat v tm nguyn nhn, v tr chy mu iu tr. - Mt mu mn tnh do giun tc, mc, rong kinh, tr, st rt dng cc thuc iu tr nguyn nhn kt hp vi b sung st v bi dng c th. - Thiu mu do gim sn xut hng cu: c th da vo th tch trung bnh hng cu dng cc thuc. Hng cu nh khi th tch trung bnh di 70 fl. Ngc li hng cu gi l to khi th tch trung bnh > 110 fl.

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. Trng hp thiu mu hng cu nh: dng st kt hp vi vitamin B6 v tng lng protid, lipid trong khu phn n v iu tr nguyn nhn. . Thiu mu hng cu to phi tm nguyn nhn iu tr kt hp dng B12 hoc acid folic. . Thiu mu do tan mu: dng cc phng php hn ch nguyn nhn gy tan mu kt hp vi dng acid folic.
3. CC THUC CHA THIU MU

3.1. St 3.1.1. Vai tr v nhu cu st ca c th C th ngi ln cha khong 3- 5 gam st, trong 1,5- 3 gam tn ti trong hng cu, phn cn li 0,5 gam cha trong sc t c (myoglobulin), mt s enzym xanthinoxidase, a- glycerophosphatoxidase. ngi bnh thng, nhu cu st hng ngy khong 0,5- 1 mg . Ph n giai on c kinh nguyt hoc c thai, cho con b nhu cu st cao hn khong 1- 2 mg v 5- 6 mg trong 24 gi. Khi thiu ht st, c th khng ch c thay i s to mu, m cn thay i chc nng ca nhiu enzym quan trng. Do vy, b sung st l bin php rt quan trng iu tr thiu mu nhc sc. 3.1.2. ng hc ca st trong c th Ngun cung cp st hng ngy cho c th ch yu t cc thc n c ngun gc ng vt v thc vt. Thc n cha lng st trn 5 mg trong 100 gam: gan, tim, trng, tht nc, gi u, hoa qu. * d dy: st t ngun thc n c th dng ion Fe2+ hoc Fe3+. Fe2+ c hp thu d dng qua nim mc d dy, rut; cn Fe3+ s kt hp vi albumin nim mc ng tiu ha, nn khng hp thu c, gy kch thch nim mc ng tiu ha. Mun hp thu c, Fe3+ phi c chuyn thnh Fe2+ nh tc dng ca acid hydrocloric d dy. * Ti rut: Fe2+ c gn vi mt albumin t bo nim mc rut l apoferritin to thnh ferritin i vo mu. Apoferritin l cht mang st, c nhim v a st vo mu xong quay tr li nim mc rut vn chuyn tip st. Khi c th thiu st th s lng apoferritin tng ln lm tng hp thu st v ngc li. Mt s cht nh vitamin C, protein c cha nhm- SH lm Fe3+ chuyn thnh Fe2+ d hp thu. Nhng c mt s cht cn tr hp thu nh: phosphat, acid nucleic, acid phytic, tanin, tetracyclin. * Trong mu: st tch ra t ferritin v c gn vi b - globulin, cht vn chuyn st c hiu to thnh transferritin. Dng phc hp st c chuyn n cc m nh tu xng, c mt phn dng d tr cn mt phn to ra hng cu v cc enzym (Hnh 28.1). * m: st i vo trong t bo c phi thng qua transferritin receptor mng t bo. Nh qu trnh nhp bo, phc hp transferritin receptor i vo trong t bo gii phng ra ion st. Sau khi gii phng st trong ni bo, transferritin quay li mng t bo lm nhim v vn chuyn st tip. Khi thiu ht st th s lng transferritin

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receptor tng v gim ferritin (gim d tr st) v ngc li, khi lng st trong c th tng cao th s lng transferritin receptor gim xung v tng dng d tr st ln (ferritin) v tng thi tr st qua phn, m hi v nc tiu.

Thc n: D dy Nim mc rut (t trng):

Fe2+ hoc HCl FeCl2

Fe3+

Fe2+ +

Apoferritin

Ferritin(Fe3+)

Thi theo phn Mu: Transferritin (Fe3+) b- globulin + Fe3+ St t hng cu B hu (Fe2+) Tu xng (to hng cu) M (to enzym, globin c) D tr: (gan, lch tu xng) Thi tr ( m hi, nc tiu, kinh nguyt)

Hnh 28.1. S vn chuyn st trong c th

3.1.3. S thiu ht st S thiu ht st c th do: - Cung cp khng y , gp nhng ngi c mc sng thp. - Mt cn bng gia cung v cu: ph n c thai, cho con b, tr em ang ln. - Gim s hp thu st ng tiu ha: gp nhng ngi ct mt phn d dy, vim rut, thiu apoferritin, dng mt s thuc hoc thc n cha mt s cht ngn cn s hp thu st. - Chy mu: ng tiu ha (giun tc, giun mc, tr), t cung cp hoc mn tnh (rong kinh)... 3.1.4. Ch nh

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- Thiu mu thiu st do cc nguyn nhn khc nhau. - Ph n c thai, cho con b, chng xanh lt ca ph n. 3.1.5. Ch phm v liu lng Trong iu tr st c th dng ring r hoc phi hp vi mt s ion hoc v cc vitamin. Trn lm sng st c th dng ng ung hoc tim tnh mch chm. Tim tnh mch khi bnh nhn khng dung np hoc ri lon hp thu st theo ng ung hoc ngi suy thn mn tnh km theo phi lc mu. Hin c 2 ch phm st dextran v st sucrose dng tim chm tnh mch hoc truyn tnh mch. Khi dng cn phi th vi liu thp trc phng phn ng phn v. Cc ch phm st thng dng ng ung trn lm sng u dng mui sulfat, clorid, fumarat, gluconat, aminoat v ascorbat. - Ngi ln liu trung bnh 2-3 mg/ kg cn nng tng ng 200 mg/ ngy. - Tr nh liu trung bnh 5 mg/ kg cn nng/ ngy. - Ph n c thai hoc cho con b liu trung bnh 4- 6 mg/ kg cn nng/ ngy. Trong qu trnh iu tr cn theo di lng hemoglobin. Khi hemoglobulin mu tr v gi tr bnh thng cn tip tc ung thuc trong 3-4 thng to s bo ho d tr st. 3.1.6. Tc dng khng mong mun - Khi dng ng ung: lm ging, bun nn, nn, to bn, a chy, kch ng ng tiu ha. - Khi dng ng tim: au ti ch tim, au u, bun nn, nn, st, shock kiu phn v khi tim tnh mch do vy khi dng cn phi tim tnh mch chm. 3.1.7. S qu liu lng Ng c st do qu liu t gp ngi ln, nhng hay gp tr em. tr em liu 1- 2 g c th gy t vong. Triu chng ng c c th xut hin sau khi ung nhm 30 pht n vi gi. - Khi gp ng c, ngoi bin php iu tr tch cc v iu tr triu chng, cc bin php loi tr cht c nh gy nn, ra rut bng dung dch natribicarbonat hoc phosphat cng c s dng. Khi st trong mu cao trn 3,5 mg/ L phi dng deferoxamin tim tnh mch hoc tim bp hoc c th dng deferipron ng ung. Hai thuc ny c tc dng to chelat vi ion st. 3.2. Vitamin B12 3.2.1. Ngun gc Vitamin B12 l tn chung ch 5 cobalamid: cyanocobalamin, hydroxycobalamin, methyl cobalamin v 5- deoxyadenosylcobalamin.Vitamin B12v cyanocobalamin c dng ch tt c cc cobalamid c hot tnh ngi. Nhng trn thc t ch c 2 cobalamid: cyanocobalamin v hydroxycobalamin c dng trong iu tr v cc cobalamid ny ng vai tr coenzym ca nhiu phn ng chuyn ha, c bit l s tng hp ADN. Hn th na, cc cobalamid ny n nh hn cc cobalamid khc.

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T bo c th khng t tng hp c vitamin B12. Ngun cung cp vitamin B12 nhiu nht l gan, tht, c, trng. Trong thc vt khng c vitamin B12. 3.2.2. Dc ng hc ca vitamin B12 Trong thc n vitamin B12 (yu t ngoi lai) c dch v v protease gii phng ra khi cc lin kt vi protein v c gn ngay vi glycoprotein d dy (yu t ni). Phc hp vitamin B12- yu t ni xung rut tc ng ln receptor c hiu trn nim mc hng trng v c chuyn vo mu. Trong mu vitamin B12 gn vo b - globulin c ngun gc gan gi l transcobalamin II. Phc hp vitamin B12- transcobalamin nhanh chng c phn phi vo cc m c bit l nhu m gan. Ngoi transcobalamin II, vitamin B12 cn c gn vo transcobalamin I v III. Phc hp transcobalamin I- B12 l dng d tr ca vitamin B12. Gan l c quan d tr 90% lng vitamin B12 ca c th (1- 10 mg). Vitamin B12 c thi tr qua phn, nc tiu. V c chu k gan rut, cho nn c trng hp sau ct d dy 3- 4 nm mi c biu hin thiu vitamin B12. 3.2.3. Vai tr ca vitamin B12 Vitamin B12 l cht cho methyl nn rt cn cho s chuyn ha acid folic tng hp acid nhn gip cho t bo nhn ln pht trin. - Chuyn homocystein thnh methionin v 5-methyltetrahydrofolic thnh acid tetrahydrofolic. - Chuyn L- methylmalonyl- CoA thnh succinyl - CoA trong chui cc phn ng chuyn ha glucid, lipid thng qua chu trnh Krebs. - Duy tr nng myelin bnh thng trong cc neuron ca h thng thn kinh. 3.2.4. Thiu ht vitamin B12 Nhu cu hng ngy ca vitamin B12 ph thuc vo tui, gii, tnh trng bnh l v nm trong khong t 0,3- 2,6 mg. Thiu vitamin B12 c th do: Cung cp khng y , gim hp thu do gim yu t ni, vim rut, ct hng trng, bnh ty tng gy thiu protease, t sinh khng th chng yu t ni, ri lon chu k gan rut hoc do gim s lng, cht lng transcobalamin II do di truyn. Khi thiu vitamin B12 gy nn thiu mu u sc hng cu to (thiu mu c tnh Biermer), tn thng neuron h thn kinh: ph n, mt myelin. C th gy cht neuron thn kinh tu sng, v no, gy ri lon cm gic, vn ng chi, ri lon tr nh, ri lon tm thn. ngi cao tui c th gp tn thng thn kinh do thiu vitamin B12 nhng khng c du hiu thiu mu. 3.2.5. Ch nh- chng ch nh - Thiu mu u sc hng cu to Biermer. - Vim au dy thn kinh, ri lon tm thn. - Suy nhc c th, chm pht trin, gi yu. - Nhim c, nhim khun. - Khng dng thuc cho ngi d ng vi thuc v ung th cc th khc nhau. 3.2.6. Ch phm v cch dng

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Vitamin B12 c th dng di dng n cht hoc kt hp vi cc vitamin v cc mui kim loi ung hoc tim bp hay tim di da. Hin nay c 2 ch phm c dng vi hm lng khc nhau l cyanocobalamin v hydroxycobalamin nhng hydroxycobalamin c s dng nhiu hn v tn ti trong c th lu hn cyanocobalamin. Ch nh dng dng thuc v liu lng da vo nguyn nhn v tn thng do thiu vitamin B12 gy ra. - Thiu ht vitamin B12 do yu t ni phi dng dng tim. - Trong iu tr thiu mu, suy nhc c th... ch cn dng liu trung bnh 100 mg/ ngy, nhng trong trng hp vim dy thn kinh, ri lon tr nh, ri lon tm thn phi dng dng tim liu 500, 1000, 5000 mg/ ngy. 3.3. Acid folic (vitamin L1, vitamin B9) L s kt hp ca pteridin, acid paraaminobenzoic v acid glutamic. Acid folic khng ch c nhiu trong tht, c, trng, gan, men bia m cn c trong rau xanh, hoa qu. Khi nu chn thc n, c bit l rau xanh 90% acid folic b phn hy. 3.3.1. Dc ng hc v vai tr ca acid folic Acid folic trong thc n tn ti di dng folatpolyglutamat. Dng ny cng l kho d tr folat trong cc t bo ngi. * ng tiu ha, folatpolyglutamat b thu phn to thnh folat monoglutamat v b kh to thnh methyltetrahydrofolat (MTHF). Nh hot tnh ca enzym pteroyl- gglutamyl- carboxypeptidase nim mc rut, MTHF c hp thu v i vo mu. * Trong mu, methyltetrahydrofolat c vn chuyn n m v thng qua nhp bo, MTHF vo trong t bo. * Trong t bo ca m, methyltetrahydrofolat ng vai tr cht cho methyl chuyn vitamin B12 thnh methylcobalamin. Methylcobalamin gip chuyn homocystein thnh methionin. Sau khi mt methyl, methyltetrahydrofolat s thnh tetrahydrofolat, tham gia vo mt s qu trnh chuyn ha quan trng nh: - Chuyn serin thnh glycin vi s tham gia ca vitamin B6. - Chuyn deoxyuridylat thnh thymidylat to ADN- thymin. Ngoi ra, tetrahydrofolat cn tham gia vo qu trnh chuyn ha histidin v tng hp base purin. * gan, methyltetrahydrofolat mt phn tham gia chuyn ha, phn khc c a vo mt thi xung t trng. t trng, MTHF c ti hp thu tr li. Ru lm gii phng MTHF t t bo gan vo mt lm gim nng folat trong mu (hnh 29.2)

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Hnh 29.2. Vai tr ca acid folic v vitamin B12 trong chuyn ha

3.3.2. S thiu ht acid folic - Hng ngy, ngi ln cn 25- 50 mg, ph n c thai, cho con b v tr em cn 100200 mg. Khi cung cp khng y hoc do mt cn bng gia cung v cu hoc do mt s bnh lm gim hp thu hoc do mt s thuc khng chuyn ha trong iu tr ung th, primaquin, trimethoprim, sulfonamid hoc do tan mu gy nn thiu ht acid folic. Khi thiu ht acid folic s gy nn thiu mu hng cu to khng km tn thng thn kinh 3.3.3. Ch nh - Thiu mu hng cu to khng c du hiu tn thng thn kinh. - Thiu mu tan mu. - Gim bch cu ht, mt bch cu ht. - D phng thiu ht acid folic khi dng mt s thuc, ph n c thai, cho con b. 3.3.4. Ch phm v liu lng Acid folic c bo ch di dng ung hoc tim bp hoc tnh mch c dng n cht hoc phi hp vi cc vitamin khc v cc mui kim loi. Liu trung bnh t 2- 5 - 15 mg/ 24 gi.

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3.4. Cc thuc chng thiu mu khc Ngoi st, acid folic v vitamin B12, vitamin B2 , vitamin B6, ng v Cobalt cng c tc dng chng thiu mu. 3.5. Erythropoietin L yu t iu ha s nhn ln ca t bo gc trong tu xng, kch thch s trng thnh ca hng cu non v gii phng hng cu khi tu xng i vo tun hon. Yu t ny c cu trc protein gm 165 acid amin, phn t lng 30400, c sn xut ch yu t bo cnh cu thn, th yu t bo gan. Trong mu ngi khng thiu mu c nng erythropoietin di 20 UI/L v c gn vo glucose khng c tc dng dc l. Khi c th thiu mu, thiu oxy s tng hp v bi tit ca yu t ny tng ln gp 100 ln so vi bnh thng. Khi cu thn b vim cp hoc mn tnh hay tn thng tu xng hoc thiu st, s bi tit erythropoietin gim xung r rt, gy nn thiu mu. Chnh v l do , erythropoietin c ch nh ch yu trong cc trng hp thiu mu do vim thn. Ngoi ra, erythropoietin cn c dng trong thiu mu do bnh AIDS, iu tr thuc chng ung th, thiu mu do mt mu sau phu thut v phng thiu mu tr non trng lng thp. - Ch phm v liu dng: + Epoetin alpha (Epogen; Eprex) ng tim cha 2000, 3000, 4000, 5000,6000,8000, 10000 v l cha 40000 n v, l erythropoietin ngi ti t hp nh k thut ti t hp ADN. Tim tnh mch hoc di da 50- 100 n v/ kg th trng,3 ln trong mt tun. ngi c suy thn mn tnh thuc c t/2 t 4-12 gi. + Epoetin beta ( NeoRecormon ) ng tim cha 500,1000, 2000, 4000 5000, 6000, 10000 v l cha 50000,100000 n v. Thuc c th tim di da hoc tim tnh mch liu khi u 40-60 n v /tun trong 4 tun lin, sau tu theo p ng ca c th m iu chnh liu ph hp. Khi dng thuc iu tr, nn cung cp thm st nhm gip tu xng sinh sn nhanh hng cu. Do thuc c th gy tng th tch mu v hematocrit v tng sc cn ngoi vi, nn phi chnh liu cho ph hp vi bnh nhn b bnh thn c cao huyt p.
CU HI T LNG GI

1. Trnh by vai tr sinh l, c im dc ng hc v ch nh ca st. 2. Trnh by ngun gc, vai tr sinh l, v ch nh ca vitamin B12. 3. Trnh by ngun gc, vai tr sinh l v ch nh ca acid folic. 4. Trnh by ngun gc vai tr , ch nh ca erythropoietin v nguyn tc iu tr thiu mu.

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Bi 30:

THUC TC DNG TRN QU TRNH NG MU V TIU FIBRIN

MC TIU HC T P: Sau khi hc xong bi ny, sinh vin c kh nng:

1. Trnh by c c ch tc dng v p dng iu tr ca vitamin K. 2. So snh c c ch tc dng, ng hc v p dng iu tr ca dn xut coumarin v heparin. 3. Phn tch c c ch tc dng v p dng iu tr ca thuc lm tiu fibrin v chng tiu fibrin.
1. THUC TC DNG LN QU TRNH NG MU

1.1. C ch ng mu ng mu l mt qu trnh mu chuyn t th lng thnh th c do chuyn fibrinogen thnh fibrin khng ha tan v cc si fibrin ny b trng hp to thnh mng li giam gi cc thnh phn ca mu lm mu ng li. Bnh thng, trong mu v trong cc m c cc cht gy ng v cht chng ng, nhng cc cht gy ng dng tin cht, khng c hot tnh. Khi mch mu b tn thng s hot ha cc yu t ng mu theo kiu dy truyn lm cho mu ng li. Qu trnh ng mu xy ra qua 3 giai on : - Giai on to thnh phc hp prothrombinase (1) - Giai on to thnh thrombin (2) - Giai on to thnh fibrin (3) Promthrombinase (1) Prothrombin Thrombin (2) Fibrinogen 1.1.1.Giai on to thnh phc hp prothrombinase L qu trnh phc tp v ko di nht thng qua hai c ch ni sinh v ngoi sinh to ra phc hp prothrombinase. * C ch ngoi sinh: Khi mch mu tn thng, mu tip xc vi v tr tn thng. M v tr tn thng gii phng ra yu t III (thromboplastin m) v phospholipid. Yu t III, IV (calci) cng yu t VII, v phosphlipid m hot ha yu t X. Yu t X hot ha cng vi yu V, phospholipid m v ion calci to thnh phc hp prothrombinase. Fibrin (3) v cc mu ng

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* C ch ni sinh : ng thi khi mu tip xc vi v tr tn thng s lm hot ha yu t XII v tiu cu lm gii phng phospho lipid. Yu t XII hot ha yu t XI v yu t XI hot ha yu t IX. Yu t IX cng vi yu t VIII hot ha, phospho lipid tiu cu v Ca+2 hot ha yu t X. Yu t X, yu t V, cng vi phospho lipid tiu cu v Ca+2 to nn phc hp prothrombinase. 1.1.2. Giai on to thnh thrombin Prothrombinase to ra theo c ch ngoi sinh v ni sinh cng vi ion calci xc tc cho phn ng chuyn prothrombin thnh thrombin 1.1.3. Giai on to thnh fibrin v cc mu ng Di tc dng ca thrombin, fibrinogen dng ha tan chuyn thnh fibrin khng ha tan. Cc si fibrin ni li vi nhau v di tc dng ca yu t XIII hot ha to ra mng li fibrin bn vng giam gi cc thnh phn ca mu lm mu ng li. 1.2. Thuc lm ng mu 1.2.1. Thuc lm ng mu ton thn 1.2.1.1. VitaminK (K: Koagulation - ng mu) + C 3 ngun cung cp vitamin K : - Vitamin K1 (phytonadion, phulloquinon) c ngun gc thc vt. - Vitamin K2 (menaquinon) do vi khun gram m ng rut tng hp. - Vitamin K3 (menadion) c ngun gc tng hp. + Vitamin K tan trong lipid, nhng ring vitamin K3 dng mui natribisulfit hoc mui tetra natri tan trong nc vo c th b chuyn ha thnh vitamin K3. * Vai tr sinh l : + Vitamin K gip cho gan tng hp cc yu t ng mu nh prothrombin (II), VII, IX v X. - C ch : Bnh thng, cc yu t II, VII, IX v X dng tin cht. Khi c mt vitamin K vi vai tr cofactor cn thit cho enzym microsom gan xc tc chuyn cc tin cht thnh cc cht c hot tnh bi s chuyn acid glutamic gn acid amin cui cng ca cc tin cht thnh g - carboxyglutamyl. Cht ny cng c mt trong protein c bi tit t ct bo v c vai tr trong s to xng. * Du hiu ca s thiu ht : Nhu cu hng ngy khong 1mg/kg. Khi thiu ht s xut hin bm mu di da, chy mu ng tiu ha, rng ming, i ra mu, chy mu trong s. * Dc ng hc : Vitamin K tan trong du, khi hp thu cn c mt ca acid mt. Loi tan trong du thng qua h bch huyt vo mu, cn dng tan trong nc hp thu i trc tip vo mu.Vitamin K1 c hp thu nh vn chuyn tch cc cn K2, K3 c hp thu nh khuych tn th ng.

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Sau hp thu vitamin K1 tp trung nhiu gan v b chuyn ha nhanh thnh cht c cc thi ra ngoi theo phn v nc tiu. * c tnh : Mc d c phm vi iu tr rng, nhng c th gp thiu mu tan mu v cht do vng da tan mu tr di 30 thng tui dng vitamin K3. Vitamin K3 cn gy kch ng da, ng h hp, gy i albumin, gy nn v c th gy tan mu ngi thiu G6PD. * Ch nh v liu dng : Vitamin K c th ung hoc tim bp, di da hoc tim tnh mch (dng tan trong nc) vi liu 100 - 200mg/ngy cho nhng bnh nhn : - Thiu vitamin K do nguyn nhn khc nhau. - Chun b phu thut ( phng chy mu trong v sau phu thut ). Nhng trng hp ny phi dng thuc trc 2 -3 ngy. - Gim prothrombin mu - Ng c dn xut coumarin. 1.2.1.2. Calci clorid: Ca+2 cn hot ha cc yu t VIII, IX v X chuyn prothrombin sang thrombin . Liu trung bnh: ung 2- 4g mi ngy, dng cch qung tng thi k 3- 4 ngy, ri ngh. Tim tnh mch cho nhng trng hp chy mu: 20ml dung dch 5%. Thuc tim ra ngoi tnh mch s gy lot. Tuyt i cm tim bp tht. 1.2.1.3. Coagulen L tinh cht mu ton phn, c bit c tinh cht ca tiu cu. Dng trong ngoi khoa ngi bnh a chy mu v trong nhng trng thi chy mu (ban chy mu, i ngoi ra mu v.v...). Ung 1-5 ng mi ngy (ng 20ml). Hemocoagulen: ng tim 5ml. Trng hp nng, c th tim ti 4 ng mi ngy. 1.2.1.4. Carbazochrom (Adrenoxyl): Lm tng sc khng mao mch, gim tnh thm thnh mch, nn lm gim thi gian chy mu. Tc dng sau khi tim 6-24 gi (tim bp 1,5 - 4,5 mg mi ngy hoc ung 10-30 mg mi ngy). Cha chy mu do gin mao mch hoc phng chy mu sau phu thut to hnh, tai mi hng, ct b tuyn tin lit. 1.2.1.5. Ethamsylat v dobesilat calci: Lm tng sc khng mao mch, gim tnh thm thnh mch. Dng phng chy mu cp trong phu thut to hnh, tai mi hng, ct b tuyn tin lit, rong kinh. Mi ngy tim bp 250-500mg hoc ung 750-1500mg. 1.2.1.6. Vitamin P (flavonoid, rutosid rutin v dn xut):

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Rutosid v dn xut ngun gc thc vt c hot tnh vitamin P u gim tnh thm thnh mch v lm tng sc khng mao mch do c ch s t oxy ha ca adrenalin, v c ch COMT gan, do ko di tc dng ca hormon ny.. Hot tnh vitamin P biu hin r trn s tng hp mucopolysacharid v glycoprotein ca m lin kt. Ung 20-40mg mi ngy, cha gin mao mch v tng tnh n hi mch mu, c tc dng sau khi ung 6 gi. 1.2.2. Thuc lm ng mu ti ch 1.2.2.1. Enzym lm ng mu * Thrombokinase (prothrombinase): l tinh cht ca ph tng ngi v ng vt, thng ly no v phi. Tinh cht ny cha thrombokinase v c nhng yu t ng mu khc. Tc dng khng chc chn bng thrombin. Dng khi chy mu t, ti ch, thng xuyn (chy mu cam, rng ming) v c trong trng hp chy mu nhiu (phi hp vi bng cht). * Thrombin: Chuyn fibrinogen thnh fibrin n phn, ri thnh fibrin polymer khng tan trong huyt tng. Ch dng ti ch, tuyt i khng tim tnh mch (v mu ang chy s gy ng mu nguy him). Ung cha chy mu d dy. 1.2.2.2. Nhng loi khc - Cc keo cao phn t gip tng nhanh ng mu : Pectin, albumin v.v... - Gelatin, fibrin dng xp tng din tip xc, qua hy tiu cu nhiu hn, mu ng nhanh hn. - Mui kim loi nng: Lm bin cht albumin, lm kt ta fibrinogen v cc protein khc ca mu. Hay dng dung dch FeCl3 10% bi ti ch hoc tm bng FeCl3 p ln vt thng. - Thuc lm sn: Lm co mao mch nh, nn chng ng. Thng dng tanin, mui Al, Pb, Zn hoc KMnO4 pha long. 1.3. Thuc chng ng mu 1.3.1. Thuc dng phng th nghim v ngoi c th - gim v tiu cu, ng nghim phi trng parafin, colodion, phim silicon. ng nghim bng pyrex lm mu ng chm hn l khi dng loi bnh thng. - Dng natri oxalat, natri fluorid ngn tc ng ca Ca+2. - Natri citrat to phc hp vi Ca+2; kt hp vi fibrinogen v cc yu t II, VII, IX, X nn lm chm ng mu. Mu d tr truyn cho ngi bnh thng c natri citrat (3-4,0 gam/0,5l mu), vo c th, nng b pha long, khng c tai bin chy mu in vivo. Nu truyn nhiu, cn ch n c tnh ca natri citrat. - Cht cng cua (chelating agents) nh dinatri tetracemat (mui natri ca acid etylen diamin tetracetic, EDTA, Complexon III, Sequestren) c tc dng gp Ca+2. 1.3.2. Thuc dng lm sng Trong thc t hay dng ba loi :

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- c ch s tng hp ca cc yu t ng mu gan (yu t II, VII, IX, X): Loi ny ch tc dng in vivo: dn xut coumarin v indandion. - c ch tc dng ca cc yu t ng mu : Loi ny tc dng c in vivo v in vitro: heparin. - Chng kt dnh tiu cu: aspirin, dipyridamol, ticlopidin, clopidogel. 1.3.2.1. Thuc chng ng ng ung : Dn xut ca coumarin v indandion: L thuc tng hp, c bng B. - Dn xut 4-hydroxycoumarin c: warfarin, phenprocoumon, acenocoumarol, dicoumarol, coumetarol, tromexan. - Dn xut indadion c : phenylindadion, clophenindion. * C ch tc dng : Do dn xut coumarin v indandion c cu trc gn ging vitamin K, nn c ch cnh tranh enzym epoxid-reductase lm cn tr s kh vitamin K-epoxid thnh vitamin K cn thit cho s carboxyl ha cc tin yu t ng mu di s xc ca carboxylase thnh cc yu t ng mu II, VII, IX v X.V th cc thuc nhm ny cn c gi l thuc khng vitamin K. * Dc ng hc : Hp thu nhanh qua ng tiu ha, nhng xut hin tc dng sau khi ung 24-36 gi. Cc thuc gn vo protein t l rt cao, tromexan 90%, warfarin 97%, phenprocoumon 99%. Nhiu dn xut ca coumarin chuyn ha qua h enzym oxy ha microsom gan nh : dicoumarol, warfarin, tromexan... Cht chuyn ha thi tr qua nc tiu v mt - nhiu thuc c chu k gan rut. Thuc c th i qua rau thai, qua sa. Nng thuc trong rau thai v tr em b m cao c th gy xut huyt cho thai nhi v tr b m. Nu ung thuc vo 3 thng u thai k c th gy cho tr s sinh mt s d thng mi, mt, xng. * c tnh : - Dng liu cao, ko di gy ri lon thm phn mao mch, xut huyt, rt nguy him bnh nhn lot d dy t trng, chn thng, cao huyt p. - D ng, rng tc, vim gan, thn, tng bch cu a acid, nhng li gim hoc mt bch cu ht. - Nc tiu mu da cam. * Khi phi hp dn xut coumarin v indandion vi mt s thuc c th xy ra tng tc dn n thay i dc ng hc hoc tc dng . - Thuc lm thay i dc ng hc ca coumarin v indandion : + Gim hp thu coumarin qua ng tiu ha: Thuc lm tng pH d dy, thuc nhun trng, thuc khng cholinergic, du parafin, than hot, cholestyramin (to phc vi couramin). + Thuc y coumarin ra khi protein- huyt tng :

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Clofibrat, phenylbutazon, sulfamid, tolbutamid, salicylat, acid ethacrynic + Thuc c ch chuyn ha coumarin microsom gan: Allopurinol, chloramphenicol, cimetidin, diazepam, metronidazol, phenylbutazon, sulfinpyrazon, thuc chng trm cm loi ba vng. + Thuc cm ng enzym microsom gan lm tng chuyn ha coumarin: barbiturat, rifampicin * p dng iu tr : - Ch nh : + Phng hoc cha bnh tc nghn mch nh: vim tnh mch, tc mch phi, nhi mu c tim. + Dit chut : warfarin. - Chng ch nh: Ph n c thai, cho con b; cao huyt p, vim ty cp; lot d dy t trng tin trin; tai bin mch mu no v tng chy mu. - Liu lng - cch dng : + Tc dng chng ng ph thuc vo tng c th. + Trong qu trnh iu tr bng dn xut coumarin hoc indandion phi gim liu dn v cn theo di thi gian Quick, thi gian Howell chnh liu nhm duy tr t l prothrombin khong 20% so vi bnh thng. Sau khi dng 36-48 gi lm xt nghi m nh gi tc dng, chn liu duy tr ph hp. Giai on iu tr duy tr c sau 2 tun cho xt nghim 1 ln. + Tc dng chng ng ca thuc l gin tip, lin quan n s tng hp cc yu t ng mu gan nn xut hin tc dng chm v ch tc dng trong c th, khng c tc dng trong ng nghim. Mun t hiu qu chng ng cn phi c thi gian. + Cn theo di nhng triu chng chy mu nh chng t qu liu : Chy mu cam, chy mu li, chy mu tr, nc tiu c vt mu, t mu da v.v... + Khi qu liu hoc ng c dn xut coumarin hoc indandion dng vitamin K iu tr. + Da vo thi gian xut hin tc dng, cng tc dng cc thuc chn thi gian dng thuc ph hp. Hin nay c 3 nhm chnh : Liu duy tr cc thuc i khng vitamin K c tp hp trong bng 30.1. Bng 30.1: Liu duy tr ca cc dn xut coumarin v indandion Tn thuc Acenocumarol Dicumarol Phenindion Ethylbiscoumacetat Warfarin 1.3.2.2. Heparin Bit dc Sintrom, Pindione Tromexan Coumadin Thi gian bn thi (gi) 24 24-96 5-10 1-2 36 Liu duy tr (mg/ngy) 1-8 50-100 50-150 450 - 600 3-9

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Thuc c bng B, va c tc dng trong c th v ngoi c th. * Ngun gc: Heparin lc u tm thy nm 1916 bi McLean v c nhiu gan nn t tn heparin. Ngoi gan ra, heparin cn c tm thy thn, phi, hch bch huyt, nim mc rut. Hin nay heparin c chit xut t nim mc rut ln hoc phi tru, b hoc bn tng hp. * Cu trc : Heparin khng phi n cht. L mt anion mucopolysacharid hoc glycosaminoglycan. Trong cu trc c nhm sulfat v carboxylic. Nhm sulfat cn thit cho s gn antithrombin vi thrombin. T l lu hunh trong phn t heparin chim 13,6%. * Tnh cht : + L acid ni sinh mnh nht, c ion ha mnh, rt tan trong nc v tch in m pH sinh l. + Vng bn pH trn 6,5. un si trong 20 pht nhit 120oC vn cn tc dng. Nhng ung b phn hy ng tiu ha mt hot tnh. + Trng lng phn t khc nhau dao ng t 2-20 kDa nhng tc dng sinh hc ging nhau. Khi heparin c trng lng phn t t 2-7 kDa gi l heparin trng lng phn t thp. * Tc dng : - Chng ng mu. - Chng ng vn tiu cu do kch thch tng hp v bi tit yu t hot ho plasmin t chc (t-PA). - H lipoprotein mu c bit l triglycerid do gii phng lipase gip thu phn triglycerid thnh acid bo v glycerol. Tc dng ny xut hin nhng liu thp hn liu c tc dng chng ng mu. C hin tng tng lipoprotein hi ng (rebound) khi ngng heparin. - Tng tc dng ca cc yu t pht trin nguyn bo si c tnh acid hoc base (aFGF v bFGF) lm tng s phn bo t bo ni m mao mch, t bo c trn, t bo trung m gy ra s tn to mch. * C ch chng ng mu : - Bnh thng antithrombin III trong huyt tng phn ng chm chp vi thrombin v cc yu t ng mu IX, X, XI, XII hot ha lm mt tc dng ca cc yu t ny. Khi c mt heparin, heparin to phc vi antithrombin III. Phc hp heparinantithrombin III thc y nhanh phn ng gia antithrombin v thrombin; antithrombin vi cc yu t IX, X, XI v XII. Hu qu cc yu t chng ng t hot ha mt hiu lc nhanh, mt kh nng chuyn fibrinogen thnh fibrin. - Nh tch in m do c cha cc gc sulfat nn heparin lm bin dng thrombin v prothrombin lm chng d dng to phc vi antithrombin. * Dc ng hc

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Ung khng hp thu v b phn hu ng tiu ha. Do vy, phi tim di da, tim tnh mch, khng tim bp. Heparin b heparinase ph hu v thi tr nhanh. Sau khi tim 1 gi, 30-50% c thi qua nc tiu. Khng i qua rau thai. Thi gian bn thi ph thuc vo liu lng. Liu cao v ngi suy gan, thn th thi gian bn thi ca thuc di. * Tc dng khng mong mun. - Chy mu, gim tiu cu, triu chng ny thng xut hin sau khi tim heparin 7-14 ngy v hi phc sau khi ngng thuc. - D ng, nhc u, nn, gy nt au, hoi t gn nu tim di da di ngy. Dng ko di vi liu trn 15000 n v/ngy gy long xng. - Tng AST, ALT. * p dng iu tr : - Ch nh: phng, chng huyt khi. Tc dng tng khi dng kt hp vi cc thuc chng ng vn tiu cu nh: aspirin, cc thuc chng vim phi steroid khc, dipyridamol, ticlopidin v.v...v s mt tc dng khi trn ln vi gentamicin, colistin, cefaloridin do b kt ta. - Chng ch nh: + Tng a chy mu; lot d dy- t trng tin trin; vt thng. + Gim chc nng gan, thn; c th suy nhc, vim ni tm mc, nhim trng, lao tin trin. - Ch phm v liu dng : + L 5000 - 25000 n v/ml Mt n v heparin l lng heparin ngn cn c s ng c 1ml huyt tng c lm mt calci bi citrat. + Liu dng tu thuc vo tng bnh nhn. Thng thng truyn tnh mch 6000 n v/trong 6 gi vi tc 1000 n v/gi. Hoc truyn tnh mch khi u 5000 - 10000 n v, sau cch 4-6 gi truyn 5000 - 10000 n v. Liu tip theo ph thu c vo thi gian ng mu v thi gian Howell. - Khi qu liu phi ngng haparin ngay v tim tnh mch chm protamin sulfat trung ha vi tc 50 n v/pht. Protamin sulfat l protein kim trng lng phn t thp, thi tr nhanh hn heparin nhng c kh nng phn ly phc hp antithrombin III-heaprin v kt hp vi heparin lm mt tc dng chng ng. Mt mg protamin sulfat trung ha c 100 n v heparin. * Hin c heparin trng lng phn t thp, nhng c tc dng sinh hc ch nh, chng ch nh v tai bin gn ging heparin ngun gc t nhin. Tuy nhin, c tc dng i khng yu t X hot ha mnh v thi gian tc dng di hn heparin thng thng. Do vy, ch cn tim di da mt ln/ngy. Mt s heparin trng lng phn t thp ang c s dng tm tt trong bng 30.2.

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Bng 30.2: Ch ph m v liu lng mt s heparin trng lng phn t thp Tn gc Certoparin Dalteparin Enoxaparin Reviparin Tinzaparin Bit dc Alphaparin Fragmin Clexan Clivarin Innohep Hm lng 3000 n v/0,3ml 12500, 25000n v /ml 100mg/ml 1432 n v/ 0,25ml 10000 n v /ml Liu dng/ngy 3000 n v 2500 n v 20 mg(2000 n v) 1432 n v 3500 n v

1.3.2.3. Heparinoid tng hp: L polysacharid b ester ha bi acid sulfuric, c cng thc ha hc gn ging heparin, c ch tc dng ging heparin nhng tc dng chng ng yu hn. - Partiol tc dng km heparin 7 ln. - Trebuton tc dng yu hn heparin 3-4 ln. 1.3.2.4. Hirudin L a peptid c 65 acid amin, trng lng phn t 7000- 9000 c cha trong tuyn n bo trong thc qun ca a, vt, c tc dng chng ng mu do ngn cn tc dng ca thrombin thng qua s to phc vi thrombin lm cho fibrinogen khng chuyn thnh fibrin. Thrombin (-) Hirudin Fibrinogen Fibrin

Dng Hirudin trong chn on xc nh hot tnh ca cc yu t ng mu nh thrombin (Hirudin-toleranz-test; Hirudin test). Hin cha c dng iu tr v s lng tch chit cn hn ch. Trong tng lai nh k thut gen c th sn xut c hirudin s dng trong iu tr, chng huyt khi. 1.4. Thuc chng kt dnh tiu cu Tiu cu l nhng t bo khng nhn, hnh a, tch in m mnh. Trn b mt mng tiu cu c cha cc yu t ng mu I, V, VII. C cc fibrinogen receptor (Gp IIb/IIIa) v c tnh kt dnh v kt t nn khi thnh mch b tn thng cc tiu cu dnh vo ni b tn thng v dnh vo nhau thnh tng lp to ra nt trng tiu cu cn gi l inh cm mu Hayem. Trong qu trnh kt dnh, tiu cu cn gii phng ra phospholipid gip thc y qu trnh to ra phc hp prothrombinase. S kt dnh tiu cu l yu t to ra mng x va ng mnh v gy nn tc mch. Hin c mt s thuc chng kt dnh tiu cu c s dng trong lm sng phng v iu tr huyt khi nh: thuc chng vim phi steroid (aspirin), dipyridamol, ticlopidin, clopidogrel v thuc c ch glycoprotein IIb/IIIa. 1.4.1. Aspirin (acid acetylsalicylic)

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Ngoi tc dng h st, gim au, chng vim, aspirin cn c tc dng chng ng vn tiu cu. - C ch : xin xem bi Thuc h st, gim au, chng vim. - Dng liu thp duy nht 10mg/kg cn nng, cch qung 48 gi, aspirin c ch 90% cyclooxygenase ca tiu cu, rt t nh hng n cyclooxygenase ca ni m mao mch nn nh hng khng ng k s tng hp ca prostacyclin I2. Do vy, tc dng chng kt dnh tiu cu v ko di thi gian chy mu liu ny l ti a. Dng liu cao aspirin khng ch c ch COX tiu cu m cn c ch COX ni m mao mch nn hiu qu chng kt dnh tiu cu khng cao. - Ngoi c ch COX tiu cu, aspirin cn lm n nh mng tiu cu, hn ch s gii phng ADP v phospholipid nn gim s kt dnh tiu cu v tng thi gian chy mu. - Ch nh: dng aspirin trong phng v iu tr huyt khi ng- tnh mch vi liu duy tr 75 mg/ngy.. - Chng ch nh v tc dng khng mong mun (xin xem bi thuc h st, gim au v chng vim). - Ht sc thn trng khi phi hp aspirin vi thuc chng kt dnh tiu cu khc v thuc chng ng mu nh heparin, dn xut coumarin. 1.4.2. Dipyridamol (Persantone, Peridamol) Va c tc dng gin mch vnh, va c tc dng chng ng vn tiu cu do : + c ch s nhp adenosin vo tiu cu v c ch adenosin desaminase lm tng adenosin trong mu. Adenosin tc ng ln A2-receptor lm gim s ng vn tiu cu. + c ch phosphodiesterase lm tng AMPv trong tiu cu. - Ch nh: thuc c phi hp vi warfarin trong phng huyt khi bnh nhn thay van tim nhn to. 1.4.3. Ticlopidin (Ticlid) - Do ticlopidin tng tc vi glycoprtein IIb/IIIa receptor ca fibrinogen lm c ch s gn fibrinogen vo tiu cu hot ha, ngn cn s kt dnh tiu cu. Ngoi ra, thuc cn lm tng prostaglandin D2 v E2 gp phn chng ng vn tiu cu v tng thi gian chy mu. - Thuc c dng phng huyt khi bnh nhn b bnh tn thng mch no hoc mch vnh vi liu 500mg/ngy. Khng dng thuc cho tr em. Khi dng c th gp mt s tc dng khng mong mun: chy mu, bun nn, a chy, gim bch cu trung tnh. 1.4.4. Clopidogrel (Plavix) - Thuc c tc dng chng ng vn tiu cu do: + c ch chn lc th th ADP ca tiu cu. + Ngn cn s hot ha glycoprotein IIb/IIIa ca fibrinogen trn tiu cu, lm gim s gn fibrinogen vo tiu cu.

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- Ung liu duy nht 75mg/ngy phng ng vn tiu cu. 1.4.5. Cc cht c ch glycoprotein IIb/IIIa receptor: Glycoprotein IIb/IIIa c vai tr lm tng s gn ca fibrinogen vo receptor trn tiu cu. Mt s thuc gn vo glycoprotein IIb/IIIa receptor ngn cn s gn ca fibrinogen vo tiu cu c tc dng chng ng vn tiu cu. + Abcimab (Reopro): l mt khng th n dng, khi u tim chm tnh mch 250 mcg/kg, sau truyn tnh mch 125 nanogam/kg/pht (ti a 10mcg/pht). + Eptifibatid (Integrilin): l peptid tng hp, khi u tim tnh mch 180 mcg/kg, sau truyn tnh mch 2 mcg/kg/pht lin tc trong 72-96 gi. + Tirofiban (Aggrastat): khi u tim chm tnh mch 400 nanogam/kg/pht trong 30 pht, sau truyn tnh mch 100 mcg/kg/pht trong t nht 48 gi.
2. THUC TIU FIBRIN

Cc mu ng c th tan tr li nh qu trnh tiu fibrin. l qu trnh ngc vi ng mu. Bnh thng, enzym plasmin xc tc cho s tiu fibrin trong mu th khng hot tnh gi l plasminogen. Trong iu kin nht nh, cc cht hot ha (kinase, activator) c gii phng ra khi t chc, hot ha plasminogen to thnh plasmin. Plasmin va to thnh gip fibrin tr thnh cht phn hu tan c. 2.1. Urokinase ( Abbokinase) L endopeptidase, gm 2 chui a peptid cha 411 acid amin, trng lng phn t 53000, c phn lp t nc tiu ngi (URO = urine = nc tiu) hoc t nui cy t bo phi thn ngi. Urokinase xc tc cho phn ng ct lin kt peptid ca plasminogen (plasminogen c 791 acid amin) to thnh lys-plasminogen v chuyn thnh plasmin. Lysin cui cng ca plasmin l v tr gn c i lc cao vi fibrin gip cho s thu phn fibrin. UK b chuyn ha gan v c thi gian bn thi 15-20 pht. Thuc ch c tim tnh mch, khi u 1.000 - 4.500 n v/kg th trng, sau duy tr 4.400 n v/gi. Thuc hu nh khng c tnh khng nguyn, khng b trung ha bi khng th, nhng c th gy st. 2.2. Streptokinase ( SK, Streptase) Gm mt chui apeptid, phn t lng 48000, c phn lp t lin cu tan mu nhm A. Streptokinase kt hp vi plasminogen theo t l ng phn t (equimolar) to thnh phc hp SK-plasminogen. Phc hp ny ct lin kt arginin-valin v tr 560 ca plasminogen chuyn thnh SK-plasmin c hot tnh tiu fibrin. Ngoi tiu fibrin, streptokinase cn xc tc cho phn ng thu phn nucleoprotein thnh cc base purin t do v pyrimidin nucleotid, do vy lm long cc dch ng c nh m. Sau khi tim tnh mch vi liu thp thi gian bn thi khong 18 pht, nhng khi tim liu cao hoc liu thp ko di th thi gian bn thi t 83 pht v ht hin tng kt hp khng th khng streptokinase do bo ha. Thuc b chuyn ha v thi tr qua thn.

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- Trong qu trnh dng thuc c th gp mt s tc dng khng mong mun: chy mu, d ng hay gp vo ngy th 8, nn sau khi dng thuc 8 ngy, cn phi chuyn sang dng thuc khc. - Liu dng : + Khi u tim tnh mch 500.000 n v trong 30 pht, sau mi gi tim 100.000 - 150.000 n v v dng trong 24 - 48 gi lin. Trong nhi mu c tim c th truyn tnh mch1500000 n v trong 60 pht. + C th ha tan 20.000 - 100.000 n v vo 5-20ml nc mui sinh l tim thng vo ti m sau 6 - 24 gi ht ra. 2.3. Anitreplase (Aminase) L phc hp ca plasminogen ngi tinh khit v streptokinase ca vi khun c acetyl ho bo v v tr hot ng ca enzym. Khi s dng, nhm acetyl c thu phn, gii phng phc hp streptokinase- cht tin hot ho thnh phc hp, hot ho plasminogen thnh plasmin. Thuc c tc dng trn plasminogen ca cc mu ng mnh hn plasminogen t do nn lm tan cc huyt khi nhanh. Ngoi c ch trn thuc cn lm gim yu t V,VIII v cht c ch tiu fibrin -2-antiplasmin. 2.4. Cht hot ho plasminogen m(t-PA, Alteplase) L mt protease sn phm ca ca k thut ti to gen cha 527 acid amin c tc dng trn plasminogen gn vi fibrin mnh gp vi trm ln plasminogen t do. Khi lng fibrin thp tc dng chuyn plasminogen thnh plasmin thp. Thuc c thi gian bn thi ngn 5-10 pht. Trong nhi mu c tim cp tim tnh mch 15 mg sau truyn tnh mch 50 mg trong 30 pht v trong 60 pht tip theo truyn 35 mg (tng liu truyn trong 90 pht khng vt qu 100 mg). 2.5.Reteplase (r-PA, Retavase, Rapilysin) L cht hot ho plasminogen ti t hp thuc th h th 3, tc dng ging Alteplase nhng cng v thi gian xut hin tc dng nhanh hn. Thuc c dng trong nhi mu c tim cp khi u tim chm tnh mch 10 n v trong 2 pht sau c 30 pht tim thm 10 n v. 2.6. Tenecteplase (Metalyse) Thuc mi c tc dng tiu fibrin v ch nh nh reteplase, tim tnh mch ton b liu 500-600 mcg/kg nhng khng vt qu 50mg. 2.7. Ch nh v chng ch nh ca cc thuc tiu fibrin * Ch nh: - Tc nghn ng, tnh mch - Nhi mu c tim - Vim m, ng mu mng phi hoc cc khp xng hay cc hch dng streptokinase ti ch. - Bm vo ng dn lu m trnh tc (streptokinase). * Chng ch nh:

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Sau khi phu thut cha qu 8 ngy; mi hoc sy thai cha qu 4 ngy; cao huyt p nghim trng, qu trnh cm mu bt thng; c a d ng; mi dng streptokinase cha qu 6 thng; mi b bnh do lin cu; c thai (thuc khng qua rau thai, nhng phng bong rau sm); chy mu ng tiu ha nng trong vng 3 thng; tin s tai bin mch mu no; vim mng ngoi tim cp; phu thut ng mch ch; vim ty cp; bnh gan nng. 2.8. Cht hot ha plasminogen L nhng cht gip gii phng cht hot ha (kinase, activator) hot ha plasminogen hoc tng tng hp plasminogen v cui cng lm cho fibrin tr thnh cht phn hy tan c. Thng dng ethylestrenol, phenformin, nicotinamid. Dng khi c th khng t gii phng c cht hot ha, v d khi mu tnh mch do tai bin huyt khi tnh mch, hoc phng ti pht vim tnh mch (dng ethylestrenol cng phenformin).
3. THUC CHNG TIU FIBRIN

C trng thi bnh lm tiu nhanh fibrin, gy chy mu trm trng, v d khi ngi b bnh tng plasmin trong mu. Plasmin khng nhng lm tiu fibrin, m cn kt hp vi mt s yu t ng mu v hy hoi chng, lm c ch ng mu cng ri lon. Nhng phn t mi sinh do fibrin b hy cng kt hp li vi fibrin cho phc hp khng ng c na. Nhng cht phn hu ny cn lm cho tiu cu khng ngng kt thnh cc c. Kt qu lm chy mu trm trng. Thuc lm gim s tiu fibrin s c tc dng cm mu. Hin c mt s thuc chng tiu fibrin ang c s dng trn lm sng cm mu. 3.1. Aprotinin (Trasylol) L thuc c ch protease gm 58 acid amin, c 3 cu ni disulfur, phn t lng 6500, ly t tuyn mang tai, phi, gan. iu ch t tin, thi gian bn thi ngn:150 pht; ch tim tnh mch hoc truyn tnh mch vi liu lng tu thuc vo ch nh. Phng chy mu khi phu thut tim m liu 2000000 n v, chy mu do tng plasmin mu khi u 500000-1000000 n v. Thuc to phc vi plasmin cho phc hp mi aprotinin-plasmin khng c hot tnh plasmin. Aprotinin cn c ch c cc enzym hu protein khc na, nh trypsin, chymotrypsin, kalikrein. Aprotinin thi qua nc tiu di dng mt hot tnh, nn khng dng chng tiu fibrin ng tit niu. Dng nhiu ln c th gy nhng phn ng qu mn ngi c c a d ng. 3.2. Thuc tng hp 3.2.1. Acid w - aminocaproic C cu trc ging lysine c tc dng chng tiu fibrin nh hai nhm amin v carboxyl cch nhau 0,7nm, c ch s hot ha ca plasminogen, km hm khng cho plasmin tc ng ln fibrin, lm cho fibrin khng b ging ha bi plasmin na.

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Thuc khng c ch c cc cht hot ha plasminogen (kinase, activator). Thuc c th ung 24 gam chia lm 4 ln trong ngy hoc tim chm tnh mch 5-7,5g d phng hoc iu tr chy mu. 3.2.2. Acid tranexamic (Cyclokapron ) L ng ng v c tnh cht, tc dng ging acid w - aminocaproic, c th tim tnh mch hoc ung phng chy mu sau m tuyn tin lit, nh rng ngi b hemophilia hoc qu liu thuc tiu cc mu ng hoc ph n b a kinh vi liu 2-4g/24 gi, chia lm 3 ln . 3.3. p dng iu tr ca thuc chng tiu fibrin - Ch nh: Dng trong trng thi tiu fibrin nguyn pht, tiu fibrin cp, d phng chy mu sau phu thut to hnh, tai mi hng, ct b tuyn tin lit v.v... - Chng ch nh: c tnh ca Acid w - aminocaproic v acid tranexamic rt t, tuy nhin cn dng thn trng khi suy thn nng (c th gy tch lu thuc), khi c tin s hoc c biu hin huyt khi tc tnh mch hoc ng mch. V tr tc dng ca thuc tiu fibrin v chng tiu fibrin xin xem trong cun Dc l hc lm sng.
CU HI T LNG GI

1. Trnh by c ch tc dng v p dng iu tr ca vitamin K. 2. Trnh by c ch tc dng v p dng iu tr ca heparin. 3. Trnh by c ch tc dng v p dng iu tr ca dn xut coumarin. 4. Trnh by c ch tc dng chng ng vn tiu cu v p dng iu tr ca aspirin. 5. Trnh by c ch tc dng tiu fibrin v p dng iu tr ca urokinase v streptokinase. 6. Trnh by c ch tc dng tiu fibrin v p dng iu tr ca anistreplase v cht hot ho plasminogen m. 7. Trnh by c ch tc dng chng tiu fibrin v p dng iu tr ca aprotinin v acid w - aminocaproic. 8. Hy so snh dc ng hc v c ch tc dng ca heparin v dn xut coumarin .

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PHN VI THUC TC DNG TRN CHUYN HA V M


Bi 31:

THUC IU TR RI LON LIPOPROTEIN MU

MC TIU HC T P: Sau khi hc xong bi ny, sinh vin c kh nng:

1. Trnh by c c ch tc dng, tc dng, tc dng khng mong mun v p dng iu tr ca cc thuc nh hng n hp thu v thi tr lipid mu: cholestyramin, colestipol . 2. Nu c c ch tc dng, tc dng khng mong mun, p dng iu tr

ca cc thuc nh hng n sinh tng hp lipid: acid nicotinic, dn xut ca acid fibric, dn xut statin, probucol.
1. I CNG

Tng lipoprotein mu l mt yu t gy nn va x ng mch v bnh mch vnh. iu tr ri lon lipoprotein mu, ngoi thay i ch n, c bit l n t lipid, tng cng hot ng th lc l nhng bin php rt quan trng, th khng th thiu c cc thuc h lipoprotein mu. 1.1. Cu trc v phn loi lipoprotein trong mu, cc lipid khng tan c, v vy phi kt hp vi protein nh lin kt Van-der-Walls to thnh lipoprotein. Nh to thnh lipoprotein, tan c trong nc vn chuyn n cc m. Lipoprotein c dng hnh cu vi ng knh 100-500 A gm 2 thnh phn chnh: - Phn a nc (phn v ) cha apoprotein, cholesterol t do v phospholipid .

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- Phn k nc (trung tm) cha cholesterol este ho, triglycerid. Protein gn vo cc lipid c ngun gc ti nim mc rut hoc ti gan gi l apolipoprotein. Da vo cu trc cc acid amin, phn t lng v cc chc nng, apolipoprotein c xp thnh cc nhm khc nhau theo th t ch ci A, B, C, D, E. Trong mi nhm, li c xp thnh di nhm, v d nhm A gm A1, A2, A4; nhm B gm B48, B100; C gm C1, C2, C4 v nhm E gm E1, E2, E4. Do t l protein v lipid khc nhau nn t trng dao ng t 0,9 n trn 1,2. Da vo t trng, lipoprotein c xp thnh 5 loi c chc nng khc nhau. - Ht vi th dng chp (chylomicron) - Lipoprotein t trng rt thp (VLDL: very low density lipoprotein) - Lipoprotein t trng thp (LDL: low density lipoprotein) - Lipoprotein t trng trung bnh (IDL: intermediate density lipoprotein) - Lipoprotein t trng cao (HDL: high density lipoprotein) Trong mi t bo, c bit l t bo gan, t bo ni m mao mch c cha b phn nhn cm c hiu LDL gi l LDL-receptor. Receptor ny c chc nng nhp LDL vo trong t bo v gii phng lipid thng qua enzym trong lysosom. Khi lng cholesterol trong t bo tng cao so vi nhu cu, s tng hp LDL-receptor mng t bo gim xung. Ngc li, khi lng cholesterol trong ni bo gim, th s tng hp LDL-receptor mng t bo tng ln. Cho n nay, c ch vn chuyn cholesterol ca HDL vn cn cha c bit r. Theo mt s tc gi, th di tc dng ca lecithin cholesterol acyltransferase (LCAT), cng vi s hot ha apolipoprotein AI, cholesterol t do ca VLDL v LDL b ester ha i vo phn trung tm khng phn cc ca HDL; HDL s vn chuyn cholesterol ny n gan v b chuyn ha. HDL c vai tr rt quan trng trong bnh va x ng mch, khi HDL trong mu < 0,3g/l, th t l va x ng mch cao v ngc li khi nng HDL > 0,76 g/l th t l va x ng mch rt thp. Mt thuc h lipoprotein tt l thuc lm gim mnh LDL v gy tng HDL r rt. Mi t bo cng t tng hp cholesterol t acetyl CoA nh hydroxymethyl glutaryl - CoA - reductase (HMG - CoA - reductase). Hot tnh ca enzym ny b gim khi lng cholesterol trong t bo tng cao v ngc li, hot tnh tng khi lng cholesterol trong ni bo gim xung. 1.2. Tng lipoprotein mu v phn loi s tng lipoprotein mu c th bnh thng, nng cc lipoprotein trong mu tn ti trong trng thi cn bng ng. Khi c ri lon trng thi cn bng ng ny s gy nn ri lon chuyn ha lipoprotein mu. S ri lon c th do: - Tng cng cholesterol, triglycerid ngoi sinh. - Ri lon chc nng xc tc chuyn ha lipoprotein ca lipoproteinase. - Yu t ton thn lm tng chuyn ha glucid, protid tng hp lipid v tng hot ng ca s hormon lm gim thu phn lipid trong c, gan v m nh bnh

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i tho ng, hi chng thn h, tng ure mu, suy gip, nghin ru, dng thuc trnh thai, corticoid, c ch b- giao cm... - Yu t di truyn: mt s ngi c ri lon chuyn ha lipoprotein, mang tnh cht di truyn. nhng ngi ny, thy c s gim s lng LDL-receptor hoc gim cht lng receptor ny. Da vo tng cc loi lipoprotein s tng lipoprotein mu c chia thnh 6 typ khc nhau: I, IIa, IIb, III, IV v V. n nay, 99% hi chng tng lipoprotein mu thuc typ IIa, IIb v IV. Nhiu thuc h lipoprotein c nghin cu v c dng trn lm sng vi nhiu c ch khc nhau, nhng cha c thuc no c tc dng tt trn tt c cc typ ca ri lon lipoprotein mu.
2.THUC IU TR RI LON LIPOPROTEIN MU

Da vo c ch tc dng trn lipoprotein, thuc c chia thnh 2 nhm chnh: - Lm gim hp thu v tng thi tr lipid - Lm gim tng hp lipid. 2.1. Thuc lm gim hp thu v tng thi tr lipid L nhng thuc c tnh hp th mnh, to phc vi acid mt, lm gim qu trnh nh ha cc lipid rut, dn n gim hp thu v tng thi lipid qua phn. Ngoi ra, cc thuc nhm ny gin tip lm tng chuyn ha cholesterol to thnh acid mt thng qua s thot c ch hydroxylase microsom gan (hydroxylase l enzym iu ha tng hp acid mt t cholesterol b c ch bi acid mt), v lm tng s lng v hot tnh LDL-receptor mng t bo. 2.1.1. Cholestyramin L cht nha trao i ion, c tnh base mnh, khng tan trong nc, ung hu nh khng hp thu qua ng tiu ha, nhng khng nh hng n cc enzym cc ng tiu ha. Do c s trao i ion clo vi acid mt mang in m to nn phc hp nha gn acid mt khng hp thu lm tng thi acid mt qua phn; c ch chu k gan rut ca acid mt lm tng s tng hp acid mt t cholesterol bi s thot c ch hydroxylase. Do gim acid mt nn thuc cng lm gim s hp thu sterol ngun tng hp cholesterol.. Thuc bt u c tc dng h LDL trong mu sau khi dng 4-7 ngy v tc dng ti a trong vng 2 tun. Trn hu ht bnh nhn, thuc lm tng triglycerid t 5 20% so vi trc khi iu tr, nhng dn dn s tr v gi tr ban u trong vng 4 tun. Cholestyramin lm tng HDL-cholesterol khong 5% v gim LDL cholesterol khong 10 - 35% tu theo liu lng, v c ch nh tt bnh nhn tng lipoprotein mu typ IIa. Do to c phc vi acid mt, nn thuc c th gy ri lon ng tiu ha nh: bun nn, y bng, to bn, h prothrombin. Ngoi ra do tnh hp thu mnh, nn thuc cn lm gim hp thu mt s thuc khi dng cng ng ung nh: digitoxin, pheylbutazon, phenobarbital, clorothiazid, thuc chng ng dn xut

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coumarin, thyroxin. trnh tng tc thuc, nhng thuc trn nn ung mt gi trc hoc 4 gi sau khi dng cholestyramin. + Ch phm v liu dng: - Cholestyramin (Questran) gi bt 4g, ung 16-32 gam trong 24 gi chia lm 2 - 4 ln. 2.1.2. Colestipol L polyme ca diethylpentamin v epiclohydrin, tan trong nc, ht m rt mnh. Tc dng, c ch tc dng v tc dng khng mong mun ging nh cholestyramin. Ch phm: Colestipol (Colestid) gi 5 gam hoc vin 1 gam, ung 10-30 gam/24 gi, chia 2-4 ln. Thuc c ch nh trong tng lipoprotein mu typ II. 2.1.3. Neomycin L khng sinh nhm aminoglycosid, ung lm h lipoprotein mu, c bit l h LDL-cholesterol (khng ph thuc vo tc dng khng khun) v c ch nh trong tng lipoprotein mu typ IIa. - Ung liu 0,5 - 2g/24 gi. - Tc dng khng mong mun (xin c bi Khng sinh). 2.1.4 .Ezetimib L thuc c ch s hp thu cholesterol rut c dng ring r hoc phi hp vi dn xut statin trong trng hp tng cholesterol mu do ch n hoc do di truyn vi liu 10 mg /ngy. Khi dng thuc c th gp mt s tc dng khng mong mun nh: a chy, au bng, au u, ph mch v pht ban. Khng dng thuc cho tr em di 10 tui v ngi gim chc nng gan . 2.2. Thuc lm gim tng hp lipid Gm nhng dn xut ca acid fibric ( bezafibrat, ciprofibrat, fenofibrat v gemfibrozil); dn xut statin (pravastatin, simvastatin, lovastatin, rosuvastatin); acid nicotinic; probucol. Cc dn xut acid fibric tng hot tnh lipoproteinlipase, cc dn xut statin c cu trc gn ging vi HMG-CoA nn c ch cnh tranh HMG-CoA-reductase (hydroxymethylglutaryl- CoA- reductase) lm gim tng hp cholesterol, ng thi cng lm tng sinh LDL-receptor mng t bo. Acid nicotinic l mt vitamin dng iu tr bnh Pellagra, nhng cng lm h lipoprotein mu. Tc dng ny c thng qua bi s tng sinh LDL-receptor v c ch s tch t AMP trong m, tng hot tnh triglyceridlipase lm gim LDLcholesterol. Probucol c cu trc ha hc hon ton khc vi nhm thuc trn, c ch tc dng ca thuc vn cn cha c gii thch y . Nhiu nghin cu chng minh thuc lm tng chuyn ha LDL-cholesterol khng thng qua LDL-receptor v ngi tng lipoprotein mu c thiu ht LDL-receptor do di truyn, thuc vn cn

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tc dng. C tc gi cho rng probucol ngn cn oxy ha ca acid bo v lm gim kh nng tip nhp LDL ca t bo ni m. 2.2.1. Acid nicotinic (Vitamin PP, Vitamin B3, Niacin) L vitamin tan trong nc, c nhiu trong gan, tht, c, rau, qu v ng cc. Vi khun rut c th tng hp mt lng nh vitamin PP. Ngoi vai tr NAD, NADP tham gia vo chuyn ha protid, glucid v oxy ha trong chui h hp t bo cc m, acid nicotinic cn lm h lipoprotein mu r rt. Sau 1 - 4 ngy iu tr, vitamin PP lm gim triglycerid 20 - 80%. i vi LDL-cholesterol, thuc c tc dng r sau 5 - 7 ngy. Sau 3 - 5 tun iu tr thuc c tc dng ti a. C ch tc dng ca thuc c th do gim sn xut v tng thi VLDL, c ch phn hu lipid, gim cung cp acid bo cho gan, gim tng hp triglycerid, gim vn chuyn triglycerid, VLDL v gim sn xut LDL. Thuc gy tng HDL-cholesterol nhng c ch cha r rng. Khi thiu ht vitamin PP nng s gy bnh pellagra c biu hin vim da, a chy v ri lon tr nh. - gim tc dng khng mong mun c bit l nng bong ,nga na ngi trn ca thuc, nn ung thuc vo ba n vi liu tng dn, khi u 300-600 mg chia lm 3 ln trong ngy sau 3- 4 tun s dng liu duy tr 2-6 g/ngy. Mt s tc gi khuyn nn ung aspirin 160 - 325 mg/24 gi cng c th lm gim tc dng khng mong mun ca acid nicotinic. Thuc c ch nh trong tng lipoprotein mu typ II, III, IV v V. Nn phi hp vi cholestyramin v colestipol trong iu tr s gim c liu lng v gim tc dng khng mong mun ca thuc. Ngoi ra, vitamin PP cn c ch nh trong trng hp thiu mu v ph n dng thuc trnh thai. 2.2.2. Dn xut ca acid fibric Cc thuc nhm ny hp thu tt qua ng tiu ha, gn mnh vo protein huyt v c tc dng rt khc nhau trn lipoprotein mu, nhng c cng mt c ch chung l tng hot tnh lipoprotein lipase trong t bo c bit l t bo c, dn n lm tng thu phn triglycerid v tng thoi ha VLDL. S tng HDLcholesterol vi c ch cha r rng. Cc ch phm fenofibrat (Lypanthyl), bezafibrat (Bezalip), gemfibrozil (Lopid) v ciprofibrat ( Lipanor) ang c u tin la chn s dng trong tng triglyceride nhng do cn c tc dng trn LDL nn cn c dng trong tng lipoprotein typ II, III, IV v V vi liu lng t 200 mg-1200 mg tu tng ch phm.Thuc c rt t tc dng khng mong mun, tuy nhin c th gp ri lon tiu ha, au u, chng mt, mt mi v au c, tiu c vn( c bit ngi gim chc nng thn), thiu mu, tng nh transaminase, gim phosphatase kim. - Chng ch nh ging nhau vi tt c cc thuc cng nhm: + Gim chc nng gan, thn v si mt. + Ngi c thai, cho con b, tr em di 10 tui. 2.2.3. Dn xut statin

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Cc thuc nhm ny c ch HMG-CoA nn lm gim LDL-cholesterol t 25-45% tu theo tng thuc v liu lng. Tc dng h triglycerid km hn dn xut acid fibric nn c la chn u tin trong nhng trng hp tng cholesterol mu c bit typ II, III, IV v V. Do i qua c rau thai v sa nn thuc khng dng cho ngi c chc nng gan, thn gim nng, ph n c thai v cho con b, tr em di 18 tui v thuc c th gy bt thng xng ca sc vt th nghim . Dng lu di thuc gy tng transaminase gp 3- 4 ln bnh thng, ngng thuc enzym li tr v bnh thng. Khi iu tr cn theo di chc nng gan v creatinin phosphokinase. + Thuc c tc dng khng mong mun ging nhau: - au c, tiu c vn, sn nga, au u, chng mt, ri lon tiu ha v tng cao transaminase trong mu. - Cc thuc trong nhm c tm tt trong bng 30.1. Bng 30.1: Ch ph m v liu lng mt s thuc trong nhm statin Tn gc Bit dc Liu lng (mg/ngy) Atorvastatin Fluvastatin Lovastatin Pravastatin Rosuvastatin Simvastatin Lipitor Lescol Mevacor Vasten Crestor Lodales 10-40 200-400 20- 80 10-40 10-20 10- 40

2.2.4. Probucol (Lorelco, Lurselle) C cu trc hon ton khc vi cc thuc nu trn. Rt tan trong lipid nhng hp thu km. Thc n lm tng s hp thu thuc. Do tan trong lipid, nn thuc ng li lu trong c th. Sau khi ngng thuc 6 thng, nng thuc ch gim 80% so vi nng ti a trong mu. Thuc lm h LDL-C tht thng, khng lm h triglycerid. Thuc gy h HDL-cholesterol mnh v ko di nn n ch c la chn trong iu tr sau cc thuc khc. Probucol l cht chng oxy ha mnh nn c tc dng chng x va mnh sc vt th nghim. Khi dng thuc c th gp mt s tc dng khng mong mun: a chy, y bng, au bng, bun nn.

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Khng dng thuc nhng bnh nhn mi b nhi mu c tim, c khong QTC ko di, ph n c thai, cho con b, tr em di 18 tui, ang dng cc thuc chng lon nhp tim nhm I, III, chng trm cm loi 3 vng, dn xut phenothiazin. - Vin 250 mg, ngy ung 500mg chia 2 ln. 2.2.5. D-Thyroxin D-Thyroxin l ng phn quay phi ca L-Thyroxin mt mt s tc dng ca hormon tuyn gip, nhng li c tc dng h lipoprotein mu mnh do tng chuyn cholesterol thnh acid mt v tng thi sterol qua phn. c ch nh cho tr em c lipoprotein mu cao. Khng dng cho ngi c bnh tim v d c cn nhi mu c tim v cn au vng trc tim. Liu khi u 1mg, sau tng dn, ti a 4-8 mg/24 gi. Vi liu ny, khng thy c phn ng c hi. 2.2.6. Cc acid bo khng no a tr h omega 3 Trong du mt s loi c c bit l c hi, c ng, c trch, c thu c cha mt s acid bo khng no a tr h Omega 3 c tc dng lm gim triglycerid v VLDL nhng t nh hng n LDL v HDL-cholesterol trong mu. C 2 acid bo khng no h Omega 3 hay dng l: -Omega-3-acid ethylesters: 1 gam bit dc Omacor 90% omega-3-acid ethylesters cha 46% acid eicosapentaenolic(EPA) , 38 % acid docosahexaenoic (DHA) v 4 mg a-tocopherol. -Omega-3-marin triglyceride: 1 gam bit dc Maxepa cha170 mg acid eicosapentaenolic(EPA), 115 mg acid docosahexaenoic (DHA) v di 100 n v vitamin A v 10 n v vitamin D. Liu lng cc ch phm xin xem t hng dn s dngthuc. hn ch s tng v gip h triglycerid v cc lipoprotein mu, nn tng cng n c, c bit l c hi, c thu, c ng, c trch trung bnh 30g/ngy hoc 3 ln/tun. 2.2.7.Mt s thuc iu tr ri lon lipoprotein mi - Hai thuc mi ang c th nghim trn lm sng pha II v III ngi c ri lon lipoprotein mu: + BMS-201038 l cht c ch microsomal triglycerid transfer protein lm gim s vn chuyn triglycerid v cc lipid khng phn cc n apolipoprotein v gim s bi tit triglycerid t rut dn n gim triglycerid v VLDL-cholesterol. + Avasimibe : thuc c ch ACAT1 v ACAT2(cholesterol acyltransferase) lm gim s ester ho cholesterol gan, rut, i thc bo v gim tng hp acid mt thng qua s cm ng hydroxylase gy nn gim chylomicron, VLDL, LDLcholesterol v triglycerid.
3. NGUYN T C IU TR RI LON LIPOPROTEIN MU

hn ch nguy c gy bnh tim mch cn phi h LDL v tng HDL trong mu. Theo mt s nghin cu cho thy mun ngn chn c bnh mch vnh nguyn pht hoc th pht cn phi gim cholesterol ton phn trong mu 20-25 % hoc

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LDL khong 30 %. Nhm t hiu qu iu tr cn phi p dng mt s nguyn tc sau: - Trc tin phi c ch n thch hp duy tr trng lng bnh thng v gim lipoprotein mu. nhng ngi c ch s khi c th (BMI body mass index ) cao hn bnh thng, cn c ch n cha < 300 mg cholesterol, acid bo bo ho chim 10%, acid bo khng bo ha 10 -15%, glucid 50 - 60% v protein chim 10 - 20% tng s calo/ngy. - iu tr nguyn nhn gy tng lipoprotein mu nh: i tho ng, suy gip, hi chng thn h, tng ure mu. - Gim hoc chm dt cc nguy c gy tng lipoprotein mu nh: ht thuc l, ung ru, dng cc thuc corticoid, thuc trnh thai, thuc c ch b- adrenergic. - Tng cng hot ng th lc. - Sau 3 - 6 thng thay i ch n, tng cng hot ng th lc v iu tr cc nguyn nhn v loi b cc nguy c m lipoprotein mu vn cao th phi dng thuc h lipoprotein mu. - Tu theo c ch tc dng, cc thuc c th c dng ring r hoc phi hp 2 hoc 3 thuc c c ch khc nhau t c tc dng hip ng trong iu tr nh : + Cholestyramin vi dn xut statin; + Cholestyramin phi hp vi acid nicotinic hoc cholestyramin phi hp vi dn xut statin v acid nicotinic. + Cc thuc thuc dn xut statin c la chn trc tin cho tng cholesterol cn dn xut acid fibric u tin cho trng hp tng triglycerid. Hai dn xut ny c th dng ring r hoc kt hp trong nhng trng hp tng lipoprotein hn hp. Nhng phi thn trng v theo di tc dng khng mong mun, c bit l du hiu tiu c vn. Do c tng nguy c tiu c vn nn gemfibrozil v dn xut statin khng dng phi hp trong iu tr. - Trong qu trnh iu tr, ngoi vic thng xuyn theo di lng lipoprotein mu nh gi hiu qu iu tr, bnh nhn cn c theo di tc dng khng mong mun do thuc gy ra nh vim c, tiu c vn, tng transaminase, ri lon in tim v.v...
CU HI T LNG GI

1. Trnh by tc dng, c ch tc dng v p dng iu tr ca cholestyramin v colestipol. 2. Trnh by tc dng, c ch tc dng p dng iu tr ca acid nicotinic v probucol. 3. Trnh by tc dng, c ch tc dng v p dng iu tr ca dn xut acid fibric. 4. Trnh by tc dng, c ch tc dng v p dng iu tr ca dn xut statin.

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Bi 32:

THUC H GLUCOSE MU

MC TIU HC T P: Sau khi hc xong bi ny, sinh vin c kh nng:

1. Trnh by c tc dng, c ch tc dng v p dng iu tr ca insulin 2. Trnh by c phn loi, c ch tc dng, v p dng iu tr ca dn xut sulfonylure v c ch tc dng v p dng iu tr ca dn xut biguanid v acarbose v cc thuc khc.

1. I CNG

c th bnh thng, glucose mu c duy tr nng hng nh nh s cn bng gia insulin v glucagon, hormon tng trng, cortisol, thyroxin v catecholamin. Khi c ri lon s cn bng ca h thng ny, c bit l gim s lng, cht lng cng nh s nhy cm ca cc t bo i vi insulin s gy ra bnh tng glucose mu. Da vo s lng insulin v mc nhy cm ca t bo vi insulin, bnh i tho ng c chia thnh hai nhm: - Nhm ph thuc insulin cn gi l tng glucose mu tp I, thng gp ngi gy, tr, di 40 tui c gim s lng t bo b tuyn tu v nng insulin mu rt thp. iu tr dng insulin. - Nhm khng ph thuc insulin cn gi l tng glucose mu tp II, thng gp ngi ln tui, khng gim s lng nhng c gim chc nng gy nn s ri lon bi tit insulin ca t bo b , nng insulin trong mu bnh thng hoc cao v c hin tng khng insulin cc m ngoi vi. Ngoi ra, cn c tng glucagon v gim p ng ca t bo b vi GLP1(glucagon like peptid 1)v vi GIP(glucose dependent insulin tropic peptid ). Theo cc thng k, 80 -90% bnh nhn c tng glucose mu thuc typ II. Thuc iu tr ch yu l cc thuc chng i tho ng tng hp dng ng ung.
2. CC THUC H GLUCOSE MU

Hin nay c 2 cch phn loi thuc h glucose mu: * Theo c ch tc dng, thuc h glucose mu c chia thnh 5 nhm chnh: - Insulin - Thuc kch thch bi tit insulin: sulfonylure, nateglinid. - Cc thuc lm tng nhy cm ca t bo vi insulin: dn xut biguanid, nhm thiazolindindion. - Thuc c ch a - glucosidase.

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- Cc thuc bt chc incretin (GLP1, GIP) v thuc c ch DPP4(dipeptidyl peptidase 4). * Theo ng dng v ngun gc, cc thuc h glucose mu c chia thnh 2 nhm chnh: - Insulin - Thuc h glucose mu dng ng ung. 2.1. Insulin Insulin l mt hormon gy h ng huyt do tuyn tu tit ra. Ngy nay, da vo cu trc, insulin c th c bn tng hp t insulin ln hoc nh k thut ti t hp gen thng qua vi khun hoc nm. nh gi tc dng v tinh khit, insulin c quy thnh n v chun quc t. Mt n v insulin (1 IU) l lng insulin cn lm gim glucose mu th nng 2,5kg nhn i xung cn 45mg/100ml v gy co git sau khi tim 5 gi v bng 40mg insulin. 2.1.1. Tc dng v c ch tc dng Tt c t bo ca ngi v ng vt u cha receptor c hiu cho insulin. Receptor ca insulin l mt glycoprotein gm 2 n v di a nm mt ngoi t bo v hai n v di b nm mt trong t bo. Bn n v ny gn i xng nhau bng cu disulfid. Thng qua receptor ny, insulin gn vo di n v a gy kch thch tyrosinkinase ca n v di b lm hot ha h thng vn chuyn glucose mng t bo ( glucose transporters = GLUT), lm cho glucose i vo trong t bo mt cch d dng, c bit l t bo c, gan v t bo m. Hin nay ngi ta pht hin ra 5 cht vn chuyn glucose phn b nhng t bo khc nhau. Tc dng lm h glucose mu ca insulin xut hin nhanh ch trong vng vi pht sau khi tim tnh mch v b mt tc dng bi insulinase. C ch tc dng xin c thm bi Hormon. 2.1.2. Tc dng khng mong mun Nhn chung, insulin rt t c, nhng cng c th gp: - D ng: C th xut hin sau khi tim ln u hoc sau nhiu ln tim insulin, t l d ng ni chung thp. - H glucose mu: Thng gp khi tim insulin qu liu, gy chy m hi, h thn nhit, co git, thm ch c th hn m. - Phn ng ti ch tim: Nga, au, cng (teo m di da) hoc u m vng tim. trnh tc dng ph ny, nn thay i v tr tim thng xuyn. - Tng ng huyt hi ng (rebound): Gp nhng bnh nhn dng insulin liu cao sau khi ngng thuc. 2.1.3. Ch phm Da vo dc ng hc v nhu cu iu tr insulin c xp thnh 3 nhm ch phm khc nhau: 2.1.3.1. Insulin tc dng nhanh:

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+ Insulin hydroclorid: Thi gian xut hin tc dng sau khi tim 1 gi v t ti a sau 3 gi v ko di tc dng khong 6 gi. Thuc c s dng trong hn m do i tho ng, 1ml cha 20-40 n v, c th tim bp, di da, tnh mch. + Nh dch Insulin- km: Ch tim di da; sau khi tim 1 gi bt u xut hin tc dng v ko di khong 14 gi. 2.1.3.2. Insulin tc dng trung bnh: - Insophan insulin: (NPH - Neutral Protamin Hagedorninsulin) dng nh dch, l s phi hp insulin, protamin v km trong mi trng m phosphat. C 100 n v insulin, c thm 0,4mg protamin. Tim di da, tc dng xut hin sau 2 gi v ko di khong 24 gi. - Lente insulin: Dng nh dch, tim di da xut hin tc dng sau 2 gi v ko di khong 24 gi. 2.1.3.3. Insulin tc dng chm: Insulin protamin km: Ch phm dng nh dch, c 100 n v insulin c km theo 0,2mg protamin. Thi gian xut hin tc dng sau khi tim di da 4-6 gi v ko di ti 37 gi. Insulin km tc dng chm (Ultralente insulin) tim di da, thi gian xut hin tc dng v ko di tc dng gn ging insulin protamin- km. 2.1.4. p dng iu tr - Tt c cc bnh nhn tng glucose mu thuc tp I u c ch nh dng insulin. Ngoi ra, insulin cn c ch nh cho bnh nhn tng glucose mu tp II, sau khi thay i ch n v dng cc thuc chng tng glucose mu tng hp khng c tc dng. - Tng glucose mu sau ct b ty tng, ph n c thai. - Tng glucose mu c ceton mu v niu cao. Trn c s nh lng insulin trong mu ca ngi bnh thng, ta thy lng insulin bi tit trung bnh vo khong 18 - 40 n v/24 gi, mt na s c gi l insulin c s, lng insulin cn li c bi tit theo ba n. V vy, duy tr lng glucose mu n nh, insulin nn dng khong 0,2 - 0,5 n v cho 1 kilogam th trng/24 gi. Cho n nay, duy nht c insulin l dng ng tim, cn cc thuc h glucose mu khc c c ch tc dng khc nhau nhng ng dng duy nht l ung iu tr tng glucose mu typ II sau t nht 3 thng thay i ch n, tng cng tp luyn th lc khng c kt qu. Cc thuc ny khng thay th ch n gim glucid, gim nng lng v tng cng hot ng th lc trong qu trnh iu tr. Da vo c ch, cc thuc chng tng glucose mung ung c chia thnh: - Thuc kch thch bi tit insulin - Thuc lm tng nhy cm ca t bo ch vi insulin - Thuc lm gim hp thu glucose rut.

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- Cc thuc bt chc incretin(incretin mimetic) v thuc c ch DPP4(dipeptidyl peptidase 4 inhibitor). 2.2. Thuc kch thch bi tit insulin 2.2.1. Dn xut Sulfonylure T nhng nm 1942, Janbon v cng s pht hin c tc dng h glucose mu ca mt s sulfonamid sc vt th nghim v bnh nhn iu tr thng hn. Nh pht hin ny, carbutamid, mt sulfonamid c tng hp c tc dng h glucose mu, s dng trn lm sng. Nhng do c tc dng c ch tu xng, thuc b lng qun. Song nhu cu iu tr bnh i tho ng ngy cng cao, khong 20 thuc c tng hp v da vo cng tc dng v dc ng hc cc thuc xp thnh hai th h I v II. - Th h I gm: tolbutamid, acetohexamid, tolazamid, clopropamid. - Th h II: tc dng mnh gp khong 100 ln v c thi gian tc dng di hn th h I nn ch cn dng 1 ln trong mt ngy, gm: glibenclamid, glipizid, gliclazid. Bng 32.1: Tm tt mt s thng s dc ng hc v liu dng mt s thuc nhm sulfonylure

Th h

Thuc

Cng tc dng

Nng cao nht trong mu sau khi ung (gi) 3-5

Thi gian bn thi (gi) 5-6

Thi gian ko di tc dng (gi) 6-12

Liu trung bnh (gam)/24 gi)

Tolbutamid (Orabet) Th h 1 Acetohexamid (Dymelor) Tolazamid (Tolinase) Clopropamid (Meldian,) Glibenclamid (Maninil,) Glipizid (Glucotrol)

0,5-2,0

2-4

4-5

12-24

0,25-1,25

4-8

12-24

0,1-0,75

5-10 100200 100200

2-4 4-5

1835 4-5

40-60 24

0,1-0,5 0,0025-0,02

Th h 2

1-3

10-16

0,005-0,02

2.2.1.1. C ch tc dng: Da vo nhng nghin cu thc nghim trn tuyn ty c lp, o ty c lp v nui cy t bo b, Pfeifer v cng s (1981) chng minh rng, tc dng h glucose mu ca cc dn xut sulfonylure l do tc dng trn receptor b mt K+ATPase ca t bo b o Langerhans lm chn knh K+ nhy cm vi ATP,

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gy gim K+ i vo trong t bo to ra s kh cc mng dn n m knh calci lm tng lng calci t ngoi bo i vo trong t bo, kch thch gii phng insulin. Mt s nghin cu gn y chng minh cc thuc ny cn lm tng s lng v tng tnh nhy cm receptor ca insulin bch cu n nhn to, t bo m, hng cu, do lm tng tc dng ca insulin. Theo Krall (1985), cc dn xut sulfonylure c tc dng kch thch gii phng ra somatostatin, chnh somatostatin c ch gii phng glucagon, cho nn cng gy h glucose mu. Ngoi ra, ngi ta cn thy thuc c tc dng c ch insulinase, c ch s kt hp insulin vi khng th khng insulin v s kt gn vi protein huyt tng. 2.2.1.2. Dc ng hc Thuc c hp thu nhanh qua ng tiu ha. Nng ti a trong mu t c sau khi ung khong 2-4 gi, gn vo protein huyt tng 92-99% ch yu l albumin. Gn mnh nht l glibenclamid, gn km nht l clopropamid. Thuc c chuyn ha ch yu gan. Tolbutamid chuyn ha nh phn ng oxy ha thng qua h enzym chuyn ha microsom gan thnh mt s cht chuyn ha vn cn tc dng nh hydroxymethyl-tolbutamid, 4-hydroxymethyl-tolazamid. Clopropamid khng b chuyn ha s thi tr qua thn. Thn l ng thi tr ch yu ca cc thuc h glucose mu dng ng ung. Ring glibenclamid thi ch yu qua gan, v vy c ch nh cho nhng bnh nhn tng glucose mu c chc nng thn suy yu. 2.2.1.3. Ch nh: - Tt c bnh nhn tng glucose mu typ II, khng ph thuc insulin. - Ngi bo bu trn 40 tui c insulin mu di 40 n v mt ngy. 2.2.1.4. Chng ch nh: - Tng glucose mu typ I, ph thuc insulin - Ngi c thai, cho con b, suy chc nng gan, thn - Tng glucose mu nng trong tnh trng tin hn m hoc hn m. 2.2.1.5. Tc dng khng mong mun: - H glucose mu, d ng, ri lon tiu ha, bun nn, nn, vng da tc mt. - Tan mu, thoi ha bch cu ht. - Phn ng ging disulfuram khi dng clopropamid cng ru (gp khong 1-15% bnh nhn). - H natri mu hay gp vi clopropamid, do c tc dng ging ADH ( 50% bnh nhn). 2.2.1.6. Tng tc thuc: Thuc th h I gn mnh vo protein huyt gy nn cnh tranh v tr gn vi mt s thuc: dicoumarol, diphenylhydantoin, salicylat, phenylbutazon, sulfonamid. Th h II khng c tng tc kiu ny.

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Cloramphenicol, IMAO, probenecid lm tng tc dng h glucose mu ca c hai th h I v II, nhng corticoid, thuc trnh thai, diphenylhydantoin, rifampicin, INH, cc phenothiazin li gy gim tc dng h glucose mu ca thuc. Thuc c ch b-adrenergic dng cng vi cc dn xut sulfonylure gy nhp tim nhanh, thay i huyt ng hc v tng tc dng h glucose mu v vy trnh dng phi hp. 2.2.2 Loi khng phi sulfonylure 2.2.2.1. Nateglinid: L dn xut ca D-phenylalanin c tc dng kim sot s tng ng huyt sau ba n, do vy s ci thin tnh trng tng ng huyt sau khi n bnh nhn tng glucose mu typ II. Trong c th, nateglinid gn vo receptor c hiu (SUR 1) t bo b ca ty lm chn knh K+ nhy cm vi ATP, gy kh cc mng t bo lm m knh calci. Calci kch thch gii phng insulin. Do thuc c c im gn nhanh v tch ra nhanh khi receptor c hiu nn kch thch bi tit insulin nhanh, nn nhanh chng kim sot ng huyt sau khi n. Nhng cng do thuc tch ra khi receptor c hiu nhanh lm rt ngn giai on kch thch bi tit insulin, lm gim nguy c tng cao insulin trong mu nn trnh c tnh trng h glucose mu v s suy kit t bo b ca ty. Thuc c hp thu tt qua ng tiu ha, thc n tng hp thu thuc. Sau ung liu duy nht 60mg, nng ti a trong mu t c sau 55 pht. Thuc gn vo protein huyt vi t l 99% v c thi gian bn thi 1,4 - 2 gi. Trong c th thuc b chuyn ha qua Cyt-P450 (CyP3A4, CYP2C9) gan v thi tr qua mt v qua nc tiu. Thuc c phm vi an ton rng, t c tnh. Nghin cu trn lm sng vi liu 60, 120, 180mg ung trc ba n 20 pht, c tc dng kim sot ng huyt sau n r rt. Thuc c th dng ring r hoc kt hp vi metformin kim sot s tng ng huyt sau n ngi tng glucose mu typ II. 2.2.2.2.Repaglinid Ging nh nateglinid, repaglinid cng c tc dng kim sot ng huyt nhanh sau khi n do vy cch dng ging nhau vi liu khi u 500 mcg sau iu chnh liu ph thuc vo p ng ca bnh nhn nhng khng vt qu 16 mg/ngy. 2.3.Thuc lm tng nhy cm ca t bo ch vi insulin 2.3.1. Dn xut ca biguanid Cc dn xut ca biguanid c cu trc hon ton khc vi dn xut sulfonylure gm: phenformin (phenethylbiguanid) do gy acid lactic mu, nn b nh ch lu hnh trn th trng, hin ch cn metformin (dimethylbiguanid) . Mc d cc thuc ny c tc dng h glucose mu r rt nhng ngi tng glucose mu, nhng c ch tc dng cn cha c r. Mt s tc gi cho rng, thuc tc dng thng qua s tng dung np glucose, c ch s tn to glucose v tng tng hp glycogen gan do tng hot tnh glycogensynthetase v lm tng tc

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dng ca insulin t bo ngoi vi. Ngoi ra, thuc cn hn ch hp thu glucose rut. Thuc khng tc dng trc tip trn t bo b ca o Langerhans, v ch c tc dng khi c mt insulin ni sinh, nn thuc c ch nh bnh nhn ty cn kh nng bi tit insulin. - Metformin (Glucophage): Hp th km qua ng tiu ha, khng gn vo protein huyt tng, khng b chuyn ha, thi tr ch yu qua thn. Thi gian bn thi khong 1,3 - 4,5 gi, thi gian tc dng khong 6-8 gi, liu trung bnh 0,52,5g/24 gi, ti a 3g/24 gi v c chia lm 3 ln sau cc ba n hng ngy. + Ging nh dn xut sulfonylure, metfomin c ch nh dng ring r hoc kt hp vi cc thuc khc cho bnh nhn tng glucose mu typ II sau khi iu chnh ch n v tp luyn th lc khng c hiu qu. Metformin c th kt hp vi mt s thuc khc kch thch bung trng trong iu tr v sinh. Khng dng thuc ngi tng glucose mu c ceton mu cao v c ceton niu, ph n c thai, cho con b. + Thuc c th gy ri lon tiu ha, acid ha mu do tng acid lactic c bit bnh nhn c km theo gim chc nng gan, thn. 2.3.2.Cc thuc thuc nhm thiazolidindion L nhng thuc c cu trc v c ch tc dng hon ton khc vi dn xut sulfonylure v biguanid. Cc thuc nhm ny l nhng cht ch vn v c i lc cao vi PPARg (peroxisome proliferator activated receptor g). Receptor ny trong nhn t bo chu trch nhim iu ha mt s gen lin quan n s chuyn ha lipid v glucose. Khi thuc gn vo receptor gy nn s tng tc vi ADN c hiu lm hot ha gii m gen, lm tng nhy cm ca t bo vi insulin gip tng chuyn ho glucid v lipid. Trn thc nghim, ngi ta thy cc thuc lm tng chuyn ha glucose v tng s lng insulin receptor mng t bo, tng tng hp glycogen thng qua tng hot tnh glycogensynthetase v tng s dng glucose ngoi vi. Cc thuc thuc dn xut thiazolidindion c th dng ring r hoc phi hp vi metformin hoc cc thuc trong nhm sulfonylure nhng khng phi hp vi insulin iu tr tng glucose mu typ II. Thuc khng c dng cho ngi b suy gan, suy tim, ph n c thai, cho con b.Trong qu trnh iu tr cn thng xuyn theo di chc nng gan. Hai thuc trong nhm s dng nhiu hin nay l : Pioglitazon (Actos) vin 15,30,45 mg, ung 15-45 mg/ngy. Rosiglitazon (Avandia) vin 4;8 mg, ung 4-8 mg/ngy.

2.4. Thuc lm gim hp thu glucose rut: acarbose (Glucobay): Thuc c ch nh bnh nhn tng glucose mu typ II km theo bo bu. C ch tc dng ca thuc khng lin quan n s bi tit insulin t bo b ca ty m thng qua s c ch a- glucosidase b bn chi nim mc rut non. Ngoi ra, thuc cn c ch, glucoamylase, maltase rut. Cui cng, lm gim hp thu glucose gy h glucose mu. Thuc c th gy ri lon tiu ha nh trng bng, tiu chy v au bng.

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Khi iu tr, cn iu chnh liu cho ph hp vi tng bnh nhn, nhng nhn chung liu trung bnh cho ngi ln 300mg trong 24 gi. Cc thuc khng acid, cholestyramin, mt s cht hp ph mnh v ch phm cha enzym tiu ha lm gim tc dng ca acarbose. Khng dng thuc nhng ngi c ri lon chc nng hp thu, ph n c thai, cho con b v tr em di 18 tui. 2.5. Cc thuc bt chc incretin (incretin mimetic) v thuc c ch DPP4(dipeptidyl peptidase 4 inhibitor). Gn y ngi ta tm ra 2 peptid hormon GLP1, GIP gi chung l incretin c ngun gc ti nim mc rut, c tc dng iu ho glucose mu sau khi n thng qua s kch thch bi tit insulin v lm chm s tho rng d dy. Trn c s pht hin ny liraglutid v exenatid hai cht ging incretin (incretin mimetic) ang c th nghim lm sng pha II v III trn bnh nhn tng glucose mu typ II. GLP1 kch thch bi tit insulin sau khi n rt mnh, ngoi ra cn c ch bi tit glucagon, lm chm s tho rng d dy, kch thch s sao chp gen glucokinase v GLUT2 nhng li mt tc dng nhanh do b enzym dipeptidylpeptidase ph hu nn c thi gian bn thi di 2 pht. Vildagliptin, sitagliptin, saxagliptin l cc cht c ch DPP4 lm ko di tc dng ca GLP1 ang c th nghim lm sng pha II trn bnh nhn tng glucose mu typ II.
CU HI T LNG GI

1. Trnh by tc dng, c ch tc dng v p dng iu tr ca insulin. 2. Trnh by cch phn loi, c ch tc dng v p dng iu tr ca nhm sulfonylure. 3. Trnh by tc dng, c ch tc dng v p dng iu tr ca nhm biguanid v acarbose. 4. Trnh by tc dng, c ch tc dng v p dng iu tr ca nateglinid v nhm thiazolidindion.

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Bi 33: HISTAMIN

V THUC KHNG HISTAMIN

MC TIU HC T P: Sau khi hc xong bi ny, sinh vin c kh nng:

1. Nu c vai tr sinh l v bnh l ca histamin 2. Trnh by c c ch tc dng, cch phn loi, ch nh v c tnh ca thuc khng histamin H1.
1. HISTAMIN

1.1. Sinh tng hp v phn b histamin Histamin l cht trung gian ha hc quan trng c vai tr trong phn ng vim v d ng, trong s bi tit dch v v cng c chc nng nh cht dn truyn thn kinh v iu bin thn kinh, c to ra do s kh carboxyl ca histidin di s xc tc ca decarboxylase. Do histamin tch in dng nn d dng lin kt vi cht tch in m nh protease, chondroitin sulfat, proteoglycan hoc heparin to thnh phc hp khng c tc dng sinh hc. Phc hp ny c d tr trong cc ht trong dng bo, bch cu a base, t bo nim mc d dy, rut, t bo thn kinh v.v... Da, nim mc, cy kh ph qun l nhng m c nhiu dng bo nn d tr nhiu histamin. 1.2. S gii phng histamin Nhiu yu t kch thch s gii phng histamin, nhng ch yu l do phn ng khng nguyn - khng th xy ra trn b mt dng bo . Khi c phn ng khng nguyn - khng th lm thay i tnh thm ca mng t bo vi ion calci lm tng calci i vo trong ni bo, ng thi tng gii phng calci t kho d tr ni bo. Ca+2 ni bo tng lm v cc ht d tr gii phng histamin. nh sng mt tri, bng, nc c ca cn trng, morphin, D-tubocurarin lm tng gii phng histamin. Ngoi ra, mt s yu t khc cng c gii phng trong phn ng d ng nh: yu t hot ha tiu cu (PAF); cc prostaglandin, bradykinin, leucotrien. 1.3. Chuyn ha histamin Histamin c th chuyn ha qua 2 con ng khc nhau nh histaminase v Nmethyltransferase to thnh acid imidazol acetic v methylhistamin khng c tc dng sinh hc. 1.4. Receptor ca histamin Hin nay tm thy 4 receptor khc nhau ca histamin l H1, H2, H3 v H4. S phn b s lng receptor v chc nng ca tng loi receptor rt khc nhau. Khi histamin gn vo receptor H1 s lm tng IP3 (inositol 1,4,5-triphosphat) v diacylglycerol t phospholipid. IP3 lm tng gii phng calci t li ni bo. Diacylglycerol (DAG) v calci lm hot ha protein lipase C, protein kinase ph

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thuc Ca+2/calmodulin v phospholipasse A2 cc t bo ch khc nhau gy cc phn ng sinh hc khc nhau. Histamin gn vo receptor H2 kch thch adenylcyclase lm hot ha protein kinase ph thuc AMPv cc t bo ch gy nn phn ng sinh hc. Receptor H2 c nhiu nim mc d dy, khi kch thch gy tng tit dch v acid (xin xem bi Thuc cha vim lot d dy. Cimetidin, ranitidin, famotidin l nhng thuc khng trn receptor H2. Receptor H3 l receptor trc synap, c mt nt tn cng neuron h histaminergic thn kinh trung ng, c vai tr iu ha sinh tng hp v gii phng histamin. Cng ging receptor H1, H2, receptor H3 l receptor cp vi protein G v c phn b trong nhiu m. Hin nay tm c mt s cht ch vn v i khng trn receptor H3:thioperamid, iodophenpropit, clobenpropit, Imipromidin, Burimamid. Receptor H4 c mt t bo a acid, dng bo, t bo T v t bo hnh cy(dendritic cell).Thng qua receptor ny histamin lm thay i ho hng ng mt s t bo v s sn xut cytokin. Cc cht i khng trn receptor H4 ang nghin cu c tc dng chng vim invivo v c tc dng chng hen v vim i trng trn m hnh ng vt thc nghim. 1.5. Tc dng sinh hc ca histamin 1.5.1. Trn h tim-mch - Histamin lm gin cc mch mu nh, tiu ng mch, mao mch v tiu tnh mch lm gim sc cn ngoi vi, gim huyt p v tng cng dng mu n m: thng qua receptor H1 s xut hin tc dng nhanh, cng mnh nhng khng ko di, cn i vi receptor H2 s xut hin tc dng gin mch chm, nhng ko di. - Thng qua receptor H1 histamin lm co t bo ni m mao mch, tch s kt gn cc t bo ni m lm bc l mng c bn to thun li cho s thot dch v protein ra ngoi bo gy ph n, nng, , au. - Trn tim: Histamin c tc dng trc tip trn c tim v thn kinh ni ti lm tng co bp c tm nh, tm tht, chm kh cc nt xoang v chm dn truyn nh tht. 1.5.2. Trn kh-ph qun - phi: Thng qua receptor H1 histamin lm co c trn kh ph qun, gy cn hen. Ngoi ra, histamin cn gy xut tit nim mc kh ph qun, gy vim ph n nim mc v tng tnh thm mao mch phi. 1.5.3. Trn h tiu ha Histamin lm tng tit dch acid thng qua receptor H2, lm tng nhu ng v bi tit dch rut. 1.5.4. C trn mt s loi vt, histamin lm tng co bp c trn t cung, nhng t cung ngi, c trn bng quang, niu o, ti mt rt t b nh hng.

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1.5.5. H bi tit Histamin lm tng bi tit nc mt, nc mi, nc bt, dch ty. 1.5.6. Trn h thn kinh Kch thch u mt si thn kinh ngoi vi gy nga, au. Trn thn kinh trung ng histamin gy gim thn nhit, gy mt ng, c th chn n, tng tit ADH. Tc dng ny thng qua c 2 loi receptor H1 v H2.
2. CC THUC KHNG HISTAMIN

2.1. Cu trc - phn loi C nhiu cht i khng chn lc trn 3 receptor khc nhau ca histamin. Thuc i khng H2 receptor (xin c bi thuc cha vim lot lot d dy). Cc cht i khng H3 ang trong giai on nghin cu. Trong phm vi bi ny, ch gii thiu thuc i khng chn lc trn receptor H1. Da vo dc ng hc, tc dng, cc thuc khng H1 c xp thnh 2 th h: * Th h I: gm cc thuc c th i qua hng ro mu no d dng, c tc dng trn receptor H1 c trung ng v ngoi vi, c tc dng an thn mnh, chng nn v c tc dng khng cholinergic ging atropin. * Th h II: gm cc thuc rt t i qua hng ro mu no, c thi gian bn thi di, t tc dng trn H1 trung ng, ch c tc dng trn H1 ngoi vi, khng c tc dng khng cholinergic, khng an thn v khng c tc dng chng nn, chng say tu xe. Bng 33.1: Liu lng mt s thuc khng histamin H1 Tn gc Tn bit dc Liu lng cho ngi ln (mg) Th h I - Alimemazin - Brompheniramin - Carbinoxamin - Clemastin - Clopheniramin - Cyclizin - Dimenhydrinat - Dimethinden - Diphenhydramin Allerlene Dimetan Cardec Tavist Chlor- Trimeton Marexin Dramamin Fenistil Benadryl 5 - 20 4 - 12 4-8 1,3 - 2,7 4 - 12 50 50 - 100 4 2,5 - 50

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- Hydroxyzin - Meclizin - Promethazin -Pyrilamin Th h II - Acrivastin - Astemizol

Atarax Antivert Phenergan Nisaval

25 - 100 12,5 - 50 10 - 25 25-50

Semprex Hismanal

24; khng dng cho tr di 12 tui C tc dng khng mong mun trn tim hin khng c s dng 5 - 10 5

- Cetirizin - Desloratadin (cht chuyn ha ca Loratadin) - Fexofenadin(cht chuyn ha ca terfenadin) - Loratadin -Mizolastin Terfenadin

Zyrtec Aerius*

Telfast

60

Claritin Mizollen Seldan

10 10 C tc dng khng mong mun trn tim hin khng c s dng

2.2. Tc dng dc l 2.2.1. Tc dng khng histamin thc th Thuc khng histamin H1 c ch c cnh tranh vi histamin ti receptor H1 lm mt cc tc dng ca histamin trn recetor. Khi d tha histamin, th histamin y cht i khng ra khi receptor, t thuc gim hoc ht tc dng khng histamin. c tc dng dc l ko di, cn tm cht va i khng cnh tranh v khng cnh tranh, khi thuc chm b y khi receptor bi histamin. Terfenadin, astemizol... c hai kiu c ch (c cnh tranh v khng cnh tranh) vi histamin ti receptor, nn tc dng di hn nhng do c nhiu tc dng khng mong mun trn tim nn hai thuc ny hin nay khng c s dng. Thuc khng H1 c tc dng d phng tt hn l cha, v khi histamin c gii phng to hng lot phn ng v s gii phng ng thi cc cht trung gian khc

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m thuc khng H1 khng i khng c. Tc dng ca thuc mnh nht c trn ph qun, c trn rut. Thuc cho kt qu khng r rt trong cha hen hoc cha nhng bnh tc nghn ph qun. Cn phi hp hai loi khng H1 v khng H2 c ch ton vn s h huyt p do histamin gy nn. 2.2.2. Tc dng khc - Trn thn kinh trung ng: Cc thuc khng histamin th h I c tc dng c ch thn kinh trung ng, lm du, gim kh nng tp trung t tng, ng g, chng mt. Tc dng c ch receptor H1 trung ng ny c th ko theo tc dng khng cholinergic, lm tng tc dng lm du, gim kh nng nh. Mt s thuc khng H1 th h II, do tnh a nc v c i lc vi receptor H1 ngoi bin, nn t qua hng ro mu - no, v rt t c tc dng trung ng, v d fexofenadin, loratidin... - Trn thn kinh thc vt: + Khng cholinergic (c ch h M). Nhiu thuc khng H1 th h I nh promethazin, dimenhydrinat, diphenhydramin...) c tc dng khng cholinergic ngay vi liu iu tr v trong mt s trng hp phi chng ch nh. + Thay i h giao cm: Promethazin c ch receptor a-adrenergic, lm h huyt p. Diphenhydramin, dexclopheniramin... c ch thu hi catecholamin, lm tng tim lc tc dng ca catecholamin. - Chng say tu xe chng nn: Do khng cholinergic, an thn, chng nn; tt nht l promethazin (c hiu lc ngang scopolamin). Hin nay diphenhydramin (Nautamin) v dimenhydrin hay c dng chng nn trn lm sng. - Chng ho: Nhiu thuc khng H1 chng c ho theo c ch ngoi bin do c ch s co ph qun gy phn x ho (promethazin, oxomemazin, doxylamin, dexclopheniramin...) nhng hiu lc km thuc chng ho trung ng. Thuc khng H1 lm tng tim lc ca thuc gin ph qun khc (nh cc amin cng giao cm loi ephedrin). - Tc dng khc: + Khng serotonin receptor ti vng di i gy kch thch n ngon (cyproheptadin, doxylamin). + Chng nga, gy t (khng c lin h vi tc dng khng histamin), nh mepyramin, diphenhydramin. 2.3. Tng tc thuc Thuc dng cng khng H1 Ru ethylic, thuc ng, thuc lm du, an thn kinh, thuc gim au ngun gc trung ng Thuc khng cholinergic: Biu hin tc dng Lm tng tc dng trung ng ca thuc khng H1 Lm tng tc dng

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- Loi atropin, scopolamin - Thuc an thn kinh (tr butyrophenon) - Thuc chng trm cm loi ba vng, c ch MAO, thuc chng Parkinson, dispyramid, thuc chng co tht Thuc cng ph giao cm v c ch cholinesterase: Ambenoniclorid, neostigminbromid, pyridostigminbromid, fluostigmin, paraoxon 2.4. Tc dng khng mong mun 2.4.1. Do tc dng trung ng

khng cholinergic ca thuc khng H1

i khng vi tc dng khng cholinergic ca thuc khng H1

Thay i tu theo tng c th, thng biu hin c ch thn kinh (ng g, kh chu, gim phn x, mt), mt kt hp vn ng, chng mt. Nhng biu hin trn tng mnh nu dng thuc khng H1 cng ru ethylic hoc thuc c ch thn kinh trung ng. Cm dng khi li xe, ang vn hnh my mc hoc lm vic ni nguy him (trn cao). mt s ngi, tc dng biu hin dng kch thch (nht l tr cn b): Mt ng, d kch ng, nhc u, c khi co git nu liu cao. hn ch tc dng khng mong mun trn thn kinh trung ng c th gim liu hng ngy hoc dng lc chiu ti, hoc dng loi khng H1 th h II. 2.4.2. Do tc dng khng cholinergic Kh ming, hu hng; khc m kh; kh tiu tin, b i, lit dng; ri lon iu tit th gic, tng p lc trong mt c bit ngi c glcm gc ng, nh trng ngc; gim tit sa. 2.4.3. Phn ng qu mn v c ng C th gp qu mn nghim trng sau khi dng thuc khng H1 bi ngoi, nht l khi c xc da. C qu mn cho gia cc loi khng H1. Biu hin ngoi da (ban , chm) ngay c khi ung hoc tim, mt phn c ct ngha bi vai tr lm gii phng histamin ca thuc khng H1. 2.4.4. Tc dng khng mong mun khc - Trn tim mch: terfenadin, astemizol ko di khong QT c th a n hin tng xon nh, hin nay khng dng . - Khng dung np, thay i huyt p, ri lon mu (thiu mu tan mu, gim bch cu, thoi ha bch cu ht) tng nhy cm vi nh sng. 2.5. Ch nh v chng ch nh 2.5.1.Ch nh - Thuc khng H1 ch thun tu cha triu chng m khng cha c nguyn nhn gy ra d ng.

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Thuc khng lm thay i phn ng khng nguyn - khng th; khng i khng vi nhng cht trung gian khc c vai tr rt quan trng trong d ng, shock phn v, hen ph qun (nh leucotrien). Nh vy, thuc khng H1 hn ch trong cha hen, mt s thuc phng c cn hen (promethazin, clopheniramin, thiazinamin, diphenhydramin, clemasin...) c l do khng cholinergic. Khng H1 th h II khng khng cholinergic nh mepyramin dng d phng co tht ph qun khi tp luyn. - Thuc khng H1 t hiu qu khi cn tc dng nhanh v mnh (ph thanh mn, phn v c h thng). * Ch nh tt nht l: - D ng: s mi ma, bnh da d ng (my ay cp tnh, ph n ban ; nga do d ng (nh trong chm); ph Quincke; nga do cn trng t; d ng thuc. - Bnh huyt thanh. - Ch nh khc: Cha say tu xe (promethazin, diphenhydramin, diphenhydrinat...); gy ng (promethazin); phi hp vi thuc ho lm tng tc dng chng ho; kch thch n ngon (doxylamin, cyproheptadin) hin nay khng dng; dng cng thuc khng cholinergic phng tai bin do phn x khi thm d bng ni soi hoc khi phu thut (nh khi chc mng phi). 2.5.2. Chng ch nh + Lin quan ti tc dng khng cholinergic: Ph i tuyn tin lit, glcm gc hp, nghn ng tiu ha v ng niu, nhc c, khi dng IMAO. + Do tc dng gy d ng ca thuc khng histamin: Qu mn vi thuc; khng dng thuc khng H1 ngoi da khi tn thng da. + ngi c thai, khng dng cyclizin v dn xut (c th gy qui thai). + Khng dng cc thuc th h II nh terfenadin, astemizol vi erythromycin, ketoconazol, itraconazol. + Khi li tu xe, vn hnh my mc.
CU HI T LNG GI

1. Trnh by vai tr sinh l v bnh l ca histamin. 2. Trnh by c im dc ng hc, tc dng ca thuc khng histamin th h I. 3. Trnh by c im dc ng hc, tc dng ca thuc khng histamin th h II. 4. Trnh by cc tc dng khng mong mun v p dng iu tr ca thuc khng histamin th h I v th h II.

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Bi 34:

VITAMIN

MC TIU HC T P: Sau khi hc xong bi ny, sinh vin c kh nng:

1. Trnh by c vai tr sinh l v p dng iu tr ca 3 vitamin tan trong du:A, D, E. 2. Trnh by c vai tr sinh l v p dng iu tr ca 4 vitamin tan trong nc : B1, B2, B6 v vitamin C.
1. I CNG

- Vitamin l nhng hp cht hu c m t bo ngi v ng vt khng th t tng hp (tr vitamin D), c mt trong thc n vi s lng nh, cu trc hon ton khc vi glucid, protid v lipid nhng rt cn thit cho mt s phn ng chuyn ha gip duy tr s pht trin v s sng bnh thng, khi thiu ht s gy nn bnh l c hiu. - Tu theo gii v giai on pht trin ca c th, nhu cu vitamin rt khc nhau. C th gp tha hoc thiu vitamin. S thiu ht vitamin do nhiu nguyn nhn v ng thi c th thiu nhiu loi vitamin. Do vy, trong iu tr cn phi tm nguyn nhn v phi hp nhiu loi vitamin khc nhau. Thc t c th gp tha vitamin , c bit l cc vitamin tan trong du. Da vo tnh cht ha tan trong nc hay du cc vitamin c xp thnh 2 nhm: - Cc vitamin tan trong du: vitamin A, D, E, K thi tr chm, tha s gy nn bnh l tha vitamin. - Cc vitamin tan trong nc: vitamin nhm B ( B1, B2, B3, B5, B6, B8, B9, B12 )v vitamin C thi tr nhanh ra khi c th, nhng nu dng liu cao cng gy nn ng c.
2. CC VITAMIN TAN TRONG DU

2.1.

Vitamin A

2.1.1. Ngun gc- cu trc v tnh cht Vitamin A c 3 dng: retinol, retinal v acid retionic. Retinol l mt ru di dng ester c nhiu trong gan, b, phomat, sa, lng trng. Retinal dng aldehyd ca vitamin A. C 3 tin vitamin A: a, b , g- caroten. b- caroten c nhiu trong c, qu c mu nh gc, c rt hoc rau xanh, vo c th, ch c 1/6 lng b - caroten chuyn thnh retinol. 1E.R = 6 mg b - caroten = 3,3 IU vitamin A; (E.R l equivalent Retinal). 2.1.2. Vai tr sinh l * Trn th gic: Vitamin A ch yu l retinol v retinal ng vai tr quan trng trong hot ng ca th gic. Thiu vitamin A s gy ra bnh qung g, kh mt, lot gic mc. Acid retinoic khng c tc dng trn th gic.

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C ch: trong mu vitamin A c chuyn thnh trans- retinol v sau thnh 11- cisretinol v 11- cis- retinal. Trong bng ti 11- cis- retinal kt hp vi opsin to thnh Rhodopsin. Rhodopsin l mt sc t nhy cm vi nh sng t bo hnh nn ca vng mc gip cho vng mc nhn c cc hnh nh khi thiu nh sng. Khi ra nh sng Rhodopsin b phn hu thnh opsin v trans- retinal. Trans- retinal c th c chuyn thnh cis- retinol hoc trans- retinol i vo mu tip tc chu k ca s nhn. * Trn biu m v t chc da: c bit acid retinoic kch thch bit ha t bo biu m, sinh tit nhy, c ch s sng ha t bo biu m. Ngi thiu vitamin A d b mn cm vi cc cht gy ung th v cc t bo nn ca biu m nhng vng khc nhau tng sn r rt v gim kh nng bit ha. C ch tc dng chng ung th ca vitamin A vn cha c gii thch y . C th vitamin A iu ha s sinh tng hp protein c bit cn thit cho s bit ha t bo ca t chc biu m v c ch s nhn ln ca t bo ung th. * Trn chc nng min dch: - Vitamin A tng sc khng ca c th. Thiu vitamin A kch thc ca t chc lympho thay i. b -caroten lm tng hot ng ca t bo dit (Killer cell), tng s nhn ln ca t bo lympho B v T. * b -caroten c tc dng chng oxy ha mnh c s dng trong phng v chng lo ha. Tham gia cu to ht vi th dng chp (Chylomicron). 2.1.3. Du hiu thiu ht vitamin A Nhu cu hng ngy ngi ln cn 4000- 5000 n v/ ngy, tr em t 400- 1000 n v/ ngy. Khi thiu vitamin A c cc triu chng: tng sng ha biu m, da kh, thoi ha tuyn m hi, nhim trng da, qung g, kh mng tip hp, kh gic mc c th gp vim lot gic mc d dn n m lo v c th d b nhim trng h hp, tit niu, sinh dc v chm ln, chn n. 2.1.4. Du hiu tha vitamin A Ung liu cao ko di d gy tha vitamin A, biu hin: da kh, trc vy, nga, vim da, rng tc, au xng, tng p lc ni s, au u, chn n, mt mi, d b kch thch v c th gp xut huyt. 2.1.5. Dc ng hc Trn 90% retinol trong khu phn n di dng retinolpalmitat. Nh enzym lipase ca ty ester ny b thu phn gii phng retinol hp thu. Retinol c hp thu hon ton rut nh protein mang retinol CRBP (cellular retinol binding protein). Trong mu retinol gn vo protein i vo cc t chc v c d tr gan, gii phng ra protein mang retinol. Vitamin A thi qua mt di dng lin hp vi acid glucuronic v c chu k gan- rut. Khng thy dng cha chuyn ha trong nc tiu. 2.1.6. Ch nh v liu dng * Ch nh:

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- Bnh kh mt, qung g, tr chm ln d mc cc bnh nhim trng, suy dinh dng, bnh Kwashiorkor. - Bnh trng c, da, tc, mng kh, bnh sng, bnh vy nn, cc vt thng, vt bang. - H tr trong iu tr ung th da, c t cung, i trng, phi v phng-chng lo ho . * Ch phm v liu dng: - Vin nang, vin nn 5000 ; 50000 n v. - Vin nang du c cha lng vitamin A khc nhau tu tng ch phm v thng dao ng t 200-800 n v. - Ung 5000 n v mi ngy hoc cch 10- 15 ngy ung 50.000 n v. - Ph n c thai ung di 2500 n v/ ngy. 2.2. Vitamin D 2.2.1. Ngun gc- cu trc- tnh cht - Vitamin D1 l hn hp chng ci xng, tn mang tnh cht lch s. - Ergocalciferol (D2) c ngun gc tng hp thng c dng trong iu tr. - Cholecalciferol (D3) c ngun gc t nhin c th chit xut t du gan c v mt s cy h c (Solanaceae) hoc c th t tng hp di tc dng ca tia cc tm. - Vitamin D c coi nh mt hormon v: . c tng hp di da i vo mu n c quan ch to nn tc dng thng qua receptor c hiu. . Hot tnh enzym hydroxylase xc tc cho qu trnh chuyn ha vitamin D to thnh cht c hot tnh c iu ha theo c ch iu khin ngc thng qua nng ion calci trong mu. - Vitamin D2 v D3 d b phn hu bi nh sng, oxy, acid. 2.2.2. Vai tr sinh l - Tng hp thu calci rut v ti hp thu calci ng thn do kch thch tng sinh cc carrier vn chuyn calci. Phi hp vi hormon cn gip iu ha nng calci trong mu. - Tng tch t calci trong xng, gim bi tit phosphat v gip chuyn phosphat hu c thnh phosphat v c. - Oxy ha citrat gip cho s ha tan phc hp calci v iu ha nng calci. 2.2.3. Du hiu thiu vitamin D Thiu Vitamin D c th do gim hp thu rut, suy cn gip, dng thuc c ch enzym gan, ngi t tip xc vi nng. Thiu vitamin D c du hiu gim calci v phosphat trong mu, c th gp cn h calci mu. Thiu lu di dn n ci cng tr em v nhuyn xng ngi ln. 2.2.4. Du hiu tha vitamin

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Tr di 1 tui dng lin tc 400 n v/ ngy. Tr trn 1 tui dng lin tc trn 1000 n v / ngy c th gy ng c. Liu trn 50.000n v / ngy c th gy ng c c tr em v ngi ln. Khi ng c c biu hin tng calci mu, chn n, mt mi, i nhiu, kht nc, nn, a chy, ri lon tm thn. Tng calci mu ko di gy calci ha cc tng v c th gp suy thn. Gp ng c phi ngng ung vitamin D, c ch n t calci, dng glucocorticoid v truyn dch. 2.2.5. Dc ng hc Vitamin D c hp thu rut non; D3 hp thu tt hn D2. Trong mu vitamin D c gn vo a - globulin v c tch lu gan v t chc m. to thnh cht c tc dng, vitamin D c hydroxyl ha qua 2 giai on. gan c chuyn thnh 25 hydroxycalciferol hay calcifediol sau i vo mu n thn b hydroxyl ha ln th 2 to thnh 1 , 25 dihydroxylcalciferol hay calcitrol c hot tnh. Enzym tham gia phn ng hydroxyl ha vitamin D gan v thn c th gy cm ng hoc tng hot tnh bi s thiu vitamin D, calci, phosphat, hormon cn gip, prolactin v estrogen. Thi tr ch yu qua mt, phn nh thi qua nc tiu. Thuc ha c chu k gan rut. 2.2.6. Ch nh- ch phm v liu dng * Ch nh: - Phng v chng ci xng tr em, phng v chng long xng, nhuyn xng ngi ln, ngi gy xng lu lnh. - Phng v chng co git trong suy cn gip. - Hi chng Fanconi. * Ch phm v liu dng Mt n v quc t vitamin D bng 25 nanogam ergocalciferol hoc colecalciferol. Hin nay c nhiu ch phm dng vin nang, vin nn, dung dch ung hoc tim bp cha ergocalciferol, colecalciferol, alfacalcidol, calcitriol, hoc dihydrotachysterol hm lng khc nhau. - Phng bnh (tr em): ung 500- 1000 n v/ ngy hoc cch 6 thng ung liu duy nht 200.000 n v. - iu tr ci xng: ung 10.000- 20.000 n v (chia 3 ln/ ngy). Ngi ln ung 400- 800 n v/ ngy. - Chng co git do suy cn gip: ung hoc tim bp 50.000- 200.000 n v/ ngy. Tun dng 2 ln. 2.3. Vitamin E 2.3.1. Ngun gc- cu trc- tnh cht Vitamin E gm 3 dng: a, b v g- tocopherol c cu trc v tc dng dc l tng t nhau. Ring a- tocopherol chim 90% lng tocopherol trong t chc v c tc dng sinh hc cao nht nn c s dng nhiu trn lm sng. D - a- tocopherol c hot tnh mnh hn L- a tocopherol, 1 mg d- a- tocopherol = 1,5 n v vitamin E.

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Vitamin E c nhiu trong cc ht ng cc, la m, ng, u, gi , du lc, du olive, rau xanh, gan, m, b, lng trng, b t t mt tc dng trong khng kh, tia cc tm, nhit cao, FeCl3 v peroxid. 2.3.2. Vai tr sinh l - Tng sn xut tinh trng v kh nng th thai, lm t ca trng th thai. - Ngn cn s to thnh gc t do, lm vng bn mng t bo c bit khi c mt vitamin C v cc cht c cha nhm SH. - Tng hp thu v d tr vitamin A, nhng li lm gim mt s triu chng ca s tha vitamin A. 2.3.3. Du hiu thiu ht Nhu cu hng ngy ca ngi ln l 10- 30 mg. Thiu ht ko di s gp mt s triu chng sau: gim phn x, tht iu, gim nhy cm xc gic, yu c, teo c ph i, gim sn xut tinh trng, gim kh nng th thai, do xy thai, non, tn thng c tim , thiu mu, tan mu v rung git nhn cu. 2.3.4. Du hiu tha vitamin Dng liu cao trn 300 n v/ ngy c th gy bun nn, nn, y hi, i lng, vim rut hoi t. Tim tnh mch c th gy ri lon chc nng gan- thn, do hin nay khng dng. 2.3.5. Dc ng hc Sau khi thu phn rut non, thng qua cc ht vi dng chp i vo dng bch huyt vo mu. Trong mu gn vo b -lipoprotein v c phn phi vo hu ht cc t chc. D tr nhiu trong gan v t chc m. i qua hng ro rau thai km. 2.3.6. Ch nh v liu dng * Ch nh: - Do xy thai, ph n b xy thai lin tip,v sinh - Teo c ; thiu mu, tan mu, bnh x cng b tr em v lipid mu cao. - Chng lo ha: vitamin E c phi hp vi coenzym Q, acid amin cha lu hunh hoc b - caroten, vitamin C v selen. - Cn th tin trin do gim s oxy ho ca b- caroten. - Chng i dm sau hoc ri lon kinh nguyt. * Ch phm v liu dng: - Ch phm : Vin nang: 200, 400, v 600 mg;vin nn hoc vin bao ng: 10, 50, 100 v 200 mg; ng tim : 30, 50, 100 hoc 300 mg/mL - Liu lng: Thuc c th ung hoc tim bp. Liu thng dng cho ngi c biu hin thiu ht cao gp 4- 5 ln nhu cu hoc 40-50 mg/ngy. 2.4. Vitamin K (xem bi "thuc tc dng trn qu trnh ng mu")
3. CC VITAMIN TAN TRONG NC

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3.1.

Vitamin B1 (thiamin, Aneurin)

3.1.1. Ngun gc, cu trc v tnh cht C nhiu trong men bia (6- 10 mg/ 100g), cm go, u tng. Ngoi ra c lng nh vitamin B1 trong sa, trng, tht nc, gan, thn. Khng n nh vi nh sng v m. Mt hot tnh trong mi trng trung tnh v base. n nh tnh cht pH = 4. Enzym diphosphatkinase xc tc cho s chuyn ha thiamin thnh thiamin pyrophosphat b c ch bi cc cht khng thiamin: neopyrithiamin v oxythiamin. 3.1.2 . Vai tr sinh l - Dng hot tnh ca thiamin l thiaminpyrophosphat c vai tr mt coenzym ca decarboxylase, transketolase gip cho qu trnh chuyn ha pyrurat, a- ketoglutarat thnh cc aldehyd v acid carboxylic v chuyn ha pentose trong chu trnh hexosemonophosphat. Khi thiu thiamin nng pyrurat trong mu tng cao v transketolase trong hng cu gim r rt. - Tham gia tng hp acetylcholin v kh carboxyl ca valin, leucin v isoleucin. 3.1.3.Du hiu thiu ht Khi thiu vitamin B1 c th lm cho c th mt mi, chn n, gim tr nh, au, vim dy thn kinh, gim trng lc c. Nu thiu nng v ko di c th dn n bnh t ph Beri-Beri v suy tim, ngy nay t gp. 3.1.4.Dc ng hc Hp thu rut nh qu trnh vn chuyn tch cc, liu cao c th khuch tn th ng qua nim mc rut. Bo ha ngng hp thu vi liu 8- 15 mg nhng chia nh liu v ung ri rc cng vi thc n s tng s hp thu. Thiamin c tp trung cao nht gan, no, thn, tim. Khi cc m qu nhu cu thiamin s b thi tr qua nc tiu di dng cha chuyn ha, hoc dng pyrimidin. 3.1.5.Ch nh v liu dng * Ch nh: - Bnh t ph Beri- Beri - Vim au dy thn kinh, c bit ngi nghin ru, ph n c thai. - Ri lon tiu ha: chn n, kh tiu, a chy ko di, vim lot i trng. - Bnh tim mch, ngi c ch nui dng nhn to v nhc c. * Liu dng: - Trung bnh ngi ln ung 0,04- 0,1g/ ngy hoc tim bp 0,05 g/ ngy. - Liu cao 0,1- 1,0g/ ngy (chia 2- 3 ln) dng iu t vim dy thn kinh, au khp, au mnh my. - Khi nhu cu s dng glucid tng th cn tng liu lng thiamin. C 1000 calo c ngun t glucid cn 0,5 mg thiamin.

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* Khng tim trc tip vitamin B1 vo tnh mch gy shock c th dn n t vong. C th pha 100 mg thiamin trong 1 lt dung dch glucose nh git tnh mch. 3.2. Vitamin B2 (Riboflavin) v vitamin B6 (Pyridoxin) - Vitamin B2: c mu vng v c mt trong hu ht cc thc phm, vi khun rut c kh nng tng hp vitamin B2. t tan trong nc hn cc vitamin nhm B khc v d b phn hu trong mi trng nc v base, l thnh phn cu to nn Flavomononucleotid (FMN) v Flavoadenindinucleotid (FAD). FMN v FAD l cofactor ca cyt- c- reductase, oxydase v dehydrogenase gip tng cng chuyn ha glucid, lipid, protid v vn chuyn in t trong chui h hp t bo. t gp thiu ht ring r vitamin B2. nhng ngi nui dng nhn to, vim da, nim mc, thiu mu v ri lon th gic c th ung vitamin B2 (5- 10 mg/ ngy). - Vitamin B6: c mt trong nhiu loi thc phm ging vitamin B1 v rt d phn hu nhit cao hoc tip xc vi cht oxy ha hay tia cc tm. Di s xc tc ca pyridoxalkinase, vitamin B6 chuyn thnh pyridoxalphosphat mt coenzym ca transaminase, decarboxylase v desaminase. Ngoi ra, vitamin B6 cn tham gia tng hp GABA v chuyn ha acid oxalic, vitamin B12, acid folic. C th gp thiu vitamin B6 ngi suy dinh dng hoc dng INH, hydralazin, pencilamin Thuc c dng ng ung, tim bp hoc di da 0,05- 0,1g/ ngy cho nhng ngi c vim dy thn kinh ngoi vi, thn kinh th gic, x va ng mch, ng kinh, chng ma vn tr em, ngi say tu xe, vim nim mc ming, thiu mu, gim bch cu ht hoc khi dng km 1 s thuc. 3.3. Vitamin B3 (acid nicotinic, Niacin, vitamin PP): Xin xem bi thuc h lipoprotein mu. 3.4. Vitamin B5 v B8 t gp thiu ht 2vitamin ny ring r Vitamin B5 (acid panthothenic) : C mt trong hu ht cc loi thc phm, l thnh phn rt quan trng cu to nn coenzym A, gip cho s chuyn ha glucid, lipid, tng hp cc sterol trong c hormon steroid v porphyrin. Thuc c ch nh trong ri lon chuyn ha do cc nguyn nhn khc nhau, bnh ngoi da, chng mt do khng sinh aminoglycosid gy ra, phng v chng sc sau m v vim nhim ng h hp. Vitamin B8 (vitamin H, Biotin): C nhiu trong cc ph tng, lng trng, c, cc loi ht v l cofactor ca enzym carboxylase tham gia phn ng kh carboxyl ca 4 c cht: Pyrurat- CoA, acetylCoA, Propionyl- CoA v b - methylcrotonyl- CoA gip cho s chuyn ha glucid v lipid. Tuy nhin, vitamin B8 thng c ch nh trong bnh da tng tit b nhn, bnh nhn c ch n nhn to v thiu ht enzym ph thuc biotin c tnh di truyn. 3.5. Vitamin C (acid ascorbic) 3.5.1. Ngun gc- tnh cht

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- C trong hu ht rau, qu c bit trong rau ci xoong, cam, qut, chanh, bi, c chua. Tan mnh trong nc nhng d b phn hu bi nhit , cc cht oxy ha v trong mi trng base. 3.5.2. Vai tr sinh l Trong c th, acid ascorbic b oxy ha to thnh acid dehydroascorbic vn cn y hot tnh v 2 in t. y l phn ng thun nghch. Nh c nhm endiol trong phn t nn vitamin C l cofactor ca nhiu phn ng oxy ha kh quan trng trong s tng hp collagen, carnitin, chuyn acid folic thnh acid folinic, c ch hyaluronidase lm vng bn thnh mch. - Chuyn dopamin thnh noradrenalin, tng hp serotonin t tryptrophan, tng hp hormon thng thn v s tng hp collagen, proteoglycan v cc thnh phn hu c khc rng, xng, ni m mao mch. - Gip chuyn Fe+3 thnh Fe+2 lm tng s hp thu st rut. - Ngoi ra, vitamin C cn c tc dng hip ng vi vitamin E, b - caroten, selen lm ngn cn s to gc t do gy c t, bo tng tng hp interferon, gim nhy cm ca t bo vi histamin. 3.5.3. Du hiu thiu ht - Thiu trm trng vitamin C gy bnh Scorbut- ngy nay t gp, in hnh c du hiu: chy mu di da, rng ming, rng rng, tng sng ha nang lng, vim li .Thiu va phi biu hin: mt mi, vim li, ming, thiu mu, gim sc khng d b nhim trng. 3.5.4. Du hiu tha vitamin C Tuy t tch lu, nhng khi dng liu cao trn 1g/ ngy v di ngy c th gp tha vitamin C, biu hin: mt ng, kch ng, i lng, vim lot d dy- rut, gim sc bn hng cu c th gy tan mu c bit ngi thiu G6PD. Ph n mang thai dng liu cao di ngy c th gy bnh Scorbut cho con. C th gp si thn oxalat do dehydroascorbic chuyn thnh acid oxalic v tng huyt p. 3.5.5. Ch nh v liu dng * Ch nh: - Phng v iu tr bnh Scorbut, chy mu do thiu vitamin C. - Tng sc khng trong nhim trng, nhim c, thai nghn. - Thiu mu, d ng v ngi nghin ru, nghin thuc l. * Liu dng: - Ung trung bnh 0,2- 0,5g/ ngy, nn chia liu nh ung nhiu ln trong ngy. - Tim di da hoc tnh mch khng vt qu 1g/ ngy. Ch c th gp schock khi tim, c bit khi tim tnh mch. - Tr em dng mt na liu ngi ln.
CU HI T LNG GI

1. Trnh by vai tr sinh l v p dng iu tr ca vitamin A.

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2. Trnh by vai tr sinh l v p dng iu tr ca vitamin D. 3. Trnh by vai tr sinh l v p dng iu tr ca vitamin E. 4. Trnh by vai tr sinh l v p dng iu tr ca vitamin B1. 5. Trnh by vai tr sinh l v p dng iu tr ca vitamin B2 v vitamin B6. 6. Trnh by vai tr sinh l v p dng iu tr ca vitamin C.

PHN VII HORMON V CC THUC IU CHNH RI LON NI TIT


Bi 35:

HORMON V THUC KHNG HORMON

MC TIU HC T P: Sau khi hc xong bi ny, sinh vin c kh nng:

1. Trnh by c c ch tc dng v p dng iu tr ca hormon gip trng v khng gip trng tng hp. 2. Trnh by c tc dng v c ch tc dng ca insulin 3. Trnh by c c ch tc dng, p dng lm sng ca glucocorticoid. 4. Phn tch c tc dng khng mong mun ca corticoid, cch theo di v d phng. 5. Nu c tc dng v p dng iu tr ca androgen v thuc khng androgen. 6. Nu c tc dng v p dng iu tr ca estrogen v thuc khng estrogen. 7. Trnh by c tc dng v p dng iu tr ca progesteron v thuc khng progesteron. 8. Trnh by c tc dng v p dng iu tr ca cc thuc chng th thai.
1. HORMON TUYN GIP

Tuyn gip sn xut 2 loi hormon khc nhau: - Thyroxin v triiodothyronin c vai tr quan trng trong s pht trin bnh thng ca c th v chuyn ha nng lng. - Calcitonin (thyrocalcitonin) l hormon iu ha chuyn ha calci v phospho. 1.1.Thyroxin v triiodothyronin (T4 v T3) 1.1.1. Tc dng sinh l

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- iu ha pht trin c th: kim tra hu ht cc qu trnh tng hp protein v s pht trin ca h thn kinh. Rt nhiu enzym chuyn ha lipid, protid v glucid chu nh hng ca thyroxin. Thiu thyroxin th enzym gim hot ng. - Lm tng qu trnh chuyn ha ca c th, c bit l chuyn ha ca cc t chc tim, gan, thn. C vai tr quan trng trong to nhit v iu ho thn nhit ca ng vt ng nhit. Khi chc phn tuyn gip km th gy ph nim dch, chuyn ha c s gim, thn nhit h, rng tc, mch chm, rut gim nhu ng, km n, sc kho v tr khn gim ( tr em, gi l chng n n). Ngoi cc triu chng trn, tr chm ln, tuyn gip to ra v tuyn yn vn bi tit thm cc cht kch thch tuyn gip. Trong tuyn y cht dng keo, nhng rt km v s lng hormon. vi vng ni, nc ung t iod cng gy bu c a phng. Bnh thng mi ngy ta cn 0,075 g iod. Khi cng tuyn th gy Basedow: bu c, mt li, tay run, mch nhanh, cholesterolmu gim, chuyn ha c s tng (vt trn 20%). Thyroxin mu tng, nhng v c ri lon tin yn- gip, nn tuyn gip vn to ra (cng c trng hp khng to). T bo tuyn c thyreoglobulin, khi b thu phn s cho thyroxin (3,5 diiodothyrozinT4) v 3, 5, 3' triiodotyronin (T3). T l T4/ T3 trong thyreoglobulin l 5/1, ngha l phn ln hormon c gii phng l thyroxin, cn phn ln T3 tun hon trong mu li l t chuyn ha ngoi bin ca T4. Tc dng ca T3 mnh hn T4 3- 4 ln. trong huyt tng, T3 v T4 gn vo thyroxin- binding globulin (TBG), dng t do ca T4 ch bng khong 0,04% tng lng v T3 l khong 0,4%.
I O I
3' 2'

5'

6'

HO

CH2CHCOOH I
3 2

NH2

3 ,5 ,3 '

triiodothryronin (T3)

I HO I

6'

I O I CH 2CHCOOH NH 2

Thyroxin (T4)

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S kh iod ca T4 c th xy ra vng trong, to ra 3, 3, 5 triodotyronin, c gi l T3 ngc (reverse T3 hoc r T3), khng c hot tnh. Thuc chn , corticoid, i lu ngy, c ch enzym chuyn T4 thnh T3, lm gim lng T3 v lm tng r T3 trong huyt tng. Hormon TSH iu ha s thu phn thyreoglobulin v s nhp iod vo tuyn gip. Ngc li m thyroxyn v 3, 5, 3' triod tironin trong huyt tng iu ha s tit TSH. Trong huyt tng, c mt gama globulin tng hp trong lympho tc ng cng tng t nh TSH, nhng thi gian lu hn, l yu t L.A.T.S. (long- acting thyroid stimulator). 1.1.2. Ch nh v ch phm Hai ch nh chnh l suy tuyn gip (hay myxoedme) v bu c a phng. - Thyreoidin; bt tuyn gip kh ca ng vt (c 0,17- 0,23% iod), ung 0,1- 0,2g mi ln, mi ngy ung 2- 3 ln. Liu ti a mt ln 0,3g, mt ngy 1,0g. - Thyroxin: vin 0,1 mg; dung dch ung 1 git = 5 mg. Ung liu u 0,1 mg. Sau tng dn tng 0,025 mg. - Kali iodid: trn 1 mg vo 100 g mui n thng gi l mui iod d phng bu c a phng. - Levothyroxin (Levothyrox, Thyrax, Berithyrox) vin nn 25- 50- 100- 150 mg. L ch phm tng hp c nhiu u im nn l thuc c chn la trong iu tr: thuc c tnh n nh cao, thun nht, khng c protein ngoi lai nn khng gy d ng, d xc nh nng trong huyt tng, thi gian bn thi di (7 ngy), gi thnh h. Liu lng: i t liu thp, tng dn tng 25 mg tu theo tnh trng bnh v tui bnh nhn. 1.2. Calcitonin 1.2.1. Tc dng sinh l L hormon lm h calci mu, c tc dng ngc vi hormon cn gip trng, do "t bo C" ca tuyn gip bi tit. L mt chui a peptid hoc gm 32 acid amin c trng lng phn t l 3600. Tc dng chnh ba ni: - Xng: c ch tiu xng bng c ch hot tnh ca cc hu ct bo (ostoclaste), ng thi lm tng to xng do kch thch to ct bo (ostoblaste). - Thn: gy tng thi tr calci v phosphat qua nc tiu do tc dng trc tip. Tuy nhin, do c ch tiu xng nn calcitonin lm gim bi tit Ca2+, Mg2+ v hydroxyprolin qua nc tiu. - ng tiu ha: lm tng hp thu calci Tm li, calcitonin nh mt hormon d tr, hormon tit kim calci v n lm ngng s hu xng v lm tng hp thu calci qua tiu ha. 1.2.2. Ch nh

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- Calcitonin c tc dng lm h calci- mu v phosphat- mu trong cc trng hp cng cn gip trng, tng calci mu khng r nguyn nhn tr em, nhim c vitamin D, di cn ung th gy tiu xng, bnh Paget (c ng ha v d ha ca xng u tng rt mnh). - Cc bnh long xng: sau mn kinh, tui cao, dng corticoid ko di. - Ngoi ra, calcitonin cn c tc dng gim au xng, c dng trong cc di cn ung th. 1.2.3. Tc dng khng mong mun - Triu chng tiu ha: bun nn, nn, tiu chy, au bng - Triu chng v mch mu: nng mt, mt, nng chi v c cm gic kin b. - Thn: i tiu nhiu ln, a niu 1.2.4. Ch phm - Calcitonin: 100 UI/ ngy u, sau gim xung 50 UI mi tun 3 ln. - Calcitonin ca c hi (salmon): Miacalcic ng 1 mL cha 50 UI- chai xt nh liu 50 v 200 UI. Tim di da hoc xt vo mi 50- 100 UI mi ngy hoc cch ngy. Calcitonin ca c hi mnh hn calcitonin ca ngi v ln t 10- 40 ln v tc dng lu hn 10 ln. 1.3. Thuc khng gip trng tng hp Qu trnh tng hp thyroxin c 4 giai on: - Gn iodid v c vo tuyn (iodid l iod dng ion I-) - Oxy ha iodid thnh iod t do - To mono- v diiodotyrosin (MIT- DIT) - Ghp 2 iodotyrozin thnh L- thyroxin- tetraiodotyrosin T4 (TIT) (xem hnh ) Thuc khng gip trng c dng cha cng gip (bnh Basedow). C th chia thnh 4 nhm:

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Hnh 35.1.V tr tc dng ca thuc khng gip trng MIT: monoiodotyrosin, DIT: diiodo- tyrosin (1): Thiocyanat, perclorat (2): Nhm thiamid carbimazol, benzylthiouracil, propylthiouracil, methimazol (3): Lithium

1.3.1. Thuc c ch gn iodid vo tuyn c ch qu trnh vn chuyn iod nh thiocyanat (SCN-), perclorat (ClO4-), nitrat. c v thng gy mt bch cu ht, khng c dng trong lm sng. 1.3.2. Thuc c ch trc tip tng hp thyroxin: Thioamid S N C R 1.3.2.1. C ch

Loi ny khng c ch gn iod vo tuyn gip, nhng c ch to thnh cc phc hp hu c ca iod do c ch mt s enzym nh iod peroxydase, cc enzym oxy ha iod. V vy tuyn khng tng hp c mono- v diiodotyrosin. 1.3.2.2. c tnh Dng thuc c ch tng hp thyroxin ko di, lng thyroxin gim, lm tuyn yn tng tit TSH. TSH tng, kch thch tuyn gip nhp iod, lm tng sinh, dn n chng ph nim (tuyn gip cha nhiu cht dng keo, nhng t hormon) Nhm thuc ny t gy tai bin. Tai bin nng nht l gim bch cu ht (0,3- 0,6%) thng xy ra sau vi thng iu tr. V vy cn kim tra s lng bch cu c nh k v nn dng thuc ngt qung. Cc tai bin khc: pht ban, st, au khp, nhc u, bun nn, vim gan, vim thn. Thng ngng thuc hoc i thuc khc s ht.

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1.3.2.3.

Ch phm

Cc loi thuc ny thng c dng lm sng cha cng tuyn gip, gm: - Aminothiazol: mi ngy 0,6- 0,8g. Gim dn, ri dng liu duy tr 0,2g. Hin nay t dng v c. - Thio- uracil: mi ln 0,5g. Mi ngy 2- 3 ln, tai bin 5,8%. R = CH3 R = C3H7 R = CH2 - C6H5 metyl thiouracil (MTU) propyl thiouracil (PTU) benzyl thiouracil (Basden)

- Thiamazol (Basolan): mi ngy ung 15- 60 mg. Tai bin 3,4%. - Carbimazol (Neomecazol): mi ngy ung 15- 60 mg. Vo c th chuyn thnh methiazol, cht ny mnh gp 10 ln PTU nn a dng hn. 1.3.2.4. Cch dng Ung thuc lm 3 giai on: - Tn cng: 3- 6 tun vi liu 150- 200 mg - Duy tr: 3- 6 thng vi liu 100 mg - Cng c: hng thng. Liu hng ngy bng 1/4 liu tn cng. 1.3.3. Iod Nhu cu hng ngy l 150 mg. Khi thc n khng cung cp iod, s gy bu c n thun. Tri li, khi lng iod trong mu qu cao s lm gim tc dng ca TSH trn AMPv. Lm gim gii phng thyroxin. - Ch nh: chun b bnh nhn trc khi m ct tuyn gip. - Dng cng vi thuc khng gip trng v thuc phong to b adrenergic trong iu tr tng nng tuyn gip. - Ch phm: dung dch Lugol (iod 1g, kali iodid 2g, nc va 20mL), ung XXX git mi ngy (XX git cha 10mg iod). - c tnh: thng t v hi phc khi ngng dng: trng c, sng tuyn nc bt, lot nim mc, chy mi... (tng t nh nhim c brom) 1.3.4. Ph hu t chc tuyn: iod phng x 1.3.5. Thuc phong to h adrenergic Nhiu triu chng ca cng gip l cng giao cm. V vy dng guanethidin, reserpin. Nhng tt hn c l thuc chn propranolol. Nhm thuc ny ch c tc dng cha triu chng, khng tc dng vo tuyn.
2. HORMON TUYN TY

o Langerhans ca tuyn ty c 4 loi t bo bi tit:

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- T bo A (a) chim 20%, tit glucagon v proglucagon - T bo B (b) chim 75%, tit insulin, proinsulin v C peptid - T bo C ( d) chim 3%, tit somatostatin - T bo F (PP) chim < 2%, tit pancreatic polypeptid (PP) Bi ny ch trnh by 2 hormon quan trng l insulin l glucagon. 2.1. Insulin Insulin l mt protein c trng lng phn t l 5800 Da, gm 2 chui peptid A (21 acid amin) v B (30 acid amin) ni vi nhau bng 2 cu disulfid. Ton b tuyn ty ca ngi c 8 mg insulin, tng ng 200 n v sinh hc. Khi i, tuyn ty tit khong 40 mg (1 n v) insulin vo tnh mch ca. Glucose l tc nhn ch yu gy tit insulin, thi gian bn thi trong huyt tng l 5- 6 pht vi insulin v khong 17 pht vi proinsulin. Insulin b ging ha ch yu gan v thn do b ct ng ni disulfid gia chui A v B bi insulinase. 2.1.1. Tc dng v c ch Insulin iu ha ng huyt ti cc m ch ch yu l gan, c v m. Insulin l hormon ch yu kim tra s thu hi, s dng v d tr cc cht dinh dng cho t bo. Insulin kch thch cc qu trnh ng ha ca t bo (s dng v d tr glucose, acid amin, acid bo), ng thi c ch cc qu trnh d ha (phn hu glycogen, m v protein). Tc dng chung l kch thch vn chuyn cc c cht v ion vo trong t bo, hot ha v bt hot cc enzym c hiu. Glucose nhp vo t bo bng s khuch tn thun li nh vo cc cht vn chuyn glucose (glucose transporters- GLUT): GLUT 1 c mi m, c bit l hng cu v no GLUT 2 c t bo b ca ty, gan, thn, rut GLUT 3 c no, thn, rau thai GLUT 4 c c v m m GLUT 5 c rut v thn Glucose c s dng l nh vo h thng enzym hexokinase chuyn thnh glucose- 6- phosphat (GGP). Sau G6P s chuyn thnh glycogen d tr hoc b oxy ha cung cp nng lng cho m. Hexokinase IV l mt glucokinase c thy kt hp vi GLUT 2 trong gan v t bo b ca ty; hexokinase II li c thy kt hp vi GLUT 4 trong t bo c vn, c tim v m m. C 2 hexokinase ny u c iu ha bi insulin ngay mc phin m di truyn. 2.1.1.1. Tc dng ca insulin ti gan - c ch hy glycogen (c ch phosphorylase) - c ch chuyn acid bo v acid amin thnh keto acid - c ch chuyn acid amin thnh glucose - Thc y d tr glucose di dng glycogen (gy cm ng glucokinase v glycogen synthetase)

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- Lm tng tng hp triglycerid v VLDL. 2.1.1.2. Tc dng ca insulin ti c vn - Lm tng tng hp protein, tng nhp acid amin vo t bo - Lm tng tng hp glycogen, tng nhp glucose vo t bo 2.1.1.3. Tc dng ca insulin ti m m - Lm tng d tr triglycerid v lm gim acid bo t do trong tun hon theo 3 c ch: . Gy cm ng lipoproteinlipase tun hon nn lm tng thu phn triglycerid t lipoprotein tun hon. . Este ha cc acid bo t thu phn lipoprotein . c ch trc tip lipase trong t bo nn lm gim lipolyse ca triglycerid d tr. 2.1.2. Receptor ca insulin Hu nh mi t bo ca ng vt c v u c receptor vi insulin, nhng s lng rt khc nhau: mng t bo hng cu ch c 40 receptor trong khi mng t bo m, t bo gan c ti 300.000. Khi insulin gn vo receptor, n s hot ha cc tyrosin kinase trong t bo (ngi truyn tin th 2) v thc y cc qu trnh phosphoryl ha gy ra s chuyn v ca cc cht vn chuyn glucose (GLUT) v pha mng t bo nhp glucose vo trong t bo. Khi thiu insulin, t bo s khng s dng c glucose, glucose huyt s tng gi l bnh i tho ng. C 2 loi (typ) i tho ng. (Xin xem thm bi Thuc h glucose mu). - i tho ng typ I, do tn thng t bo b ca ty, ty khng bi tit insulin nn phi iu tr b bng insulin ngoi lai, gi l bnh i tho ng ph thuc vo insulin. Bnh thng gp ngi tr, th gy. - i tho ng typ II, do tn thng ti receptor (gim s lng hoc gim tnh c m th ca receptor vi insulin), insulin mu vn bnh thng hoc c khi cn tng nn gi l bnh i tho ng khng ph thuc vo insulin. Bnh thng gp ngi trn 40 tui, bo bu. 2.1.3. p dng iu tr - Bnh i tho ng v cc bin chng ca n (xin xem thm bi "Thuc h glucose mu") - Nn, tr gy yu, km n: dng insulin vi glucose 2.1.4. Cc ch phm chnh Cc ch phm thng c ngun gc t b, ln hoc bng k thut ti t hp DNA ca insulin ngi. Insulin b mang tnh khng nguyn nhiu hn ln. Cc loi ch phm: xin xem bi Thuc h glucose mu. 2.2. Glucagon Do t bo alpha ca o Langerhans tit ra, glucagon c tc dng tng glucose mu, tng acid lactic mu, tng acid pyruvic mu, tng acid bo t do huyt tng. Vi liu cao, glucagon kch thch thng thn bi tit catecholamin.

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Glucagon lm tng sc co bp ca c tim, nhp tim v cung lng tim, h huyt p, tng t nh isoprenalin (thuc c tc dng cng b adrenergic). Liu cao lm gin c trn ca rut khng thng qua AMPv. 2.2.1. C ch tc dng Glucagon hot ha adenylcyclase, lm tng m 3', 5' AMP vng, 3', 5' AMP vng hot ha phosphorylase gan, chuyn glycogen thnh glucose. C vn khng c receptor vi glucagon. C ch ny cng ging nh c ch v tc dng ca catecholamin hot ha cc receptor b adrenergic. 2.2.2. Ch nh - H glucose- mu do dng qu liu insulin (kt hp vi glucose tim tnh mch), hoc cn sc insulin ko di. - Sc (glucagon c dng thay isoprenalin). - nh gi d tr glycogen trong gan, phn loi cc th bnh v glycogen. 2.2.3. Ch phm Glucagon: 1 mL = 1mg. Tim di da, tim bp hoc tnh mch. Tc dng xut hin nhanh. Cng tc dng ph thuc vo d tr glycogen ca gan.
3. HORMON V THNG THN: GLUCOCORTICOID

V thng thn c 3 vng sn xut hormon: - Vng cun pha ngoi, sn xut hormon iu ha thng bng in gii (mineralocorticoid), i din l aldosteron, chu s kim tra chnh ca h reninangiotensin. - Vng b v vng li pha trong, sn xut hormon iu ha glucose (glucocorticoid- hydrocortison hay cortisol) v androgen, chu s kim tra chnh ca ACTH tuyn yn. Trong lm sng thng dng glucocorticoid nn y ch trnh by nhm thuc ny. Corticoid iu ha glucose: CORTISOL (hydrocortison) 3.1. Tc dng sinh l v tai bin Mi tc dng sinh l ca corticoid u l ngun gc ca cc tai bin khi dng ko di. 3.1.1. Trn chuyn ha - Chuyn ha glucid: corticoid thc y to glucose t protid, tp trung thm glycogen gan, lm gim s dng glucose ca cc m, nn lm tng glucose mu. V th c khuynh hng gy ra hoc lm nng thm bnh i tho ng. - Chuyn ha protid: corticoid lm gim nhp acid amin vo trong t bo, tng acid amin tun hon, dn n teo c, thng bng nit (-). Do tng d ha protid, nhiu m b nh hng: m lin kt km bn vng (gy nhng vch rn di da), m lympho b teo (tuyn hung, lch, hch lympho), xng b tha do lm teo cc thm m lin kt, ni lng ng cc cht v c to nn khung xng (do xng di d b gy, t sng b ln, hoi t v khun c xng i).

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- Chuyn ha lipid: corticoid va c tc dng hu lipid trong cc t bo m, lm tng acid bo t do; va c tc dng phn b li lipid trong c th, lm m ng nhiu mt (khun mt mt trng), c, na thn trn (nh dng Cushing), trong khi cc chi v na thn di th teo li. C gi thit gii thch rng t bo m ca na thn trn p ng ch yu vi tng insulin do glucocorticoid gy tng ng huyt, trong khi cc t bo m khc li km nhy cm vi insulin v p ng vi tc dng hu lipid. - Chuyn ha nc v in gii: . Na+: lm tng ti hp thu Na+ v nc ti ng thn, d gy ph v tng huyt p. . K+: lm tng thi K+ (v c H+), d gy base mu gim K+ (v c base mu gim Cl-). . Ca2+; lm tng thi Ca2+ qua thn, gim hp thu Ca2+ rut do i khng vi vitamin D. Khuynh hng lm gim Ca- mu ny dn ti cng cn gip trng phn ng ko Ca2+ t xng ra, cng lm xng b tha, lm tr em chm ln. . Nc: nc thng i theo cc ion. Khi ph do aldosteron tng th corticoid gy i nhiu (nh trong x gan) v n i khng vi aldosteron ti thn. 3.1.2. Trn cc c quan, m - Kch thch thn kinh trung ng, gy lc quan, c th l do ci thin nhanh c tnh trng bnh l. V sau lm bt rt, bn chn, lo u, kh ng (c th l do ri lon trao i ion Na+, K+ trong dch no tu). Gy thm n, do tc dng trn vng i. - Lm tng ng mu, tng s lng hng cu, bch cu, tiu cu, nhng lm gim s lng t bo lympho do hu cc c quan lympho. - Trn ng tiu ha: corticoid va c tc dng gin tip, va c tc dng trc tip lm tng tit dch v acid v pepsin, lm gim sn xut cht nhy, gim tng hp prostaglandin E1, E2 c vai tr trong vic bo v nim mc d dy. V vy, corticoid c th gy vim lot d dy. Tai bin ny thng gp khi dng thuc ko di hoc dng liu cao. - Do c ch cu to nguyn bo si, c ch cc m ht, corticoid lm chm ln so cc vt thng. 3.2. Cc tc dng c dng trong iu tr Ba tc dng chnh c dng trong iu tr l chng vim, chng d ng v c ch min dch. Tuy nhin, cc tc dng ny ch t c khi nng cortisol trong mu cao hn nng sinh l, l nguyn nhn d dn n cc tai bin trong iu tr. V vy, trong trng hp c th, nn dng thuc ti ch trnh tc dng ton thn v nng cao hiu qu iu tr n ti a. C ch tc dng ca corticoid rt phc tp v c nhiu tc dng trn mt t bo ch, v li c nhiu t bo ch. 3.2.1. Tc dng chng vim Glucocorticoid tc dng trn nhiu giai on khc nhau ca qu trnh vim, khng ph thuc vo nguyn nhn gy vim: - c ch mnh s di chuyn bch cu v vim. - Lm gim sn xut v gim hot tnh ca nhiu cht trung gian ha hc ca vim nh histamin, serotonin, bradykinin, cc dn xut ca acid arachidonic (s 1). Glucocorticoid c ch phospholipase A2, lm gim tng hp v gii phng leucotrien,

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prostaglandin. Tc dng ny l gin tip v glucocorticoid lm tng sn xut lipocortin, l protein c mt trong t bo, c tc dng c ch phospholipase A2. Khi phospholipase A2 b c ch, phospholipid khng chuyn c thnh acid arachidonic. - c ch gii phng cc men tiu th, cc ion superoxyd (cc gc t do), lm gim hot tnh ca cc yu t ha hng ng, cc cht hot ha ca plasminogen, collagenase, elastase... - Lm gim hot ng thc bo ca i thc bo, bch cu a nhn, gim sn xut cc cytokin. Phospholipid mng GLUCOCORTICOID (-) Phospholipase A2 Lipocortin Acid arachidonic Lipo- oxygenase Leucotrien THUC CHNG VIM KHNG STEROID Cyclooxygenase (-)

Prostaglandin
Hnh 35.2. v tr tc dng ca glucocorticoid v thuc chng vim phi steroid trong tng hp cc prostaglandin

3.2.2. Tc dng chng d ng Cc phn ng d ng xy ra do s gn ca cc IgE hot ha trn cc receptor c hiu dng bo (mastocyte) v bch cu base tnh di tc dng ca d nguyn. S gn hot ha phospholipase C, cht ny tch phosphatidyl- inositol diphosphat mng t bo thnh diacyl- glycerol v inositoltriphosphat. Hai cht ny ng vai tr "ngi truyn tin th hai", lm cc ht bo tng ca t bo gii phng cc cht trung gian ha hc ca phn ng d ng: histamin, serotonin... (hnh 7.2).

Phosphatidyl- inositol diphosphat

KN + KT GLUCOCORTICOID (-) Phospholipase C

Diacylglycerol

Inositol triphosphat

Hot ha "ngi truyn tin th hai"

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HISTAMIN SEROTONIN
Hnh 35.3. Tc dng chng d ng ca glucocorticoid

Bng cch c ch phospholipase C, glucocorticoid phong to gii phng trung gian ha hc ca phn ng d ng. Nh vy, IgE gn trn dng bo nhng khng hot ha c nhng t bo . Glucocorticoid l nhng cht chng d ng mnh. 3.2.3. Tc dng c ch min dch Glucocorticoid tc dng ch yu trn min dch t bo, t nh hng n min dch th dch. Tc dng c ch min dch biu hin nhiu khu: - c ch tng sinh cc t bo lympho T do lm gim sn xut interleukin 1 (t i thc bo) v interleukin 2 (t T4). - Gim hot tnh gy c t bo ca cc lympho T (T8) v cc t bo NK (natural killer: t bo dit t nhin) do c ch sn xut interleukin 2 v interferon gamma. - Do c ch sn xut TNF (yu t hoi t u) v c interferon, glucocorticoid lm suy gim hot tnh dit khun, gy c t bo v nhn dng khng nguyn ca i thc bo. Mt s tc dng ny cng ng thi l tc dng chng vim. Do c ch tng sinh, glucocorticoid c tc dng tt trong iu tr bnh bch cu lympho cp, bnh Hodgkin. 3.3. Ch nh 3.3.1. Ch nh bt buc: thay th s thiu ht hormon 3.3.1.1. Suy thng thn cp - B th tch tun hon v mui: NaCl 0,9% 1lt (5% trng lng c th trong 24 gi). - Glucocorticoid liu cao: Hydrocortison 100 mg t/m. Sau 50- 100 mg 8h/ ln trong ngy u. Sau 24 n 72 gi thay bng tim bp hoc ung 25 mg 8h/ ln. 3.3.1.2. Suy thng thn mn tnh (bnh Addison) Hydrocortison 20 mg ung vo bui sng v 10 mg vo bui tra. 3.3.2. Ch nh thng thng trong chng vim v c ch min dch 3.3.2.1. Vim khp, vim khp dng thp - Mt khi dng corticoid th phi dng hng nm ! V th rt d c tai bin. - Liu u tin thng l prednison 10 mg (hoc tng ng) - Khi au qu: triamcinolon acetonid 5- 20 mg tim khp (ch lm ti bnh vin, tht v khun)

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3.3.2.2. Bnh thp tim - Ch dng corticoid khi salicylat khng c tc dng - Bnh nng, corticoid c hiu qu nhanh. Liu prednison 40mg/ngy - Khi ngng corticoid, bnh c th tr li. Nn phi hp vi salicylat 3.3.2.3. Cc bnh thn Hi chng thn h v lupus ban : prednison 60 mg/ ngy (tr em 2mg/ kg) 3- 4 tun. Liu duy tr 3 ngy/ tun, ko di ti hng nm . 3.3.2.4. Cc bnh dy h (collagenose) - Nm da cng (sclerodermia): khng chu thuc - Vim nhiu c, vim nt quanh mch, vim au nhiu c do thp: prednison 1mg/ kg/ ngy. Gim dn - Lupus ban ton thn bt pht: prednison 1 mg/ kg/ ngy. Sau 48 gi nu khng gim bnh, tng mi ngy 20 mg cho n khi c p ng. Sau dng liu duy tr 5 mg/ tun. C th dng thm salicylat, azathioprin, cyclophosphamid. 3.3.2.5. Bnh d ng - Dng thuc chng d ng: khng histamin, adrenalin trong cc biu hin cp tnh. - Corticoid c tc dng chm 3.3.2.6. Hen - Dng corticoid dng kh dung, cng vi cc thuc gin ph qun (thuc cng b 2 adrenergic, theophylin...). phng tai bin nm candida ng mi hng 3.3.2.7. Bnh ngoi da - Ngoi tc dng chung, khi bi ngoi, corticoid c ch ti ch s phn bo, v vy c tc dng tt trong iu tr bnh vy nn v cc bnh da c tng sinh t bo. - Trn da bnh thng, khong 1% liu hydrocortison c hp thu. Nu bng p, c th lm tng hp thu n 10 ln. S hp thu tu thuc tng vng da bi thuc, tng cao vng da vim, nht l vng trc vy. * Tc dng khng mong mun - Bi thuc trn din rng, ko di, nht l cho tr em, thuc c th c hp thu, gy tai bin ton thn, tr chm ln. - Tc dng ti ch: teo da, xut hin cc im gin mao mch, chm xut huyt, ban , sn, mn m, trng c, mt sc t da, tng p lc nhn cu... * Mt s ch phm Flucinolon acetonid (Synalar) 0,01%- 0,025%- 0,2% Triamcinolon acetonid (Aristocor, Kenalog) 0,025%- 0,1% Betametason dipropionat (Diproson) 0,05%- 0,1% (tc dng mnh)

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Cc ch phm trn thng c bo ch di cc dng khc nhau nh thuc m (thch hp vi da kh), kem (da mm, tn thng c dch r, cc hc ca c th nh m o...), dng gel (dng cho vng da u, nch, bn). Khi bi thuc, cn xoa u thnh lp mng, 1- 2 ln/ ngy, theo ng ch dn, nht l thuc c tc dng mnh. 3.4. Chng ch nh - Mi nhim khun hoc nm cha c iu tr c hiu. - Lot d dy- hnh t trng, long xng. - Vim gan siu vi A v B, v khng A khng B. - Ch nh thn trng trong i tho ng, tng huyt p. 3.5. Nhng im cn ch khi dng thuc - Khi dng corticoid thin nhin (cortisol, hydrocortison) phi n nht. i vi thuc tng hp, n tng i nht. - Lun cho mt liu duy nht vo 8 gi sng. Nu dng liu cao th 2/3 liu ung vo bui sng, 1/3 cn li ung vo bui chiu. - Tm liu ti thiu c tc dng. - Kim tra nh k nc tiu, huyt p, in quang d dy ct sng, ng mu, kali mu, thm d chc phn trc h khu no- tuyn yn- thng thn. - Dng thuc phi hp: tng liu insulin i vi bnh nhn i tho ng, phi hp khng sinh nu c nhim khun. - Ch n: nhiu protein, calci v kali; t mui, ng v lipid. C th dng thm vitamin D nh Dedrogyl 5 git/ ngy (mi git cha 0,005mg 25- OH vitamin D3) - Tuyt i v khun khi dng corticoid tim vo khp. - Sau mt t dng ko di (trn hai tun) vi liu cao khi ngng thuc t ngt bnh nhn c th cht do suy thng thn cp: cc triu chng tiu ha, mt nc, gim Na, gim K mu, suy nhc, ng lm, tt huyt p. V th khng ngng thuc t ngt. Hin c xu hng dng liu cch nht, gim dn, c v "an ton" cho tuyn thng thn hn. Mt s th d: . ang ung prednison 40 mg/ ngy: c th dng 80 mg/ ngy, cch nht; gim dn 5 mg mi tun (hoc gim 10% tng 10 ngy) . ang dng 5- 10 mg/ ngy: gim 1 mg/ tun . ang dng 5 mg/ ngy: gim 1 mg/ thng . Mt phc in hnh cho bnh nhn dng liu prednison duy tr 50 mg/ ngy c th thay nh sau: Ngy 1: 50 mg Ngy 2: 40 mg Ngy 3: 60 mg Ngy 4: 30 mg Ngy 7: 75 mg Ngy 8: 5 mg Ngy 9: 70 mg Ngy 10: 5 mg

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Ngy 5: 70 mg Ngy 6: 10 mg

Ngy 11: 65 mg Ngy 12: 5 mg v.v...

3.6. Lin quan gia cu trc v tc dng Mi corticoid dng trong iu tr u l dn xut ca cortisol hay hydrocortison (hormon thin nhin c OH v tr 11). Bng cch thay i cu trc ca cortisol, ta c th lm tng rt nhiu tc dng chng vim v thi gian bn thi tr ca thuc, ng thi lm gim kh nng gi mui v nc. Cu trc steroid c 4 vng:

- Vng A: khi c thm ng ni kp gia v tr 1- 2, tc dng chng vim tng v gi mui gim (prednison, prednisolon). - Vng B: thm -CH3 v tr 6 a (methylprednisolon), hoc F 9 a, hoc c 2 v tr 9- 6 a (fludrocortison, flucinonid), tc dng chng vim cng mnh v ko di t1/2. Nhng F v tr 9 a li lm tng tc dng gi Na+ - Vng D: thm -CH3 hay -OH v tr 16 a, lm gim mnh kh nng gi mui ca hp cht 9 a F (triamcinolon, dexametason betametason). V th hin nay c rt nhiu ch phm corticoid mnh v tc dng di. Liu lng v thi gian dng rt khc nhau. Thy thuc cn lu trnh tai bin cho bnh nhn. 3.7. Dc ng hc Glucocorticoid hp thu d dng qua ng tiu ha, t1/2 huyt tng khong t 90- 300 pht. Trong huyt tng, cortisol gn vi transcortin (90%) v vi albumin (6%). Cortisol b chuyn ha ch yu gan bng kh ng ni 4- 5 v kh ceton v tr 3. Thi tr qua thn di dng sulfo- v glycuro- hp. Tc dng sinh hc (t1/2 sinh hc) ln hn rt nhiu so vi t1/2 huyt tng. Bng 35.1: Lit k mt s corticoid thng dng Tn thuc Tc dng Tc dng Chuyn t1/2 sinh chng vim gi Na ha hc ng Tc dng ngn (12h) Cortison 0,8 0,8 0,8 8- 12 h

Liu tng ng 25 mg

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Hydrocortison Tc dng trung bnh (12- 36h) Prednison Prednisolon Metylprednisolon Triamcinolon Tc dng di (36-54 h) Betametason Dexametason

1 4 4 5 5 25- 30 25- 30

1 0,8 0,8 0,5 0 0 0

1 4 4 5 5 25 25

8- 12 h 12- 36 12- 36 12- 36 12- 36 36- 54 36- 54

20 mg 5 5 4 4 0,75 0,75

Mt s ch phm dng tim c t dc l polyetylen glycol, glysorbat... lm thuc thi tr rt chm, tu theo bnh v liu lng, c th ch tim 1 tun, 2 tun hoc 1 thng 1 ln, nh Depomedrol (cha metylprednisolon acetat 40 mg trong 1 mL ), Rotexmedica, Kenacort (cha triamcinolon acetonid 40 - 80 mg/ mL). Tuy nhin, loi ny thng c nhiu tc dng ph nh teo da, teo c, xp xng v ri lon ni tit.
4. HORMON TUYN SINH DC

4.1. Androgen (testosteron) Ging nh bung trng, tinh hon va c chc nng sn xut tinh trng (t tinh nguyn bo v t bo Sertoli, di nh hng ca FSH tuyn yn), va c chc nng ni tit (t bo Leydig bi tit androgen di nh hng ca LH tuyn yn). ngi, androgen quan trng nht do tinh hon tit ra l testosteron. Cc androgen khc l androstenedion, dehydroepiandrosteron u c tc dng yu. Mi ngy c th sn xut khong 8 mg testosteron. Trong , 95% l do t bo Leydig, cn 5% l do thng thn. Nng testosteron trong mu ca nam khong 0,6 mg/ dL vo sau tui dy th; sau tui 55, nng gim dn. Huyt tng ph n c nng testosteron khong 0,03 mg/ dL do ngun gc t bung trng v thng thn. Khong 65% testosteron trong mu gn vo sex hormone- binding globulin (TeBG), phn ln s cn li gn vo albumin, ch khong 2% dng t do c kh nng nhp vo t bo gn vo receptor ni bo. 4.1.1. Tc dng - Lm pht trin tuyn tin lit, ti tinh, c quan sinh dc nam v c tnh sinh dc th yu. - i khng vi oestrogen - Lm tng tng hp protein, pht trin xng, lm cho c th pht trin nhanh khi dy th (c bp n nang, xng di ra). Sau sn ni b ct ha. - Kch thch to hng cu, lm tng tng hp heme v globin. Testosteron khng phi l dng c hot tnh mnh. Ti t bo ch, di tc dng ca 5 a- reductase, n chuyn thnh dihydrotestosteron c hot tnh. C 2 cng gn vo receptor trong bo tng pht huy tc dng. Trong bnh lng tnh gi, tuy c th vn tit testosteron bnh thng, nhng t bo ch thiu 5 a- reductase hoc thiu protein receptor vi testosteron v dihydrotestosteron (Griffin, 1982), nn testosteron khng pht huy c tc dng.

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Di tc dng ca aromatase mt s m (m, gan, h khu no), testosteron c th chuyn thnh estradiol, c vai tr iu ha chc phn sinh dc. 4.1.2. Ch nh Testosteron v cc mui c sp xp vo bng B - Chm pht trin c quan sinh dc nam, dy th mun. - Ri lon kinh nguyt (kinh nhiu, ko di, hnh kinh au, ung th v, tc dng i khng vi oestrogen. - Suy nhc c nng, gy yu,. - Long xng. Dng ring hoc cng vi estrogen. - Ngi cao tui, nh mt liu php thay th. 4.1.3. Ch phm v liu lng Testosteron tim l dung dch tan trong du, c hp thu, chuyn ha v thi tr nhanh nn km tc dng. Loi ung cng c hp thu nhanh, nhng cng km tc dng v b chuyn ha nhiu khi qua gan ln u. Cc este ca testosteron (testosteron propionat, cypionat v enantat) u t phn cc hn, c hp thu t t nn duy tr c tc dng di. Nhiu androgen tng hp b chuyn ha chm nn c thi gian bn thi di. * Loi c tc dng hormon: - Testosteron propionat (hoc acetat): mi ngy tim bp 10- 25 mg, hoc cch 2- 3 ngy tim 1 ln 50 mg. Liu ti a mi ngy: 50 mg. - Metyl- 17 testosteron: 2- 3 ln yu hn testosteron. C th ung. Tt hn l t di li thm qua nim mc. Liu 5- 25 mg. Liu ti a 50 mg mt ln, 100 mg mt ngy. - Testosteron chm: Dung dch du testosteron onantat: 1 mL = 0,25g. Mi ln tim bp 1 mL. Hn dch tinh th testosteron isobutyrat: tim bp, di da 50 mg, 15 ngy 1 ln. Vin testosteron acetat: 0,1g testosteron acetat cy trong c, 1- 2 thng 1 ln. * Loi c tc dng ng ha: Loi ny u l dn cht ca testosteron v methyl- 17- testosteron khng c tc dng hormon (khng lm nam tnh ha), nhng cn tc dng ng ha mnh: tng ng ha protid, gi nit v cc mui K+, Na+, phospho... nn lm pht trin c xng, tng cn (tt nhin l ch n phi gi c cn i v cc thnh phn, nht l v acid amin)

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V cu trc ha hc, cc androgen ng ha khc vi methyl testosteron l hoc mt methyl C17, hoc mt ceton C3, hoc thay i v tr ng ni kp C4- C5. Th d (xem cng thc):

Androgen ng ha Androtanolon Nortestosteron Metandienon Stanozolol

Liu (gam) 0,01- 0,05 0,01- 0,025 0,005- 0,02 0,004- 0,08

Cng thc Mt ng kp Thay CH3 bng C2H5 Thm ni kp 1- 2 Mt ceton C3

Ch nh: gy st, tha xng, km n, mi m dy, sau m v cc thuc trn vn cn rt t tc dng hormon, cho nn khng dng cho tr em di 15 tui. Thuc cn b lm dng dng cho cc vn ng vin th thao vi liu rt cao, thuc loi doping, b cm. 4.1.4. Tai bin ca androgen Liu cao v ko di : gy nam tnh, qu sn tuyn tin lit mt gan: ngng thuc th ht. 4.1.5. Chng ch nh - Tr di 15 tui - Ph n c thai - Ung th tuyn tin lit (phi dng estrogen) 4.1.6. Tthuc khng androgen Thuc khng androgen do c ch tng hp hoc i khng tc dng ca androgen ti receptor. Thuc thng c dng iu tr qu sn hoc carcinom tuyn tin lit, trng c, hi u ca nam, chng nhiu lng ca n, dy th sm. 4.1.6.1. Thuc c ch 5 a reductase: Finasterid mt s m (tuyn tin lit, nang lng), di tc dng ca 5 a reductase, testosteron mi c chuyn thnh dng hot tnh l dihydrotestosteron. V vy, thuc c ch 5 a reductase s c ch chn lc tc dng androgen trn nhng m ny, nhng khng lm gim nng testosteron v LH huyt tng. Finasterid c dng iu tr qu sn v u tin lit tuyn vi liu 5 mg/ ngy. Tc dng sau ung 8 ting v ko di 24 ting. Cn c ch nh cho hi u. 4.1.6.2. Thuc i khng ti receptor - Cyproteron v cyproteron acetat Tranh chp vi dihydrotestosteron gn vo receptor ca m ch. Dng acetat cn c tc dng progesteron, c ch tng tit LH v FSH theo c ch iu ha ngc nn tc dng khng androgen cng mnh.

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Ch nh trong chng rm lng n, trng c. Vi nam, dng iu tr hi, u tuyn tin lit, dy th sm. Thuc cn ang c theo di, nh gi. - Flutamid: Flutamid l thuc khng androgen khng mang nhn steroid nn trnh c hot tnh hormon khc. Vo c th, c chuyn thnh 2 hydroxyflutamid, gn tranh chp vi dihydrotestosteron ti receptor. Ch nh trong u tin lit tuyn. Vin nang, 750 mg/ ngy. 4.2. Estrogen ph n, cc estrogen c sn xut l estradiol (E2- 17 b estradiol), estron (E1) v estriol (E3). Estradiol l sn phm ni tit chnh ca bung trng. Phn ln estron v estriol u l cht chuyn ha ca estradiol gan hoc m ngoi bin t androstenediol v cc androgen khc. ph n bnh thng, nng E2 trong huyt tng thay i theo chu k kinh nguyt: giai on u l 50 pg/ mL v thi k tin phng non l 350- 850 pg/ mL. Trong mu, E2 gn ch yu vo a2 globulin (SHBG- sex hormone- binding globulin) v mt phn vo albumin. Ti m ch, n c gii phng ra dng t do, vt qua mng t bo gn vo receptor ni bo. 4.2.1. Tc dng - L nguyn nhn chnh ca cc thay i xy ra trong tui dy th con gi v cc c tnh sinh dc ca ph n (vai tr th yu l androgen; pht trin xng, lng, trng c...). - C tc dng trc tip lm pht trin v trng thnh m o, t cung, vi trng. Ngoi tc dng lm pht trin c t cung E2 cn c vai tr quan trng lm pht trin ni mc t cung. - Trn chuyn ha: . E2 c vai tr c bit duy tr cu trc bnh thng ca da v thnh mch ph n. . Lm gim tc tiu xng do c tc dng i khng vi PTH ti xng, nhng khng kch thch to xng. . Trn chuyn ha lipid: lm tng HDL, lm gim nh LDL, gim cholesterol, nhng lm tng nh triglycerid. - Trn ng mu: estrogen lm tng ng mu, do lm tng yu t II, VII, IX v X, lm gim antithrombin III. Ngoi ra cn lm tng hm lng plasminogen v lm gim s kt dnh tiu cu. - Cc tc dng khc: estrogen lm d thot dch t lng mch ra khong gian bo, gy ph. Khi th tch mu gim, thn s gi Na+ v nc, thc y tng hp receptor ca progesteron. - Trn nam gii, estrogen liu cao lm teo tinh hon, lm ngng to tinh trng v lm ngng pht trin, lm teo c quan sinh dc ngoi. 4.2.2. Ch nh

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4.2.2.1. L thnh phn ca thuc trnh thai theo ng ung (xem bi "Thuc trnh thai"). 4.2.2.2. Thay th hormon sau thi k mn kinh Bung trng gim bi tit estrogen dn dn, ko di vi nm sau khi mn kinh. Nhng khi ct b bung trng th s c ri lon t ngt, cn dng hormon thay th ngay. Trong iu tr ri lon sau mn kinh, estrogen c ch nh trong d phng cc biu hin sau: - Chng long xng: long xng l do mt hydroxyapatit (phc hp calciphosphat) v cht c bn protein hoc cht keo (to khung xng), lm xng mng, yu, d gy t nhin (ct sng, c xng i, c tay). Estrogen lm gim tiu xng, c tc dng d phng nhiu hn iu tr chng long xng. Thng dng phi hp vi calci, vitamin D, biphosphonat. - Triu chng ri lon vn mch: cn nng bng, bc ha vi cm gic n lnh, v m hi, d cm. Estrogen rt c hiu qu. - D phng bnh tim mch: khi thiu estrogen, d dn n tng cholesterol mu, tng LDL, s lng receptor LDL ca t bo gim. Tuy nhin, nng HDL, VLDL v triglycerid t chu nh hng. Nhiu thng k cho thy sau tui mn kinh, bnh tim mch v nhi mu c tim thng tng nhanh v l nguyn nhn gy t vong. Tuy nhin, dng estrogen iu tr thay th ch nn mc liu thp, thi gian ngn, trnh nguy c ung th v. 4.2.2.3. Cc ch nh khc - Chm pht trin, suy gim bung trng tui dy th - Tc dng i khng vi androgen: trng c, rm lng n, vim tinh hon do quai b, u tin lit tuyn. Hin c xu hng dng cc cht tng t GnRH (Leuprolid) c tc dng c ch tng hp andrrogen. 4.2.3. Tc dng khng mong mun Estrogen c hiu qu rt tt cho phn ln cc ch nh iu tr. Tuy nhin, mi khi quyt nh cn cn nhc gia li ch v nguy c cho tng bnh nhn. Nhng nguy c thng c coi l do estrogen gm; ung th (v, ni mc t cung), vim tc mch, thay i chuyn ha ng v lipid, tng huyt p, bnh ti mt (do tng cholesterol trong mt), bun nn, thay i tnh tnh. 4.2.4. Chng ch nh - Tuyt i khng dng cho trc tui dy th, khi c thai - Khi u ph thuc vo estrogen nh carcinom ni mc t cung, v. - Chy mu ng sinh dc, bnh gan ang trong giai on chn on, c tin s vim tc mch. 4.2.5. Ch phm v liu lng Cc estrogen ch khc nhau v cng tc dng v ng dng do b chuyn ha nhiu gan. Estradiol l estrogen thin nhin mnh nht sau l estron v estriol. Khi ung, b chuyn ho qua gan ln th nht nn mt tc dng nhanh. Mt khc, mt cht chuyn ha quan trng ca n l 2- hydroxyestron (catechol estrogen) c tc dng

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nh mt cht dn truyn thn kinh no. V vy cc ch phm ca estradiol v estron c th gy tc dng ph trn thn kinh trung ng nhiu hn cc ch phm tng hp. C 2 nhm ch phm tng hp: nhm c nhn steroid ging estrogen t nhin nh ethinyl estradiol, mestranol, quinestrol; nhm khng c nhn steroid nh diethylstilbestrol (DES), mnh ngang estradiol nhng t/2 di), clorotrianisen, methallenestril. Trong mt s cy v nm, trong mt s thuc tr su tng hp (p p'DDT) cng c nhiu estrogen khng mang nhn steroid c hot tnh ging estrogen hoc ngc li, khng estrogen v c cha vng phenol ging vi vng A ca estrogen l v tr gn vo receptor ca estrogen. Cc ch phm tng hp c th dng di dng ung, tim, hp thu qua da, bi ti ch. C dng tc dng ngay, c dng tc dng ko di vi ngy hoc dng gii phng lin tc. - Estradiol (Estrace) Ung: vin nn 0,5- 1- 2 mg Kem bi m o: 0,1 mg/ g - Estradiol valerat Dung dch du 10- 20- 40 mg/ ml tim bp - Estradiol qua da (Estraderm) Cao dn gii phng hot cht chm thm qua da vi cc tc khc nhau 0,050,075- 0,1 mg/ ngy. - Ethinyl estradiol (Estinyl) Ung: vin nn 0,02- 0,05- 0,5 mg 4.2.6. Cc thuc khng estrogen Cc thuc khng oestrogen l cc thuc c tc dng i khng vi tc dng sinh hc ca estrogen. C 2 thuc c dng lm sng: 4.2.6.1. Clomifen (Clomid) Clomifen citrat l mt cht khng mang nhn steroid. C ch Clomifen tranh chp vi oestrogen ni sinh ti cc receptor vng di i v tuyn yn, i lp vi c ch c ch ngc chiu, v vy lm tng bi tit LHRH ca vng di i v tng bi tit FSH, LH ca tuyn yn. kt qu l lm tng gii phng oestrogen ca bung trng. Nu iu tr vo trc giai on phng non, s gy c phng non. Ch nh - Dng chn on d tr gonadotrophin ca tuyn yn - Dng trong iu tr v sinh do khng phng non. Cch dng

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Clomid vin 50 mg. Liu u tin ung 1 vin/ ngy, ung 5 ngy lin k t ngy th 5 ca chu k kinh. Nu khng thnh cng, phi i 30 ngy, trc khi bt u t iu tr th hai bng ung 1 hoc 2 vin/ ngy. 4.2.6.2. Tamoxifen (Nolvadex) Tamoxifen l dn xut ca triphenyl ethylen khng mang nhn steroid. C ch Cc thuc ny ngn cn phc hp oestrogen- receptor gn vo v tr tc dng trn ADN ca t bo ch. V vy, ngn cn s pht trin ca cc khi u ph thuc vo estrogen. Ch nh Ung th v ph thuc vo hormon trn ph n mn kinh Cch dng - Nolvadex, vin nn 10 v 20 mg - Liu trung bnh t 20- 40 mg, ung lm 2 ln. 4.3. Progestin Cc progestin bao gm hormon thin nhin progesteron t c dng trong iu tr,v cc ch phm tng hp c hot tnh ging progesteron. Progesteron l progestin quan trng nht ngi. Ngoi tc dng hormon, n cn l cht tin thn tng hp estrogen, androgen v steroid v thng thn. Progesteron c tng hp t cholesterol ch yu l vt th vng ca bung trng, sau l tinh hon v v thng thn. Khi c thai, rau thai tng hp mt s lng ln. na u ca chu k kinh, mi ngy ch vi mg progesteron c bi tit, sang na sau ca chu k s lng bi tit tng ti 10- 20 mg/ ngy v vo cui thi k mang thai l vi tr m mg. nam l khong 1- 5 mg/ ngy. 4.3.1. Tc dng - Trn t cung: progesteron c bi tit nhiu na sau ca chu k kinh (giai on hong th) s lm chm giai on tng sinh ca ni mc t cung ca estrogen na u ca chu k v lm pht trin ni mc xut tit, to iu kin cho trng lm t. Cui chu k kinh, hong th t ngt gim gii phng progesteron l yu t chnh khi pht kinh nguyt. Khi c thai, progesteron c ch to vng kinh v c ch co bp t cung, c tc dng gi thai. - Trn tuyn v: na sau ca chu k kinh v nht l khi c thai, cng vi estrogen, progesteron lm tng sinh chm nang tuyn v chun b cho vic tit sa. Tri vi tuyn v, s tng sinh ni mc t cung li x y ra mnh nht l di nh hng ca estrogen. Cn ghi nh s khc bit ny s dng trong iu tr v nhn nh v tc dng khng mong mun. - Trn thn nhit: gia chu k kinh, khi phng non, thn nhit thng tng 0,560C v duy tr cho n ngy thy kinh. C ch chnh xc cn cha r, nhng c vai tr ca progesteron v h khu no.

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- Trn chuyn ha: progesteron kch thch hot tnh ca lipoproteinlipase v lm tng ng m, lm gim LDH v lm gim tc dng c li ca estrogen trn chuyn ha m. Tuy nhin, tc dng cn ph thuc vo ch phm, liu lng v ng dng. Progesteron cng c th lm gim tc dng ca aldosteron trn ng thn, lm gim ti hp thu natri, do d lm tng bi tit b aldosteron. 4.3.2. Ch nh Hai ch nh rt thng dng l: - Phi hp vi estrogen hoc dng ring trong "vin trnh thai" (xem bi "thuc trnh thai") - Liu php thay th hormon sau thi k mn kinh. Thng phi hp vi estrogen lm gim nguy c gy ung th v, t cung. Ngoi ra, cn dng trong mt s trng hp sau: - c ch bung trng trong cc triu chng au kinh, chy mu t cung, rm lng, bnh lc mng trong t cung: dng liu cao theo ng tim (th d medroxyprogesteron acetat 150 mg tim bp cch 90 ngy/ ln) Trc y, cn dng chng da xy thai do tc dng c ch co bp t cung. Hin khng dng v c nhiu thuc gin t cung khc tt hn (thuc cng 2, thuc c ch tng hp prostaglandin) v prgesteron d c nguy c cho thai ( gy nam ha v d dng sinh dc) 4.3.3. Thn trng v chng ch nh - C thai - Tng lipid mu. Progestin trong thuc trnh thai hoc dng mt mnh c th gy tng huyt p trn mt s bnh nhn. 4.3.4. Cc ch phm Progesteron thin nhin t dng trong iu tr v b chuyn ha nhanh. Cc progestin tng hp c chia lm 2 nhm: - Nhm c 21 carbon c tc dng chn lc cao v ph hot tnh ging vi hormon ni sinh. Thng c dng phi hp vi estrogen trong iu tr thay th hormon ph n sau mn kinh. - Nhm dn xut t 19- nortestosteron (th h 3), khng c C 19, C20 v C 21 do c hot tnh progestin mnh nhng cn cc tc dng estrogen, androgen v chuyn ha, tuy yu (lin quan n tc dng khng mong mun) v ung c.

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Bng 35.2: Mt s ch phm thng dng


ng dng Progesteron v dx - Progesteron -Hydroxyprogesteron caproat - Medroxyprogesteron acetat dx 19- Nortestosteron - Desogestrel - Norethynadrel - Lynestrenol - L- Norgestrel Ghi ch: ung ung ung ung tb: tim bp (+): c hot tnh 1- 3 ngy 1- 3 ngy 1- 3 ngy 1- 3 ngy + + + + + + tb tb 8- 14 ngy 4 - 12 tun 1- 3 ngy + tb 1 ngy Thi gian tc dng Estrogen Hot tnh Androgen Chuyn ha

(-): khng c hot tnh (): hot tnh yu

4.4. Thuc khng progestin Mifepriston c dng u tin Php vo nm 1988 Mifepriston l dn xut ca 19- norprogestin, gn mnh vo receptor ca progesteron. Nu c mt progestin, mifepriston tc dng nh mt cht i khng tranh chp ti receptor, nu tc dng mt mnh th mifepriston li c tc dng nh progestin, nhng yu (ng vn mt phn- partial agonist) Dng vo giai on sm ca thai k, mifepriston lm bong mng rng do phong ta cc receptor progesteron ca t cung, dn n bong ti mm (blastocyst), lm gim sn xut choriogonadotropin (CG). Chnh nhng tc dng ny s lm hong th gim tit progesteron, cng lm bong thm mng rng. Progesteron gim lm tng sn xut prostaglandin ti t cung, gy co bp t cung v sy thai. Mifepriston cng c dng trnh th thai sau giao hp do ngn cn trng lm t. Tc dng c th cn hn c thuc phi hp estrogen progestin liu cao. Ngoi ra mifepriston cn c dng y thai cht lu trong t cung, bnh lc mng trong t cung. Ung th v, u c trn (leiomyomas) Cc thuc loi ny c dng t khong 1998- 2000 v cn cn theo di lm sng. Gy sy thai trong qu u bng cho ung ung 400- 600 mg/ ngy 4 ngy; hoc 800 mg/ ngy 2 ngy. Kt qu ti 85%. Nu ung 1 liu 600 mg mifepriston, sau 48h cho ung hoc t m o misoprostol (tng t PGE1), kt qu sy thai c th ti 95%.
5. THUC TRNH THAI

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5.1.C s sinh l Trong na u chu k kinh nguyt, di tc dng ca hormon gii phng FSH (FSH- RH) ca vng di i, tuyn yn bi tit FSH, lm cho nang trng trng thnh, tit foliculin (oestrogen). Sau , vng di i tit hormon gii phng LH (LH- RH), lm tuyn yn bi tit LH, n ngy th 14, khi FSH/LH t c t l thch hp th bung trng s phng non. Nu gp tinh trng, trng s th tinh v lm t. 5.2. Cc loi thuc chnh 5.2.1. Thuc trnh thai phi hp Phi hp oestrogen v progesteron tng hp. Cc loi thuc ny u dng estrogen l ethinylestradiol. Nhng thuc c cha 50 mg ethinyl estradiol u c gi l chun (standard) phn bit vi loi liu thp (minidosage) ch cha 3040 mg ethinyl estradiol. Hm lng v bn cht ca progesteron phi hp th thay i theo tng loi, phn ln l 19 nortestosteron. Ngoi ra cn phn bit loi 1 pha (monophasic pills) l loi c hm lng hormon khng i trong sut chu k kinh, loi 2 v 3 pha (diphasic, triphasic pills) c hm lng progesteron tng dn trong khi hm lng estrogen khng thay i hoc hi tng vo gia chu k kinh. Loi 2 hoc 3 pha c tng lng progesteron thp hn loi 1 pha. 5.2.1.1. C ch tc dng - Tc dng trung ng: theo c ch iu ha ngc chiu, estrogen c ch bi tit FSH- RH v LH- RH, tuyn yn s gim tit FSH v LH, do khng t c nng v t l thch hp cho s phng non, cc nang bo km pht trin. - Tc dng ngoi bin: lm thay i dch nhy ca c t cung, tinh trng kh hot ng, ng thi lm nim mc ni mc t cung km pht trin, trng khng lm t c. + Tc dng ca estrogen vi nhng liu t 50- 100 mg cho t ngy th 5 ca chu l kinh l c ch phng non. Trn bung trng, lm ngng pht trin nang trng: trn ni mc t cung, lm qu sn nim mc cho nn l nguyn nhn ca rong kinh: trn t cung, lm tng tit cc tuyn: trn m o, lm dy thnh v trc vy. Nhng thay i ny lm d nhim candida v trichomonas. + Tc dng ca progesteron: trn bung trng lm ngng pht trin, gim th tch: trn ni mc t cung, lm teo: t cung mm, c t cung t bi tit, lm dch tit nhy hn, tinh trng kh chuyn ng. Gy mc lng, tng cn. Do nhng bt li ca tng hormon, nn thng dng phi hp hai th cng mt lc, hoc ni tip nhau, c hai u c gim liu. S phi hp m bo cho t cung, m o t thay i so vi bnh thng. Sau ngng thuc, chu k bnh thng tr li ti 98% trng hp. 5.2.1.2. Cc tc dng dc l Trn bung trng: c ch chc phn ca bung trng, nang trng khng pht trin v khi dng lu, bung trng nh dn.

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Sau khi ngng thuc, khong 75% s li phng non trong chu k u v 97% trong chu k th 3, khong 2% vn gi v kinh sau vi nm. Trn t cung: sau thi gian di dng thuc c th c qu sn t cung v hnh thnh polyp. Cc thuc c cha 19 nor progestin v t estrogen s lm teo tuyn nhiu hn v thng t chy mu. Trn v: thuc cha estrogen thng gy kch thch, n v. Trn mu: xy ra huyt khi tc mch. C th l do tng cc yu t ng mu II, VII, IX, X v lm gim antithrombin III. Nhiu ngi b thiu acid folic. Trn chuyn ha lipid: estrogen lm tng triglycerid, tng cholesterol este ha v cholesterol t do, tng phospholipid, tng HDL. Cn LDL li thng gim. Chuyn ha ng: ging nh ngi mang thai, gim hp thu ng qua tiu ha. Progesteron lm tng mc insulin c s. Da: lm tng sc t da i khi tng b nhn, trng c (do progestin). Tuy nhin, v androgen ca bung trng gim nn nhiu ngi c gim b nhn, trng c v pht trin tc. 5.2.1.3. Tc dng khng mong mun Loi nh: - Bun nn, au v, kinh nhiu, ph do estrogen trong thuc. Thay thuc c t estrogen hn hoc nhiu progesteron. - Nhc u nh, thong qua. i khi c migren. Thay thuc. - V kinh i khi xy ra, lm nhm vi c thai. Thay thuc. Loi trung bnh: Cn ngng thuc. - Kinh nhiu: thay bng loi 2- 3 pha, lng hormon t hn. - Tng cn - Da sm mu: khong 5% sau mt nm v 40% sau 8 nm dng thuc. - Thiu vitamin B cng lm tng mu da. Phc hi chm khi ngng thuc. - Trng c: vi ch phm cha nhiu androgen. - Rm lng: ch phm c 19 nortestosteron. - Nhim khun m o: thng gp v kh iu tr. - V kinh: t gp, 95% phc hi sau ngng thuc. Loi nng: - Huyt khi tc mch, vim tc tnh mch: khong 1/1000

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- Nhi mu c tim: d gp ngi bo c tin s tin sn git tng huyt p, tng lipid mu, i tho ng, ht thuc. Tai bin thng gim i nhng ngi dng thuc khng lin tc. - Bnh mch no: d gp ngi trn 35 tui vi t l 37 ca/ 100.000 ngi/ nm. - Trm cm, i hi phi ngng thuc khong 6%. - Ung th: cha c mi lin quan vi dng thuc. 5.2.1.4. Chng ch nh Cao huyt p, cc bnh v mch mu (nh vim tc mch) vim gan, ung th vt cung, i tho ng, bo bu, ph n trn 40 tui (v d c tai bin v mch u). 5.2.1.5. Tng tc thuc Lm gim tc dng chng th thai - Cc thuc gy cm ng enzym chuyn ha thuc gan, lm tng ging ha oestrogen v progesteron: Rifampicin, phenytoin, phenobarbital. - Cc thuc lm thay i vi khun ng rut, tng thi tr oestrogen-progesteron qua phn: ampicilin, neomycin, tetracyclin, penicilin, cloramphenicol, nitrofuratoin. Lm tng c tnh i vi gan ca thuc chng th thai Cc thuc chng trm cm loi 3 vng, IMAO, troleandromycin 5.2.1.6. Ch phm C rt nhiu loi. Th d: - Marvelon 21: vin c Desogestrel 150 mcg + Ethinylestradiol 30 mcg. Mi v c 21 vin thuc + 7 vin khng thuc - Nordette: mi vin c Levonorgestrel 150 mcg + Ethinylestradiol 30 mcg. - Rigevidon 21 + 7 v Rigevidon 21 + 7 Fe (st: Fe fumarat 25 mg): mi vin c Levonnorgestrel 150 mcg + Ethinylestradiol 30 mcg. - Tri- regol: Hot cht Levonorgestrel Ethinylestradiol 6 vin vng 0,05 mg 0,03 mg 5 vin m chn 0,075 mg 0,04 mg 10 vin trng 0,125 mg 0,03 mg

T ngy th 5 sau kinh, vin vng ung trc, sau n vin mu m chn ri vin trng. Nu khong cch gia hai vin trn 36 gi th khng an ton. Thuc thng ng thnh v 21 vin c hot cht + 7 vin khng c hot cht ung theo th t, mi ngy ung 1 vin vo bui chiu sau ba n. Ngy bt u thy kinh, tnh l ngy th nht, nu vng kinh l 28 ngy.

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Nu hm trc qun, th hm sau ung b. Nu gin on qu 36 gi, tc dng khng m bo. 5.2.2. Thuc trnh thai c progesteron n thun 5.2.2.1 C ch Do ch c progesteron, nn tc dng ch yu l ngoi bin: thay i dch nhy c t cung v lm km pht trin nim mc ni mc t cung. Hiu qu trnh thai khng bng thuc phi hp. Hiu lc ch c sau 15 ngy dng thuc, v ch m bo nu ung u, khng qun. Thng dng cho ph n c bnh gan, tng huyt p, c vim tc mch. Chm kinh, bnh tm thn. 5.2.2.2. Tai bin - Do khng c oestrogen nn khng c tai bin tim mch - Ri lon kinh nguyt. Thng xy ra trong nm u, l nguyn nhn gy b thuc. Dn dn kinh nguyt s tr v bnh thng sau 1 nm. - Nhc u, chng mt, ph, tng cn. 5.2.2.3. Chng ch nh Do thuc c tc dng lm kh nim mc dch m o, cho nn khng dng cho ph n di 40 tui. 5.2.2.4. Ch phm v cch dng Tt c u l loi norsteroid Loi liu cao: Dng khng lin tc, ung t ngy th 5 n ngy th 25 ca chu k, c dng cho nhng ph n c tai bin mch, hoc ph n trn 50 tui, tai bin v mch thng cao. - Khng dng cho ngi c cao huyt p, i tho ng hoc c lipid mu cao. - Cc ch phm: Lynesterol, Orgametrin vin 5 mg, ung 2 vin/ ngy. Loi liu thp Dng lin tc hng ngy, ngay c khi thy kinh. Ch nh cho nhng ngi khng dng c oestrogen, hoc c chng ch nh vi thuc trnh thai loi phi hp. Cc ch phm . Norgesstrel (Microval) vin 0,03 mg. Ung 1 vin/ ngy . Lynestrenol (Exluton) vin 0,5 mg. Ngy u thy kinh bt u ung, ung lin tc 28 ngy. Cc thuc khc - Cc polyme tng hp, cc vi nang silastic c mang thuc chng th thai c cy, ghp vo c th, c th gii phng mt lng thuc n nh vo mu sut trong 6 thng.

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- Cc loi kem v thuc si bt c tc dng ti ch, dng bi vo cc mng ngn hoc bm vo m o trc khi giao hp dit tinh trng. - Ortho- crem; c acid ricinoleic, acid boric v lauryl natri sulfat. - Nonoxynol- 9: cha nonylphenoxy- polytoxyetanol. Thuc trnh thai dng cho nam gii Thuc c ch sn xut tinh trng: tuy c nhiu hng nghin cu, nhng cho ti nay cha c mt thuc no c hiu qu v an ton. 5.2.3. Thuc trnh thai sau giao hp. Cn gi l vin trnh thai khn cp Dng thuc phi hp hoc mt mnh estrogen trong vng 72 gi c hiu qu ti 99%. Ethinyl estradiol 2,5 mg 2 ln/ ngy 5 ngy; Diethylstilbestrol 50 mg/ ngy 5 ngy: Norgestrel 0,5 mg ethinyl estradiol 0,05 mg 2 vin 2 ln/ 2 gi. Thuc c th tc dng theo nhiu c ch: c ch hoc lm chm phng non; lm ni mc t cung khng tip nhn c trng; sn xut dch nhy c t cung, lm gim s xm nhp ca tinh trng; cn tr s di chuyn ca tinh trng, trng trong vi t cung. Tc dng ph 40% bun nn v nn (dng km thuc chng nn) nhc u, chngmt, cng v, au bng, chut rt. V phi dng liu cao nn c nhiu tc dng ph, trnh s dng rng ri (FDA ca M khng cho dng). . Postinor (thuc c dng Vit nam). Mi vin cha Levononorgestrel (progesteron) 0,75 mg. Dng cho ph n giao hp khng c k hoch. Nu c giao hp thng xuyn, nn dng loi thuc phi hp. Liu dng: ung 1 vin trong vng 1 gi sau giao hp. Nu c giao hp li, ung thm 1 vin sau vin u 8 gi. Ni chung, hng thng ung khng qu 4 vin. Chng ch nh: ang c thai hoc nghi ng c thai, chy mu m o cha r nguyn nhn, bnh gan- thn, c tin s carxinom v, bung trng hoc t cung. Li ch khng lin quan n tc dng trnh thai Sau hng chc nm dng thuc trnh thai phi hp, ngoi hiu qu trnh thai cao (ti 98- 99%), ngi ta cn nhn thy 1 s li ch sau ca thuc: - Lm gim nguy c u nang bung trng, ung th bung trng v ni mc t cung sau 6 thng dng thuc. Sau 2 nm dng thuc t l mi mc gim ti 50%. - Lm gim u lnh tnh tuyn v. - Lm gim cc bnh vim nhim vng h chu. - iu ha c kinh nguyt, lm gim mt mu khi thy kinh, do gim c t l thiu mu thiu st. - Gim c t l lot tiu ha, vim khp dng thp, ci thin c trng c, rm lng.
CU HI T LNG GI

1. Trnh by tc dng sinh l ca T3- T4 v p dng iu tr.

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2. Trnh by c ch tc dng v p dng iu tr ca thuc khng gip trng tng hp. 3. Trnh by tc dng v c ch tc dng ca insulin 4. Phn tch cc tc dng sinh l, tai bin, cch theo di v phng tai bin ca glucocorticoid. 5. Phn tch v so snh tc dng chng vim ca steroid (glucocorticoid) v thuc chng vim khng phi steroid. 6. Trnh by c ch tc dng chng d ng v c ch min dch ca glucocorticoid. 7. Gii thch v cc ch nh v chng ch nh ca glucocorticoid. 8. Trnh by v nhng im cn ch khi dng glucocorticoid. 9. Trnh by ch nh v chng ch nh ca testosteron. 10. Da vo tc dng sinh l ca estrogen, phn tch ch nh v chng ch nh ca estrogen. 11. Phn tch c ch tc dng v p dng lm sng ca thuc khng estrogen clomifen v tamoxifen. 12. Da vo tc dng sinh l, phn tch ch nh v chng ch nh ca progesteron. 13. Trnh by c ch tc dng v p dng lm sng ca thuc khng progesteron: mifepriston. 14. Trnh by c ch tc dng ca thuc trnh thai phi hp. Cc loi thuc phihp? 15. Phn tch c ch tc dng, u nhc im ca thuc trnh thai c progesteron n thun.

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PHN VIII IU TR NG C THUC CP TNH


Bi 36: IU

TR NG C THUC CP TNH

MC TIU HC T P: Sau khi hc xong bi ny, sinh vin c kh nng:

1. Trnh by c nguyn tc loi tr cht c ra khi c th 2. Gii thch c nguyn tc trung ha cht c trong c th 3. Trnh by c nguyn tc iu tr triu chng v hi sc trong ng c thuc Ng c thuc thng l do nhm ln (ca thy thuc, ca ngi bnh) hoc do c (t t, u c). Nhng trng hp nhm ln thng khng nng lm, v c chn on ng v sm nn x l kp thi. Cn nhng trng hp c th thng rt nng v nn nhn che giu tn thuc dng, liu thuc nhim c li qu ln v lc a n iu tr thng mun, cho nn chn on kh khn, x tr nhiu khi phi m mm. Ch c rt t thuc c triu chng ng c c hiu v cch iu tr c hiu. V vy, cc x tr ng c thuc ni chung l loi tr nhanh chng cht c ra khi c th, trung ha phn thuc c hp thu v iu tr cc triu chng nhm hi sc cho nn nhn.
1. LOI TR CHT C RA KHI C TH

1.1.

Qua ng tiu ha

- Gy nn: Apomorphin hin khng dng v nhiu tc dng ph - Ipeca: Dng di dng siro t 15- 20 ml, pha long trong 250 ml nc. Nu sau 15 pht khng nn, c th dng li. Thng dng cho tr em trn 1 tui. Trong trng hp khng c thuc, nn nhn cn tnh, c th ngoy hng hoc dng mn tht cho ung.

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- Ra d dy bng nc m hoc thuc tm (KMnO4) dung dch mt phn nghn (1: 1000 )cho n khi nc ra tr thnh trong. Vi cc thuc hp thu nhanh nh aspirin, cloroquin, meprobamat, barbituric, colchicin, thuc chng rung tim, ra d dy v gy nn ch c tc dng trong 6 gi u, khi cht trng c cn d dy. i vi loi benzodiazepin, thuc chng rung tim, hoc nhim c hn hp, hoc nhng cht khng r, c th ra trong vng 24 gi. Dng thn trng khi nn nhn hn m v d a nhm ng cao su vo kh qun, hoc cht nn quay ngc ng v ph. Tuyt i trnh ra d dy cho nhng ngi b trng c cc cht n mn nh acid mnh, base, v ng cao su c th lm rch thc qun. Sau ra d dy, cho than hot, v c nhiu u im: Hon ton khng c, ngn cn c chu k gan- rut i vi cc thuc thi theo ng mt, do tng thi theo phn. Liu 50- 100g. Mt trm gam than hot c th hp ph c 4 g thuc chng trm cm loi tricyclic. Thng cho 30- 40 g, cch 4 gi 1 ln. 1.2. Qua ng h hp Ng c cc thuc thi qua ng h hp nh cc thuc m bay hi, ru, kh t, xng, aceton..., cn lm tng h hp bng cc thuc kch thch nh cardiazol (tim tnh mch ng 5 ml, dung dch 10%), lobelin (tim tnh mch ng 1 ml, dung dch 1%), hoc h hp nhn to. 1.3. Qua ng tit niu 1.3.1. Thng dng cc thuc li niu thm thu Nh manitol (10%; 25%), glucose u trng (10%; 30%), dung dch Ringer. Phi chc chn rng chc phn thn cn tt. Khng c dng khi c suy thn, suy tim, ph phi cp, huyt p cao, try tim mch nng. Khi dng cc thuc li niu ny th cc khng sinh cng b tng thi, cho nn cn phi nng liu cao hn. 1.3.2. Kim ho nc tiu Trong trng hp ng c cc acid nh (barbituric, salicylat, dn xut pyrazolol). Thngdng hai th: - Natri bicarbonat (NaHCO3): Dung dch 14%0, truyn nh git tnh mch 2- 3 lt mt ngy. Nhng c nhc im l a thm Na+ vo c th, v vy khi chc phn thn khng c tt, d gy tai bin ph no. - T.H.A.M. (trihydroxymetylaminmetan), truy n tnh mch 300- 500 ml. HO- H2C HO- H2C HO- H2C C NH2 + H
+

HO- H2C HO- H2C HO- H2C

C- + NH3

THAM c u im l khng mang Na+ v d thm vo c trong t bo. 1.3.3. Acid ha nc tiu

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lm tng thi cc base hu c nh cloroquin, dn xut quinolein, imipramin, mecamylamin, dn xut acridin, nicotin, procain, quinin, phenothiazin. Cc thuc lm acid ha nc tiu thng dng l amoni alorid ung 3,0- 6,0g hoc acid phosphoric 15- 100 git mt ngy. Acid ha kh thc hin hn kim ha v c th chu ng tnh trng toan km hn trng thi nhim kim, cho nn cng d gy nguy him.
2. TRUNG HA CH T C

Thng dng cc cht tng k ngn cn h p thu cht c, lm mt hot tnh hoc i khng vi tc dng ca cht c. 2.1. Cc cht tng k ha hc ti d dy ngn cn hp th cht c, thng dng ra d dy bng cc dung dch: - Tanin 1- 2%: 100- 200 ml (c th thay th bng nc ch c), c tc dng lm kt ta mt s alcaloid v kim loi nh strychnin, calcaloid ca cy quinquina, apomorphin, cocain, mui km, coban, ng, thu ngn, ch... - Sa, lng trng trng (6 qu cho 1 lt nc) ngn cn hp thu cc mui thy ngn, phenol. - Than hot (nh dch 2%), hoc bt go rang chy, kaolin c tc dng hp ph cc cht c nh HgCl2 (sublim), strycnin, morphin... Than hot cn hp ph mnh c cc cht mang in tch dng cng nh m, cho nn c th dng c trong hu ht cc trng hp nhim c ng tiu ha. 2.2. Cc cht tng k ha hc dng ng ton thn - To methemoglobin (bng natri nitrit 3%- 10ml) khi b ng c acid cyanhydric (thng gp trong ng c sn). Acid cyanhydric rt c i lc vi cytocrom oxydase (c Fe+++) l cc enzym h hp ca m. Khi b ng c, cc enzym ny b c ch. Nhng acid cyanhydric li c i lc mnh hn vi Fe+++ ca methemoglobin, nn khi gy c methemoglobin, acid cyanhydric s hp vi methemoglobin to thnh cyanomethemoglobin v gii phng cytochrom- oxydase. - Dng B.A.L. khi b ng c cc kim loi nng nh Hg, As, Pb. - Dng EDTA hoc mui Na v calci ca acid ny khi b ng c cc ion ha tr 2: Ch, st, mangan, crm, ng v digitalis ( thi tr calci). 2.3. S dng cc thuc i khng dc l c hiu Dng naloxon tim tnh mch khi b ng c morphin v cc opiat khc; dng vitamin K liu cao khi ng c dicumarol; truyn tnh mch dung dch glucose khi b ng c insulin... Phng php ny dng iu tr c hiu qu nhanh v tt, nhng ch c rt t thuc c tc dng i khng dc l c hiu, cho nn phn ln phi iu tr theo triu chng.
3. IU TR TRIU CHNG V HI SC CHO NGI BNH

3.1.

p dng i khng sinh l

Dng thuc kch thch thn kinh khi ng c cc thuc c ch (dng bemegrid, amphetamin khi ng c barbiturat), dng thuc lm mm c khi ng c cc thuc co

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git (dng cura khi ng c strrynin)..., hoc ngc li, dng barbiturat khi ng c amphetamin, long no, cardiazol. Phng php ny khng tt lm v thuc i khng cng phi dng vi liu cao, thng l liu c, cho nn c hi i vi nn nhn. 3.2. Hi sc cho ngi bnh - Tr tim, gi huyt p, chng try tim mch: Dng cc thuc tr tim thng thng, noradrenalin 1- 4 mg ha trong 500- 1000ml dung dch glucose ng trng, truyn nh git tnh mch. C th dng D.O.C dung dch du 1- 5 mg tim bp. - Tr h hp: Cc thuc kch thch h hp (cardiazol, cafein), h hp nhn to, th oxy. - Thm phn phc mc hoc thn nhn to: Ch dng trong trng hp nhim c nng, thn suy, cc phng php iu tr thng thng khng mang li kt qu, hoc cc trng hp chng ch nh dng cc thuc li niu thm thu. Thng gp ng c kim loi nng, sulfonamid liu cao, barbiturat liu cao. - Thay mu c ch nh trong cc trng hp: . Nhim c phospho trng: Phi lm trc 8 gi mi c kh nng cu c nn nhn. . Nhim c vi liu cht: Cc thuc chng st rt, cht c t bo, isoniazid, dn xut salicylat (nht l vi tr em). . Cc cht lm tan mu: Saponin, sulfon... . Cc cht gy methemoglobin: Phenacetin, anilin, nitrit, cloroquin... C th iu tr bng xanh methylen ng 1%- 10 ml ha trong 500 ml dung dch glucose ng trng truyn nh git tnh mch; hoc tim tnh mch vitamin C 4,0- 6,0g trong 24 gi. Khi khng c kt qu th thay mu. Cn phi sm v khi lng mu thay th phi c nhiu (t nht l 7 lt). Nu hm sau mu cn cha nhiu hemoglobin ha tan th c th phi truyn li. 3.3. Cng tc chm sc ngi bnh - Ch dinh dng: Cho n cc thuc n nh, d tiu, calo, hoc truyn hu mn nu c tn thng thc qun (nhim c acid). Cn cho thm nhiu vitamin, c bit l vitamin B, C; cho thm insulin khi phi truyn nhiu ng (ose): - Cc khng sinh phng nhim khun th pht. - Lm tt cng tc h l: Ht m, ri, v sinh chng lot... 3.4. Bng k mt s thuc trng c thng gp v cch iu tr Trong bng ny ch k mt s thuc thng gy c v cc thuc c tc dng iu tr c hiu. Ngoi nhng thuc iu tr ny cn phi hp thm cc thuc v phng php hi sinh tng hp tu theo tnh trng trng c. Nhng thuc khng k trong bng ny, khi trng c phn nhiu l ch iu tr triu chng kt hp vi hi sc.
Thuc ng c Aspirin (Nhm Thuc gii c chnh - Na bicarbonat Trnh by Dung dch 12,5%o Liu lng v cch dng - Truyn nh git t/m 1,5- 3,0g mt ngy,

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salicylat) - Vitamin K - Cc dung dch b nc Na, K+, glucose - Natri bicarbonat - Cc thuc v phng php hi sinh tng hp. Flumazenil (Anexate) - Adrenalin - Diazepam - Prostigmin v cc loi phong to cholinesterase - Pilocarpin - Tanin EDTA calci Xanh methylen Vitamin C ng 1ml = 0,05g - Dung dch 12,5%o ng 5 ml = 0,5 mg ng 1ml= 1 mg ng 2ml= 10 mg ng 0,5 mg

Barbiturat Benzodiazepin Cloroquin Nivaquin (Amino 4 quinolein) Curare loi tranh chp vi acetylcholin C c dc (belladon) v cc ch phm c atropin Ch Cht sinh methemoglobin

nu c toan huyt. - Tim t/m hoc tim bp 4 ng/ ngy - B nc, Na+, K+, glucose tu theo tnh trng bnh. Truyn nh git tnh mch 1,5- 3,0 lt / ngy Tim t/m liu u 0,3 mg nu cha tnh, sau mi pht tim nhc li liu ti a l 2 mg. - Tim t/m 0,25 mcg/ kg/ pht. - Truyn t/m 2mg/ kg trong 30 pht, sau 1- 2 mg/ kg/ ngy trong 48 gi... Tim t/m tng liu 0,5 mg, khng vt qu 3,0 mg (c th tim trc 1mg atropin ngn cn tc dng ca prostigmin trn h M) - Tim di da 10 mg mt ln cho ti khi c n c bt - Ung 100 ml - 1,0g ha trong 500 ml dung dch glucose ng trng truyn nh git tnh mch. - Pha 1 ng trong 500 ml dung dch glucose ng trng truyn nh git tnh mch - Tim t/m 4,0- 6,0g/ 24 gi

ng bt 0,1g 1- 2% ng 10 ml = 0,5g ng 1% = 10 ml ng 0,1g

Thuc ng c Cht phong ta cholinesterase Digitalin

Thuc gii c chnh Contrathion (P.A.M) Atropin EDTA natri KCl

Trnh by L 200 mg ng 1 mg ng 10 ml = 0,2g

Isoniazid IMAO

- Vitamin B6 - Diazepam Acid folic Vitamin K1 B.A.L

ng 2ml = 0,05g ng 2ml= 10 mg ng 1 ml= 2,5g ng 1 ml = 0,5g ng 2 ml = 200 mg

Khng filic Khng protrombin Kim loi nng (As, Au, Hg) Morphin v cc opiat khc Muscarin (nm c) Phong ta b

- Naloxon - Naltrexon - Tanin - Thuc tm Atropin

0,4 mg Dung dch 1- 2% Dung dch 1%o ng1/4 mg hoc 1 mg ng 1 mg

Liu lng v cch dng - Truyn t/m dung dch c 400 mg contrathion ha trong 25 ml NaCL 9%o mi pht 1 ml - Tim t/m tng mg. - 3,0g ha trong 250 ml dung dch glucose ng trng truyn tnh mch trong 30 pht. - Truyn nh git tnh mch 20- 40 mEq/ gi Tng liu 120 mEq. - Tim bp hoc t/m mi ngy 50- 500 mg. C th ti vi gam. - Tim chm t/m 1- 2 ng nu c co git - Tim bp 3- 6 mg mt ngy - Tim tnh mch hoc tim bp 4- 6 ng mt ngy. - 2- 3 mg/ kg cho mt ln tim bp. Ngy th nht v 2, cch 4 gi tim mt ln; ngy th 3, cch 6 gi; nhng ngy sau, 2 ln trong 1 ngy. - Tim bp 0,4- 0,6 mg - Ung 100ml - Ra d dy - Tim di da hoc tnh mch tng liu 0,5- 1,0 mg - Tim tnh mch 1- 2 ng

- Atropin

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adrenergic Phospho Quinidin Strychnin

- Glucagon - Thuc tm - ng sulfat - Nc oxy gi - Natri lactat - Barbiturat - Curare

ng 1 mg Dung dch 1%o Dung dch 0,5% Dung dch 1% L 250- 500 ml - Barbital phenobarbital - Nesdonal - Remyolan ng 5 ml = 0,1g - Dung dch 2% - ng 10 ml = 1,0g

- Tim bp hoc tnh mch 1- 2 ng duy tr co bp tim - Ra d dy - Ra d dy 500 ml - Ung nhiu ln trong ngy Truyn t/m 250 ml trong 30 pht Nhc li nu cn - Dng cho ti khi xut hin ng - Tim t/m tng liu 50- 100 mg ti khi khng cn co git - Tim chm t/m 10- 20 ml - Tim chm t/m 30- 50 ml

Cyanur (acid cyanhydric)

- Natri nitrit - Natri hyposulfit

4. MT S THUC C HIU DNG TRONG NHIM C

4.1.

Dimercaprol

Trong chin tranh th gii th hai, Anh nghin cu cc cht chng li cht c ha hc cha hi asen, tm ra dimercaprol. Do dimercaprol cn gi l Britishanti- Lewisite (vit tt l B.A.L). 4.1.1. Cu trc ha hc v l ha tnh Dimercaprol l 2, 3- dimercaptopropanol: L cht lng snh, khng mu, mi kh chu, tan trong du thc vt, trong ru v cc cht ha tan hu c khc. 4.1.2. Tc dng v c ch Dimercaprol ngn nga c tnh ca nhng phc hp thiol- kim loi, bng cch phn ng vi kim loi hnh thnh phc hp dimercaprol- kim loi, ng thi gii phng h enzym c thiol; nh trong ng c asen, dimercaprol tc dng vi asen theo cch sau: R _ As S _ Pr S Pr
_

HS _ CH2 | _ HS CH | _ HO CH2
B.A.L

R As

CH + 2Pr _ SH | HO _ CH2 Enym cha SH

S | S

CH2

Dng kt hp cht asen vi enzym cha - SH

Phc hp dimercaprol v hp cht asen tan trong nc, thi theo nc tiu

Kh nng to chelat ca dimercaprol thay i tu tng kim loi, mnh nht vi thu ngn, mui vng v na kim loi nh asen. Ngoi tc dng ln h enzym cha nhm - SH, dimercaprol cn tc dng trc tip ln cc enzym c hot ha bi cc ion kim loi nh: Catalase, anhydrase carbonic, peroxydase.

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4.1.3. Tc dng ph ca dimercaprol - Nhc u, bun nn, nn, au bng - Tng huyt p, tim p nhanh. - Bong tm thi cc nim mc, vim kt mc, chy nc mi, tng tit nc bt. - au c v vng sau xng c - Kh chu im tim, i khi p xe. - tr em, st, gim bch cu, i khi co git - c ch chc nng ca tuyn gip trong trng hp dng ko di. - Thiu mu tan mu trong trng hp thiu G6PD. 4.1.4. Ch nh, liu lng Dng trong iu tr ng c asen, thu ngn, mui vng. N cng c gi tr nh mt cht b tr cho CaNa2 EDTA trong ng c ch v cho penicilamin trong bnh Wilson. t hiu lc trong nhim c bismuth, tali, ng, crm v nicken. - Tm tnh cm th ca ngi bnh: Ln tim u tin 50 mg. - Ng c cp: cch 4 gi tim 4 mg/ kg cho 48 gi u, ri 3 mg/ kg 2 ln mt ngy trong 8 ngy (liu ti a 5 mg/ kg/ ngy). - Ng c mn: cch 4 gi tim 2,5 mg/ kg cho 48 gi u, ri 2,5 mg/ kg 1 ln mt ngy trong 10- 15 ngy. - Tim bp su, mi ln tim, chuyn ch tim; dng bm tim bng thu tinh. - Kim ha nc tiu trong thi gian iu tr ( bo v thn i vi tc dng c ca nhng kim loi c gii phng). 4.2. EDTA calci dinatri v EDTA dinatri Tc dng 4.2.1. EDTA dinatri (Na2 EDTA) 4.2.1.1. Tc nhn chelat khng c calci, khi vo c th to phc d dng vi calci. Thi qua thn di dng chelat ca calci: 72% thi qua nc tiu trong 24 gi. 4.2.1.2. Ch nh: Dng iu tr nhng trng hp qu ti calci: - Da: Bnh cng b, hi chng Thibierge- Weissenbach. - Mu: Tng calci- mu. 4.2.1.3. 4.2.1.4. Chng ch nh: Suy thn nng Cch dng v liu lng:

ng tim 10 ml, dung dch tim 5%. Ch dng trong nhng trng hp cp, 1- 2 ng tim c ha long trong dung dch huyt thanh mn hay ngt ng trng, truyn nh git tnh mch rt chm trong ngy ( trnh him ha bnh tetani). Mt t iu tr trong 5 ngy v gia nhng ngy phi c theo di, c thi gian ngh 7 ngy.

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Vin bc ng: 0,25g Dng cho iu tr ngoi tr v liu duy tr t 6 - 8 vin bc ng/ ngy. Liu dng: 5 ngy/ tun l. 4.2.2. EDTA calci dinatri 4.2.2.1. Tc dng EDTA l ethylendiamin tetra acetic acid. Thng dng mui dinatra (Na2EDTA, dinatri edetat) lm tan nc, c kh nng gp (chelate) calci. Nhng Na2EDTA gy tetani do h calci mu, nn khi ng c kim loi ha tr 2 hoc 3 (ch, ng, st, coban, cadimi, cht phng x) th dng dinatri calci edetat (CaNa2EDTA) s to thnh nhng phc bn, mt ton b hot tnh ion v c tnh ca n v khng b tai bin h calci mu: c thi qua thn: trong 24 gi, 72% thuc c tm thy di dng chelat trong nc tiu, thi gian na thi tr huyt tng l 40 pht. Khng khuch tn qua dch no- ty. 4.2.2.2. Ch nh - Ng c ch - Ng c kim loi nng: Crm (eczma ca ximang), st (chng nhim hemosiderin), coban, ng, cht phng x... 4.2.2.3. Chng ch nh Suy thn nng 4.2.2.4. Tc dng ph - c tnh vi thn: Thng tn ng thn, albumin- niu, gim niu, suy thn (thng thng c hi phc). - Bun nn, i lng, chut rt c, st, au c. - Ko di thi gian prothrombin. - iu tr ko di c th gy mt magnesi (ngng iu tr v dng mt mui magnesi). - Vim tnh mch huyt khi trong trng hp dng nhng dung dch qu c c. 4.2.2.5. Cch dng v liu lng ng tim 10 ml, c 0,50g. - ng tnh mch: 15- 25 mg/ kg c th, truyn nh git tnh mch trong 250- 500 ml dung dch huyt thanh ngt ng trng trong 1- 2 gi, 2 ln/ ngy; liu ti a 50 mg/ kg/ ngy; chu k iu tr trong 5 ngy lin, vi khong cch ti thiu 2 ngy gia nhng chu k iu tr. Kim tra nc tiu hng ngy v ngng iu tr trong trng hp bt thng. - ng tim bp (dung dch 20%): c ch nh trong bnh no do ng c ch, vi tng p lc ca dch no tu; 4- 6 gi tim 12,5 mg/ kg (ti a 50 mg/ kg/ ngy). Dung dch c ha thm vi procain 1% tim. 4.3. Penicilamin

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Penicilamin (D- bta, bta- dimethylcystein) l cht thu phn ca penicilin, c th tng hp. To chelat vi kim loi nng, hp vi nhng cht ny thnh nhng phc ha tan v c thi qua nc tiu. Trong cystein niu, penicilamin hp thnh vi cystein mt phc hp ho tan. Hp thu tt qua ng tiu ha; thi gian na thi tr l 2- 3 gi, thi qua nc tiu di dng disulfid. 4.3.1. Ch nh v liu lng - Bnh Wilson: 500 mg/ ngy vi 25 mg/ pyridoxin; iu tr cn c theo ui sut i. - Ng c ch v thu ngn: 500 mg- 1,5g/ ngy trong 1- 2 thng. Tr em 30- 40 mg/ kg cn nng. - Cystein- niu mn ( phng bnh si): 250 mg/ ngy, liu c tng dn ti 500 mg, 4 ln/ ngy tu theo s chu thuc. - Vim nhiu khp mn tin trin: Thng u 300 mg/ ngy; thng th hai, th ba: 600 mg/ ngy, nu sau 3 thng iu tr khng thy c kt qu th ngng thuc. - Ung thuc lc i, 2 gi trc hoc 3 gi sau khi n. 4.3.2. Chng ch nh - C thai, bnh mu, bnh thn, chng nhc c - D ng vi penicilin. 4.3.3. Tc dng ph - D ng, protein niu, mt v gic, khu gic. - Vim nhiu dy thn kinh - Vng da mt - c ch tu xng: Thiu mu, gim bch cu, tiu cu. 4.4. Pralidoxim (2- PAM) Xin xem bi Thuc tc dng trn h cholinergic, phn iu tr ng c hp cht phospho hu c.
CU HI T LNG GI

1. Nu 3 nguyn tc trong iu tr ng c thuc cp tnh 2. Trnh by nguyn tc loi tr cht c qua ng tiu ha. 3. Trnh by nguyn tc loi tr cht c qua ng tit niu 4. Trnh by v phn tch c ch ca nguyn tc trung ha cht c trong c th. 5. Trnh by c ch tc dng v cch dng EDTA, penicilamin. 6. Trnh by cc phng php iu tr triu chng v hi chng trong nhim c thuc cp tnh.

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TI LIU THAM KHO


1. B mn Dc lm sng Trng i hc Dc H Ni (2000): Dc lm sng i cng- NXBYH. 2. B mn Dc l Trng i hc Y H Ni (1998): Dc l hc NXBYH. 3. B mn Dc l Trng i hc Y H Ni (2005): Dc l hc lm sng- ti bn ln th nht NXBYH. 4. B Y t- Dc th Quc gia Vit Nam- ln xut bn th nht H Ni 2002. 5. B Y t- Danh mc thuc thit yu Vit Nam ln th V (2005). 6. B mn K sinh trng Trng i hc Y H Ni (1997): K sinh trng Y hcNXBYH. 7. Cc b mn Ni Trng i hc Y H Ni (2000): iu tr hc Ni khoaNXBYH. 8. American Medical Association (1993): Drug evaluation annual. 9. Bart Chernow (1994): The pharmacologic approach to the critically ill patient, 3rd edition- Williams & Wilkins. 10. Bertram G. Katzung (1998): Basic and clinical pharmacology. 7th edition Appleton & Lange USA. 11. British national formulary (2004). BNF 47. British Medical Association and Royal pharmaceutical society of Great Britain. 12. Bradley R. Williams (1994): Essentials of clinical pharmacology in nursing, 2nd edition- Springhouse corporation Pennsylvania. 13. Cohen Y (2001): Pharmacologie. Masson.

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14. Eric J. Nestler (2001): Molecular neuropharmacology- McGraw- Hill Companies, Inc. 15. Drug information (2002) American hospital formulary service (AHFS) 16. Goodman & Gilmans (2001): The pharmacological basis of therapeutics. 10th edition- McGraw- Hill. 17. Graham Smith D.G (2002) Aronson J.K: Oxford textbook of clinical pharmacology and drug therapy. 3rd edition- Oxford university press. 18. Harrisons principles of internal medicine (1998), 14th edition- McGraw- Hill. 19. Ingeborg C. Radde (1993): Pediatric pharmacology & therapeutics- Mosby. 20. Lechat P (2002): Phamacologie mdicale- Masson. Paris 21. Martindale (2005). The complete drug reference, 34th edition. 22. Michael J. Neal (2002). Medical pharmacology at a glance, 4th edition. Blackwell science. 23. PDR (2003). Physicaial desk references. Publisher: Edward R. Barnhart. 24. Rang .H.P, Date. M. M, Ritter.J.M (2000): Pharmacology- 4th editionChurchill Livingstone. 25. Smith and Reynard (1992): Textbook of pharmacology- W.B. Saunders company. 26. Wingard, L.B (1991): Human pharmacology. Mosby. 27. Yakoub Aden Abdi (1995): Handbook of drugs infections. 2nd edition- Taylor & Francis. for tropical parasitic

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