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B Y T
DC L HC
TP 1
(DNG CHO O TO BC S A KHOA) M s: .01.Y.14
NH XUT BN GIO DC H NI 2007
Ch o bin son: V KHOA HC V O TO - B Y T Ch bin: GS.TS. O VN PHAN Nhng ngi bin son: PGS.TS. NGUYN TRN TH GING HNG GS.TS. O VN PHAN
file:///C:/Windows/Temp/ugpmsddehh/duoc_ly_hoc.htm
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PGS.TS. NGUYN TRNG THNG Th k bin son: NGUYN KIU VN Tham gia t chc bn tho: ThS. PH VN THM TS. NGUYN MNH PHA
Bn quyn thuc B Y t (V Khoa hc v o to)

874 - 2007/CXB/9 - 1918/GD M s: 7K729M7 - DAI
Li gii thiu
Thc hin mt s iu ca Lut Gio dc, B Gio dc & o to v B Y t ban hnh chng trnh khung o to Bc s a khoa. B Y t t chc bin son ti liu dy - hc cc mn c s v chuyn mn theo chng trnh trn nhm tng bc xy dng b sch t chun chuyn mn trong cng tc o to nhn lc y t. Sch DC L HC c bin son da trn chng trnh gio dc ca Trng i hc Y H Ni trn c s chng trnh khung c ph duyt. Sch c cc tc gi PGS.TS. Nguyn Trn th Ging Hng, GS.TS. o Vn Phan, PGS.TS. Nguyn Trng Thng bin son theo phng chm: kin thc c bn, h thng; ni dung chnh xc, khoa hc, cp nht cc tin b khoa hc, k thut hin i v thc tin Vit Nam. Sch DC L HC c Hi ng chuyn mn thm nh sch v ti liu dy - hc chuyn ngnh Bc s a khoa ca B Y t thm nh nm 2007. B Y t quyt nh ban hnh l ti liu dy - hc t chun chuyn mn ca ngnh trong giai on hin nay. Trong thi gian t 3 n 5 nm, sch phi c chnh l, b sung v cp nht. B Y t xin chn thnh cm n cc tc gi v Hi ng chuyn mn thm nh gip hon thnh cun sch; Cm n GS.TSKH. Hong Tch Huyn, PGS.TS. Mai Phng Mai c v phn bin cun sch sm hon thnh kp thi phc v cho cng tc o to nhn lc y t.
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Ln u xut bn, chng ti mong nhn c kin ng gp ca ng nghip, cc bn sinh vin v cc c gi ln xut bn sau c hon thin hn. V KHOA HC V O TO - B Y T
LI NI U
Cun sch ny c bin son dng ging dy mn DC L HC cho cc Trng i hc Y, o to Bc s a khoa nh hng cng ng. Ngy nay, trn th trng Vit Nam c ti hn 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 c bin son 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, cc thy thuc 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 im ca cc thuc c th s dng c "an ton v hp l". Khoa hc k thut ang khng ngng pht trin. Cc loi 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 bin son 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 ca ng o bn c v cc ng nghip trong ngnh y dc. CC TC GI
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 mi 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 nng ca c quan trong c th.
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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, mui vng) hoc l t cc cht bn tng hp, tng hp ho 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 thy c trn sc vt (bun nn, chng mt, nhc u, phn ng d ng...). 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 ho, 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. Mi loi 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, mi thuc li 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 phi, chuyn ho 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 tnh mch...), s ln dng thuc trong ngy, liu lng thuc tu theo tng trng hp (tui, trng thi bnh, trng thi sinh l...). 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 bi cc thay i ca mi trng sng nh nh sng, nhit , m... Cc hot ng ny bin i nhp nhng, c chu k, gi 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 G PD rt d b thiu mu tan 6 mu do dng sulfamid, thuc chng st rt... ngay c vi liu iu tr thng thng. C th ni Dc l
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di truyn l mn giao thoa gia Dc l - Di truyn - Ho 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 hi nm c cc kin thc dc l ca cc thuc mi hoc nhng hiu bit mi, nhng p dng mi ca cc thuc c.
Chng I DC L HC I CNG
Bi 1 I CNG V DC NG HC
MC TIU
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1. Phn tch c qu trnh hp thu v phn phi thuc trong c th. 2. Nu c ngha 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 ho thuc trong c th. 5. K ra c ngha thng s dc ng hc v h s thanh thi, thi gian bn thi (t1/2) 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 (Hnh 1.1). Cc qu trnh l: - S hp thu (Absorption) - S phn phi (Distribution) - S chuyn ho (Metabolism) - S thi tr (Excretion).
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 ho ca thuc v mng sinh hc c nh hng n cc qu trnh vn chuyn . 1. CC CCH VN CHUYN THUC QUA MNG SINH HC 1.1. c tnh l ho ca thuc - Thuc l cc phn t thng c khi lng phn t PM 600. Chng u l cc acid hoc cc base
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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 - 1.000. gn "kht" vo mt 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 1.000, 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 m) v mt proton (in tch dng).
Mt s thuc l base yu: l mt phn t trung tnh c th to thnh mt cation (in tch dng) bng cch kt hp vi mt proton:
- Cc phn t thuc c sn xut di cc dng bo ch khc nhau : + Tan c trong nc (dch tiu ho, dch khe), do d c hp thu. + Tan c trong lipid 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 lipid 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:
Cho mt acid
Cho mt base
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K l hng s phn ly ca mt acid; pKa = -logK pKa dng cho c acid v base. Mt acid hu c c pKa thp l mt acid mnh v ngc li. Mt base c pKa thp l mt 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 ho (khng khuch tn c qua mng) v 50% dng khng ion ho (c th khuch tn c). V khi , nng phn t/nng ion = 1 v log1 = 0. Ni chung, mt thuc phn tn tt, d c hp thu khi: + C trng lng phn t thp. + t b ion ho: ph thuc vo hng s phn ly (pKa) ca thuc v pH ca mi trng. + D tan trong dch tiu ho (tan trong nc). + Tan c trong lipid ca mng t bo. 1.2. Vn chuyn thuc bng cch lc Nhng thuc c khi lng phn t thp (100 - 200), tan c trong nc nhng khng tan c trong lipid s chui qua cc ng dn (d = 4 - 40) ca mng sinh hc do s chnh lch p lc thu tnh. ng dn ca mao mch c vn c ng knh l 30, ca mao mch no l 7 - 9, v th nhiu thuc khng vo c thn kinh trung ng. 1.3. Vn chuyn bng khuch tn th ng Nhng phn t thuc tan c trong nc/lipid 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 ho s d tan trong nc, cn cht khng ion ho s tan c trong lipid 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. V 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 (Hnh 1.2).
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Hnh 1.2. S khuch tn qua mng
p dng phng trnh Henderson - Hasselbach, ta c: gian 1 (d dy):
gian 2 (mu):
V ch phn khng ion ho v c nng cao mi khuch tn c qua mng cho nn acid ny s chuyn t gian 1 (d dy) sang gian 2 (huyt tng) v c hp thu. Tr s pKa ca mt s thuc l acid yu v base yu c ghi bng 1.1. 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 Acid salicylic Acid acetylsalicylic Sulfadiazin Barbital Acid boric pKa 3,00 3,49 6,48 7,91 9,24 Base yu Reserpin Codein Quinin Procain Atropin pKa 6,6 7,9 8,4 8,8 9,65
S ion ho ca thuc cn ph thuc vo pH mi trng.

Bng 1.2. nh hng ca pH n s ion ho ca acid salicylic c pKa = 3
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pH 1 2 3 4 5 6
% khng ion ho 99,0 90,9 50,0 9,09 0,99 0,10
Nh vy, acid salicylic (aspirin) c hp thu nhiu d dy v phn trn ca ng tiu ho. 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. V 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 ho 50%. Khi nng pH ca nc tiu ln 8, ion ho 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 ho nc tiu, thuc s b tng thi tr. i vi mt cht kh (v d thuc m bay hi), s khuch tn t khng kh ti ph nang vo mu ph thuc vo p lc ring phn ca cht kh gy m c trong khng kh th vo v ho 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 ho: do s lng carrier c hn. - C tnh c hiu: mi 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 mt carrier, cht no c i lc mnh hn s gn c nhiu hn. - 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: khi km theo carrier li c c s chnh lch bc thang nng , v vy s vn chuyn ny khng cn nng lng. V d vn chuyn glucose, pyramidon. - Vn chuyn tch cc thc th: l vn chuyn i ngc bc thang nng , t ni c nng thp
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sang ni c nng cao hn. V vy i hi phi c nng lng c cung cp do ATP thu phn, thng c gi l cc "bm", v 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 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: - ho 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 ho 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 tnh mch, trong qu trnh hp thu vo vng tun hon, mt phn thuc s b ph hu do cc enzym ca ng tiu ho, 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 ho do hp thu hay chuyn ho 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 (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 ho u im l d dng v l ng hp thu t nhin.
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Nhc im l b cc enzym tiu ho ph hu hoc thuc to phc vi thc n lm chm hp thu. i khi thuc kch thch nim mc tiu ho, 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 ho qua gan ln th nht. 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 ho, 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 ho nhng nu t hoc khng tan trong lipid (sulfaguanidin, streptomycin) th t c hp thu. - Thuc mang amin bc 4 s b ion ho mnh kh hp thu, v d cc loi cura. - Cc anion sulfat SO42 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 ho ph hu, khong 50% thuc hp thu qua trc trng s qua gan, chu chuyn ho 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 - 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 tnh mch: thuc hp thu nhanh, hon ton, c th iu chnh liu c nhanh. Dng tim cc
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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 lipid 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 mng manh, tnh thm mnh, d b kch ng cho nn cn thn trng khi s dng, hn ch din tch bi thuc. - 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 - 100m2) 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, ho tan ca thuc m trong mu (hay h s phn ly mu: kh ). 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
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phn nh s hp thu thuc. 2.1.5.2. ngha - Khi thay i t dc, cch bo ch thuc s lm thay i ho tan ca thuc (hot cht) v lm thay i F ca thuc. Nh vy, hai dng bo ch ca cng mt sn phm c th c hai 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 mt hot cht: F1/F2. - Khi thay i cu trc ho hc, c th lm F thay i: Ampicilin c F = 50% Amoxicilin (gn thm nhm OH) c F = 95%. - S chuyn ho thuc khi qua gan ln th nht, hay chuyn ho 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 ho 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. V d propranolol c sinh kh dng theo ng ung l 30% nhng gan n c chuyn ho 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 ho. + 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 tng (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 ho ri thi tr (H1). Gia nng thuc t do (T) v phc hp protein - thuc (P - T) lun c s cn bng ng:
Qu trnh phn phi thuc ph thuc nhiu vo tun hon khu vc. Tu theo s ti mu, thng chia c th thnh 3 gian (H1.4).
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Hnh 1.4. H phn phi thuc 3 gian
Hai loi yu t c nh hng n s phn phi 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: khi lng phn t, t l tan trong nc v trong lipid, tnh acid hay base, ion ho, 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 huyt tng (cc thuc l acid yu) v vo 1 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 1.3).
Bng 1.3. T l gn thuc vo protein huyt tng
S gn thuc vo protein huyt tng ph thuc vo 3 yu t: - S lng v tr gn thuc trn protein huyt tng. - Nng phn t ca cc protein gn thuc.
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- 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 tng 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 khe lun trng thi cn bng. Khi nng thuc dch khe gim, thuc huyt tng s i ra, protein gn thuc s nh thuc gi cn bng. - Nhiu thuc c th cng gn vo mt v tr ca protein huyt tng, gy ra s tranh chp, ph thuc vo i lc ca thuc. Thuc b y khi protein s tng tc dng, c th gy c. V 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 khi v tr gn vi protein. - Trong iu tr, lc u dng liu tn cng bo ho 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 lipid, c tc dng trn thn kinh trung ng v dng thuc theo ng tnh mch. V d in hnh ca hin tng ny l gy m bng thiopental, mt thuc tan nhiu trong lipid. 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 sung 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" - 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.
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- 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 tng. - Mc ion ho ca phn thuc t do (ph thuc vo pH v pKa). - H s phn b lipid/nc ca phn thuc t do khng ion ho ( 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. * Kt qu ca s vn chuyn: - Cc thuc tan nhiu trong lipid s thm rt nhanh vo no, nhng li khng li c lu (xem "s phn phi li"). Thuc b ion ho nhiu, kh tan trong lipid, kh thm vo thn kinh trung ng: atropin sulfat, mang amin bc 3, t ion ho, vo c thn kinh trung ng (TKT); cn atropin methyl bromid, mang amin bc 4, ion ho mnh, khng vo c TKT. - C th thay i s phn phi thuc gia huyt tng v no bng cch 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 tu (7,3), lm cho nng dng ion ho trong huyt tng ca phenobarbital tng cao, nng dng khng ion ho gim thp s ko dng khng ion ho ca thuc t dch no tu vo mu. 2.2.3.2. Vn chuyn thuc qua nhau thai * Phng thc vn chuyn - 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 nhau 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 lipid s khuch tn th ng: thuc m hi (protoxyd nit, halothan, cyclopropan), thiopental.
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- Vn chuyn tch cc: cc acid amin, cc ion Ca2+, Mg2+. - Thm bo (pinocytosis) vi cc git huyt tng ca m * Kt qu ca s vn chuyn - Tr cc thuc tan trong nc c khi lng phn t ln trn 1000 (nh dextran) v cc amin bc 4 (galamin, neostigmin) khng qua c nhau thai, rt nhiu thuc c th vo c mu thai nhi, gy nguy him cho thai (phenobarbital, sulfamid, morphin), v vy, khng nn coi l c "hng ro nhau 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 con cn thc. - Ngoi ra, nhau thai cn c nhiu enzym nh cholinesterase, monoamin oxydase, hydroxylase c th chuyn ho thuc, lm gim tc dng bo v thai nhi. 2.2.4. S tch lu thuc Mt s thuc hoc cht c c mi lin kt rt cht ch (thng l lin kt cng ho tr) vi mt s m trong c th v c gi li rt lu, hng thng n hng chc nm sau khi dng thuc, c khi ch l mt 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 (xem "s phn phi 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 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: 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 phi v trc khi thi tr. Vd: th tch khng c thc, tnh bng L (lt) hoc L/kg. V d: mt ngi nng 60 kg, c lng nc trong c th l 36 L (60% khi lng c th), ung
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0,5mg (500g) digoxin c F theo ng ung l 0,7. o nng digoxin trong huyt tng thy Cp = 0,7ng/mL (0,0007mg/mL). Vy:
Vd = 500 L, 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 tng (3L hoc 0,04 L/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 2.3. S chuyn ho thuc 2.3.1. Mc ch ca chuyn ho thuc thi tr cht l (thuc) ra khi c th. Nhng nh ta bit, thuc l nhng phn t tan c trong lipid, khng b ion ho, d thm qua mng t bo, gn vo protein huyt tng v gi li trong c th. Mun thi tr, c th phi chuyn ho nhng thuc ny sao cho chng tr nn cc phc hp c cc, d b ion ho, do tr nn t tan trong lipid, 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 ho, mt s thuc rt d tan trong lipid (nh pentothal) c th b gi li trong c th hn 100 nm! 2.3.2. V tr chuyn ho v cc enzym chnh xc tc cho chuyn ho - Nim mc rut: protease, lipase, decarboxylase - Huyt thanh: esterase - Phi: oxydase - Vi khun rut: reductase, decarboxylase - H thn kinh trung ng: mono amin oxydase, decarboxylase - Gan: l ni chuyn ho chnh, cha hu ht cc enzym tham gia chuyn ho thuc, s trnh by di y 2.3.3. Cc phn ng chuyn ho chnh Mt cht A c a vo c th s i theo mt hoc cc con ng sau:
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- c hp thu v thi tr khng bin i: bromid, lithi, saccharin. - Chuyn ho thnh cht B (pha I), ri cht C (pha II) v thi tr. - Chuyn ho thnh cht D (pha II) ri thi tr. 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 ho loi B, C hoc D...
Hnh 1.5. Cc phn ng chuyn ho thuc c phn lm 2 pha
2.3.3.1. Cc phn ng pha I Qua pha ny, thuc ang dng tan c trong lipid 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 v d:
Cc phn ng chnh pha ny gm:
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- Phn ng oxy ho: l phn ng rt thng gp, c xc tc bi cc enzym ca microsom gan, c bit l hemoprotein, cytochrom P450. - Phn ng kh. - Phn ng thu phn do cc enzym esterase, amidase, protease... Ngoi gan, huyt thanh v cc m khc (phi, thn...) cng c cc enzym ny. * Phn ng oxy ho y l phn ng ph bin nht, c xc tc bi cc enzym oxy ho (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 ni bo nhn ca t bo gan v vi m khc. Trong c th ngi hin thy c ti 17 typ v rt nhiu di typ cytochrom P450 tham gia chuyn ho cc cht ni sinh v ngoi sinh t mi trng, thuc. Phn ng oxy ho loi ny i hi NADPH v O2 theo phc sau:
Phn ng c thc hin theo nhiu bc: 1. C cht (thuc, RH) phn ng vi dng oxy ho 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 mt phn t oxy v mt electron th 2 t NADPH to thnh phc hp oxy hot ho. 4. Cui cng, mt nguyn t oxy c gii phng, to H2O. Cn nguyn t oxy th 2 s oxy ho c cht (thuc): RH ROH, v Cyt.P450 c ti to. Qu trnh phn ng c tm tt s sau:
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Hnh 1.6. S oxy ho thuc ca cytochrom 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).
Bng 1.4. Cc phn ng chnh trong chuyn ho thuc pha I
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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 ho 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 ni sinh (acid glucuronic, glutathion, sulfat, glycin, acetyl) s ghp vi mt nhm ho 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 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 ho, methyl ho. Cc phn ng ny i hi nng lng v c cht ni sinh, l c im ca pha II. Ngoi ra, c mt s thuc hon ton khng b chuyn ho, l nhng hp cht c cc cao (nh acid, base mnh), khng thm qua c lp lipid ca microsom. Phn ln c thi tr nhanh nh
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hexamethonium, methotrexat. Mt s hot cht khng c cc cng c th khng b chuyn ho: barbital, ether, halothan, dieldrin.
Bng 1.5. Cc phn ng chnh trong chuyn ho thuc pha II
Mt thuc c th b chuyn ho qua nhiu phn ng xy ra cng mt lc hoc tip ni nhau. V d paracetamol b glucuro-hp v sulfo-hp cng mt lc; chlorpromazin b chuyn ho nhn phenothiazin qua nhiu phn ng, sau l nhnh bn cng qua mt lot phn ng cui cng cho ti hn 30 cht chuyn ho khc nhau. 2.3.4. Cc yu t lm thay i tc chuyn ho thuc 2.3.4.1. Tui - Tr s sinh thiu nhiu enzym chuyn ho 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.
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- Isoniazid (INH) b mt tc dng do acetyl ho. Trong mt nghin cu, cho ung 10 mg/kg isoniazid, sau 6 gi thy lng isoniazid trong mu mt nhm l 3 - 6 g/mL, nhm khc ch l 2,5g/mL. Nhm u l nhm acetyl ho chm, cn gim liu v d c vi TKT. V di truyn, thuc nhm acetyl ho chm, thy 60% l ngi da trng, 40% l da en v 20% l da vng. Nhm sau l nhm acetyl ho nhanh, cn phi tng liu, nhng sn phm chuyn ho 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 ho: c tc dng lm tng sinh cc enzym microsom gan, lm tng hot tnh cc enzym ny. V d: phenobarbital, meprobamat, clorpromazin, phenylbutazon, v hng trm thuc khc: khi dng nhng thuc ny vi cc thuc b chuyn ho 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 ho 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 ho: mt s thuc khc nh cloramphenicol, dicumarol, isoniazid, quinin, cimetidin... li c tc dng c ch, lm gim hot tnh chuyn ho thuc ca enzym, do lm tng tc dng ca thuc phi hp. 2.3.4.4. Yu t bnh l - Cc bnh lm tn thng chc nng gan s lm suy gim sinh chuyn ho thuc ca gan: vim gan, gan nhim lipid, x gan, ung th gan... d lm tng tc dng hoc c tnh ca thuc chuyn ho qua gan nh tolbutamid, diazepam. - Cc bnh lm gim lu lng mu ti gan nh suy tim hoc dng thuc chn giao cm ko di s lm gim h s chit xut ca gan, lm ko di thi gian bn thi (t1/2) 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 ho. 2.4.1. Thi tr qua thn y l ng thi tr quan trng nht ca cc thuc tan trong nc, c khi 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
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thi tr. V 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-hp 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 li c ti hp thu vo mu. l cc thuc tan trong lipid, khng b ion ho 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 ho nc tiu, th cc acid yu (acid barbituric) s b thi tr nhanh hn v b ion ho nhiu nn ti hp thu gim. Ngc li, khi acid ho 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 ho nc tiu, lm tng ion ho ca phenobarbital, tng thi tr khi b nhim c phenobarbital (xem "khuch tn th ng"). - Trong trng hp suy thn, cn gim liu thuc dng. 2.4.2. Thi tr qua mt - Sau khi chuyn ho gan, cc cht chuyn ho s thi tr qua mt theo phn ra ngoi. Phn ln sau khi b chuyn ho thm rut s c ti hp thu vo mu thi tr qua thn. - Mt s hp cht chuyn ho glycuronid ca thuc c khi lng phn t trn 300 sau khi thi tr qua mt xung rut c th b thu phn bi glycuronidase ri li c ti hp thu v gan theo ng tnh mch ca li vo vng tun hon, c gi l thuc c chu k rut - gan. 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 khi 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.
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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 ho v thi tr thuc Mc ch ca chuyn ho l lm cho thuc mt hot tnh, d tan trong nc v thi tr. V vy, qu trnh chuyn ho 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 ho v thi tr thuc. 2.4.6.1. thanh thi (clearance CL) * nh ngha: thanh thi (CL) biu th kh nng ca mt 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. Hoc c khi tnh theo kg khi lng c th: mL/pht/kg.
V: tc thi tr ca thuc qua c quan (mg/pht) Cp: nng thuc trong huyt tng (mg/L) 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 khi huyt tng sau mt khong thi gian l 7 t1/2. Hai c quan chnh tham gia thi tr thuc khi c th l gan (lng thuc b chuyn ho 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 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)
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* nh ngha: Thi gian bn thi c phn bit lm hai loi: - t1/2 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 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 hoc t/2. * ngha: - T cng thc trn ta thy t1/2 t l nghch vi CL (clearance). Khi CL thay i theo nguyn nhn sinh l hoc bnh l s lm t1/2 thay i, hiu qu ca iu tr b nh hng. Cn phi hiu chnh liu lng hoc khong cch gia cc liu. - 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 khi c th (xem bng).
Lng thuc c thi tr theo t1/2 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 mi thuc, thi gian bn thi l ging nhau cho mi 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 tnh mch lin tc hoc sn xut dng thuc gii phng chm. + Khi t1/2 t 6 n 24h: dng liu thuc vi khong cch ng bng t1/2.
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+ Khi t1/2 > 24h: dng liu duy nht 1 ln mi ngy. 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 ho, 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 nhau 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 ho thuc pha I, kt qu v ngha? 8. K tn cc phn ng chnh (khng vit cng thc) ca chuyn ho thuc pha II, kt qu v ngha? 9. Trnh by cc cch thi tr thuc qua thn, qua gan, qua sa v ngha lm sng. 10. thanh thi l g? ngha? 11. Thi gian bn thi l g? ngha?
Bi 2 I CNG V DC LC HC
MC TIU 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 ho, 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.
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Dc lc hc nghin cu tc dng ca thuc ln c th sng, gii thch c ch ca cc tc dng sinh ho 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 ho 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 nng: 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 ho hc: - Lin kt ion: cc cht ho hc mang in tch (nh nhm amoni bc 4 ca 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 mi 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 mi lin kt ny. Cc lc lin kt trn u l thun nghch. - Lin kt cng ho 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 c cht xc tc. Loi lin kt ny t gp. V d lin kt gia cht alkyl ho 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. V d: acetylcholin gn vo receptor M - cholinergic:
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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 ho bi cc ligand gn trn cc v tr c hiu ca ADN nm trong cc vng iu ho 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 ho 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, phi, 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 khi 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 1.2.1. Tc dng ca thuc thng qua receptor Thuc tc dng trc tip trn cc receptor ca cc cht ni 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 ni 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 ni 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.
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- Mt s thuc thng qua vic gii phng cc cht ni 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 ho hoc iu ho cc qu trnh sinh ho c th b thuc c ch hoc hot ho: + 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 ho enzym: cc yu t vi lng nh Mg2+, Cu2+, Zn3+ hot ho nhiu enzym protein kinase, phosphokinase tc dng ln nhiu qu trnh chuyn ho 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 ho, khng c hiu: Cc mui cha cc ion kh hp thu qua mng sinh hc nh MgSO4, khi ung s "gi 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 lc 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 ho tr 2, y chng ra khi 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 ho 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 ho bnh thng, c th thm nhp vo cc thnh phn cu trc ca t bo, lm thay i chc nng ca t bo. Thuc ging purin, ging 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.
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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 ho (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 ho 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 d - tubocurarin vo tnh 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 tu, lm ngi bnh hi tnh. 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 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 ho, gim bch cu, tt huyt p th ng... V d: aspirin l thuc h st, gim au, chng vim (tc dng chnh), nhng gy chy mu tiu ho (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, tng 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. V d ung thuc chn 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 nng 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 nng ca t bo, c quan. V 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 tu xng.
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2.4. Tc dng chn lc Tc dng chn lc l tc dng iu tr xy ra sm nht, r rt nht. V d aspirin ung liu 1 - 2 g/ngy c tc dng h st v gim au, ung liu 4 - 6 g/ngy c c tc dng chng vim; 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 2 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 ho 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 kho v thuc l cha kho. Mt s thay i nh v cu trc ho 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 cortisol (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.
Tr thnh cht i khng tc dng: PABA l nguyn liu tng hp thc n cho vi khun. Sulfanilamid c cng thc gn ging PABA, lm vi khun s dng "nhm", khng pht trin c. V vy, sulfanilamid c tc dng km khun.
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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 adrenergic 500 ln mnh hn D-isoprenalin. 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 1, 2, 1, 2, 3, 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 ho ca thuc thay i, nh hng n s ho tan ca thuc trong nc hoc trong lipid, nh hng n s gn thuc vo protein, ion ho 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 ho mnh gan. Dn xut ethinyl estradiol (C CH gn v tr 17) rt t b chuyn ho nn ung c. - Tolbutamid b microsom gan oxy ho gc CH3 v tr para, c t1/2 huyt tng l 4 - 8 gi. Thay gc CH3 bng Cl (Clorpropamid) s rt kh b chuyn ho, lm t1/2 ca thuc ko di ti 35 gi. - 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 nng gn vo receptor. Khi thay i cu trc ca nhm hoc vng chc nng, dc lc hc ca thuc s thay i. Cn khi thay i cu trc ngoi vng chc nng, c th thay i dc ng hc ca thuc. 3.2. Dng thuc
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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:
Qua s , ta thy t mt 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 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. 3.2.2. T dc T dc khng phi ch l "cht n" bao gi thuc m cn nh hng n ho 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 ho. 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
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3.3.1. c im v tui (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 tng cn gn bilirubin, d b thuc y ra, gy ng c bilirubin. - H enzym chuyn ho 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 em (TE) t 2 - 12 tui
2. Cng thc ca Cowling: dng cho tr em t 2 - 12 tui
V d: liu cho ngi ln l 2,0. Liu cho tr 4 tui l
3. Cng thc ca Fried: dng cho nh nhi
4. Cng thc ca Clark
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Tuy nhin tnh liu theo din tch c th th tt hn. Khi dng cng thc:
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 ho". - 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 (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 tng 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 nng pht trin ca cc c quan. Trong 3 thng cui, thuc c th gy sy 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 mi 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
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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 t - WHO). ADR l tn gi chung cho mi 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. Do thuc l mt 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 ho ca n cng c th gy d ng, chng c gi l bn khng nguyn hay "hapten". Vo c th, hapten c kh nng gn vi mt protein ni sinh theo ng ni cng ho 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 ho v sn phm oxy ho s d gn vi nhm-SH ca protein ni 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 ho hc trung gian nh histamin, leucotrien, prostaglandin, gy gin mch, ph v vim. Cc c quan ch ca phn ng ny l ng tiu ho (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 lactam,
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aminoglycosid, huyt thanh, globulin, vacxin, vitamin B1 tim tnh 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 ho h b th. M ch ca phn ng ny l cc t bo ca h tun hon. V 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 ni mc mch mu, gy tn thng vim hu hoi, c gi l bnh huyt thanh. Biu hin lm sng thng l: my ay, ban , au, vim khp, ni 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 thy thuc cn hi k 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 tnh 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 (xem bi "Thuc chng st rt"), sulfamid, nitrofuran... 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 n 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 ho 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 mt enzym no . 4.4. Quen thuc
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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 hi 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 ho 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 hi phi tng dn liu. 4.4.1. Quen thuc nhanh (tachyphylaxis) Thc nghim dng nhng liu ephedrin bng nhau, tim tnh 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 ni 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 mi". - To cht chuyn ho c tc dng i khng vi cht m: isoprenalin (cng giao cm) qua chuyn ho gan, to ra 3 - orthomethylisoprenalin c tc dng hu . 4.4.2. Quen thuc chm Sau mt thi gian dng thuc lin tc, tc dng ca thuc gim dn, i hi phi tng liu hoc i thuc khc. C nhiu nguyn nhn: - Do gy cm ng enzym chuyn ho thuc, lm nhng liu thuc sau b chuyn ho nhanh, mt tc dng nhanh. Barbiturat, diazepam, tolbutamid, ru ethylic... u l nhng thuc gy cm ng enzym chuyn ho ca chnh n. - Do gim s lng receptor cm ng vi thuc mng t bo (iu ho 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 ho tng - up regulation) nh dng thuc hu giao cm, thuc an thn c ch h dopaminergic. Khi ngng thuc d gy hin tng hi 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 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 mi cch c thuc dng, k c hnh vi phm php.
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- 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 hi - Khi cai thuc s b thuc " vt" hay ln cn "i thuc": vt v, ln ln, 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 ni sinh; lm ri lon chc nng 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 hi phi c loi tr. 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
MC TIU 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.
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Trong lm sng, thy thuc mun phi 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 ti 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 trong khi c tnh li c th tng hn: CVKS, aminosid vi dy VIII. 1.1.2. Tng tc trn cc receptor khc nhau: tng tc chc nng - C cng ch tc dng: do lm tng hiu qu iu tr. V 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 nng i lp, dng iu tr nhim c: strychnin liu cao, kch thch tu 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 1 gy co mch, tng huyt p. 1.2. Tng tc dc ng hc L cc tng tc nh hng ln nhau thng qua cc qu trnh hp thu, phn phi, chuyn ho 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 ho ca thuc: Nh ta bit, ch nhng phn khng ion ho 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 ho 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 cc thuc d tan trong lipid, khi dng cng vi parafin (hoc thc n c lipid) s lm tng hp thu.
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- 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 (protamin - 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 Ca2+ hoc cc cation kim loi khc rut, b gim hp thu. Cholestyramin lm ta mui 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 ho, lm kh hp thu cc thuc khc. trnh s to phc hoc cn tr hp thu, hai 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 khi protein huyt tng, c th gy nhim c. 1.2.3. Thay i chuyn ho Nhiu thuc b chuyn ho gan do cc enzym chuyn ho thuc ca microsom gan (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 t1/2, gim hiu lc (nu l thuc gy cm ng enzym) hoc lm tng t1/2, tng hiu lc (nu l thuc c ch enzym) ca thuc dng 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 phi 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
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phenytoin, c th s b "v k hoch" do estrogen trong thuc trnh thai b gim hiu qu v b chuyn ho nhanh, hm lng tr nn thp. 1.2.4. Thay i thi tr thuc Thi tr (elimination) thuc gm hai qu trnh l chuyn ho 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 ho ca thuc dng km, lm thay i bi xut ca thuc. V d barbital c pKa = 7,5; pH = 7,5 th 50% thuc b ion ho; pH = 6,5 th ch c 9% b ion ho; pH = 9,5 th 91% barbital b ion ho. V vy, khi ng c cc thuc barbiturat, truyn dch NaHCO3 base ho nc tiu s tng bi xut barbiturat. Cc thuc l acid yu (vitamin C, amoni clorid) dng liu cao, lm acid ho nc tiu s lm tng thi tr thuc loi alcaloid (quinin, morphin). - Bi xut tranh chp ti ng thn: do hai 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 phi 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 ho:
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+ Acid gp base: to mui khng tan. Khng tim khng sinh loi acid (nhm lactam) vo ng dn dch truyn c tnh base. + Thuc oxy ho (vitamin C, B1, penicilin) khng trn vi thuc oxy kh (vitamin B2). + Thuc c bn cht l protein (insulin, heparin) khi gp mui kim loi s d kt ta. + Than hot, tanin hp ph hoc lm kt ta nhiu alcaloid (quinin, atropin) v cc mui 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. V d: acetylcholin v atropin ti receptor M - cholinergic; histamin v cimetidin trn receptor H2 d dy. + i khng chc nng: hai cht ng vn (agonist) tc dng trn hai receptor khc nhau nhng chc nng 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 2 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 thch receptor adrenergic (co mch, tng huyt p), va c tc dng kch thch receptor adrenergic (gin mch, h huyt p). Khi dng mt mnh, do tc dng mnh hn nn adrenelin gy tng huyt p. Khi dng phentolamin (Regitin) l thuc c ch chn lc receptor ri mi tim adrenalin th do ch kch thch c receptor 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 ho...). - 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. TNG TC THUC - THC N - UNG
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2.1. 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 ho. Tuy nhin, do pH rt acid (khi i, pH khong 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 Ca2+ 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 ho, 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 ho v thi tr thuc Thc n c th nh hng n enzym chuyn ho thuc ca gan, nh hng n pH ca nc tiu v qua nh hng n chuyn ho v bi xut thuc. Tuy nhin, nh hng khng ln. Ngc li, thuc c th nh hng n chuyn ho mt s cht trong thc n. Thuc c ch enzym mono - amin - oxydase (MAOI) nh iproniazid - l enzym kh amin - oxy ho ca nhiu amin ni, ngoi sinh - c th gy cn tng huyt p kch pht khi n cc thc n c nhiu tyramin (nh phomat), do khng c chuyn ho kp, tyramin 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 mi loi thuc v khng xy ra tng k khi ho tan thuc. - Nc l phng tin dn thuc (dng vin) vo d dy - rut, lm tng tan r v ho tan hot cht, gip hp thu d dng. V vy, cn ung nc (100 - 200 mL cho mi ln ung thuc) trnh ng vin thuc ti thc qun, c th gy kch ng, lot.
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- 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 ho 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, mui Fe...) Nhng thuc d tan trong lipid s tan trong lipid ca sa, lm 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, tng 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 ho 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 ho. Ngi nghin ru cn b gim protein huyt tng, suy gim chc nng gan, nhng li gy cm ng enzym chuyn ho thuc ca gan (xem bi "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 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 khong 1;
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ung lc no (sau n), thuc b gi li 1 - 4 gi vi pH khong 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 loi 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 ho (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 ho: cc thuc chng vim phi steroid, mui 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. T LNG GI
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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.
Chng II THUC TC DNG TRN H THN KINH THC VT

Bi 4 I CNG V PHN LOI
MC TIU 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 ho chc nng 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 trn. 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 hai h giao cm v ph giao cm khc nhau v c gii phu v chc nng sinh l. 1. PHN LOI THEO GII PHU 1.1. im xut pht - H giao cm xut pht t nhng t bo thn kinh sng bn ca tu sng t t sng ngc th
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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 phi cc c quan trong h chu. 1.2. Hch - H giao cm c ba 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 hoc ngay trong thnh c quan. 1.3. Si thn kinh - H giao cm: mt si tin hch thng tip ni 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 ni 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 ni vi khong 8000 si hu hch. V hch nm ngay cnh c quan, cho nn cc si hu hch ph giao cm rt ngn. 2. CHC NNG SINH L 2.1. Chc nng sinh l Chc nng sinh l ca hai h giao cm v ph giao cm trn cc c quan ni chung l i khng nhau (bng 4.1).
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Hnh 4.1. Cu to gii phu ca h thn kinh thc vt
Bng 4.1. p ng ca c quan vi h thn kinh thc vt Kch thch giao cm C quan Loi receptor p ng p ng Kch thch ph giao cm
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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
Co (gin ng t) ++ Co (co ng t) +++
1 (2) 1 (2)
Tng tn s ++ Tng bin ++
Gim tn s ngng tim Gim bin ++
1, 2, 2 , 2 1, 2 1 1, 2 1, 2, 1, 2 1, 2 2
Co +; gin ++ Co ++; gin ++ Co +++ Co nh Co +++; Gin + Co +++; gin + Co ++; gin ++ Gin +
Gin + Gin + Gin Gin Co ++
1, 2, 2 1 2
Gim + Co + c ch
Tng +++ Gin + Tng +++
1, 1 1, 2
Gim +; tng ++ Cha: co ( 1); gin ( 2) Khng cha; gin ( 2)
Thay i theo chu k kinh...
C quan sinh dc nam Bng quang
Phng tinh +++
Cng +++
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C bng quang C trn Gan Ty Acini T bo
2 1 1, 2
Gin + Co ++ Hu glycogen v tn to glucose +++
Co +++ Gin ++ -
1 2
Gim tit + Gim tit +++ tng tit ++ Hu lipid +++
Tng tit ++ -
T bo m
2, 1 (3)
Ghi ch:
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 ho 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 ho 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 nng 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 (ACh), cn hu hch giao cm l noradrenalin (NA), adrenalin (Adr) v dopamin (DA), gi chung l catecholamin (CA). 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 ho). Ion Ca2+ ng vai tr quan trng trong s gii phng cht dn truyn thn kinh.
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Hnh 4.2. Xinap v 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 v noradrenalin, 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), 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 phi 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, noncholinergic (NANC) transmission]. Burnstock (1969, 1986) thy c cc si thn kinh purinergic chi phi c trn ng tiu ho, 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 ho guanylyl cyclase, lm tng tng
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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 ho 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 phi 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 ho 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 hai h lun lun c mi lin quan cht ch vi nhau m bo tnh thng nht ca c th. Nhng mi lin quan v ang c tm thy vng di i, h vin (systema limbicus), hi hi m (hyppocampus), l nhng ni c cc trung tm iu ho thn nhit, chuyn ho nc, ng, lipid, iu ho 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. 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 gi 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 ho 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 hai 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
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adrenalin, gi l h adrenergic (ch gm 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 hai 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 ( ) v bta ( ).
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 hi cht dn truyn thn kinh v ngn dy thn kinh. + Kch thch trc tip cc receptor.
Cc thuc c ch c th l:
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+ Ngn cn tng hp cht dn truyn thn kinh + Ngn cn gii phng cht dn truyn thn kinh + Phong to ti receptor. T LNG GI 1. Trnh by c im gii phu v chc nng 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.
Bi 5 THUC TC DNG TRN H CHOLINERGIC

MC TIU 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 hai 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 ho 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.
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Sau khi tng hp, acetylcholin c lu tr trong cc nang c ng knh khong 300 - 600 ngn dy cholinergic di th phc hp khng c hot tnh. Di nh hng ca xung ng thn kinh v ca ion Ca2+, acetylcholin c gii phng ra dng t do, ng vai tr mt cht trung gian ho 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.
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. - Butyryl cholinesterase, hay cholinesterase 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 nng 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. 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 g/kg tim tnh 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. + 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.
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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.
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 thn kinh 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 ho ngay ti ch, c vai tr kch thch cc yu t cm th (nh cc receptor nhn cm ho hc), tng phn x tu, 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 Cht ch vn T chc (m) p ng C ch phn t
Cht i
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khng Nicotinic muscle (Nm) (N c vn) Nicotinic nron (Nn) (hch tk) Phenyltrimethyl ammonium tubocurarin Tm vn ng thn kinh - c Kh cc ti tm vn ng, co c M knh cation ti receptor Nm
Dimethylphenyl piperazin (DMPP)
Trimethaphan
Hch thc vt Tu thng thn Trung ng TK
Kh cc si sau hch Tit catecholamin
M knh cation ti receptor Nn
Cha xc nh Kh cc chm Cha xc nh Kch thch phospholipase C to IP3 v DAG; tng Ca2+ trong cytosol
Hu hch ph giao cm M1
Oxotremorin
Atropin Pirenzepin
Hch thc vt Trung ng TK
M2 (M4)
Atropin AF; DX 15
Tim Xoang nh Nt nh tht Tm tht Chm kh cc t pht Gim dn truyn Gim lc co bp Co tht tng tit Hot ho knh K+ c ch adenylcyclase (tc dng trn protein Gi) Hot ho knh K+ c ch adenylcyclase (tc dng trn protein Gi)
M3
Atropin Hexahydro siladifenidol
C trn Tuyn tit
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 ni 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 ni m mch (endotheliumderived relaxing factor - EDRF) m bn cht l nitric oxyd nn gy gin mch. Nu ni m mch b tn thng, ACh khng gy c gin mch. Tim di da hoc tim bp 0,05 - 0,1 g, mi 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.
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1.2.1. Betanechol (Urecholin) - Dn xut tng hp Tc dng chn lc trn ng tiu ho 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 Raynaud), 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. - 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, tiu chy, i dm, tim p chm, huyt p h... iu tr: atropin liu cao. C th tim tnh 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
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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 ni 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 phi ca ph giao cm nn atropin khng c nh hng. - 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 (physostigmin) tim tnh mch cch 2 gi mt ln v chng triu chng kch thch thn kinh trung ng bng benzodiazepin.
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2.1.2. Chuyn ho D hp thu qua ng tiu ho 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 mng 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 nghn 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 tnh 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.
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Ung hoc tim di da 0,25 - 0,5 mg. Liu ti a mi 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 phi 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 ho v thi tr theo phn. Tc dng ti a sau 30 - 90 pht v t1/2 > 4 gi. Ch phm: Ipratropium bromid (Atrovent, Berodual) dng kh dung nh liu, 20 g/nht bp 200 liu. Ngi ln mi 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 ( - pyridyl - metyl pyrrolidin) c, bng A. C trong thuc l, thuc lo di hnh thc acid hu c (0,5 8,0%). 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 60 mg. Trn hch thc vt, liu nh (0,02 - 1,0 mg/kg trn ch, tim tnh 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:
Nicotin
- 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.
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- Trn h hp, kch thch lm tng bin v tn s. - Gin ng t, tng tit dch, tng 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 ho hc xoang cnh kch thch phn x ln trung tm h hp. - 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 3,4 benzpyren, c th l mt trong nhng nguyn nhn gy ung th phi). 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 hai 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 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.
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Cc c quan thng nhn s chi phi 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
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 phi 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 th 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.
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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 phi 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 ho tr 2, cho nn d hp thu qua ng tiu ho, c th ung c. Tc dng ko di 4 - 12 gi. Dng lu tc dng s gim dn Ung mi ln 2,5 mg, mi ngy 2 ln. Tng dn cho ti khi t c hiu qu iu tr, c th ung ti 30 mg mi 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 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 nng cc c s c hi 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
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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 ging atropin nn lm tim p chm, khng lm gii phng histamin v km c hn d-tubocurarin 10 n 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 n 6 pht v ko di 120 n 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 n 4 pht v ko di 80 n 100 pht. L cha bt pha tim 4 mg + 2 mL dung mi. Tim tnh 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 ging 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 ho hc nh 2 phn t ACh gn vo nhau.
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 tnh mch t 1 mg/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...
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- 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 ho nn phi tim tnh 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
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 ho tr vi nguyn t C ca nhm carboxyl ca este:
Sau , phn gn vi v tr anion s c tch thnh cholin, cn phn gn vi v tr este s phn ng rt nhanh vi nc thnh acid acetic, enym c hot ng tr li.
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Cc thuc khng cholinesterase lm mt hot tnh ca enzym, nn lm vng bn acetylcholin ni sinh, gy cc triu chng cng h cholinergic ngoi bin v trung ng. Cc thuc c chia lm hai loi: loi c ch c hi phc (c dng trong iu tr) v loi c ch khng hi phc hoc rt kh hi phc (dng lm thuc dit cn trng hoc cht c chin tranh). 5.1. Loi c ch c hi phc Cc thuc loi ny kt hp vi cholinesterase hoc ch mt v tr anion (nh edrophonium tetraethylamoni) hoc c hai v tr tc dng ca enzym (nh physostigmin, prostigmin), nhng khng to thnh phc hp vng bn, cui cng vn b thu phn v enzym c hot ho tr li. Phn ln u cha nhm carbamat ( OCONR'R"). V l tc dng gin tip lm vng bn acetylcholin nn khng c tc dng trn nhng c quan, b phn ct b thn kinh. Carbaril l thuc dit su nhm carbamat, dng trong nng nghip v trong vn nh v t c.
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, mi 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.
Prostigmin
p dng: - Ch nh tt trong bnh nhc c bm sinh (myasthenia gravis) v thiu ht acetylcholin bn vn
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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 mi ngy 0,5 - 2,0 mg. - Ung mi 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 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 ho rt vng bn, kh c thu phn hi phc tr li, i hi 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:
Tensilon
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...).
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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, xung 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. - Du hiu kch thch h N: mt mi, 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 ba 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 tnh 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 ho 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 to v hot ho tr li. Cht thng dng l pralidoxim (2 - PAM) tc dng ln ChE phosphoryl ho, to oximphosphonat b thi tr v gii phng cholinesterase. Pralidoxim (2 - PAM): l 1g km ng nc 20 mL. Mi u, tim tnh mch 1 - 2g, sau truyn nh git tnh mch mi 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 tnh mch) hoc natri thiopental (2,5% tim tnh mch). iu tr sc. T LNG GI 1. Trnh by sinh chuyn ho, 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 hai 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 to khng hi phc cholinnesterase.
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Bi 6 THUC TC DNG TRN H ADRENERGIC

MC TIU 1. Trnh by c chu trnh chuyn ho ca catecholamin ti ngn dy thn kinh giao cm. 2. Phn bit c tc dng ca adrenalin, noradrenalin v DA 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 hu giao cm. 6. Phn bit c c ch tc dng v p dng iu tr ca thuc hu 1.
H adrenergic l h hu hch giao cm, gii phng cht trung gian ho hc gi chung l catecholamin, v u mang nhn catechol (vng benzen c hai nhm-OH v tr ortho v mt gc amin chui bn). Cc catecholamin gm 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). 1. CHUYN HO 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 (hnh 6.1). Sau khi c tng hp, mt phn catecholamin s kt hp vi ATP hoc vi mt dng protein ho 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 tng (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 hydroxylase theo c ch iu ho ngc chiu: khi noradrenalin tng th hot tnh ca enzym gim, v ngc li. Mt khc, cc cht cng receptor 2 lm gim gii phng noradrenalin ra khe xinap v do tr lng ca noradrenalin trong bo tng s tng ln.
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Hnh 6 .1. Sinh tng hp catecholamin
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 Ca2+ 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 ho, cn phn ln (trn 80%) s c thu hi li, phn nh khc b mt hot tnh ngay trong bo tng.
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Hnh 6.2. Chuyn vn ca catecholamin ti u 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 ho 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 ho thnh NA. in th hot ng lm m knh calci, Ca2+ vo t bo, gii phng NA t ti d tr.
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Hnh 6.3. S phn ca noradrenalin khi c gii phng 1 . Tc dng trn receptor sau (1a) v trc (1b) xinap 2. Thu hi 3. Vo tun hon v b chuyn ho bi COMT 4. Chuyn ho trong bo tng bi MAO
Catecholamin b mt hot tnh bi qu trnh oxy ho kh amin do hai enzym MAO (mono - amin oxydase) v COMT (catechol - oxy - transferase) cui cng thnh acid 3 - methoxy - 4 hydroxy mandelic (hay vanyl mandelic acid - VMA) thi tr qua nc tiu. MAO c nhiu trong ty th (mitochondria), v vy n ng vai tr ging ho 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 ho 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 v do chng c tc dng khc nhau trn cc c quan (bng 6.1). Ta thy rng tc dng cng c tnh cht kch thch, lm co tht cc c trn, ch c c trn thnh rut l gin. Ngc li, tc dng cng c tnh cht c ch, lm gin c, tr c tim li lm p nhanh v p mnh. Land, Arnold v Mc Auliff (1966) cn chia cc receptor thnh hai nhm 1 (tc dng trn tim v chuyn ho lipid) v nhm 2 (lm gin mch, gin kh o v chuyn ho ng). Receptor 2 trc xinap kch thch lm tng gii phng NA, c vai tr iu ho ngc vi 2.
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Bng 6.1. Cc receptor adrenergic Chti khng Prazosin
Receptor 1
Cht ch vn Adr NA >>Iso Phenylephrin
M - C trn thnh mch - C trn sinh dc tit niu
p ng Co tht Co tht
C ch phn t Kch thch phospholipase C to IP3 v DAG; tng Ca2+ cytosol
Hu glycogen - Gan Tn to ng u cc ho v gin - C trn rut Tng co bp, lon nhp - Tim 2 Adr NA >> Iso Clonidin Ngng kt - Tiu cu Gim tit NA - Tn cng si TK Co - C trn thnh mch 1 Iso>Adr = NA Dobutamin - T bo gn cu thn 2 Iso>Adr >> NA Terbutalin ICI 118551 - C trn (mch kh qun,rut...) - C vn - Gan 3 Iso = NA>Adr ICI 118551 CGP 20712A Iso*: Isoproterenol Adr: adrenalin NA: noradrenalin M m Metoprolol - Tim Tng tn s, bin v tc dn truyn A -V - Tng lung Ca, tng Ca2+ trong cytosol Hot ho adenylcyclase v knh Ca - c ch knh Ca2+ Yohimbin - T bo ca ty Gim tit insulin - c ch adenylcyclase (Gi)- Hot ho knh K+ - c ch dng K+ - Hot ho knh K+ ph thuc vo Ca2+
Tng tit renin - Gin - Hu glycogen gn K+ - Hu glycogen - Tn to ng Hu lipid Hot ho adenylcyclase Hot ho adenylcyclase
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Ghi ch ca bng 3: - Mi receptor 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 2, tri li, c ch adenylcyclase thng qua protein Gi, ng thi hot ho knh kali, c ch knh calci. - Receptor 1 kch thch lm tng calci ni bo thng qua 2 cht trung gian Diacylglycerol (DAG) v Inositol triphosphat (IP3).
Theo xut ca Langer (1974), cc receptor c chia thnh hai loi: loi 1 l receptor sau xinap, lm co mch tng huyt p, loi 2 l receptor trc xinap, c tc dng iu ho, khi kch thch s lm gim gii phng noradrenalin ra khe xinap, ng thi lm gim tit renin, gy h huyt p. Cc receptor 2 c nhiu h giao cm trung ng. Hin cng thy c receptor 2 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 ni 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 - ). 2. THUC KCH THCH 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 ni sinh nh tyramin (khng dng trong iu tr), ephedrin, amphetamin v phenyl-ethyl-amin. 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 bta 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 v receptor. - Trn tim mch:
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Adrenalin lm tim p nhanh, mnh (tc dng ) 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. Mt khc, adrenalin gy co mch mt s vng (mch da, mch tng - receptor ) nhng li gy gin mch mt s vng khc (mch c vn, mch phi - receptor ...) 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 ho 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 phi) do d gy cc bin chng v mch no hoc ph phi 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 ho: Adrenalin lm tng hu glycogen gan, lm tng glucose mu, lm tng acid bo t do trong mu, tng chuyn ho c bn, tng s dng oxy ca m. Cc c ch tc dng ca adrenalin hay catecholamin ni chung l lm tng tng hp adenosin 3' - 5' - monophosphat (AMP - vng) t ATP do hot ho adenylcyclase (xem s ). 2.1.1.2. p dng iu tr - 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 tnh. - Sc ngt: dng adrenalin tng huyt p tm thi bng cch tim tnh 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: mi ln 1 mL; 24 gi: 5 mL. ng 1 mL = 0,001g adrenalin hydroclorid.
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S tc ng ca catecholamin ln chuyn ho ng v lipid
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 , rt yu trn , 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 2. - Tc dng trn dinh dng v chuyn ho u km adrenalin. Trn nhiu c quan, tc dng ca NA trn receptor km hn adrenalin mt cht. Nhng do t l cng tc dng gia v khc nhau
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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, 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 ho 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 Dopamin l cht tin thn ca noradrenalin v l cht trung gian ho 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 g/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 hi th tch mu km theo). - Ti thn, "liu thn" ca dopamin lm tng nc tiu, tng thi Na+, K+, Cl-, Ca2+, tng sn xut prostaglandin E2 nn lm gin mch thn gip thn chu ng c thiu oxy. - Liu trung bnh > 2 - 10 g/kg/pht, tc dng trn receptor 1, lm tng bin v tn s tim. Sc cn ngoi bin ni chung khng thay i. - Liu cao trn 10g/kg/pht tc dng trn receptor 1, 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 tnh mch 2 - 5 g/kg/pht. Tng gim s git theo hiu qu mong mun. Chng ch nh: cc bnh mch vnh
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2.2. Thuc cng receptor 2.2.1. Metaraminol (Aramin) Tc dng u tin trn receptor 1. 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 ho. 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 tnh mch 0,5 - 5,0 mg trong trng hp cp cu. Truyn chm tnh 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 1. 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 2 trc xinap trung ng v thuc qua c hng ro mu - no. Tc dng cng 2 sau xinap ngoi bin ch thong qua nn gy tng huyt p ngn. Sau , do tc dng cng 2 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 li niu. ng thi c tc dng an thn, gim au v gy mt mi. 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 (xem bi "Thuc cha tng 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.
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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 C 4 tc dng dc l chnh. - Tc dng gin ph qun, dng cha hen: loi cng 2. - Tc dng gin mch: loi cng 2. - Tc dng kch thch 1 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 2 lm gim co bp c dng chng do sy thai. 2.3.1. Isoproterenol (Isoprenalin, Isuprel, Aleudrin, Novodrin, Isopropyl noradrenalin) Tc dng u tin trn receptor (1 v 2). 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 nhi mu c tim: truyn tnh 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 ho 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 1 receptor. Tc dng phc tp do dobutamin raxemic c hai ng phn; ng phn (-) dobutamin c tc dng cng 1 mnh, gy tng huyt p; trong khi ng phn (+) dobutamin li c tc dng i lp hu 1. C hai ng phn u c tc dng cng , nhng ng phn (+) 10 ln mnh hn ng phn (-). Tc dng ca dobutamin raxemic l tng hp ca c hai ng phn. 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 hn 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, nhi mu c tim.
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V thi gian bn thi ch khong 2 pht nn ch dng bng ng truyn chm tnh mch. Ch phm: Dobutamin hydroclorid (Dobutrex) l 20 mL cha 250 mg dobutamin. Khi dng, ho long trong 50 mL dung dch dextrose 5%, truyn tnh mch vi liu 2,5 - 10 g/kg/pht. Nu nhp tim tng nhanh, gim tc truyn. 2.3.3. Thuc cng u tin (chn lc) receptor 2 L thuc thng c dng iu tr ct cn hen. Tuy nhin, liu cao cng vn kch thch c 1, 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 1 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 2 dng di dng kh dung, ngoi tc dng lm gin ph qun cn c th c ch gii phng leucotrien v histamin khi 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 2 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 ho. 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 g/nht bp 2 nht/ln 3 - 4 ln/ngy cch nhau 4 ting. 2.3.3.3. Ritodrin Dng lm gin t cung, chng non. 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
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hp c. Trong y hc, dng loi t tuyn v raxemic. L thuc va c tc dng gin tip lm gii phng catecholamin ra khi ni d tr, va c tc dng trc tip trn receptor. 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 iu tr 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 mi ng. Vng bn vi MAO. Chuyn ho gan, khong 40% thi tr nguyn cht qua nc tiu. Dng di th mui clohydrat hoc sulfat d ho 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, tng 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, raxemic -phenylisopropanolamin. Tc dng dc l theo kiu ephedrin, gin tip lm gii phng noradrenalin (v c th cn c dopamin v serotonin) ra khi 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 ho (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, dimethoxyam-phetamin...) kch thch thn trung ng rt mnh, gy lon thn, u xp vo cht ma tu. 2.4.3. Phenylpropanolamin t tc dng ln thn kinh trung ng hn. ngoi bin, tc dng co mch thng c dng
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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 I KHNG 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, li mt, gin ng t, tng h hp; chnh l nhng du hiu cng giao cm). Cc thuc c chia thnh hai nhm: - Thuc hu 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 ni sinh, tnh cm th ca cc receptor sau xinap vi catecholamin ngoi lai s tng ln. - 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 ni 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 methyl dopa (Aldomet) phong to dopa decarboxylase, lm dopa khng chuyn thnh dopamin v 5 - hydroxytryptophan khng chuyn thnh 5 - hydroxytryptamin (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 methyldopa cn c th chuyn thnh methyl noradrenalin, tc dng nh mt cht trung gian ho 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 methyl dopa. Carbidopa v bemerazid, c ch dopa decarboxylase ngoi bin. c dng phi hp vi L - dopa 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
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p). Reserpin cn cn tr qu trnh gn catecholamin (c ni 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 ho 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 Ca2+ m lm cho catecholamin khng c gii phng ra. 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 xung tc kch thch dy giao cm nh mt cht trung gian ho hc, c gi l cht trung gian ho hc gi: - methyldopa to thnh methyl noradrenalin. - Thuc c ch MAO: tyramin chuyn thnh octopamin. - Guanetidin. 3.2. Thuc hu adrenalin Cc thuc phong to 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 v , 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 v thuc hu adrenergic.
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3.2.1. Thuc hu - adrenergic V phong to cc receptor 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 . Hin tng o ngc tc dng tng p ca adrenalin c gii thch l cc mao mch c c hai loi receptor v , adrenalin tc dng trn c hai loi receptor , nhng bnh thng, tc dng chim u th nn adrenalin lm tng huyt p. Khi dng thuc phong to , adrenalin ch cn gy c tc dng kch thch trn cc receptor 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 1A 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 v thi gian tc dng. 3.2.1.1. Nhm haloalkylamin C phenoxybenzamin (dibenzylin) v dibenamin. V ho 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 theo lin kt cng ho tr (ch yu l receptor 1), 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 1 v 2 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. 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 hoc tim tnh 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 1 Dng iu tr tng huyt p, ung 1 - 20 mg mt ngy (xem bi "Thuc cha tng huyt p") 3.2.1.4. Alcaloid nhn indol
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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 . 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 ho ca cc ergot (nh dihydroergotamin, hydroergotoxin) c tc dng phong to tng ln trong khi tc dng co c trn gim xung. Ngoi tc dng phong to receptor , 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 ho hc gn ging reserpin, tranh chp vi NA ti receptor 2. 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 adrenergic Cn gi l thuc "phong to " (" blocking agent") hay thuc chn giao cm, 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 : l tnh cht chung duy nht ca tt c cc thuc hu . - 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 m nt. Ch yu l do hu 1. - Trn kh qun: lm co, d gy hen. Ch yu l do hu 2, gy tc dng khng mong mun. - Trn thn: lm gim tit renin, h huyt p trn ngi c HA cao. - Trn chuyn ho: c ch hu glycogen v hu lipid. * Tc dng lm n nh mng: ging quinidin, lm gim tnh thm ca mng t bo vi s trao i ion nn c tc dng chng lon nhp tim.
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* C hot tnh ni ti kch thch receptor : mt s thuc phong to 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 i lp vi tt c cc tc dng cng giao cm ca (1: tim v 2: mch, kh qun). Nhng mt s thuc li ch phong to c mt trong hai loi receptor (1 hoc 2), v th phn bit thnh cc loi phong to chn lc trn giao cm : - Loi tc dng chn lc trn 1 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 2 ca kh qun nn hn ch c tai bin co tht kh qun. Km tc dng trn 2 ca thnh mch s c li cho iu tr cao huyt p (gim co mch ngoi bin) Do rt km tc dng trn 2 ca thnh mch vnh nn khng bc l tc dng cng - adrenergic (tc dng co mch vnh ca CA tun hon trong mu). Bnh thng, do c tc dng th tc dng ca b lu m. Khi b phong to th tc dng ca 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 2, 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 nhi mu c tim, tim tnh mch ngay t gi u s lm gim lan rng nhi 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 (xem thm bi "Thuc cha tng huyt p"). - Mt s ch nh khc; cng gip, migren, glocm 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 ni ti trong c tim.
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- Hen ph qun. Loi c tc dng chn lc trn receptor 1 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: * Loi tai bin l hu qu ca s phong to receptor . - Tim: suy tim do lm yu co bp ca c tim, chm nhp tim, nh tht phn ly. - Mch: hi chng Raynaud, tm lnh u chi, i khp khing, (thng gp vi propranolol, do b phong to th s cng). Cc thuc chn lc trn 1 v c hot tnh kch thch ni ti th t tai bin ny hn. - Phi: cc thuc c tc dng hu 2 > 1 s gy co kh qun, kh th. Khng dng cho ngi hen. - Thn kinh trung ng: mt mi, mt ng hay ng m, o nh, trm cm, thng gp hn vi cc thuc d tan trong lipid v d thm vo t bo thn kinh (propranolol, metoprolol), loi t tan trong lipid (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 - 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 m 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 ho gan nh phenytoin, rifampin, phenobarbital, ht thuc l, s lm tng chuyn ho, gim tc dng ca thuc hu . - Cc mui nhm, cholestyramin lm gim hp thu.
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- Cc thuc hu 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 . 3.2.2.6. Phn loi
Khng c tc dng "chn lc trn tim" n nh mng Khng cng ni ti Propranolol Khng n nh mng Sotalol Timolol C cng ni ti Alprenolol Oxprenolol Pindolol Acebutolol Metoprolol Practolol C tc dng "chn lc trn tim" n nh mng Khng n nh mng Esmolol Atenolol
S phn loi ny gip cho chn thuc trong iu tr. V 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 ni ti " 3.2.2.7. Mt s thuc chnh * Propranolol (Inderal, Avlocardyl) L isopropyl aminonaphtyl oxypropranolol. C tc dng phong to nh nhau trn c 1 v 2, khng c hot tnh ni 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 ni 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.
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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 tnh 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 ho do tan nhiu trong lipid. Gn vo protein huyt tng ti 90 - 95%, m ti a trong mu t c sau khi ung t 1 - 2 gi. Chuyn ho thnh hydroxy - 4 - propranolol v acid naphtoxyl acetic rt nhanh ti gan nn ch khong 25% liu ung vo c vng tun hon, t1/2: 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 ni ti v khng nh hng n vn chuyn ca ion Ca2+ 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 lipid, sinh kh dng 75% v t1/2 = 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 1 - rt tan trong nc nn t thm vo thn kinh trung ng, sinh kh dng 50%, t1/2 = 5 - 8 gi. Ung 50 - 100 mg/ngy. * Metoprolol (Lopressor): c tc dng chn lc trn tim (1) nn gy cn hen ph qun (2). Ung 50 - 150 mg/ngy. Hp thu nhanh qua ng ung, sinh kh dng 40% v t1/2 = 3 - 4 gi. T LNG GI 1. Trnh by sinh chuyn ho 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 giao cm, nu v d 2 thuc. 8. Trnh by tc dng dc l v p dng lm sng ca thuc hu .
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9. Trnh by cc tc dng khng mong mun ca thuc hu .
Chng III THUC TC DNG TRN H THN KINH TRUNG NG

Bi 7 THUC T
MC TIU 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 nng 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 nng thn kinh c hi 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.
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- 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 ging nhau, tng t lidocain, gm ba phn chnh: cc a lipid, cc a nc v chui trung gian:
- Cc a lipid l nhn thm, c nh hng n s khuch tn v hiu lc ca tc dng gy t. Tnh a lipid 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 ho ca thuc. Nhm amin l cht nhn H+ theo phn ng: R - NH2 +H2O R - NH3 + OH- Chui trung gian: c 4 - 6 nguyn t (di 6 - 9nm) nh hng n c tnh ca thuc, chuyn ho v thi gian tc dng ca thuc. Ngoi gii hn , tc dng s km dn. Trong chui ny c th c: * Nhm mang ng ni ester (- COO- , nh procain) b thu phn nhanh gan v mu do cc esterase, nn c thi gian tc dng ngn. * Nhm mang ng ni 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.
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Hu ht cc thuc t u c pKa l 8,0 - 9,0, v vy, pH ca dch c th phn ln u 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 theo s :
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
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gic nng, ri n xc gic su. Khi ht thuc, tc dng hi 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 bng cch tim di da thuc ngm c vo tn 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 thn kinh, phong to hch, gy t ngoi mng cng, gy t tu sng (xem s hnh 7.2).
Hnh 7.2. S cc cch gy t
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 hiu 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, gim dn
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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 ho O - toluidin gy oxy ho, bin Hb thnh metHb. 1.6. Tc dng khng mong mun v c tnh 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...). 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. 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 ni 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 mui 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 ho v thi tr ph thuc ch yu vo cu trc. Cc thuc t c chc amid (nh lidocain) b chuyn ho gan bi cyt P450. Tc chuyn ho t nhanh n chm l prilocain > etidocain > lidocain > mepivacain > bupivacain. ngi bnh thng, t1/2 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, t1/2 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 phi 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 adrenergic (lm ri lon dn truyn c tim). - Thuc t hip ng vi tc dng ca cura. Sulfamid i khng hai chiu vi cc thuc t dn xut t acid para amino benzoic (nh procain).
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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 c, bng A: gy 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 mi (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 hi 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, hi hp, lo s, d b ngt), kch thch thn kinh trung ng (o gic, co git).
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- Mn: d gy quen thuc v nghin, mt nht nht, ng t gin, hoi t vch mi. 2.2. Procain (novocaine) c, bng B. Thuc tng hp (1905). - L thuc t mang ng ni 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 to hch li lm gin mch, h huyt p. Khi gy t nn phi hp vi adrenalin lm co mch, tng thi gian gy t. - 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) Thuc tng hp (1948). Hin dng rt rng ri. - L thuc t mang ng ni amid, tan trong nc. - L thuc gy t b mt v gy t dn truyn tt. Tc dng mnh hn procain ba ln, nhng c hn hai ln. - Tc dng nhanh v ko di do b chuyn ho chm. Hai cht chuyn ho 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 ni 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 to 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
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gy t tu sng c t trng 1,020 37oC (ng 4mL = 20mg bupivacain clohydrat): tim tu sng 3mL t th ngi, tc dng t v mm c (c bng, c chi di ko di 2 - 2,5 gi). - D tan trong lipid, gn vo protein huyt tng 95%, hon ton chuyn ho gan do Cyt.P450 v thi tr qua thn. - c tnh: c tnh trn tim mnh hn lidocain: gy lon 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: Chch p xe, mn nht, chn thng th thao. - Thuc ng trong l thu tinh, c van kim loi, tin s dng khi phun vo ni cn gy t. T LNG GI 1. Trnh by c ch tc dng v tc dng dc l ca thuc t. 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.
Bi 8 THUC NG V RU
MC TIU 1. Nu c mi lin quan gia cu trc ho 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 tr ng c ca thuc ng barbiturat (phenobarbital). 4. Trnh by c tc dng, ng c cp v mn, iu tr ng c ru ethylic.
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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 ur.
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 ho 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 chui R1 v R2 s tng tc dng gy ng. Tc dng c ch thn kinh trung ng s mnh hn khi R1 v R2 l chui nhnh hoc gc carbua hydro vng hoc cha no.
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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 ging gic ng sinh l, lm cho gic ng n nhanh, gim 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 gi 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 tu sng, lm gim phn x a synap v c th lm gim 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 gm phn trc (phn i ln) hot ho v phn sau (phn i xung) c tnh c ch. Barbiturat tc ng bng cch c ch chc nng ca h li m vai tr l dn dt, chn lc nhng thng tin t ngoi bin vo v no. Thuc c th ngn cn xung tc thn kinh qua cc trc h li - v no, ngoi bin - i no - v 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 ho. 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).
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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 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 ho 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 hi chng au khp, ri lon chuyn ho 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 ho 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. Cui 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 hi sc trc.
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- 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 hp ph cht c. - Tng o thi: + Gy bi niu cng bc: truyn dung dch mn ng trng hoc dung dch glucose 5% (4 - 6 lt/ngy). Dng thuc li niu thm thu (truyn tnh mch chm dung dch manitol 100 g/lt) tng thi barbiturat. + Base ho huyt tng: truyn tnh 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 tt 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 bi 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 ho 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,
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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 vi 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 ri lon tm thn, mt iu ho, 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 Ca2+ ca glutamat. - 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 ho. - Tiu ho: 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 dch 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 ho ca ru). Do , ngi ng c ru d b h thn nhit v khi gp lnh d b cht cng.
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Ru cn lm gin c t cung. 4.1.2. Dc ng hc Ru hp thu nhanh qua ng tiu ho. 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 phi nhanh vo cc m v dch ca c th (qua c nhau thai). Nng ru trong m tng ng vi nng trong mu. Trn 90% ru c oxy ho gan, phn cn li c thi tr nguyn vn qua phi v thn. C hai con ng chuyn ho ru thnh acetaldehyd. - Chuyn ho 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). Ngay sau , acetaldehyd s c chuyn ho tip nh aldehyd oxydase cui cng thnh CO2 v H2O. - Chuyn ho qua h microsomal ethanol oxidizing system (MEOS) khi nng ru trong mu trn 100 mg/dL (22 mmol/L), ru c chuyn ho qua h MEOS. nhng ngi nghin ru, hot tnh ca cc enzym tng ln, lm tng chuyn ho ca chnh ru v mt s thuc c chuyn ho 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, ri lon tm thn, co git, gim kh nng lm vic tr c, m sng... thng gp ngi nghin ru nng. - Ung ru mnh v ko di, c tim d b tn thng v x ho. 5% ngi nghin ru b tng huyt p. - Ru c nh hng ti h thng min dch (thay i s ho 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 phi, lao...
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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 nng 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 oxydase, 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 ho nhng nng thuc trong mu thp v disulfiram b chuyn ho thnh diethyldithiocarbamate (cht chuyn ho 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 di, bun nn, nn, v m hi, tt huyt p v bi ri. 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 phi hp vi ru ethylic cng gy nhng phn ng nh disulfiram. Cc nghin cu gn y cho thy c th phi hp Naltrexon (cht i khng trn receptor opioid) vi disulfiram cha nghin ru. S phi 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 loi opioid lm tng tc dng ca ru trn thn kinh trung ng. - Ru lm tng tc dng ph trn ng tiu ho nh vim, lot, chy mu ca cc thuc chng vim phi steroid (aspirin...), ung ru cng vi paracetamol lm tng nguy c vim gan.
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- Khi ung ko di, ru gy cm ng mt s enzym chuyn ho thuc microsom gan, lm tng chuyn ho v gim hiu qu iu tr ca mt s thuc: sulfamid h ng huyt, thuc chng ng mu loi cumarin, meprobamat, diphenylhydantoin, carbamazepin... - 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 ho 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). 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 ho v suy thn (do lng ng cc tinh th oxalat ng thn). T LNG GI 1. Phn tch cu trc ho hc v cc c tnh l ho ca cc barbiturat. 2. Phn tch mi lin quan gia cu trc ho 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.
Bi 9 THUC GIM AU LOI MORPHIN

MC TIU 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.
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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 ho 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 ho 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 ho 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
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Trong lm sng dng mui morphin clohydrat d tan trong nc, cha 75% morphin. 2.1.1. Tc dng 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 ba loi chnh v mi 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 phi hnh vi (hnh nhn, hi hi m, nhn lc, v no), vng iu ho h thn kinh thc vt (hnh no) v chc nng ni tit (li gia). ngoi bin, cc receptor c tu thng thn, tuyn ngoi tit d dy, m ri thn kinh tng. V mt iu tr, mi receptor c coi nh c chc nng ring.
Tc dng ca cc receptor
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:
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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: 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 2 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 nhau 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 bta endorphin. Cc opioid kch thch receptor muy, lm tng 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
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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 . Trn chuyn ho: lm gim oxy ho, 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 ho nhm ny, v d codein (methyl morphin). Ngc li, tc dng ca morphin s c tng cng nu nhm phenol v tr 3 b ester ho, nh acetyl morphin (acetyl ho). 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 ester ho. Tc dng gim au v gy nghin s tng mnh khi c hai nhm phenol v ru u b acetyl ho, v d heroin (diacetyl morphin). 2.1.3. Dc ng hc 2.1.3.1. Hp thu
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Morphin d hp thu qua ng tiu ho, ch yu t trng, hp thu qua nim mc trc trng, song v phi qua chuyn ho 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 lipid hn cc opioid khc, nh codein, heroin v methadon. 2.1.3.3. Chuyn ho Con ng chnh chuyn ho 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 ho 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 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 ho 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 cui ca bnh, au do ung th...). gim au nhng bnh khng cha khi c (nh ung th thi k cui), c th dng morphin qu 7 ngy. - Phi hp khi gy m v tin m.
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2.1.5.2. Chng ch nh - Tr em di 30 thng tui. - Triu chng au bng cp cha r nguyn nhn. - Suy h hp. - Suy gan nng. - Chn thng no hoc tng 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 do ph i tuyn 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 phi 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 loi 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 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.
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Nu hn m ko di c th cht v vim phi. 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 tnh 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 ni sinh, ngi ta ct ngha c hin tng quen thuc: trng thi bnh thng cht ch vn ni sinh ca receptor morphinic l enkephalin b ging ho qu nhanh, nn khng gy quen. 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 morphin lp i lp li, c th phn ng bng tng tng hp AMP vng, v vy liu morphin sau i hi 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 ni sinh. S thiu ht morphin ni 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 ni sinh khng , cc receptor
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ca morphin 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 lng, chy nc mi, run, 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 to tc dng gy khoi cm ca cc cht dng thuc phin do lm cc triu chng ca hi 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 hai 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, mi 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 - - acetylmethadon) trong cai nghin heroin v thuc c thi gian tc dng rt di, 3 ngy mi 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 2 adrenergic trc synap, c tc dng lm gim tit noradrenalin. Clonidin thng c dng 0,1 mg/ln, mi 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. 2.3. Cc opioid thng dng
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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 - 10 ln). 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. 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 ho 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 mi ln, ngy dng 2 - 3 ln Tim bp 1 mL dung dch 1%, liu ti a: 0,05 g mi 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
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- Scopolamin, barbiturat v ru lm tng c tnh ca pethidin, do phi gim liu pethidin khi dng ng thi. 2.3.2. Methadon (Dolophin, Amidon, 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 ho, 90% gn vi protein huyt tng. Nh c nhm ceton v amin trong cu trc nn methadon c lin kt ng ho tr bn vi protein no. Thuc c th tch lu nu dng lin tip. Chuyn ho 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 ging 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 Trn lm sng, methadon c dng gim au v cai nghin morphin, heroin. Liu lng: ung mi ln 2,5 mg, ngy 2 - 3 ln, tu thuc mc au v phn ng ca bnh nhn. 2.3.3. Fentanyl (Sublimaze, 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, nhau thai v sa. Fentanyl b chuyn ho gan v mt hot tnh. Thi tr qua nc tiu (khong10% di dng cha chuyn ho). 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.
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- Ton thn: chng mt, ng l m, l ln, o gic, ra m hi, bng mt, sng khoi. - Tiu ho: 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 g, c th tim bp 30 - 60 pht trc khi gy m. - Gim au trong phu thut: 0,07 - 1,4 g/kg th trng, c th nhc li trong 1 - 2 gi nu cn. 2.3.3.5. Tng tc thuc - 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 phi hp. - Huyt p gim mnh khi phi hp fentanyl vi thuc c ch - adrenergic v thuc chn knh calci.
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2.3.3.6. Ch phm 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 tnh mch 8 g/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, phi hp vi thuc m loi barbiturat, nitoxyd. 2.3.4. Propoxyphen 2.3.4.1. Tc dng Propoxyphen c cng thc gn ging 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 ho ch yu qua gan, nh phn ng N - kh methyl. Thi gian bn thi t 6 - 12 gi. Cht chuyn ho 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... 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 ging morphin.
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* Tc dng: Thuc c tc dng i khng ti receptor muy nhng li c tc dng hip ng ti receptor kappa1, gy an thn, gim au v c ch h hp. Tc dng gim au nh morphin nhng khng gy sng khoi. Khi dng liu cao, pentazocin lm tng huyt p v nhp tim. * Dc ng hc: Hp thu d qua ng tiu ho. 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 ho ln u gan nn ch 20% pentazocin vo c vng tun hon. Thuc qua c hng ro nhau 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 mi ln, sau 4 gi c th tim li. Hin nay c nhng ch phm phi hp gia pentazocin vi aspirin hay acetaminophen. 2.3.5.2. Buprenorphin L thuc tng hp, dn xut ca thebain. Buprenorphin hip ng mt 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 tng khong 96%, thi gian bn thi 3 gi. c dng gim au trn lm sng. Thng tim bp hoc tnh mch 0,3 mg mi ln, ngy dng 3 - 4 ln. 2.4. Thuc i khng vi opioid Thay i cng thc ho 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 nalorphin
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Levorphanol levallorphan Oxymorphon 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 (Narcan, Narcanti) 2.4.1.1. Tc dng Khc vi levallorphan hoc nalorphin, naloxon t hoc khng c hot 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 hi 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 Mc d c hp thu d qua ng tiu ho nhng naloxon b chuyn ho 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 tnh 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 ho: 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 cho ngi ln: 0,4 - 2 mg, tim tnh 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
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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 ho thnh 6 - naltrexon (c hot 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 (phi 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 ni sinh c chia thnh 3 h: - Enkephalin (Met-enkephalin v leu-enkephalin). - Endorphin. - Dynorphin. Mi loi c cht tin thn khc nhau v phn b nhng v tr khc nhau trn thn kinh trung ng. Cc morphin ni 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. tu sng, morphin ni sinh c ch gii phng cht P, l mt decapeptid (10 acid amin) c gii phng ti ngn dy thn kinh 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 ho 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 (xem bi "Thuc h st gim 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.
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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 (xem 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 (xem 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 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. 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 ho hc v tc dng dc l ca cc thuc loi morphin. 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 tnh v cch cai nghin morphin.
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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.
Bi 10 THUC H S T -GIM AU CHNG V I M

MC TIU 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 ho 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. T C DNG CH NH V CH C 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 ho 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 ngng kt tiu cu. Cc CVKS c ch COX nn c ch c cc phn ng vim (xem s hnh 10.1).
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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 hi phc s ngng kt 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 gi l COX - 1 v COX - 2 c chc nng khc nhau v cc thuc chng vim tc dng vi mc khc nhau trn COX - 1 v COX - 2 (s hnh 10.2).
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Hnh 10.2. Vai tr sinh l ca COX-1 v COX-2
- 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, ni 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 nng sinh l. - COX-2 hay PGG/H synthetase-2 c chc nng 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 ho mnh COX-2. V vy COX-2 cn c gi l "enzym cm ng". Nh vy, thuc c ch COX-1 nhiu s gy nhiu tc dng khng mong mun, thuc c ch COX-2 mnh s c tc dng chng vim mnh m t gy tc dng ph. 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 lipid, d thm nhp vo mng t bo hoc mng ty th, nht l vo cc bch cu a nhn, nn
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: + c ch tit cc enzym ca cc th tiu bo. + c ch sn xut cc gc t do. + c ch ngng kt v kt dnh cc bch cu a nhn trung tnh. + c ch cc chc nng 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 hi phc cyclooxygenase (COX), lm gim PGE2 v F1 l nhng trung gian ho 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 li 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 ni tng, khng gy ng, khng gy khoan khoi v khng gy nghin. Theo Moncada v Vane (1978), do lm gim tng hp PGF2 nn cc CVKS lm gim tnh cm th ca cc ngn dy thn kinh 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 ho 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, TNF ...). Cht ny hot ho prostaglandin synthetase, lm tng tng hp PG (c bit l PGE1, E2) t acid arachidonic ca vng di i, gy st do lm tng qu trnh to nhit (rung c, tng h hp, tng chuyn ho) 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.
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 PGG2/H2 thnh thromboxan A2 (ch tn ti 1 pht) c tc dng lm ng vn tiu cu. Nhng ni mc mch cng rt giu prostacyclin synthetase, l enzym tng hp PGI2 c tc dng i lp vi thromboxan A2. V vy tiu cu chy trong mch bnh thng khng b ng vn. Khi ni 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 10.4).
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Hnh 10.4. C ch c ch ng vn tiu cu
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) 2. CC DN XUT
Phn loi ho 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
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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
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...
Acid salicylic
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 ho ca acid salicylic gim tnh kch ng nn ung c.
Acid acetyl salicylic
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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 ngng kt tiu cu) nn lm gim ngng kt tiu cu. Liu cao hn, c ch cyclooxygenase ca thnh mch, lm gim tng hp PGI2 (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 ho: Nim mc d dy - rut sn xut ra PG, c bit l PGE2, c tc dng lm tng to cht nhy v c th l c kch thch phn bo thay th cc t bo nim mc b ph hu. Nh vy, vai tr ca PGE l bo v nim mc ng tiu ho. 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 ho cho nn d khuch tn qua mng, c hp th tng i nhanh vo mu ri b thu phn thnh acid salicylic, khong 50 - 80% gn vi protein huyt tng, b chuyn ho 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. 2.1.2.3. c tnh - Mc du cc dn xut salicylic u t c, d ung, nhng dng lu c th gy "hi chng salicyle" ("salicylisme"): bun nn, tai, ic, nhc u, l ln. - D ng: ph, my 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 10 g. 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,
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a n hu qu nhim acid do chuyn ho (hay gp tr em v c ch iu ho cha n nh). Liu cht i vi ngi ln khong 20g. 2.1.2.4. Liu lng v ch phm - Ung 1 - 6 g/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 mui ho tan, mi l tng ng vi 0,5g aspirin. Tim tnh 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
Methyl salicylac
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 200 mg 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. Trong tng lai gn s khng dng loi thuc ny. 2.3. Dn xut indol 2.3.1. Indometacin
Indometacin
2.3.1.1. c im tc dng - Tc dng gim vim mnh hn phenylbutazon 20 - 80 ln v mnh hn hydrocortison 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 huyt 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 ho, 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 25 mg. Thuc n 50 - 100 mg. 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 ho thnh dn cht sulfat c hot tnh sinh hc mnh, c ch cyclooxygenase 500 ln mnh hn sulindac. V cu trc ho hc, sulindac l indometacin c thay methoxy bng fluor v thay Cl bng gc
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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; mi ngy ung 1 - 2 vin, liu ti a 400mg/ngy, l liu tng ng vi 4g aspirin hoc 125 mg indometacin. 2.3.3. Etodolac L thuc c tc dng c ch u tin COX-2, hp thu nhanh qua tiu ho, 99% gn vo protein huyt tng, 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 tng ti 99%. V thi gian bn thi qu di, d c nguy c tch lu thuc. - t tan trong lipid so vi cc CVKS khc, cho nn d thm vo m 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 tnh 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 ho 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; t1/2 = 20 gi. Lc u, da vo kt qu 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.
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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 ho, v vy c dng nhiu trong cc vim khp mn tnh. - Ch phm v liu lng: Ibuprofen: - Tc dng chng vim v gim au tng t aspirin, nhng tc dng ph trn tiu ho th thp hn nhiu, d c dung np hn. - c hp thu nhanh qua ng tiu ho, nng ti a t c trong huyt tng sau 1 - 2 gi. Thuc b chuyn ho 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: + Vin nn 100, 150, 200, 300 v 400 mg. + Vin nang 200 mg. + n trc trng 500 mg. Vim khp: thng dng 1,2 - 1,8 g/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 250 mg 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.
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- Hp thu nhanh v hon ton qua ng tiu ho, nhng ch 50% vo c tun hon v b chuyn ho trong qu trnh hp thu. Thi gian bn thi = 1 - 2 h, nhng tch lu dch bao khp nn tc dng vn gi c lu. - Ch nh trong vim khp mn tnh. 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 enzym aminotransferase gan gp 3 ln, nhng hi 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 hai 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 tnh mch 15 30 mg/ngy, khng dng qu 5 ngy. 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 ho, mu, thn, cn hen... gim i rt r rt, ch cn t 0,1 - 1%.
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- Thi gian bn thi di, khong 20 gi cho nn ch cn ung mi ngy 1 ln. - Hp thu d dng qua ng tiu ho, 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 nhi mu c tim. Vn cn dng aspirin. 2.8.1. Nhm coxib Ngoi nhng u im trn, sau 5 nm s dng cc nghin cu a trung tm trn th gii cho thy cc coxib lm gim to thnh PGI2 ca t bo ni mc mch mnh hn lm gim TXA2 ca tiu cu rt nhiu, do c th lm tng nguy c huyt khi tc mch, gy tai bin t qu. Bnh thng, PGE2 v PGI2 gy gin mch thn, khi b gim tng hp, mch thn co, gy tit renin, lm huyt p tng. Thuc c ch COX-2 d gy tng huyt p hn thuc CVKS. V th, c mt s thuc b rt khi th trng tu theo quyt nh ca tng nc, nh rofecoxib (Vioxx), valdecoxib (Bextra), lumiracoxib, parecoxib (Dynastat).
Celecoxib (Celebrex)
Thuc c ch COX-2 mnh hn COX-1 t 100 n 400 ln, c dng t 1998. Hp thu qua tiu ho, t nng ti a trong huyt tng sau 2 4 gi. Gn mnh vo protein huyt tng. Phn ln b chuyn ho gan. Thi gian bn thi l 11 gi. Liu thng dng l 100 mg 2 ln/ngy. Trong thp khp c th tng liu ti 200 mg 2 ln/ngy.
Etoricoxib (Arcoxia)
Etoricoxib khng c hp thu hon ton (ch 83%), thi gian bn thi di khong 20 26 gi. Hin ang c nh gi lm sng. Liu thng dng: Ung 60 90 hoc 120 mg/ngy. 2.8.2. Nhm acid indol acetic Etodolac: (xem 2.3.3) 2.8.3. Nhm sulfonanilid Nimesulid: Ngoi tc dng c ch COX-2 cn c ch hot ho bch cu trung tnh, lm gim sn xut cytokin v c tc dng chng oxy ho. Liu dng: vin nn 100mg, mi ngy ung 1 2 vin. Mi y, TCYTTG cnh bo v Cc Qun l Dc Vit Nam (ngy 14/8/2007) cng thng bo v shock phn v, nga pht ban, kh th ca thuc ny. Mt s nc ngng ng k thuc ny. 2.9. Dn xut para aminophenol: Acetaminophen, paracetamol
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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 c 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 ho 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 ho, ri lon ng mu). 2.9.2. Dc ng hc Hp thu nhanh qua tiu ho, sinh kh dng l 80 - 90%, thi gian bn thi l 2 gi, hu nh khng gn vo protein huyt tng. Chuyn ho 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 ho, khng gy mt thng bng acid-base, khng gy ri 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 ho gan cho N - acetyl parabenzoquinonimin. Bnh thng, cht chuyn ho ny b kh c ngay bng lin hp vi glutathion ca gan. Nhng khi dng liu cao, N - acetyl parabenzoquinonimin 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 ho, 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 0,5 g; gi bt 0,08 g; 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:
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Trnh by: l thuc bt + dung mi. Pha ngay trc khi dng, khng qu 30 pht. Tim bp su hay tim tnh 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 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 ho do t b ion ho 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 ho gan (tr acid salicylic), thi qua thn di dng cn hot tnh khi dng vi liu chng vim v liu c. - Cc thuc khc nhau v thi tr, thi gian bn thi 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 tnh vi liu 1 ln/ngy. Da theo thi gian bn thi ca thuc, c th chia cc CVKS lm 3 nhm (bng 10).
Bng 10. Phn loi thuc theo thi gian bn thi (t1/2) Loi thuc Tn thuc Aspirin t1/2 (h) 0,25 S ln dng/ngy 3-4
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Diclofenac t1/2 ngn Ketoprofen Salicylat Ibuprofen Indomethacin Naproxen t1/2 trung bnh Sulindac Meloxicam Tenidap Piroxicam t1/2 di Tenoxicam Phenylbutazon
1,1 1,8 2,0 - 15 2,1 4,6 14 14 20 20 - 30 40 - 45 60 - 75 68
2-4 2-4 3-4 3-4 3-4 2 2 1 1 1 1 1
3.2. Cc tc dng khng mong mun 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 PGE2 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 tnh, gim chc nng 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 phi, lin quan n vic ng sm ng ng mch ca bo thai trong t cung. Mt khc, do lm gim PGE v F, CVKS c th ko di thi gian mang thai, lm chm chuyn d v PGE, PGF lm tng co bp 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 ho theo ng lipooxygenase (tng leucotrien).
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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 lithium qua thn, gy tch lu. - CVKS lm tng tc dng ca phenytoin v sulfamid h ng huyt do y chng ra khi 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 thi gian bn thi trung bnh hoc di. 3.4.2. Cc bnh thp cp v mn - V t l c tnh tiu ho/hiu qu chng vim ging nhau cho mi 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. - V d: + Vim a khp dng thp: dn xut propionic, diclofenac (Voltaren). + Vim khp mn ca ngi tr: aspirin. + Vim cng khp: indometacin. + Thoi ho 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, polyp 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
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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 ho 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 PGE2, PGI2 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 PGE1 l Misoprostol (Cytotec), tc 15 deoxy - 16 hydroxy - 16 metyl - PGE1 c tc dng chng lot d dy tng t thuc khng H2. c bit c dng cho nhng ngi phi iu tr ko di bng CVKS. Tc dng ph: tiu chy (30%), au qun bng, sy thai. Liu lng: vin 200 g 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 nng 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 phi hp thuc: + Khng dng phi 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 khi 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 ho hoc i khng ti ni tc dng, nh meprobamat, androgen, li niu furosemid. T LNG GI 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.
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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.
Bi 11 THUC CHA GT
MC TIU Trnh by c c ch tc dng, ch nh ca 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 ho cui cng ca purin. Bnh c th nguyn pht do ri lon chuyn ho acid uric di truyn, hoc th pht do bnh thn, do dng cc thuc phong to 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 (synoviocytes). Trong qu trnh thc bo, cc t bo ny gii phng ra cc prostaglandin, cc enzym tiu th v interleukin - 1. Cc cht trung gian ho hc ny li "gi" cc bch cu ht ti khp v lm nng thm qu trnh vim: s lng bch cu ht, i thc bo tng, lng cht ho hc trung gian gy vim tng. Cc thuc iu tr cn gt cp tnh s c ch cc giai on hot ho 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 XVIII. Tc dng iu tr c hiu cn gt cp tnh, lm gim au v gim vim trong vng 12 - 24 gi u
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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 bch 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 ho" 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 ho), c ch tu xng, rng tc, vim thn kinh, c vi thn... 1.3. Dc ng hc Hp thu nhanh qua ng ung, t nng ti a trong huyt tng sau 0,5 - 2 gi. Chuyn ho 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 ho 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 mi 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... Probenecid khng c tc dng gim au. Khi cn gim au, c th dng cng vi paracetamol.
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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 6 - 12 gi. Tc dng ph rt t (2 - 8%): bun nn, nn, mng da, st. Khi lm i nhiu acid uric, c th gy cn si urat vi cn qun thn (khi cn base ho nc tiu). Liu lng: vin 0,5 g. Tun u ung 250 mg 2 ln/ngy. Tng dn tng tun. Ti a 2 g/ngy, chia lm 4 ln. Ung nhiu nc trnh si 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. Liu lng: vin 50 mg 4 ln/ngy, tng dn ti 400 mg hoc 800 mg 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 ri 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. Nh vy, allopurinol cn ngn nga c s to si acid uric trong thn.
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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 phi 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 mi 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 M). Liu lng: Allopurinol (Zyloprim) vin 100 - 300 mg. Liu u 100mg, tng dn ti 300 mg/ngy tu theo nng acid uric mu. T LNG GI 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 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.
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1. THUC AN THN KINH (THUC AN THN CH YU) Cc thuc loi ny c ba 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. Do , thuc c tc dng vi bnh tm thn phn lit. - Cloprozamin gy hi 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 ho 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 to receptor 1 adrenergic ngoi bin.
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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 1 - adrenergic tng i c ngha, c th phong to 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 phi hp trong thi gian ngn. 1.1.3. C ch tc dng Sinh l hc ca hot 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 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 ho 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 ho ngc trung ng. Cn cc triu chng m tnh (cm xc cn mn, quan h km, v cm, t duy tru
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tng kh khn) l do ri lon chc nng 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 chng 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 XX tr li y) u c c hai tc dng phong to 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 lipid, gn nhiu vo protein huyt tng, tp trung no v m m, qua nhau thai d dng. Thi gian bn thi 20 - 40 gi. Hiu lc sinh hc ca liu mt ln thng tn ti t nht l 24 gi nn ch cn dng liu 1 ln mi 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 mi, 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 tnh... 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
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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. - Hi chng st cao c tnh: st cao, da ti nht, m hi nh nhi, trng thi sc. Phi iu tr hi 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 khi, 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 nhau thai) - Khoa gy m: tin m, gy m h thn nhit, h huyt p. - Khoa ni: 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, hi chng Parkinson cng r. 1.2.1. Ch nh - Cc trng thi thao cung, hoang tng. - 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
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dopaminergic b haloperidol phong to. 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, hi chng ngoi b thp, ri lon ni tit. 1.2.4. Liu lng ng 5mg/mL 1 - 4 ng/ngy. Tim bp. Vin 5mg 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): - 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 lit, thao cung, o gic. 1.3.3. Tc dng khng mong mun - Ri lon ni tit v chuyn ho: tng tit sa, tng 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.
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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 mnh hn khong 20 ln 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 ho 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. - 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
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- 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 tnh mch) Liu cao, c ch trung tm h hp v vn mch. 2.1.2. Tc dng ngoi bin - Gin mch vnh khi tim tnh mch. - Vi liu cao, phong to 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 ni sinh chim gi, lm cho GABA (trung gian ho 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 ho (hnh 12.1). Cc receptor ca BZD c lin quan v gii phu v chc nng vi receptor ca GABA.
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
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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 tng 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 ho hoc iu ho 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 thi gian bn thi cng ngn (triazolam thi gian bn thi = 3 gi), cng d gy nghin. 2.4. Dc ng hc Hp thu hu nh hon ton qua tiu ho, 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 nhau 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. V d flurazepam c thi gian bn thi 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 thi gian bn thi, cc Bzd c chia lm 4 loi: - Loi tc dng cc ngn, thi gian bn thi < 3 gi c midazolam,triazolam. - Loi tc dng ngn, thi gian bn thi t 3 - 6 gi c zolpidem (non -benzodiazepin) v zopiclon. - Loi tc dng trung bnh, thi gian bn thi t 6 - 24 gi c estazolam v temazepam. - Loi tc dng di, thi gian bn thi >24 gi c flurazepam, quazepam, diazepam. 2.5. p dng 2.5.1. An thn: liu trung bnh 24 gi: Diazepam (Valium): 0,005 - 0,01g. Ung. 2.5.2. Chng co git Diazepam (Valium): 0,010 - 0,020g. Tim bp, tnh mch.
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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. 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 - 0,020 g. Ung, tim bp, tim tnh mch. Tetrazepam (Myolastan): 0,050 - 0,150 g. Ung, tim bp, tim tnh 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 (1 tun - 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: buspiron, 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.
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+ 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 5HT1A c nhiu h vin, hi 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 Clqua 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. - ng hc: Hp thu nhanh qua ng ung nhng c chuyn ho qua gan ln th nht do hydroxy ho v mt alkyl, tuy nhin li to ra nhiu cht chuyn ho cn hot tnh vo c thn kinh trung ng, c cht c tc dng phong to c receptor 2. Thi gian bn thi l 2 - 4 gi. Liu lng: vin 5 - 10 mg (Buspar), dng t liu thp, 3 ln/ngy. 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.
Bi 13 THUC CHA NG KINH

MC TIU 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.
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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 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 mt trn v no v tu theo vng chc nng m th hin ra triu chng. V 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: ngay t u lan rng ton b hai 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 ng kinh ton th: Khng cn co git Cn git rung Cn co cng - git rung Clonazepam, ethosuximid, valproat valproat Carbamazepin, phenobarbital, phenytoin, primidon, Lamotrigin Lamotrigin Lamotrigin Carbamazepin, phenytoin, phenobarbital, primidon, valproat Carbamazepin, phenytoin, phenobarbital, primidon, valproat Gabapentin Lamotrigin Gabapentin Lamotrigin Thuc thng thng Thuc mi
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valproat
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 Ca2+ 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 mi 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 ho 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 ho chm v i khi khng hon ton. Nng ti a trong mu t c sau 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 ho gan v thi tr qua thn di dng lin hp, ch 5% di dng khng chuyn ho. Thi gian bn thi t 6 - 24 gi. 2.1.3. Tc dng khng mong mun - 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 to s hp thu acid folic ti rut),
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gim bch cu... - Tiu ho: nn, cn au bng cp. - Thn kinh - tm thn: lin quan n nng thuc trong mu: 20 g/mL c tc dng iu tr. = 30 g/mL lm rung git nhn cu. = 40 g/mL gy mt phi hp ng tc. > 40 g/mL gy ri lon tm thn. - Xng: ci xng hoc mm xng, c th l do ri lon chuyn ho vitamin D, nht l khi phi 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 ho. Tri li, carbamazepin lm tng chuyn ho 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 - 100 mg; ng tim 50 mg/mL. Liu u 3 - 5 mg/kg (300 mg/ngy). Theo di nng thuc trong mu, khi t c nng c tc dng, ngh 1 tun. Liu cao 300mg/ngy th khong cch ngh gia cc t iu tr l 2 tun. C th dng liu 1 ln/ngy. Phenytoin tim tnh mch khng vt qu 50 mg/pht, pha long trong NaCl 0,9% v thuc c pH base, kch thch. Khng tim bp, gy tn thng m. 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 Ca2+ 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.
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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 ging nh phenytoin, nhng: - 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 ho, nng ti a trong mu t c sau 4 - 8 gi v gi c ti 24 gi. Gn vo protein huyt tng 75% v phn phi vo mi m. Nng trong dch no tu tng ng vi dng t do trong huyt tng. B chuyn ho 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 lo, 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 nng 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 - 200 mg. Liu u 200 mg 2 ln/ngy. Tng dn liu ti 600 - 1200 mg. Tr em 20 - 30 mg/kg. Nn chia liu hng ngy lm 3 4 ln gi c nng hng nh trong mu.
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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 (Mac Donald, 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 Ca2+ qua knh. 2.4.2. Dc ng hc Hp thu nhanh v hon ton qua tiu ho. 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 ho gan, trong c mt cht chuyn ho 2 - propyl - 2 - pentanoic acid vn cn hot tnh nh cht m. Thi gian bn thi l 15 gi. 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 250 mg; sir 5 mL c 250 mg hot cht. Liu u 15 mg/kg, tng dn hng tun 5 - 10 mg/kg cho ti 60 mg/kg. Nng iu tr trong mu t 30 n 100 g/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.
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- 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 acid valproic. - 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. 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. 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.
Chng IV HO HC TR LIU
Bi 14 THUC KHNG SINH KHNG KHUN
MC TIU 1. Pht biu c nh ngha khng sinh, tc dng km khun v dit khun.
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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 v 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 K nguyn hin i ca ho 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 ho 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 14.1. S c ch tc ng ca cc h khng sinh chnh
1.3. Ph khng khun Do khng sinh c tc dng theo c ch c hiu nn mi 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 gi l khng sinh dit khun. Tc dng km khun v dit khun thng ph thuc vo nng
Khi t l > 4, khng sinh c tc dng km khun. Kh t l gn bng1, khng sinh c xp vo loi dit khun.
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Hnh 14.2. Cc khng sinh c ch qu trnh tng hp protein
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Hnh 14.3. V tr tc dng ca khng sinh c ch tng hp protein 1. c ch to cu peptid (Cloramphenicol) 2. Ngn cn chuyn ng chuyn on ca ribosom theo mARN (Erythromycin) 3. Ngn cn s gn kt ca tARN vo phc hp ribosom mARN (Tetracyclin) 4. Lm thay i hnh dng 30S m ho trn mARN nn c nhm (Streptomycin)
1.5. Phn loi Cc khng sinh c phn loi theo cu trc ho 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. Mt s h (hoc nhm) khng sinh chnh: - Nhm 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 lactam V cu trc u c vng lactam (hnh 14.4).
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Hnh 14.4. Cc khng sinh c ch tng hp vch t bo vi khun
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 chui glycan ni cho vi nhau bng chui peptid. Khong 30 enzym ca vi khun tham gia tng hp peptidoglycan, trong c transpeptidase (hay PBP). Cc lactam v khng sinh loi glycopeptid (nh vancomycin) to phc hp bn vng vi transpeptidase, c ch to vch vi khun, lm ly gii hoc bin dng vi khun. Vch vi khun 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 mt 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 v 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
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lactam (thuc hu nh khng c). Tuy nhin vng lactam rt d gy d ng. Cc khng sinh lactam c chia thnh 4 nhm da theo cu trc ho hc - Cc penam: vng A c 5 cnh bo ho, gm cc penicilin v cc cht phong to lactamase. - Cc cephem: vng A c 6 cnh khng bo ho, gm cc cephalosporin. - Cc penem: vng A c 5 cnh khng bo ho, gm cc imipenem, ertapenem. - Cc monobactam: khng c vng A, l khng sinh c th tng hp nh aztreonam.
Hnh 14.5. Cu trc c bn ca 4 nhm lactam (B: vng lactam)
2.1.1. Cc penicilin c Fleming tm ra u tin nm 1928, t nm Penicillium notatum hay P. chrysogenum. Sau nghin cu ca Florey v Chain, c dng vo iu tr t 1941, m ra k nguyn khng sinh vi penicilin G. C 4 nhm penicilin. 2.1.1.1. Penicilin G L nhm thuc tiu biu, c tm ra u tin. * Ngun gc v c tnh l ho Trong sn xut cng nghip, ly t Penicillium notatum, 1 mL mi trng nui cy cho 300 UI; 1 n v quc t (UI) = 0,6 g 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
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* Ph khng khun - Cu khun Gr (+); lin cu (nht l loi 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 phi: 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 tng. Trn ngi bnh thng, t1/2 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 mi 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 tnh 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 mui t tan v chm hp thu s ko di c tc dng ca penicilin G: + Bipenicilin (natri benzylpenicilinat + procain benzylpenicilinat): mi 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 hu, hp thu t trng, nhng phi dng liu gp i penicilin G mi t c nng huyt thanh tng t. Cch 6h/ln.
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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 c. Mt s thuc khc vng bn vi dch v, ung c: oxacilin (Bristopen), cloxacilin (Orbenin): ung 2 - 8g mt ngy chia lm 4 ln. Ch nh tt trong nhim t cu sn xut penicilinase (t cu vng). C th gp vim thn k, c ch tu 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 loi vi khun Gram (-): E. coli, Salmonella, Shigella, Proteus, Hemophilus influenzae - B penicilinase ph hu. - Khng b dch v ph hu, 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 dng vin ung 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, nhim 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, nhim khun tit niu, vim phi. Cc khng sinh ny u l bn tng hp v vn b men 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.
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2.1.2. Cc cephalosporin c chit xut t nm cephalosporin hoc bn tng hp, u l dn xut ca acid amino - 7 cephalosporanic, c mang vng 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 ( 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 - 8 g/ngy, Theo ng ung c cefalexin (Keforal), cefaclor (Alfatil), liu 2 g/ngy. 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 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 lactamase hn th h 3, c bit dng ch nh trong nhim trc khun Gram (-) hiu kh khng vi th h 3.
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Ch phm: cefepim, tim tnh mch 2g 2 ln/ngy. 2.1.3. Cc cht c ch lactamase (cu trc Penam) L nhng cht c tc dng khng sinh yu, nhng gn khng hi phc vi lactamase v c i lc vi lactam, cho nn khi phi hp vi khng sinh nhm lactam s lm vng bn v tng cng hot tnh khng khun ca khng sinh ny. Hin c cc ch phm sau:
Cht (-) lactamase Acid clavulinic Khng sinh phi hp Amoxicilin Bit dc - Augmentin: vin nn 250, 500 mg, l 500 mg, 1g tim tnh mch - Timentin Unasyn: vin nn 220 mg ng tim 500 - 1000 mg Tazobactam Piperacilin Zosyn
Ticarcilin Sulbactam Ampicilin
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. c dng trong nhim khun sinh dc - tit niu, ng h hp di, m mm, xng - khp, nhim khun bnh vin. Khng hp thu qua ng ung. Ch tim tnh mch liu 1 - 2g/ngy.
Ertapenem:
Ph khng khun nh imipenem, nhng mnh hn trn Gram (-). Tim bp hoc truyn tnh mch 1g/ngy. 2.1.5. Monobactam: Aztreonam Km tc dng trn khun Gram (+) v vi khun k kh. Tri li, tc dng mnh trn vi khun Gram (-), tng t cephalosporin th h 3 hoc aminoglycosid. Khng lactamase. Khng tc dng theo ng ung. Dung np tt, c th dng cho bnh nhn d ng vi penicilin hoc cephalosporin. Tim bp 1 - 4 g/ngy. Trng hp nng, tim tnh mch 2g, cch 6 - 8 gi/ln.
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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 to 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 lactamase v khng methicilin. Hip ng vi gentamycin v streptomycin trn enterococcus. ng hc: c hp thu rt t qua ng tiu ho nn ch c dng iu tr vim rut kt gi mc cng vi tetracyclin, clindamycin. Tim truyn tnh 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 g/mL (di 60 g/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 ho 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 ho v c PM cao. - Cng mt c ch tc dng. - Ph khng khun rng. Dng ch yu chng vi khun hiu kh Gram (-). - c tnh chn lc vi dy thn kinh VIII v vi thn (tng creatinin mu, protein - niu. Thng phc hi). Thuc tiu biu trong nhm ny l streptomycin. Ngoi ra cn: Neomycin, kanamycin, amikacin, gentamycin, tobramycin. 2.2.1. Streptomycin 2.2.1.1. Ngun gc v c tnh Ly t nm streptomyces griseus (1944). Thng dng di dng mui d tan, vng bn nhit
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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 mARN, 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 ti u l 7,8 (cho nn cn alcali (kim) ho 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 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 mi ngy 1 ln. Gn vo protein huyt tng 30 - 40%. - Phn phi: do tan nhiu trong nc v b ion ho pH huyt tng, streptomycin kh thm ra ngoi mch. Gn nhiu hn vo thn, c, phi, 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 thn kinh s 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 khi, 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 (ngi 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 dnh cho cc nhim khun sau:
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- Lao: phi hp vi 1 hoc 2 khng sinh khc (xem bi "Thuc chng lao"). - Mt s nhim khun tit niu, dch hch, brucellose: phi hp vi tetracyclin - Nhim khun huyt nng do lin cu: phi 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. 2.2.2. Cc aminosid khc - Kanamycin: Tc dng, dc ng hc v c tnh tng t nh streptomycin. Thng dng phi 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 phi hp vi penicilin trong st gim bch cu v nhim trc khun Gram (-) nh vim ni 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 vi 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 bi nhim. Dng neomycin n c hoc phi hp vi polymyxin, bacitracin, khng sinh khc hoc corticoid. 2.3. Cloramphenicol v dn xut 2.3.1. Ngun gc v tnh cht l ho 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 50 S ca ribosom nn ngn cn mARN gn vo ribosom, ng thi c ch transferase nn acid amin c m ho khng gn c vo
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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 70 S nh vi khun), hng cu ng vt c v c bit nhy cm vi cloramphenicol. Ph khng khun rt rng: phn ln cc vi khun Gram (+) v Gram (-), xon khun, tc dng c hiu trn vi khun 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, thi gian bn thi t 1,5 - 3 gi, khong 60% gn vo protein huyt tng. - Phn phi: 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 nhau thai. - Chuyn ho: phn ln b mt hot tnh do qu trnh glycuro - hp gan hoc qu trnh kh. - Thi tr: ch yu qua thn, 90% di dng chuyn ho. 2.3.4. c tnh Hai c tnh rt nguy him: - Suy ty: + Loi ph thuc vo liu: khi liu cao qu 25 g/mL c th thy sau 5 - 7 ngy xut hin thiu mu nng, gim mnh hng cu li, bch cu, hng cu non. Liu ung 0,5g s c pic huyt thanh 6 - 10 g/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 : 6000. - 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 khun cht gii phng qu nhiu ni 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 ho thuc gan nn ko di thi gian bn thi 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
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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 vy liu dng gp 2 ln cloramphenicol. Khng dng cho ngi suy thn nng. 2.4. N h m tetracyclin
2.4.1. Ngun gc v tnh cht l ho 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 vi tetracyclin khc c th vn cn nhy cm vi minocyclin. Tc dng km khun l do gn trn tiu phn 30 S ca ribosom vi khun, ngn cn tRNA chuyn acid amin vo v tr A trn phc hp mARN - 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.
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- 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 chuyn ho lipid thnh acid bo t do gy kch ng vim. Dng liu thp 250 mg 2 ln/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 ho 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 phi: gn vo protein huyt tng t 30% (oxytetracyclin) n 50% (tetracyclin) hoc trn 90% (doxycyclin). Thm c vo dch no tu, nhau thai, sa nhng t. c bit l thm c vo trong t bo nn c tc dng tt trong iu tr cc bnh do brucella. Gn mnh vo h li ni 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 Hp thu theo ng ung (%) 30 60 - 70 90 - 100 thanh thi ca thn (mL/pht) 35 90 65 35 31 16 10 Thi gian bn thi 6 - 8h 12h 16 - 18h Tc dng Trung bnh Tc dng di
Tn thuc Chlortetracyclin Oxytetracyclin Tetracyclin Demeclocyclin Methacyclin Doxycyclin Minocyclin
Phn loi tc dng Tc dng ngn -
2.4.5. c tnh - Ri lon tiu ho: 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 ho (trong t cung
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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 ho lipid, ur mu cao dn n t vong. - Cc ri lon t gp hn: d ng, xut huyt gim tiu cu, tng p lc ni s tr ang b, nhc u, ph gai th... V vy, phi thn trng theo di khi s dng v trnh dng: + Cho ph n c thai. + 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, mi - hng, phi. 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 TM 1 - 2 g. - Oxytetracyclin (Terramycin): ung 1 - 2 g; tim bp, TM 200 mg - 1g. - Minocyclin (Mynocin): ung 100 mg 2 ln; tim bp hoc TM 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 25 - 50 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.
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- Gia chng c khng cho do c ch tng t. - 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 50 S ca ribosom vi khun, cn tr to chui a peptid (ngn cn chuyn v ca tARN) 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 mi ngy. Gn vo protein huyt tng khong 70% (lincomycin) n 90% (erythromycin), t1/2 t 1h30' n 3 h. Thm mnh vo cc m, c bit l phi, 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 phi 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 ni 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 ri lon tiu ho nh (bun nn, nn, tiu chy) v d ng ngoi da. Tuy nhin, lincomycin v clindamycin c th gy vim rut kt gi mc, i khi nng, dn 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 tnh mch 1,5 triu UI 3 ln/ngy.
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- Azithromycin: thm rt nhiu vo m (tr dch no tu), t nng cao hn huyt tng ti 10 100 ln, sau c gii phng ra t t nn thi gian bn thi khong 3 ngy. V th cho php dng liu 1 ln/ngy v thi gian iu tr ngn. V d vi vim phi 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. Tim bp, TM: 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 mi hng, vim phi, nhim khun ng h hp. Nhm lincosamid do thm mnh c vo xng nn cn c ch nh tt cho cc vim xng tu. 2.6. Nhm Quinolon 2.6.1. Ngun gc v tnh cht l ho 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 mARN nn c ch tng hp protein vi khun. Cc quinolon u l thuc dit khun. Acid nalidixic (cn gi l quinolon th h 1) ch c ch ADN gyrase nn ch c tc dng dit khun Gram (-) ng tit niu v ng tiu ho. 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 khun 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 gm: 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
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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 ng tiu ho 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 hot 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 ho 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 - 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 phi hp vi khng sinh chng vi khun k kh (clindamycin, metronidazol) - Nhim khun ng tiu ho: 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 phi 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 phi 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 ni s (chng mt, nhc u, l ln, co git, o gic). Trn tr nh, c acid chuyn ho, au v sng khp, au c. Thc nghim trn sc vt cn non, thy m sn b hu hoi cho nn khng dng cho tr em di 18 tui, ph n c thai v ang nui con b. Khng dng cho ngi thiu men G6PD. 2.6.6. Ch phm v cch dng
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2.6.6.1. Loi quinolon kinh in, acid nalidixic (Negram): nhim khun tit niu do trc khun Gram (-), tr Pseudomonas aeruginosa. Ung 2 g/ngy, chia 2 ln. ng tim tnh mch 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 phi, 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 ng tiu ho tt, t nng huyt tng gn vi truyn tnh mch. - Phn phi rng, c cc m ngoi mch. - Thi gian bn thi di, khng cn dng nhiu ln. - D dng nn c th iu tr ngoi tr. - 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 ho pH sinh l, khuch tn nhanh qua mng sinh hc. u tin nm (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
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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, to ra cc sn phm c, dit c vi khun, lm thay i cu trc ca ADN. Ph khng khun: mi 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 ng tiu ho, t gn vo protein huyt tng, thm c vo mi m, k c mng no, thi gian bn thi t 9h (metronidazol) n 14h (ornidazol). Thi tr qua nc tiu phn ln di dng cn hot tnh, lm nc tiu c th b sm 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, p xe no, d phng nhim khun sau phu thut vng bng - h chu... C tc dng hip ng vi khng sinh nhm lactam v aminosid. Metronidazol (Flagyl), ornidazol (Tiberal): ung 1,5g hoc 30 - 40 mg/kg/24h. (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 ho 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 hnh 14.6). 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 nhau thai, gy c. - Cc qu trnh chuyn ho ch yu gan ca sulfamid gm: + Acetyl ho, t 10 - 50% tu loi. Cc sn phm acetyl ho rt t tan, d gy tai bin khi thi tr qua thn. Cc sulfamid mi c t l acetyl ho thp (6 - 16%) v sn phm acetyl ho li d tan. + Hp vi acid glucuronic (sulfadimethoxin), rt d tan. + Oxy ho. Thi tr: ch yu qua thn (lc qua cu thn v bi xut qua ng thn). Dn xut acetyl ho (25 60% trong nc tiu) khng tan, to 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. Thi gian bn thi t 6 - 8 h, thi tr 95% trong 24 h. Gm 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).
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- Loi thi tr chm: duy tr c nng iu tr trong mu lu, thi gian bn thi c th ti 7 - 9 ngy nn ch cn ung 1 ln ngy. Hin dng sulfadoxin (Fanasil), phi hp vi pyrimethamin trong Fansidar d phng v iu tr st rt khng cloroquin. - 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 ho: bun nn, nn, tiu chy. - Thn: do sulfamid t tan v cc dn xut acetyl ho kt ta trong ng thn gy cn au bng thn, i mu, v niu (iu tr, d phng bng ung nhiu nc v base ho nc tiu). Vim ng k thn do d ng. - Ngoi da: cc biu hin d ng t nh n rt nng nh hi chng Stevens - Johnson, hi 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 tu. - 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 (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 ho: + Sulfaguanidin (Ganidan): vin nn 0,5 g ung 3 - 4 g/ngy. + Sulfasalazin (Azalin): vin nn 0,5 g ung 3 - 4 g/ngy. - Dng bi ti ch: Bc sulfadiazin (Silvaden): 10mg/g kem bi
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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. Trimethoprim l mt cht ho 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 2.000 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.
Hnh 14.5. V tr tc dng ca sulfamid v trimethoprim trong qu trnh tng hp acid folic
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 thi gian bn hu xp x 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 g/mL huyt tng sulfamethoxazol v 2 g/mL trimethoprim). C hai thuc c hp thu qua ng ung, phn phi 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 phi hp ny c tt 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).
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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 ho (thng hn, t), bnh hoa liu (clamydia). - Phi hp trimethoprim + sulfamethoxazol: + Vin Bactrim, Cotrimoxazol, gm 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. 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, dng khng sinh 5 - 7 ngy. Cc nhim khun c bit, dng lu hn, nh: vim ni tm mc Osler, nhim khun tit niu (vim b thn): 2 - 4 tun; vim tuyn tin lit: 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 ho, 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
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3.3.1. Khng t nhin: vi khun c tnh khng t trc khi tip xc vi khng sinh, nh sn xut 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 ho. 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 khun 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 hai 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 lactam + cht c ch lactamase 4. Phng nga xut hin vi khun khng khng sinh Ch phi 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.
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Tng c tnh ca khng sinh. Hip ng i khng. Gi thnh iu tr cao. Ni chung, nn hn ch phi 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.
Bng 14.2. La chn khng sinh trong iu tr nhim khun Thuc c chn Vi khun Cu khun Gr (+) T cu vng Vim ni tm mc Vim phi Vim xng - tu Lin cu sinh m (nhm A) Vim hng Vim tai gia, xoang Vim phi Nhim khun huyt Streptococcus viridans Vim ni tm mc Nhim khun huyt Ph cu Vim phi Vim khp Vim xoang Vim tai Cu khun Gr(-) Moraxella catarrhalis Vim tai Vim xoang Ampi+ Amox+ clavulinat Cephalosporin II III Ciprofloxacin Tetracyclin Penicilin G Gentamycin Penicilin Amoxicilin Cephalosporin I TMP - SMZ Chloramphenicol Macrolid Clindamycin Ceptriaxon (III) Vancomycin Penicilin Amoxicilin Cephalosporin I Vancomycin Erythromycin Clindamycin Trim+ sulfamethoxazol Ciprofloxacin + rifampin p xe Nhim khun huyt Bnh Th nht Oxacillin Nafcillin Th hai Cephalosporin I Vancomycin Th ba Clindamycin Erythromycin
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Vim phi
sulbactam TMP + SMZ
Erythromycin
Neisseria meningitis Trckhun Gr (+) Corynebacterium diphteriae Vim hng Vim phi Vim thanh ph qun Vim ni tm mc Nhim khun huyt
Pen. G Rifampin Erythromycin
Ceft. Cefot. Minocyclin Clindamycin
Ciprofloxacin Cephalosporin I Rifampin
Corynebacterium species, i kh
Penicilin G + aminoglycosid Vancomycin
Rifampicin + penicilin G Ampicilin + sulbactam
Trc khun Gr() Escheria coli
Nhim khun tit niu
TMP - SMZ Ciprofloxacin
Pen + c ch penicilinase Aminoglycosid
Aztreonam Nitrofurantoin Doxycycline
Ampi+ Aminogl Proteus Nhim khun tit niu Ampi/Amox Cephalosporin Aminoglycosid Pseudomonas aeruginosa Nhim khun tit niu Pen. ph rng Ceftazidim Ciprofloxacin Vim phi Pen.ph rng Ceftazidim + Aminogl Ciprofloxacin Aminoglycosid Aztreonam
Ciprofloxacin hoc Ofloxacin
Imipenem
Imipenem + aminogl
Nhim khun huyt
Aminoglycosid
Aztreonam + aminoglycosid Chloramphenicol
Salmonella
Thng hn Ph thng hn Nhim khun huyt
Ciprofloxacin Ceftriaxon TMP + SMZ Ciprofloxacin TMP + SMZ Amoxicilin +
Ampicilin
Shigella Hemophilus influeuzae
Vim rut cp Vim tai gia Vim xoang
TMP + SMZ Cefuroxim Amox/Ampi
Amoxicilin Ciprofloxacin Azithromycin
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Vim phi Vibrio cholerae T
clavulinat Doxycyclin Ciprofloxacin TMP + SMZ Chloramphenicol
T LNG GI 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 ho 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.
Bi 15 THUC KHNG VIRUS
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(Nhm khng virus sao chp ngc)

MC TIU 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 gm c mt hoc hai chui ADN hoc ARN c bc trong mt v protein gi 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 ADN 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 mARN bi mARN polymerase ca t bo vt ch, mARN 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 gm 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 mARN cho n, hoc l ARN virus c dng nh chnh mARN ca n. mARN c dch m thnh cc protein virus, k c ARN polymerase, enzym chi phi s tng hp nhiu mARN virus. Mt nhm ARN virus trong loi ny l retrovirus c cha enzym reverse transcriptase (enzym sao m ngc), to 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 mARN 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 phi 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.
Bng 15.1. Cc giai on sao chp ca virus v mc tiu tc ng ca thuc chng virus Giai on sao chp Cc nhm thuc
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- Bm dnh v xm nhp Bm dnh Xm nhp - Tho v Gii phng genom ca virus - Sao m ca genom virus
- By receptor ho 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. - Cc cht c ch protein iu ho
- Dch m ca protein virus Cc protein iu ho (sm) Cc protein cu trc (mun) - Thay i sau dch m - Tp hp cc thnh phn ca virion - Thot khi t bo vt ch
- Cc cht c ch protease - Interferon, cc cht c ch protein tp hp
Cht c ch neuraminidase, khng th khng virus.
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. Hnh 15.1 di y trnh by cc giai on pht trin ca HIV v mc tiu c th tc ng ca thuc.
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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) Ho 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; : ARN virus; . 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 ho 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)
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- Km hm s lp rp hay s t hp li ca virus v s ny chi (6). mi 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 ho mi tr nn c hot tnh. L nhm thuc quan trng nht trong cng thc phi 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 ho nh NRTI v ch c tc ng trn HIV - 1. Tt c u chuyn ho gan qua Cyt. P450, gy cm ng enzym nn lm tng chuyn ho ca chnh n (phi tng liu khi dng ko di) v mt s thuc dng cng. 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:
Cc thuc chng HIV ang c dng (bng 15.2) hin cn rt t v nhiu thuc cn ang giai on th nghim lm sng.
Bng 15.2. Cc thuc chng HIV
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Tn gc c ch nucleosid reverse transcriptase(NRT) Zidovudin Didanosin Stavudin Zalcitabin Lamivudin c ch nonnucleosid reverse transcriptase (NNRT) Nevirapin Efavirenz c ch protease Saquinavir
Tn thng mi
Hiu qu khng HIV
AZT, Retrovir, Videx EC ddI, Videx D4T, Zerit ddC, Hivid 3 TC, Epivir
++ ++ ++ + ++
Viramune Sustiva
+++ +++
Invirase, Fortovase Indinavir Crixivan Ritonavir Norvir Nelfinavir Viracept Amprenavir Agenerase Lopinavir 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
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Sau khi nhp vo t bo, zidovudin cng phi c phosphoryl ho 3 ln thnh zidovudin 5 triphosphat mi c hot tnh. Trong t bo, dng hot tnh c t1/2 khong 3 gi. Zidovudin 5 triphosphat 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 chui 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 ho v phn b vo mi m, nng trong dch no tu bng 60% trong huyt tng. Sinh kh dng khong 65%; thi gian bn thi huyt tng l 1,1 gi, nhng dng hot tnh trong t bo c thi gian bn thi khong 3 gi. Thi tr 90% qua thn di dng chuyn ho v khng chuyn ho. 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 mi, 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, hi chng ging vim nhiu c. - Cc thuc c ch phn ng glucuronyl transferase gan (phn ng ging ho 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 phi hp vi 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) 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 ho ni bo, didanosin c 3 ln phosphoryl ho 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 chui ADN, ngn cn tng hp ADN provirus. 1.2.2. Dc ng hc
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Didanosin b ph hu nhanh mi trng acid, v vy mi ch phm ung u cha cht trung ho pH ca dch v. Cn ung lc i. Ung sau ba n, lm gim hp thu ti 50%. Nng nh huyt tng ca liu ung 300 mg l 1 g/mL. Nng trong dch no tu bng 20% nng huyt tng. Thi gian bn thi l 0,6 - 1,5 gi, nhng thi gian bn thi 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% gm bun nn, nn, st, rt run, nhc u, au c, i acid uric... - Mt s ri lon sinh ho - 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 ho 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. 2.2. Dc ng hc D hp thu qua ng tiu ho, thm c qua nhau thai v sa. Nng trong dch no tu bng 45% nng huyt tng. Thi gian bn thi l 25 - 30 gi. Chuyn ho gan qua cytocrom P450.
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2.3. Tc dng khng mong mun Pht ban, st, nhc u ng g v tng transaminase. 2.4. Liu lng Nevirapin (Viramune) vin 200 mg 1 - 2 vin/ngy. 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 ho 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 ho, t b, tng 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, T chc Y t Th gii (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.
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- Ph n mang thai v tr nh cng phi c iu tr phi hp thuc ti u. 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 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 hai loi, nhim nm ton thn v nhim nm ngoi da, nim mc. Cc thuc chng nm v th cng c chia lm hai loi, ton thn v ti ch. Nhng thc ra thuc ton thn cng c tc dng ti ch v ngc li. 1. THUC KHNG 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 - lipoprotein. Ch dng ng truyn tnh mch, thm nhiu vo cc m gan, lch phi, thn. Nng trong dch bao
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khp bng khong 2/3 nng huyt tng, nhng ch 2 - 3% 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+, Mg2+. Truyn dung dch NaCl 0,9% c th lm gim c tnh cho thn. Ngoi ra c th thy bt thng test chc nng gan, thiu mu do gim sn xut erythropoietin ca thn. 1.1.5. Ch phm v liu lng - Amphoterincin B (Fungizon) tim, truyn tnh mch. L 50 mg bt ng kh pha thnh dch treo trong glucose 5%, truyn 0,5 - 0,6mg/kg trong 4 gi. - 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 phi hp trnh khng thuc. 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 ADN, v thnh fluorouridin tri phosphat (FUTP) c ch tng hp ARN. 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 ho (> 90%), t pic huyt tng sau 1 - 2gi, t gn vo protein huyt tng, 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.
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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 phi 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, clotrimazol 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: 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
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theo liu, ung 800mg th thi gian bn thi = 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 chuyn 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 nh v 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, thi gian bn thi khong 1 - 1,5 ngy. Gn vo protein huyt tng ti 99,8%. Gn vo cc m sng (da, mng) vi nng cao hn huyt tng 4 ln v gi rt lu t vi tun n vi thng sau ngng iu tr. Nng trong m mm (phi, 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/ngy 3 ngy. + Nm da, lang ben: ung 200 mg/ngy 7 ngy. + Candida ming: 100 mg/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)
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C gn thm 2 nguyn t Fluo. - Ung hp thu hon ton, khng chu nh hng ca thc n hay acid dch v. Tan nhiu trong nc nn c th tim tnh mch. Nng trong huyt tng ca ng ung gn bng ng tim tnh mch. Gn vo protein huyt tng 11 - 12%, thi gian bn thi = 25 gi, khong 90% thi qua thn di dng khng i. Thm vo mi 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. - 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, phi, da), nhim nm trong AIDS (lm tng sinh kh dng ca Zidovudin khong 20% v lm gim chuyn ho 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 ho 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 tinh th. Thc n c lipid s d hp thu v thuc khng tan trong nc. t pic sau 4 gi v thi gian bn thi = 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 mc s khng b bnh. 1.4.4. c tnh
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Thng nh: nhc u (15%), vim thn kinh, ng g, khng lm c vic kho lo, mt mi, nhn m, ri lon tiu ho... 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 KHNG 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 mc 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 Thuc nhm azol dng ngoi. Bi ngoi da ch hp thu 0,5%; bi m o, hp thu 3 - 10%. 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. 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.
Bi 17 THUC CHNG LAO THUC IU TR PHONG
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MC TIU 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 khi 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 ba 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 khuch tn ca cc thuc chng lao vo trong t bo v sc khng ca vi khun vi cc tc nhn ho 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 ho 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 ho gi l qun th D. S lng vi khun lao khng ln khng pht trin c gi l trc khun "ng". Cc thuc chng lao khng c tc dng trn qun th vi khun ny.
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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... Hin nay thuc chng lao c chia thnh hai nhm: 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, para - aminosalicylic (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 g/mL. Khi nng cao trn 500 g/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 t 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 ri lon chuyn ho ca trc khun lao. 1.1.1.2. Dc ng hc Thuc c hp thu nhanh qua ng tiu ho. Sau khi ung 1 - 2 gi, nng thuc trong mu t ti 3 - 5 g/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 phi, 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 ho gan nh phn ng acetyl ho, thu phn v lin hp vi glycin. S acetyl ho 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
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dng chuyn ho. Gn y, mt s tc gi cho rng dng acetyl ho 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. - 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 ho ca isoniazid b chuyn ho 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 ho ca phenytoin, c th gy ng c phenytoin khi iu tr phi hp thuc. 1.1.1.4. p dng iu tr - Rimifon: vin nn 50 - 100 - 300 mg; ng tim 2 mL cha 50 mg hoc 100 mg/mL; Siro 10 mg/mL. - Phi hp vi cc thuc chng lao khc iu tr tt c cc th lao. Ngi ln dng 5 mg/kg th trng, tr em 10 - 20 mg/kg th trng, ti a 300 mg/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 300 mg/24 gi, tr em 10 mg/kg th trng, ti a 300 mg/24 gi ko di 3 - 6 thng. Khi iu tr, cn dng km vitamin B6: 10 - 50 mg/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 ho 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
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gp 5 ln. 1.1.2.2. C ch tc dng Rifampicin gn vo chui ca ARN - polymerase ph thuc ADN ca vi khun lm ngn cn s to thnh chui 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 ho. 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 ho thuc gan, sau iu tr khong 14 ngy thi gian bn thi ca thuc b rt ngn li. Thuc c chu k gan - rut. Rifampicin lm tng chuyn ho mt s thuc thng qua tc dng gy cm ng cytocrom - P450 nh: thuc trnh thai, phong to - 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 dng khng mong mun ny tng ln khi dng phi hp vi isoniazid. 1.1.2.5. p dng iu tr - Ch phm Rifampicin (Rifampin, Rimactan, Rifadin) vin nang hoc vin nn 150 - 300 mg, siro 100mg/mL, dung dch tim truyn 300 - 600 mg/l. - 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 600 mg/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
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L thuc tng hp, tan mnh trong nc v vng bn nhit cao, c tc dng km trc 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 ho, 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, phi, nc bt, thn kinh th gic, gan, ty... Sau 24 gi, mt na lng thuc ung vo c thi ra ngoi qua thn, 15% di dng chuyn ho. 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 ho, 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 ri 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 400 mg c phi hp vi cc thuc chng lao iu tr cc th lao, ngi ln ung liu khi u 25 mg/kg/ngy trong 2 thng sau gim liu xung 15 mg/kg/ngy. Tr em ung 15 mg/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. 1.1.4. Streptomycin (SM, S) L khng sinh thuc nhm aminoglycosid c tc dng dit trc khun lao mnh c bit vi khun trong hang lao v mt s vi khun Gram (+) v Gram (-). Nng 10 g/mL c tc dng dit trc khun lao. c phi hp vi cc thuc chng lao khc iu tr lao. Tim bp hng ngy hoc cch ngy liu 15 mg/kg th trng, ti a khng vt qu 1 g/ngy. i vi ngi cao tui, liu dng 500 - 750 mg/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
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c pH acid v t bo n nhn vi nng 12,5 g/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 sulfonylurea. 1.1.5.4. p dng iu tr Vin nn 500 mg. Pyrazinamid thng phi 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 35 mg/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 ho, sau 3 gi t nng ti a trong mu v thi tr ch yu qua thn di dng chuyn ho. - Thuc c ch nh khi vi khun lao khng vi cc thuc nhm I. Ngoi ra, ethionamid cn c dng phi hp vi dapson, rifampin iu tr phong vi liu 10 mg/kg th trng. - 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 500 mg cch 5 ngy tng 125 mg n khi t 15 - 20 mg/kg th trng v khng vt qu 1 gam/24gi. 1.2.2. Acid paraaminosalicylic (PAS) L thuc km trc khun lao c c ch tc dng ging sulfonamid, nhng khng c tc dng trn cc vi khun khc. Liu dng: 200 - 300 mg/kg/ngy, ti a 14 - 16 g/ngy. PAS c th gy a lng, nn,
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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 g/mL. Liu iu tr lao 1 g/24 gi. - Capreomycin l mt peptid vng c tc dng chng lao vi liu 15 - 30 mg/kg/24 gi. - Ofloxacin v ciprofloxacin l hai khng sinh nhm fluorquinolon c nng trong t chc phi cao hn trong huyt tng c nng c ch ti thiu trn trc khun lao rt thp t 0,25 - 3 g/mL. Trong iu tr lao ciprofloxacin ung 1,5 g chia 2 ln/ngy; ofloxacin ung 600 - 800 mg/ngy. - Azithromycin v clarithromycin l hai 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 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 1 g/mL. Trong lm sng c th phi 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 200 mg/24 gi. (Chi tit 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 ba 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. - a khng thuc l hin tng vi khun lao khng li t nht hai 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
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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 phi 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 10 mm 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.
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- 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 R: Rifampicin Z: pyrazinamid E: Ethambutol S: Streptomycin
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 ging para - acid aminobenzoic 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 ho. 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 tng khong 50% v khuch tn nhanh vo cc t chc: da, c, gan, thn v dch no tu. Dapson c chuyn ho gan nh phn ng acetyl ho to thnh monoacetyl - DDS khng c tc dng km khun. S chuyn ho 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 trc khun phong, khng dit khun. C ch tc dng ging sulfonamid. C ch chi tit 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
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5 - 6 tun. Biu hin: st, vng da, hoi t gan, vim da, met - Hb v thiu mu.y l hi chng rt nng, cn phi ngng thuc ngay v hi 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 25 mg, 100mg ung khi u liu thp 50 mg/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 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 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 100 mg - phi hp vi dapson v rifampin iu tr mt s th phong vi liu 50 mg/24 gi hoc 100 - 300 mg/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 ho 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.
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2.4.2. Thalidomid L thuc an thn, nhng c tc dng iu tr phong, c bit th phong c. Liu dng 100 300mg/24 gi. Do gy qui thai, c bit giai on 24 - 36 tun u ca thi 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 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 ho tr liu, khng dng mt loi thuc iu tr phong v thng dng 3 thuc dapson, rifampicin v clofazimin. - Phi hp ho 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. - Thi gian iu tr ko di tu thuc vo mc nhim trc khun. 2.5.1. Phc iu tr nhm c nhiu trc khun
Dapson 100 mg t ung mi ngy Rifampicin 600 mg mi thng ung 1 ln c gim st Clofazimin 300 mg mi thng ung 1 ln c gim st + 50 mg 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 (trong 5 nm)
2.5.2. Phc iu tr nhm t vi khun

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

Clofazimin Cn nng tr Rifampicin hng thng c kim tra Dapson Hng thng c gim st Hng tun, hng ngy t t ung hng Thi gian iu tr
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(ung) 20 kg 21 - 30 kg 31 - 50 kg 150 mg 300 mg 450 mg
(ung) 100 mg 150 - 200 mg 200 - 300 mg
ung 100 mg (hng tun) 150 mg (hng tun) 50 mg (hng tun)
ngy 25 mg 25 - 50 mg 50 - 75 mg t nht 2 nm n khi hoc
xt nghim m tnh
2.5.4. Phc iu tr nhm bnh t vi khun tr em

Cn nng tr 20kg 21 30 kg 31 50 kg Rifampicin hng thng c gim st (ung) 150 mg 300 mg 450 mg Dapson hng ngy t ung 25 mg 25 50 mg 50 70 mg 6 thng Thi gian iu tr
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.
TI LIU THAM KHO

1. B mn Dc lm sng Trng i hc Dc H Ni (2000): Dc lm sng i cng NXBYH.
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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 hc - NXBYH. 7. Cc b mn Ni Trng i hc Y H Ni (2000): iu tr hc Ni khoa - NXBYH. 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 (2007): Basic and clinical pharmacology. 10th edition Appleton & Lange USA. 11. British national formulary (2004). BNF 47th. 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. 14. Eric J. Nestler (2001): Molecular neuropharmacology - McGraw - Hill Companies, Inc. 15. Drug information (2002) American hospital formulary service (AHFS) 16. Goodman & Gilmans (2006): The pharmacological basis of therapeutics. 11th 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. Page Cl., M. Cintis, M. Walker, B. Hoffman (2007): Integrated pharmacology 3rd edition Mosby Elsevier. 24. PDR (2003). Physical desk references. Edward R. Barnhart. 25. Rang and Dale's (2007): Pharmacology - 6th edition - Churchill Livingstone. Elsevier. 26. Smith and Reynard (1992): Textbook of pharmacology - W.B. Saunders company. 27. Wingard, L.B (1991): Human pharmacology. Mosby.
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28. Yakoub Aden Abdi (1995): Handbook of drugs for tropical parasitic infections. 2nd edition Taylor & Francis.
Chu trch nhim xut bn: Ch tch HQT kim Tng Gim c NG TRN I Ph Tng Gim c kim Tng bin tp NGUYN QU THAO Chu trch nhim ni dung: Ch tch HQT kim Gim c Cng ty CP Sch H DN TRN NHT TN Bin tp v sa bn in: V TH BNH Trnh by ba: BI QUANG TUN Ch bn: THI SN
DC L HC TP 1
M s: 7K729M7 DAI In bn, (Q: ) kh 19 27 cm, ti
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S KKH xut bn: 874 2007/CXB/9 1918/GD In xong v np lu chiu thng 1 nm 2008.
7/14/2011

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Dc l hc - B Y t

NH XUT BN GIO DC H NI 2007

Bn quyn thuc B Y t (V Khoa hc v o to)

Hnh 1.1. S chuyn vn ca thuc trong c th

Hnh 1.2. S khuch tn qua mng

p dng phng trnh Henderson - Hasselbach, ta c: gian 1 (d dy):

S ion ho ca thuc cn ph thuc vo pH mi trng.

% khng ion ho 99,0 90,9 50,0 9,09 0,99 0,10

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

Hnh 1.4. H phn phi thuc 3 gian

Hnh 1.5. Cc phn ng chuyn ho thuc c phn lm 2 pha

Cc phn ng chnh pha ny gm:

Hnh 1.6. S oxy ho thuc ca cytochrom P450

2. Cng thc ca Cowling: dng cho tr em t 2 - 12 tui

V d: liu cho ngi ln l 2,0. Liu cho tr 4 tui l

3. Cng thc ca Fried: dng cho nh nhi

4. Cng thc ca Clark

Chng II THUC TC DNG TRN H THN KINH THC VT

Hnh 4.1. Cu to gii phu ca h thn kinh thc vt

Co (gin ng t) ++ Co (co ng t) +++

Tng tn s ++ Tng bin ++

Gim tn s ngng tim Gim bin ++

Gin + Gin + Gin Gin Co ++

Tng +++ Gin + Tng +++

Gim +; tng ++ Cha: co ( 1); gin ( 2) Khng cha; gin ( 2)

Thay i theo chu k kinh...

C quan sinh dc nam Bng quang

Phng tinh +++

C bng quang C trn Gan Ty Acini T bo

Gin + Co ++ Hu glycogen v tn to glucose +++

Gim tit + Gim tit +++ tng tit ++ Hu lipid +++

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

Hnh 4.2. Xinap v cht dn truyn thn kinh

Cc receptor ca h cholinergic cn c chia lm hai loi:

Cc thuc kch thch c th tc ng theo nhng c ch:

Bi 5 THUC TC DNG TRN H CHOLINERGIC

Dimethylphenyl piperazin (DMPP)

Hch thc vt Tu thng thn Trung ng TK

Kh cc si sau hch Tit catecholamin

M knh cation ti receptor Nn

Hch thc vt Trung ng TK

Atropin Hexahydro siladifenidol

C trn Tuyn tit

p dng: - Ch nh tt trong bnh nhc c bm sinh (myasthenia gravis) v thiu ht acetylcholin bn vn

Bi 6 THUC TC DNG TRN H ADRENERGIC

Hnh 6 .1. Sinh tng hp catecholamin

Bng 6.1. Cc receptor adrenergic Chti khng Prazosin

Cht ch vn Adr NA >>Iso Phenylephrin

M - C trn thnh mch - C trn sinh dc tit niu

C ch phn t Kch thch phospholipase C to IP3 v DAG; tng Ca2+ cytosol

S tc ng ca catecholamin ln chuyn ho ng v lipid

p). Reserpin cn cn tr qu trnh gn catecholamin (c ni sinh ln ngoi sinh) vo cc ht lu tr.

9. Trnh by cc tc dng khng mong mun ca thuc hu .

Chng III THUC TC DNG TRN H THN KINH TRUNG NG

Ngoi ra, thuc t cn lm gim tn s phng xung tc ca cc si cm gic.

Hnh 7.1. Qu trnh thm nhp ca thuc t qua mng t bo gn vo receptor

Hnh 7.2. S cc cch gy t

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