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DC LY HOC AI CNG MUC TIEU, YEU CAU : - Nam vng nhng khai niem c ban ve dc ly hoc ai cng va biet

van dung nhng khai niem ay trong cac chng muc dc ly chuyen e. - Nam vng 2 qua trnh c ban dc ly hoc : Dc lc va dc ong, biet s dung thuoc mot cach hp ly, an toan va co hieu qua. I. NHNG KHAI NIEM C BAN : 1.1. DC LC HOC : La mon khoa hoc nghien cu ve tng tac (interaction) gia thuoc (D) va he thong song (R) . Tng tac co ngha la tac ong qua lai : Thuoc tac ong len he thong song (D R), thuoc pham tru nghien cu cua dc l hoc (Pharmacodynamics), con he thong song tac ong tr lai oi vi thuoc (R D), thuoc pham tru nghien cu cua dc ong hoc (Pharmacokinetics). Dc lc va dc ong la 2 qua trnh c ban cua dc ly hoc, chung van ong, an xen vao nhau, tao ra nhng hieu ng dc ly. Van dung toi a nhng hieu ng mong muon vao muc ch ieu tr va han che het mc hieu ng khong mong muon cua thuoc, nham nang cao hieu qua ieu tr, giam thieu tai bien, gop phan bao ve sc khoe cua nhan dan, la muc tieu yeu cau chung cua dc ly hoc Dc ly hoc la mon khoa hoc ban le, noi lien gia c s va lam sang, gia ly luan va thc tien, lien he rat mat thiet en cac mon khoa hoc c ban, y hoc c s, toan hoc, thong ke sinh hoc, hoa hoc, y hoc ien t, phap y, luan ly va xa hoi hoc cac mon hoc lien he o, thuc ay dc ly hoc phat trien va s phat trien cua dc ly hoc tr lai ap ng ngay cang tot hn, mang lai hieu qua ieu tr cao hn cho thc tien lam sang. Dc ly hoc van dung phng phap phan tch va tong hp, ket hp chat che gia nguyen ly thc nghiem lam sang va ket qua lam sang, luon luon la ni kiem nghiem mot cach chnh xac toan bo cong tac nghien cu cua chung ta. e am bao at en hieu qua chung cuoc trong ieu tr, ngi thay thuoc phai nam vng s bien oi cua thuoc qua 4 giai oan sau : 1. Giai oan kha dung sinh hoc (Bioavailability) : Chon la thuoc, xac nh lieu lng, dang thuoc va con ng a thuoc vao c the.

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2. Giai oan dc ong (Pharmacokinetics) : Nam vng so phan cua thuoc trong c the. 3. Giai oan dc lc (Pharmacodynamics) : Nam vng tac ong va c che tac ong cua thuoc 4. Giai oan van dung hieu ng dc ly vao ieu tr : Ch nh, chong ch nh, anh gia ket dieu tr 1.2. THUOC : La nhng chat hoac hon hp cac chat, c dung e cha benh, phong benh va chan oan, nham phuc hoi chc nang von co cua n v song. Cac ac tnh cua thuoc : Phan t : Nhng thuoc co lng phan t t 100 en 1000, de hap thu v de khuech tan va thuan li cho viec chuyen ch thuoc qua mang te bao. Hnh khoi cau truc lap the : a so cac thuoc, tng tac vi nhng v tr chuyen biet c goi la thu the R (Receptor). o la cau truc khong gian 3 chieu cua ai phan t. Cau truc lap the hnh khoi cua thuoc phai an khp va van vi hnh khoi cua thu the ay. Co khoang 25% so thuoc c s dung, la nhng chat ong phan lap the. Chung thng rat khac biet ve cac hieu ng, cung cach thai tr thuoc ra ngoai c the, cung nh ve oc tnh. V du : L-quinin (chong sot ret) va D-quinidine (chong loan nhp tim); R (-) prilocain, thuy phan rat nhanh thanh O-toluidine, gay mathemoglobin, con S (+) prilocain thuu phan rat cham, t gay methemoglobine hn. Ca hai dang ong phan thalidomide, eu co tac dung an than gay ngu, nhng ch co dang L (-) co tng gay quai thai cho va loai ong vat v.v.. Hoa tnh : Co nhng thuoc phan ng rat manh nh nhng chat Alkyl hoa (mechlorethamine), trong khi o, cung co nhng chat tr, Xenon chang han, co tac dung gay me. Thuoc co the la carbohydrate, lipide hay proteine, co tnh acide yeu hay base yeu. o ion hoa cua thuoc, tuy thuoc pH cua moi trng tng khu vc hoac v tr cua c the Nguon goc : Thien nhien : Khoang chat, ong vat, thc vat. V du : Kaolin t at set trang. Emetine t re cay ipeca. Insuline t tuy tang. Penicilline t nam penicillium. Ban tong hp : T chat t nhien vo hoat, qua s bien oi trong phong th nghiem, co the tr thanh thuoc co hoat tnh. V du : Penicilline ban tong

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hp, c hnh thanh t 6-amino-penicillanic, chat t nhien ly trch t Penicillium. Tong hp toan phan : Chloramphenicol, Ephedrine, Phenylephrine co the tong hp toan phan, gia thuoc re hn chat t nhien, ma oc tnh lai t hn. Phan loai thuoc : Thuoc chuan (Produits officinaux) : La nhng thuoc co ac tnh lyhoa va dc ly, c ghi trong dc ien quoc gia. Thuoc bao che theo toa Bac s (Preparations magistrales) : Nhng thuoc bao che danh rieng cho mot benh nhan theo ch nh cua Bac s. Dang thuoc nay nay a loi thi Biet dc (Specialites pharmaceutique) : Nhng thuoc c bao che san, trnh bay di dang bao b, ong goi ac biet. c ac ten rieng va c bay ban th trng sau khi Bo Y te kiem nh va cho phep. Thuoc chu yeu (Medicaments essentiels) : Co khoang 200 hoat chat can thiet, khong the mien tr ma moi Bac si phai co, e ieu tr nhng beng thong thong. Thuoc n le (Medicaments orphelins) : La nhng thuoc c san xuat mot lng t oi, e cha cho mot so ngi mac benh hiem hoi, do khong co li nhuan cao, nen t c cac nha cong nghe dc pham quan tam. at ten thuoc : Ten khoa hoc (Denomination Scientifique) : Nhng hoa chat phai tuan thu cac qui luat at ten theo danh phap quoc te IUP (Union International de chimie pure et appliquee), nhng ten khoa hoc thng qua dai va phc tap cho ngi ke toa dung thuoc. V du : Acide acetyl salicylique - (3,4 dihydroxyphenyl) - methylamino ethanol. Ten thng mai (Denomination commerciale) : Ten kieu cach nhan hieu, cau chng (Registereo trade mark name) cua cac biet dc, co the cha mot hay nhieu chat ma cac nha bao che san xuat ra bang nhieu ten thng mai khac nhau. V du : acide acetyl salicylique c bay ban di nhieu ten biet dc nh Aspirine Bayer, Aspirine du Rhone 500, Aspro, Aspan pH8. Ten thong thng (denomination commun) : e khac phuc nhc iem gay phien toai t ten khoa hoc, ten thng mai. To chc Y te the gii co hng dan cach at ten thuoc chung cho tat ca cac nc, da tren c s

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nhng tiep au ng (prefix) hay tiep v ng (suffixe) can he en cac nhom thuoc, tat nhien cung co mot so ngoai le : - ctide Polypeptides tong hp t cac corticotrophine ong vat - ac Cac chat chong viem nhom Ubufenac - andro Steroides androgenes - arol Cac chat ong mau nhom dicoumarol - astine Cac thuoc khang histamine - azepam Cac chat nhom diazepam - bol Cac steroides ong hoa (anabolisants) - caine Cac thuoc te - cef Cac thuoc khang sinh t acide Cephalosporanique - cilline Cac thuoc khang sinh t acid 6 amino-penicillanique - cycline Cac thuoc khang sinh nhom tetracyclines - dipine Cac chat dan mach ngoai bien nhom nifedipine - estr Cac chat Estrogenes - fibrate Cac chat nhom clofibrate - formine Cac chat ha ng huyet nhom Phenformine - gest Cac Steoides Progestogenese - gly Cac Sulfamides ha ng huyet - Io Cac chat co Iode - ium Cac ammonium bac IV - metacine Cac chat khang viem nhom Indomethacine - mycine Cac thuoc khang sinh t cac chung Streptomyces - nidazol Cac chat cha nguyen sinh ong vat cua nhom metronidazol - olol Cac chat phong toa nhom propranolol - onide Steroides dung tai cho cha nhom Acetal - orex Cac chat gay thieu Oxy dan xuat t phenethylamine - pramine Cac chat trong nhom imipramine - pride Cac chat thuoc nhom Sulpiride - profene Cac chat khang viem nhom ibuprofene - reline Cac Peptides kch thch phong thch hormones tuyen yen - sulfa Cac Sulfamides - terol Cac chat dan phe quan t phenethylamine - tidine Cac chat oi khang recepteur H 2 - trexate Cac chat oi khang acide folique - verine Cac chat chong co that nhu papaverine - vin Cac alcaloides Vinca
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Nguyen tac ke toa thuoc : Toa thuoc c xem nh c lieu phap y Ch viet tren toa, phai chan phng de oc, ro rang khong gay nham lan cho ngi thc hien. Khong c ke toa bang but ch, de tay xoa. Noi dung ke toa phai hp ly, chnh xac va gay gon. Moi toa thuoc c cho, gom 6 muc theo th t sau : Ho ten, hoc v, chc danh a ch cua ngi ke toa, nhat la ch ky va ngay thang nam ke toa, o la nhng c lieu quan trong e co c s truy cu ve sau. Ho ten, tuoi, phai tnh cua benh nhan. Nham xac nh nhng thuoc c ke cho benh nhan nay ch khong phai benh nhan khac. Ten thuoc : Co the dung ten thuoc thong thng, hay ten biet dc va khong c viet tac cac ten thuoc. Neu trong 1 toa ke nhieu loai thuoc, thuoc tien ghi trc, cac thuoc ho tr ghi tiep theo, co the ghi ham lng cung hang vi ten thuoc. Lieu lng : Ghi ro lieu lng va so lan cho thuoc (uong, tiem, dung tai cho) trong moi ngay. Tong so ngay ieu tr va tong so thuoc c yeu cau Cach dung : o ng mieng : nuot, nhai nhuyen.? o ng tiem : Tiem bap, tiem tnh mach? o Thuoc ac vao hau mon, am ao? o Khoang cach lan cho thuoc trong ngay ? o Uong luc bung trong hay sau khi an ? o Co lac chai trc khi uong ? Tai cap : Toa thuoc sau khi dung xong, con c tai cap ? oi vi nhng thuoc co oc tnh (A,B) Thuoc oc bang A : Tat ca viet bang ch cac ham lng, lieu lng. Trng hp do yeu cau bat buoc cho thuoc qua lieu, thay thuoc ghi cau toi cho lieu nay va ky ten chu trach nhiem Toa thuoc co thuoc oc bang A va B c dung < 10 ngay, lieu lng thuoc ghi bang ch va thuoc ngu ch c dung toi a 3 ngay 1.3. DC ONG HOC (PHARMACOKINETICS): La mot phan cua dc ly hoc, nham nghien cu qua trnh hap thu, phan phoi, chuyen hoa va thai tr cua thuoc.

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Dc ong hoc c ban : Nham xac nh nhng tham so dc ong tren vat th nghiem va tren ngi khoe manh. Dc ong hoc lam sang : Nghien cu ve s bien oi dc ong tren benh nhan va tren cac phe ieu tr phoi hp, e xac nh lieu cho (Posologie) thch hp. - Nhng thong so dc ong o lng c t xac nh nong o thuoc (hoac chuyen hoa cua chung) huyet tng, hoac nc tieu, sau khi cho thuoc vao c the bang cac con ng khac nhau 1.4. DC LC HOC (PHARMACODYNAMICS) La mot phan cua dc ly hoc, nham nghien cu nhng hieu ng sinh hoa-sinh ly cua thuoc tren hng c quan, nhng he thong (quan sat s bien oi ve hnh thai va sinh ly, sinh hoa) cua c the. - Co gang chng minh c che tac dung cua thuoc II. C CHE TAC ONG CUA THUOC : 2.1.CAC CACH TAC ONG CUA THUOC : Tac ong vat ly hoa hoc : - Thuoc khang toan, lam tang pH dch v (pH bnh thng da day : (1,2 3,5)) bao ve niem mac da day. - Thuoc hap phu (adsorbants), nh than hoat, hut cac oc to, thuoc. - Resine trao oi Ion nh cho Lestyramine (Questran), trao oi Ion vi cac acides beo, nh o c che s hap thu cholesterol. Tac ong tren Enzymes chuyen hoa : - Aspirine hoac cac chat khang viem khong steroides, c che men Cyclo oxygenase - Cac chat c che men MAO (Inhibiteur de la Mono oxydase) - Theophylline c che men Phosphodiesterase, duy tr AMP vong. Tac ong len s chuyen van (Transport) : - Digitaline ngan chan Na-K / ATPase cua mang te bao. - (Ca + + ) noi bao tang gay tang co bop c tim - Thuoc li tieu nhom Thiazides, c che trao oi Na + / K + ong ln xa. - Nhng thuoc phong toa kenh Calcium, ngan chan Ca + + tham vao c tim va thanh ong mach, nen lam giam co bop c tim. Tac ong len s tong hp ai phan t : Proteine, AND, ARN - Sulfamides, gay bien oi s tong hp ARN cua vi trung. - Aminosides, c che s tong hp proteine cua vi trung Tac ong len cac v tr thu the chuyen biet R (Receptor)
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- a so cac thuoc, noi ket vao R t nhien trong c the (von la cho noi ket cuaq cac chat noi sinh, e am bao cac chc nang bnh thng va mot so tnh trang bnh ly)

Hnh 1: thu the chuyen biet S noi ket nay, se dan ti nhng phan ng tng t nh nhng chat noi sinh. Ve mat nay, ngi ta quan niem thuoc la chat ong van (agoniste) cua R. Va ngc lai, neu no ngan chan tac ong cua chat noi sinh, ngi ta goi thuoc o la chat oi van (antagoniste) cua R. 2.2. CHAT NOI KET (LIGANDS) Chat noi la tat ca nhng chat co the noi ket vao R. Nh the chat noi gom co : Chat noi sinh va nhng chat ong van hoac oi van vi chat noi sinh cua R. - Nhng chat noi sinh : La nhng chat t nhien c tao ra trong c the, nh chat trung gian than kinh (neuromediateurs), co nhieu tac dung tren cac c va cac tuyen : Nor-adrenaline, Acetyl choline nh cac kch thch to (hormones), c phong thch vao mau, tac ong len mo ch va nh cac autacoides noi sinh, chung tac ong va nh chat trung gian trong qua trnh benh ly, gay d ng, gay viem, au, sot: histamine, serotonine, prostaglandines, PAF (Platelet-Activating-Factor), Angiotensine, Neuropeptides - Nhng chat ong van, oi van cua R : la nhng chat noi nhan tao. Cau truc lap the cua cac chat noi rat quan trong, chnh ieu o tao ra cac chat ong phan lap the, co hieu ng chnh, hieu ng ngoai y muon, oc tnh rat khac biet nhau. Gan ket gia chat noi va R : Chat noi co the gan ket vi R mot cach thuan nghch va khong thuan nghch.

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- Gan ket thuan nghch (Liasion resersible) :La loai gan ket khong ben vng, phan ng xay ra thuan nghch hai chieu : D + R DR. ay D va R noi ket vi nhau bang nhieu ng noi khac nhau - Noi ion : Hai phan t cha hai loai ion mang ien tch trai dau (anion, cation) chung se hut nhau. Phan ng nay phu thuoc vao o phan ly (P K ) cua phc hp DR cua moi trng (v pH anh hng en o phan ly P K cua phc hp DR) - Noi hydrogen : Protone H + nhan ien t t nguyen t cho khac, tao thanh cau noi dai 3A O (g = 2 5 Kcal/mol) - Noi Van der Waals : Trong hay gia phan t cua D va R co s tng tac gia hai cc tch ien trai dau, gia vung ien dng va ien am (g < 1 Kcal/mol). - Tng tac k nc (interation hydrophobe) : la tng tac gia phan khong phan cc cua cac phan t (g = 1 Kcal/mol). Mc o va thi gian e gan ket D va R, phu thuoc vao tnh chat va kieu noi thuan nghch tng ng - Gan ket khong thuan nghch (Liason irreversible): La kieu noi ben chat, phan ng ch xay ra mot chieu : D + R DR. D va R la hai phan t dung chung cap ien t vi ng noi cong hoa tr, phong thch, thu vao, mot nang lng ang ke (g = 100 Kcal/mol), nen hieu ng cua D keo dai. V du : Hp chat phosphore hu c gan ket khong thuan nghch vi men cholinesterase. 2.3. RECEPTOR R Ban chat cua R : R la cau truc khong gian 3 chieu cua ai phan t, khi chat noi gan vao se cho nhng ap ng sinh ly, sinh hoa chuyen biet. Ban chat cua R la Proteine : Glycoproteine, acide desoxyribonuclei-que (AND) va polysaccharides Nh o, R co kha nang nhan dien va gan ket cac thuoc hoac chat noi sinh thch hp vi no V tr, phan bo phan loai cac R: - R co nhieu nhat mang te bao Receptor ACTH, receptor cac catecholamines, co trong bao tng (kch thch to tuyen giap) va co trong nhan te bao (receptor cua actinomycine, cua kch thch to tuyen giap). - Cung mot loai R co the phan bo : cung mot loai mo phan bo nhieu ni nh c trn. V du : receptor Muscarinic M 3 khi b kch thch se ap ng duy nhat : co c trn phe quan va c trn tieu hoa. nhieu loai mo khac nhau. V du : R- 1 cua nor-adrenaline, gay ap ng tren c tim (tang
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nhp va tang co bop), tren tieu ong mach (co mach) va tren mo m (tieu m). - Cung mot chat noi, co the co nhieu loai receptor va cho nhau loai hieu ng khac nhau. V du : nor-adrenaline t nhat co hai loai receptor va . - Nh kham pha ra cac chat ong van, oi van, ngi ta phan loai c cac receptor khac nhau cua cung mot chat noi. V du : mot chat noi sinh histamine cho nhieu ap ng tren c trn kh quan, ruot, t cung va tren niem mac da day. - Cromoglycate la chat c che chuyen biet tac ong histamine tren kh quan. Cimetidine c che chuyen biet tac ong cua histamin tren tang tiet dch da day. Nh o ngi ta hieu c rang histamine co t nhat hai loai receptor H 1 va H 2 . Cromoglycate la chat oi van H 1 con Cimetidine la chat oi van H 2 .

Hnh 2: Thu the alpha va beta 2.4. CHAT ONG VAN CHAT OI VAN: CHAT ONG VAN Chat ong van la chat va co ai tnh (affinite) va co hoat tnh (activete) cua mot receptor. Khi tat ca cac receptor eu gan ket vi chat ong van (tat ca eu c hoat hoa) se cho mot hieu ng toi a E max (Effet maximal). Hnh 3: chat ong van tren thu the chuyen biet cung kch hoat protein Gq.

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Vi 4 chat oi van A, B, C, D, do hoat tnh noi tai (activite intrinseque) cua chung khac nhau, nen ng bieu hien hieu ng theo Log nong o cung nh cho ap ng E max cua chung cung khac nhau = 1 oi vi AB = 0,5 oi vi C = 0,4 oi vi D V A va B at hieu ng toi a E max = 100%. Nong o C at 50% E max . Nong o D at 40% E max Hoat tnh noi tai ( ) cua mot chat ong van bang t so cua hieu ng toi a ma no at c, tren hieu ng toi a cua mot chat ong van khac Ai tnh cua chat ong van D nghch ao cua hang so phan ly (Ka) phc hp DR, hoac bang hang so phc hp DR : D + R DR tai iem can bang nong o DR. Theo nh luat tac ong khoi lng (action de mass)

[D] Nong o chat ong van t do [R] Nong o R t do

[D][ . R] = Ka [DR]

Ka : Hang so phan ly cua phc hp DR Nghch ao cua Ka = hang so phc hp DR (ai tnh cua D), c dien ta bang pD. Log 1 Ka = Log Ka = pD Tnh gia tr cua ai tnh trong thc te la xac nh nong o chat ong van (D) sao cho u e tao ra hieu ng bang 1 2 E max va thi iem o, so R t do bang so R a gan ket vi D. Hay [D] = [DR] . Trong bieu thc 1 co the viet:

[D][ [D][ . R] . DR ] = =D [DR] [DR] c biet [D] = Ka pD = - Log Ka = - Log [D]


Ka =

PD Ai tnh : la am logarithme nong o phan t cua mot chat ong van, cho mot ap ng bang 50% ap ng toi a co the co c. Chat ong van toan phan va tng phan :

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- A, B, C la 3 chat ong van. A va B co hoat tnh noi tai bang nhau ( = 1). Nhng A manh hn B (hieu lc cua A>B). Hoac ai tnh cua A>B (50 Log D 50 A > -Log D B ) ta goi A va B la chat ong van toan phan. - Co hoat tnh noi tai thap hn A va B (( = 0,5), nhng ai tnh cua C 50 cao hn cua B (-Log D 50 C > -Log D B ) ta goi C la mot chat ong van tng phan.

Hnh 4: Cac mc o hieu qua do chat ong van tac ong len thu the. CHAT OI VAN Hnh 5 ng bieu dien hoat tnh cua thuoc; chat ong van va chat oi van.

- Chat oi van canh tranh B gan ket thuan nghch vi R, ay ng bieu dien cua chat ong van A sang phai, ta goi o la chat oi van canh tranh. Giam ai tnh cua chat ong van Bao ton hoat tnh noi tai cua chat ong van Phai tang lieu chat ong van mi at c hieu qua toi a - Chat oi van khong canh tranh: C gan ket khong thuan nghch vi R. Chat oi van khong canh tranh: Bao ton hoat tinh cua chat ong van A Giam hoat tnh noi tai cua chat ong van A Du co tang lieu cho A, cung khong canh tranh noi vi C. Khong phuc hoi c hieu qua toi a.
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2.5. S IEU HOA RECEPTOR: - Trong thc nghiem, neu kch thch nhieu lan R, bang mot chat ong van vi tan so ln hoac lieu cao, ta se thay s ap ng dc ly se giam bt hoac mat dan. Neu s kien xay ra mot cach nhanh chong, ta goi o la s giam mien nhanh .(Tachyphylaxis), neu xay ra t t cham rai, ta goi la s dung nhan (Tolerance) ma khong nen goi la giam nhay cam mac phai (Hyposensibilite acquise), hay mat nhay cam (desensibilite) nh trong d ng. S giam ap ng nay c phat hien trong thc nghiem bang nhng chat ong van cua Receptor kh phe quan, hoac serotonine tren hoi trang co lap - o la do so R di chuyen t mang te bao qua hien tng nhap bao (+) R c ieu chnh xuong thap (down regulation); Do thay oi hoa tr cua R, hoac do cac R b tieu huy nh trong benh nhao c, tieu ng, khang insuline. Hien tng o, giup ta hieu c dung nhan thng xay ra va phat trien tang lieu nhng chat gay nghien. - So R cung tang hay giam trong tnh trang sinh ly hoac benh ly nh b hoan (castration), R cua androgene se b giam. Ngc lai trong thi ong duc, R progesterone tang va R oestrogene giam. - S gia tang tong hp cac R, hoac s dung dai han cac chat oi van, co the lam tang tnh nhay cam, tang tnh hoat ong cua chat ong van oi vi cac R cua no, gay ra hieu ng doi ngc, hoac giam ngng kch thch R cua ca chat kch thch ong van. V du s dung propranolol dai han, neu ngng thuoc ot ngot, se b hien tng doi ngc lam cho huyet ap tang vot, vt mc bnh thng. - ac biet, s tong hp cac R d thng co the do gene sinh ung bu (oncogeneux) hoac do cac hormones cua c the, dan ti s bien oi cac te bao thng thanh te bao ac tnh III. S HAP THU THUOC TRONG C THE : So phan cua thuoc trong c the trai qua 4 giai oan noi tiep sau ay : - Hap thu : - T ni tiep xuc vi c the, thuoc vao tuan hoan (tr tiem thang vao mach mau). - Phan phoi : T mau, thuoc en cac mo. - Chuyen hoa : Thuoc bien oi sinh hoc chu yeu tai gan. - Thai tr : Thuoc bai thai ra ngoai c the chu yeu qua gan va than. Hnh 6 :S o bieu dien s hap thu chuyen hoa va thai tr thuoc cua he thong song.

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3.1. O KHA DUNG SINH HOC CUA THUOC:(BIOAVAILABILITY) - Trc khi c hap thu, mot t le hoat chat c phong thch ri khoi dc pham D (hoat chat X va ta dc E) e cho hieu ng. o kha dung sinh hoc la t so gia lng thuoc cho vao va lng thuoc thc te co mat trong tuan hoan - o kha dung sinh hoc, phan anh t suat (%) cua lng thuoc cho qua ng uong va lng thuoc thc te co mat trong tuan hoan sau khi qua ruot va gan. T suat o c tnh bang AUC - AUC (Area under concentration time-curve) - AUC la dien tch di ng bieu dien nong o cua thuoc trong mau theo thi gian.

- o kha dung sinh hoc ky hieu bang F. Thuoc tiem trc tiep vao tnh mach co o kha dung sinh hoc 100%. F = 1. Neu s dung thuoc qua ng uong, v du propranolol uong, o kha dung sinh hoc ch at 30%, F = 0,3 v phai qua chuyen hoa thuoc bc au ruot va gan. - CHUYEN HOA BC AU (First pass metabolism) Trc khi thuoc uong c hap thu, thuoc phai qua chuyen hoa trc tuan hoan (Presystemic metabolism), ruot gan, nen lng thuoc thc te co mat trong tuan hoan thng giam so vi lieu thuoc uong ban au. 3.2. S CHUYEN VAN CUA THUOC :

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T ni tiep xuc vi c the, thuoc phai vt qua nhieu vat can e vao mau. o la mang te bao mot lp (te bao thng b ruot) va nhieu lp (te bao thng b da). Co nhieu c che xuyen mac khac nhau: Khuyech tan thu ong : pho thong nhat oi vi thuoc. Khuyech tan gian d (can cha tai) Chuyen ch thu ong. (can chat tai) Loc Am bao va xuat bao.

Hnh 8 hien tng nhap bao (endocytosis-am bao) Mang te bao va mang sinh vat Ben ngoai cua tat ca cac loai te bao, eu co mang bao boc xung quanh, c goi la mang te bao (cell membrane), v chat cha ng ben trong la bao tng (cytoplasma), nen con c goi la mang bao tng (Plasma membrane, plasmalemma). Mang te bao, khong ch la mang loc, la ranh gii gia cac te bao ma con la ni trao oi chat (vat chat, chat dinh dng), la dien tiep xuc vi tn hieu hoan canh ben ngoai. Khai niem mang te bao noi tren c m rong va hieu sau hn o la mang sinh hoc. No bao gom ca cac mang trong noi bao : Mang hat, mang men, mang he noi vong, nhat la mang ti the. Mang bao tng co tnh ban tham, day o 7,5 mm (7,5 A O ), laa mot cau truc kham gom tap hp nhng phan t, sap xep thanh 3 lp, 2 lp lipide va 1 lp protein xen gia

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- Hai lp lipide cha nhieu phospholipde, mot au la phosphate hu c a nc, hng ra ngoai hai ben mang, con au k nc hng vao ben trong. - Mot lp proteine gom 5 loai phan t, co phan hu cc a nc hng ra mat ngoai mang, phan vo cc k nc nam trong mang. Nhng proteine cua mang co the la: Bm (pump) : e ay cac ion qua mang ( Na + va Ca + + ) ngc khuynh o nong o, can nang lng. Kenh (channels) : e cho cac ion vao mang ( Na + va Ca + + ) theo khuyng o nong o va khong can nang lng. Enzymes cua mang. Proteine cau truc cua mang Receptor cua chat noi sinh va thuoc Nhng c che chuyen van thuoc qua mang Khuech tan thu ong (diffusion passive) Nhng chat khong ien ly, nhng chat kem ien ly va nhng chat khong ion hoa, chuyen van qua mang bang c che khuech tan thu ong, tc theo chieu khuynh o nong o (nh luat Fick)
dQ S = D.K . (C 2 C 1) dt e

dQ = Toc o khuech tan cua thuoc D dt

Mng

D = He so khech tan cua thuoc D K 1 = He so phan ly cua thuoc D (Lipid/ nc) S = Dien tch cua mang E = Be day cua mang

C 2 > C1 Mang te bao cha nhieu lipide. Thuoc khuech tan qua mang rat phu thuoc vao tnh hoa tan trong lipide cua no va he so phan ly lipide/ nc. Tnh hoa tan trong lipide cua thuoc phu thuoc vao o ion hoa cua D, ma o ion hoa cua D lai phu thuoc vao pH cua moi trng va hang so phan ly cua D. Cac chat khong ien ly : khong ion hoa trong moi trng, de tan trong lipide, thuoc khuech tan t le vi khuyng o nong o va o tan trong lipide.

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Cac chat ien ly manh (ion hoa moi pH) : Chat muoi cua cac acide manh va base manh rat tan trong nc, rat kho xuyen mang (CaCl 2 , MgSO 4 , NH + 4 , Neomycine SO 4 , Streptomycine SO 4 ) Cac chat ien ly yeu : La cac acide va base hu c t nhieu ion hoa trong moi trng: phan ion hoa [Ci] se tan trong nc, phan khong ion hoa [Cni] se tan trong lipide. T le ion hoa theo pH cua moi trng va theo hang so phan ly cua acide hay base yeu. Phng trnh Henderson Hasselbalch xac nh: - oi vi acide yeu : AH A + H +

[A ][ .H ] =K
+

Ci = [A ] = Nong o phan ion hoa C ni = [AH ] = Nong o phan khong ion hoa K A = Hang so phan ly cua acide yeu Khi [A ] = [AH ] pK A = pH pK A = pH + log
Cni Ci

[AH ]

Ngha la, khi acide yeu t ion hoa trong moi trng pH acides se c hap thu nhieu hn. - oi vi base yeu : BH + B + H + pK B = pH + log

[B ][H ] = K
+

[BH ]

Ci Cin

Ngha la, khi cac base yeu t ion hoa trong moi trng pH base se c hap thu nhieu hn. Anh hng cua he so phan ly lipide/ nc (K 1 trong cong thc Fick). Do hang so phan ly (K A hay K B ) co nh, yeu to K A khong oi, nen o tan trong lipide tr nen quan trong. Neu K 1 bang vo nh thuoc tan hoan trong lipide, se khong vao c pha nc trong c the, th khong c hap thu (Vaseline). Ngc lai, thuoc (cac phan t cua D) hoan toan tan het trong nc, cung se nh vay. Cho nen gia tnh tan trong lipide va tnh tan trong nc phai c can bang. Mot thuoc tot phai la thuoc va hoa tan c trong lipide va tan c trong nc. Khuech tan gian d (diffusion facilitee)
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S xuyen mang te bao cua thuoc qua trung gian cua chat tai theo khuynh o nong o ma khong can en nang lng. V du : S hap thu Ca 2+ ta trang, s xuyen vao au tan cung si cholineergic cua choline, cung nh s hap thu tetracyclines, pralidoxime, hexamethonium. Chuyen ch thu ong (transport actif) Mot chat khong tan trong te bao, nhng co the xuyen mang vao trong te bao, nh tao thanh phc chat tam thi vi mot phan t dung lam chat tai (transporteur). S chuyen ch chu ong nay can nang lng (t ATP c thuy phan do ATPase) va ngc chieu vi khuynh o nong o. - Chuyen ch chu ong co 5 ac tnh : I X (C1) MANG TE BAO XP P XP II X (C2) C2 > C1

- Tnh bao hoa (so chat tai co nh). - Tnh chuyen biet (theo cau truc hoa hoc). - Tnh co the b c che (neu thuoc va chat tai gan ket khong thuan nghch). - Tnh co the b giam chat tai (neu co hai loai phan t cung canh tranh mot chat tai) - Co gia tr oi vi cac phan t sinh ly hoac thuoc can (Penicilline, acide amines, Vitamines K, Na + , glucose), va nhng cau truc hoa hoc tng t (base hu c Purine va Pyrimidine). Loc : La phng thc xuyen mang cua nhng phan t tan trong nc qua lo cua mang te bao (khong co he than kinh trung ng). Nh vay kch thc cua cac phan t xuyen mang nay phai nho (<150) va phai co o doc (tham thau, ien) nao o hai ben mang. Am bao (ponocytose) : La s tham nhap vao ben trong mang te bao (invanigation) cua mot boc cha chat long, t moi trng ben ngoai vao bao tng. Nhng thuoc co lng phan t > 1000 (a so la polipeptides) tham nhap vao noi bao bang cach nay Xuat bao (Exocytose) : la hien tng te bao phong thch ra ngoai nhng chat noi sinh tch luy trong boc (Acetylcholine, Catecholamines). 3.3. HAP THU T NG RUOT (VOIE ENTERALE)
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DA DAY pH cua da day vao khoang 1-3,5 Nhng chat tan trong lipide, se c khuech tan thu ong qua niem mac da day. Nhng chat ien ly manh (rat phan ly), thc te khong c hap thu. Nhng chat ien ly yeu : acide yeu : c hap thu tot tren ly thuyet. V du :
Cni Ci Cni Ci = 8,4) ( pH = 1,4 Cni = 10 7 Ci rat t c hap

Aspirine (pK A = 3) pK A = pH + log

C ni = 100C i 3 = 1 + log

Base quinin (pK B thu

Nhng chat ien ly rat yeu : Hau nh khong ion hoa, du pH cua moi trng ra sao (cafeine, barbiturates). Le ra nhng chat nay, c hap thu nhieu hn, nhng do s khong tan trong nc cua dang ion hoa, nen se co phan nho khong c khuech tan co the gay nen phan ng phu (Digoxine tren ng tieu hoa). Nhng yeu to anh hng en mc o hap thu : - Da day trong, (1- 1/2 gi trc khi an hoac 2 gi sau o) se hap thu tot hn v khong b thc an can tr. - Thc an la chat beo, tat nhien de dang hap thu nhng thuoc tan trong lipide. (griseofulvine, vitamine K ). Khoi lng thc an cung lam cham s hap thu thuoc, v se phai keo dai thi gian ay thc an xuong ruot. - Nhng chat co kch ng da day, cung nh nhng thuoc gay dan mach, co the lam cham hoac lam tang s hap thu. - Kiem hoa cac chat trong da day, se lam giam hap thu cac chat toan yeu (aspirine), nhng lai lam tang hap thu cac chat kiem yeu. Nhng noi chung, do han hep cua niem mac da day, nen mc o hap thu da day co han che. RUOT Nhng ac tnh cua ruot - S phan phoi day ac cac mach mau cung nh dien tch mao mach ruot rat rong, nen se hap thu thuoc tot hn da day. - pH long ruot cao hn (pH 6 7), nhng pH mao mach hi acide (pH = 5,3-5,5), nhng acide co pK a > 3 va nhng base co pK B < 7,8 c hap thu tot ruot non. S hap thu thay oi tng oan ruot.
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- Ta trang (doudenum) : Ca 2+ , Fe. - hong trang (jejunum) : lipide (de hap thu bi muoi mat tao thanh dang micelles, xuyen qua bieu mo bang c the am bao). - Hoi trang (Ileon) : Hap thu thu ong Ca 2+ , vitamine B 12 (nh yeu to noi tai) - Ket trang (colon) : Thc te khong hap thu, tr H 2 O va Na + (chuyen ch chu ong) Ca 2+ , Cl va K + (khuech tan thu ong). Nhng c che hap thu ruot - Khuech tan thu ong : cac chat tan trong lipide, nh vitamine tan trong dau, (A, D, E, K) va cac ion Ca 2+ , Cl va K + ( hong trang). - Chuyen ch chu ong : a so cac glucides, acide amine, vitamine B1, H 2 O, Na + , Ca 2+ ta trang Nhng nhan to anh hng en hap thu. - Mot so chat can tr s hap thu (Ca 2+ va tetracylines tao nen phc hp kho hap thu) - Cung co mot so chat tao de dang cho ruot hap thu cac chat khac (Vitamine B 12 gan ket vi yeu to noi tai cua da day, nen hap thu Ca 2+ da day > hong trang). - Vitamine D giup c the hap thu Calcium tot hn. Nhng thuoc luon luon c hap thu : Sulfamides, digitoxine, aspirine, benzodiazepine. Nhng thuoc luc nao cung t c hap thu : Aminosides. (Streptomycine, Neomycine, Kanamycine) va cac muoi NH 4 (Neostigmine) Nhng thuoc c hap thu mot phan roi thay oi : Cac Penicilline, mot so glucoside, digitaques. Li va bat li cua cach cho thuoc qua ng uong Li iem : - Cach cho thuoc qua ng uong, (per os) se cho thuoc vao ng tieu hoa mot cach chac chan, vi ieu kien thuoc c tieu hoa thc s. - De ap dung va de c benh nhan chap nhan chap nhan. - Kinh te nhat - t nguy hiem nhat, neu l co qua lieu, co the lay ra bang cach cho oi hoac suc ra da day. Bat li: - Khong thch hp cho nhng thuoc co mui v kho chu, nhng thuoc kch ng hay de bi phan huy bi dch v (polypeptides insuline), hoac
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nhng thuc khong ben vng trong moi trng pH acide cua da day (penicilline G) - Kho x dung cho tre em, v cac chau khong chu nuot - Khong dung cho benh nhan hon me. Mc o hap thu khong ong eu v : - Toc o tang khi da day rong - Nhu ong ruot - Tuan hoan mau trong ong tieu hoa thay oi, khi lo lang. - Khong tiet dch do benh ly (Mat) - ac tnh cua ta dc, toc o tan, thi gian phan ra (Desintegration) Cac dang bao che cua thuoc qua ng uong - Dang ac : Thuoc phai c phong thch va hoa tan trong ong tieu hoa di nhng hnh thc thuoc goi (Cachet), vien nang (gelule), vien nhong (capsules), vien tron (pilule), hat nho (granule), vien nen (comprime), vien boc ng (dragee). - Lp ao boc vien thuoc, c ieu chnh sau cho en c ni can mi tan ra. Ta dc phai thch hp cho bao hanh, giup de hap thu, giam bt kch ng niem mac da day va ruot non. - Dang long : Hoat chat c hoa tan hay treo l lng trong dung moi : sirop, potion, dung dch treo (suspension), nhu tng (emulsion) hay dung dch trong ru (ru thuoc quinquina) - Dang co tac dung dai : e tranh phien phc phai dung thuoc nhieu lan trong ngay, mot so thuoc c : - Bao che di dang vien nen hay boc ng, co nhieu lp theo o, hoat tnh c phong ra dan dan. Can lu y dang nay, neu c hap thu qua nhanh se co nguy c trung oc. Neu c hap thu qua cham se khong at hieu qua. Ngoai ra con co nhng khac biet ca nhan ve o lam trong da day, co khi benh nhan uong thuoc, c tong ra nguyen trang. - Thuoc c nghien cu mc o phan t, e at c tnh thai tr cham nh doxycycline, flagentil. 3.4. HAP THU THUOC THEO NG NGOAI RUOT VA TIEM CHCH Tiem di da (Voie sous cutanee SC) - Nhng thuoc khuech tan trong chat nen c ban, tham c vao noi mac cua mach mau va mach bach huyet (loc qua khe h gia cac te bao noi mac; s hoa nhap, khuech tan) c dung e tiem di da. Trong trng hp b choang, tuan hoan ngoai vi suy giam, tiem di da se khong co hieu qua. Neu kem theo mot chat co mach vao dung dch tiem di da
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(thuoc gay te loai tiem), hoac mot dung dch treo dung e tiem chch nh. Hon hp insuline + protamine + zine th hap thu thuoc se cham lai. - Ni tiem chch di da thng mat sau canh tay hay mat ngoai ui. Tiem bap (Voi intramusculaire) C bap co nhieu mach mau va co rat t si than kinh cam giac, nen toc o hap thu thuoc nhanh hn va t au hn tiem di da. - Sau khi tiem bap, ch can 10-30 phut, cac phan t nho cua thuoc co the xuyen thang vao mao mach, con cac phan t ln se chui qua cac mach hach huyet i vao mau. - Do tiem bap y au hn tiem di da (tr tiem penicilline, quinine) nen tranh tiem nhng chat lang ong (depot), cung nh nhng chat gay hoai t (nh dung dch mang tnh kiem) vao bap tht. - Ni tiem bap , thng vung mong, 1/3 ngoai t gai chau trc tren en au lan mong. Tranh chch trung than kinh toa (sciaiique) - am bao vo trung va khong c tiem trung mach mau (keo piston ong tiem len coi co mau hay khong?) Tiem tnh mach (Voie intraveineuse) Tiem thang vao tnh mach, thuoc trc tiep vao tuan hoan, nen van e hap thu t at ra ay Li iem: - Hieu ng tc th, dung trong trng hp khan cap. - Hieu ng co the kiem soat c, neu thay co phan ng xau, co the ngng tiem ngay. Mat khac, bang cach tiem truyen nho giot tnh mach (perfusion) cham va lien tuc, e duy tr nong o hu hieu cua thuoc trong mau mot cach lau dai. - Apo dung cho nhng chat thuoc gay kch ng, hoai t cac mo, gay au, neu tiem di da hay tiem bap (mot so thuoc khang sinh v..v) Bat li : - Nguy hiem, tiem tnh mach, thuoc en thang tim va cac trung khu than kinh, nhanh chong kch ng hoac c che cac ni o. ieu o can he en toc o tiem va nong o cua thuoc. - Phan ng phan ve xay ra nang ne hn neu tiem vao ng tnh mach - Co kha nang gay sot, do dung dch tiem co sinh nhiet to nguon goc vi trung - Nhieu kha nang gay nhiem (AID, viem gan) Ni tiem : Tnh mach nep khuyu tay: tnh mach hien ngoai (tiem truyen lau) Nhng qui nh tiem tnh mach :
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- at kim nam gia long tnh mach, du vay thuoc van co the kch ng mo mach mau, nh thiopental. - Khong c tiem vao ong mach, thay v tiem tnh mach (nguy c hoai t) - Tiem rat cham, nh rang thi gian tiem tren mot phut, la thi gian can cho mot chu ky cua tuan hoan mau. Cho du ngng tiem tnh mach khuyu tay, thuoc van tiep tuc en nao trong 10 15 giay tiep theo. Nhng ng ngoai ruot khac - Tiem ong mach (Intra arterielle IA): Rat t x dung, neu can trong cac trng hp sau. - Cac chat gian mach, tiem vao ong mach ui benh nhan viem ong mach - Chat can quang X vao ong mach chu, ong mach canh. - Hoa tr cho benh nhan ung th (K) - Tiem trong tim (Intra cardiaque) : Cho cac trng hp tuyet vong (adrenaline) - Tiem vao cot song (Intra archidienne IR) : Tuan hoan nao tuy rat yeu, cac dch c tiem vao o, khuech tan rat cham. Tiem thuoc gay te vao cot song, nham gii hai vung te chi di va vung ho chau - Di mang nhen (sous arachnoidien, SA) con c goi la tiem trong ong tuy (intra thecal). - Ngoai mang cng (epidural). - Ngoai thuoc te ra, co the tiem glucocorticoides vao dch nao tuy, nhng phai tranh dung nhng dung dch kiem hoac acid v chung co the gay thng ton nao vnh vien. - Nhng thuoc co oc tnh cho mo than kinh, ch c tiem trong nhng trng hp vo vong (penicilline, streptomycine). Li va hai cua cac thuoc tiem chch Li iem : - Cho phep ieu tr nhng thuoc khong hap thu hoac de b huy, de kch ng, neu cho qua ng tieu hoa - am bao tac ong nhanh, hau nh tc th (IV). Bat li : - Gay kch ng tai cho (apxe, viem tac tnh mach, tiem cham vao day than kinh). - Nguy hiem do phan ng toan than ( nhat la khi tiem IV). - Khong the rut thuoc ra khoi c the neu x dung qua lieu. - Chuan b dung cu vo trung tuyet oi.
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- Gia thuoc tiem at hn thuoc uong - Tiem IM va SC co the cho y ta thc hien, con cac cach tiem khac phai do bac s lam. Nhng dang thuoc tiem: - Dung dch, trong o dung moi a so la nc cat cho nhng chat co the hoa tan trong nc, - Dung moi la nhng chat hu c, cho cac chat khong trong nc (alcoole, glycol). - Dung moi phai tng hp vi mau, khong kch ng mo di da hay c, dung dch tiem the tch ln, cang ang trng vi huyet tng cang tot. - Ong tiem co the tch 1 5 ml - Chai thuy tinh hay chat deo (125 ml 1000 ml), kem theo day truyen vo trung tuyet oi (IR, IV) 3.5. HAP THU THUOC QUA TIEP XUC VI NIEM MAC. Trc trang Li iem : - Khong bien oi thuoc bi cac enzyme tieu hoa. - Nong o cao ni tiep xuc, hap thu tot, tao hieu ng manh - Tre em b oi co the x dung c. - Ap dung cho nhng thuoc co mui v kho chu Bat li : - Khong ap dung c cho benh nhan b tieu chay. - Hap thu khong on nh oi vi thuoc khang sinh Dang thuoc : Thuoc an (Suppositoire). Nc thuc ra hau mon (Lavement). Mieng, li - Niem mac khong co lp sng, cac nhu li phan bo mach mau day ac, am bao s hap thu nhanh. - Di li (voie perlinguale) : Thuoc trc tiep vao tuan hoan, khong qua gan nh thuoc uong, nen hieu ng nhanh. - Dang thuoc : Vien nen dung e ngam (glossettes, tablettes) tren li. Dung dch nc hay alcool, nhu di li. Phe nang Niem mac phe nang co dien tch rat ln (80 100 m 2 ) , co he thong mach mau rat day, de hap thu cac chat: - Hi (Vapeur) nh ether, chloroforme - Kh (gaz) nh protoxyde dazote, halothane.

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- Kh dung (aerosol) : la nhng phu sng cua nhng hat co kch thc rat nho (0,3 3 m) nh cac kh dung cha chat adrenergiques. - Khoi (thuoc la, can sa, thuoc phien, bui Nhng chat c hap thu trc tiep vao mau, co the tac ong tai cho, hay toan than, khoi phai qua gan. 3.6. HAP THU QUA TAC DUNG TAI CHO (VOIE LOCALE) Nhng thuoc c x dung theo cach nay, nham ieu tr nhng benh tai cho. Thuoc khong can vao mau, nhng oi khi van co the gay phan ng toan than hoac phan ng khong mong muon, neu x dung tren dien kha rong. Da b - Nhng chat tan trong nc, khong hap thu c qua bieu b. - Nhng chat tan trong lipide, c hap thu qua nang long va tuyen ba, nhn (v ch co mot lp te bao khong keratine hoa). - Moi chat hoa hoc tiep xuc vi da, eu co kha nang gay nhay cam (Sensibilisant). - Nhng chat co the c da b hap thu nh alcaloides, base, steroique (oestrogene, corticoides, vitamines tan trong dau) Dang thuoc : Pommades, cremes, dc lam bang hai loai ta dc: - Ta dc kem tham, nh m heo, lanoline, vaseline, danh cho ieu tr tai cho. - Ta dc tham manh nh : stearate de glycol, polyoxyethylene glycol (PEG) rat de tham va mau, can trong khi dung (cortisone). Niem mac Mat - Thuoc te (dung e khao sat hoac e mo), thuoc chong nhiem trung, chong viem, chong tang giam nhan ap (Glaucome), co the cho tiep xuc tai mat, s hap thu thuoc qua lieu tai ay, cung co the gay tai bien (atropine, anti-cholinesterase khong thuan nghch). - Dang thuoc : thuoc nc hoac crem, dung e nho , tra mat, pH va ta dc phai nghien cu, kiem tra ky, sao cho khong kch ng mat. Tiet nieu sinh duc : Thuoc thuc ra bong ai b chan thng (khang sinh, thuoc kh trung) cung co nguy c tham vao mau. Thuoc at am ao (vien nen, noan dc nh polygynax )

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Mang phoi khp : Tiem thuoc vao mang phoi va khp (injection intrapleurale & intra articulaire) can vo trung tuyet oi, nhat la tiem corticoides vao khp. IV. S PHAN PHOI THUOC VAO C THE Sau khi c hap thu vao mau, thuoc c phan phoi en cac mo. Qua trnh phan phoi nay c chia ra lam hai giai oan : huyet tng va mo. 4.1. Giai oan huyet tng : Pha nc chiem 58% the trong cua mot ngi ln bnh thng (tre em 77%, ngi gia < 58%). Pha nc gom nc cua huyet tng (40%), nc cua dch ke (13%), nc cua te bao (41%). Nh pha nc ma thuoc nhanh chong hoa nhap vao mau va c a i khap ni (trong 1 phut thuoc a tham c vao tuan hoan mau va pha loang ong eu trong toan bo the tch mau).
Te bao m (20%)

Nc cua huyet tng (4%)

Nc cua dch ke (13%)

Nc cua te bao (41%)

Proteine cua huyet tng (albumine)

Protein cua mo

Trong mau thuoc di 2 dang : dang t do va dang gan ket vi proteine trong huyet tng. Nhng ac tnh cua noi gan ket - Thuoc co the gan ket vi mot hoac nhieu loai proteine trong huyet tng nh albumine, 1 - globuline, - globuline va lipoproteine (phu). - Moi noi gia thuoc va proteine co tnh thuan nghch. Ngha la s noi ket nay se phan ly, tra lai dang t do, khi nong o cua thuoc dang t do trong mau giam.
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- Ty le gan ket tuy thuoc 2 thong so: Proteine/mau (nhat la albumine) : v du ty le gan ket se b giam trong cac hoi chng than, x gan ( trong suy gan a en giam tong hp proteine). ac tnh cua thuoc : t le gan ket se tang khi o hoa tan trong lipide cua thuoc tang (digitaline 90%, digoxine 25%) va khi ai tnh cua thuoc tang th ty le gan ket cung tang. Tom lc lai : Nhng phan t a lipide va nhng base yeu gan ket vi 1 -globuline co tnh acide : thuoc giam au trung ng, thuoc chong co giat, thuoc chong tram cam, thuoc phong toa ( -bloquants), phenothiazine, digitalis, rifamycine co nh vi mot ai tnh yeu, tren nhieu v tr (sites) va khong bao hoa, se khong co s tng tac gia cac thuoc. - Nhng thuoc la acide yeu thng gan ket vao albumine thuoc chong ong mau loai uong, thuoc khang viem khong steroides, sulfamides, benzodiazepine, mot so penicilline, tetracycline, probenecide, acide nalidixique chung co ai tnh manh va co nh tren nhng v tr t hn, ieu o dan en bao hoa va co tng tac canh tranh gia cac thuoc. - Noi ket thuan nghch nh nhng c che t nang lng, v du nh noi tnh ien, noi ion, noi hydrogene, noi k nc (hydrophobie)(khong bao gi co noi cong hoa tr). Ket qua cua gan ket - Ch co dang thuoc t do la hoat ong, mot thuoc gan ket manh, tao nen tac ong dc ly keo dai - Gan ket tao ra mot dang d tr, ung ra la mot dang thuoc co tac dung cham (retard). - Khi au vec ieu tr, nhng lieu thuoc au tien b noi manh va vo hoat, nhng lieu tiep theo (dose de charge) se cco li e bao hoa ni co nh cua thuoc. Thuoc trong mau Dang gan ket R Thuoc (dang t do) Enzymes Dang t do Hieu ng Chuyen hoa

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Proteine tiep nhan

Dang d tr

- Co hien tng canh tranh gia cac chat tren cung mot moi noi, ieu o co the gay tai bien : thuoc chong ong mau loai uong (anti-vitamine K) dang gan ket 95%, dang t do 5%, neu b aspirine hoac phenylbutazone canh tranh, du ch b thay the 5%, nhng se tang gap oi tac dung dc ly, gay nguy c xuat huyet. Sulfamide ha ng huyet cung b aspirine thay the v tr gan ket, tao ra nguy c ha ng huyet, aspirine con thay the v tr gan ket cua methotrexate, lam tang oc tnh cua methotrexate. - Cung tng t nh vay, cac chat noi sinh b Sulfamide khang sinh thay the v tr gan ket tren proteine huyet tng, phong thch bilirubine t do, nen de gay vang da. - Dang gan ket vi proteine trong huyet tng rat a lipide lam tang tnh hoa tan cua thuoc. Khi cac proteine trong huyet tng a bao hoa, th nong o cua thuoc dang t do se tang len ot ngot. 4.2. GIAI OAN MO La giai oan t mau thuoc c phan phoi vao cac mo khac, tr hai mo ac biet : nao va nhau. S phan phoi nay tuy thuoc vao 3 yeu to : Ti mau vao mo phan bo mach mau Mo c ti nhieu mau, thuoc se c phan phoi en nhieu hn. Tuy mc o c ti mau, ngi ta chia cac mo c ti mau vao 3 ngan. - Ngan I : huyet tng - Ngan II : nhng c quan giau mach mau : tim, phoi, than, gan, nao, tuyen noi tiet. - Ngan III : nhng c quan t mach mau : trung bnh nh da, c, t nh xng, rang, gan, day chang va rat t nh mo m (tnh a lipide quan trong hn o ti mau trong gan ket thuoc ) II C quan nhieu mau (tim, phoi, gan, than, nao HNH TRANG 42 I Huyet tng III C quan t mau (te bao m, xng, rang, gan, sun)

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S tien trien theo thi gian cua nong o thuoc (C) trong cac ngan cua c the : ay la he thong co 3 ngan I, II, III. The tch phan phoi be mat vd (volume apparent de distribution) The tch phan phoi be mat Vd, la mot the tch tng tng. Theo o, thuoc phan phoi e cung co mot nong o bang nong o thuoc co trong huyet tng. The tich phan phoi be mat bang ty so gia tong lng thuoc co trong c the va nong o thuoc trong huyet tng cung thi iem.
Vd = Q/C p

Q = Tong lng thuoc C p = Nong o thuoc trong huyet tng (L/Kg, mg/L) So lng Q trong c the ch c biet cung luc vi nong o C p duy nhat thi iem : cuoi luc ieu tr bang cach tiem tnh mach (IV) lieu ln ( nhng thi iem khac nhau sau o, khong the tnh c, v khong the tnh ra tong lng thuoc a c chuyen hoa va thai tr). The tch phan phoi cua mot so chat co the tng ng vi : The tch cua huyet tng . Vd = 0,06 L/Kg (Heparine) Hoac the tch cua dch ngoai bao. Vd = 0,2 L/Kg (inuline, mannitol). Hoac the tch nc tong cong cua c the . Vd = 0,6 L/Kg (ethanol, phenazone, nc nang D 2 O) The tch phan phoi ln, co y ngha la thuoc co ai tnh manh oi vi mo noi chung hoac co ai tnh manh oi vi mot so mo khac chuyen biet. Ai tnh cua proteine mo oi vi thuoc moi mo, co s can bang ai tnh tng oi, gia proteine trong huyet tng va proteine cua mo oi vi thuoc. V du : digitaline tuy co ty le gan ket cao vi proteine trong huyet tng (90%), nhng van thch gan vi proteine mo c tim. Neu ai tnh cua thuoc oi vi proteine mo ai tnh cua thuoc oi vi proteine huyet tng, th thuoc se c phan phoi nhanh cho mo. Trng hp ngc lai, s phan phoi thuoc se cham va thai tr ra ngoai. Khi thuoc gan ket len proteine cua mo :
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Proteine ay co receptor cho hieu ng dc ly Proteine ay ch la ni tiep nhan (acceptor) khong cho hieu ng dc ly ma o co the la ni d tr. Proteine ay la enzymes cho d hoa thuoc

Mot so thuoc co tnh hng ti (Tropisme) ac biet oi vi mot so mo Thuoc Iode Griseofulvine Chloroquine Curares Tetracycline Phenothiazine Aminodarone Arsenic Than Da, long Hien tng tai phan phoi Hien tng tai phan phoi thuoc rat bien oi : Thiopental phan phoi rat nhanh, con lu gi thuoc lai rat cham (Thesaurismose). Ty le gan ket vi
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Hng ti cac mo Tuyen giap Mong tay, chan Khp cua benh nhan ve tac viem khp ly Tam ong than kinh c Rang, sun, khp Melamine cua mat da ve tac Ni nghien cu Dung phu Ni nghien cu ong dc

proteine trong huyet tng cua thiopental (Nesdonal, Pentothal) la 65%, dang ion hoa trong mau = 61%, nen thamvao mau, len nao, tac ong gay me rat nhanh.. sau o thuoc c tai phan phoi vao c va mo m trong vong vai phut (trong 30 phut, nao mat 90% nong o Thiopental ban au) hieu ng gay me se giam va mat han trong vong 30 phut. Luc nay, neu tiep tuc tiem Thiopental, se dan en bao hoa nao va ngo oc, v khong the tai hap thu c na. 4.3. THUOC KHUECH TAN QUA CAC HANG RAO NGAN CAN ac biet, co mot so thuoc khong qua c cac hang rao can e den nao va nhau thai. Hang rao mau nao bao gom : Cac mao quan, gom nhng te bao noi mac ghep kht ma thuoc phai vt qua (tan trong lipide, khuech tan thu ong, hay chuyen ch chu ong). Mang nen Lp te bao hnh sao co nhieu khe h Hang rao mau nao van co chuyen hoa thuoc : V du : te bao hnh sao cha DOPA, men decarboxylase o chuyen DOPA thanh Dopamine. am roi mang mach, cung co the thai tr thuoc (INH). Luc s sinh, hang rao mau nao cha hoan chnh, bilirubine t do xam nhap vao nhan xam trung ng, gay vang da nhan (Icterenucleaire) Nhng yeu to quyet nh e cho thuoc qua hang rao mau nao : o hoa tan trong lipide +++ (v nao la mo giau lipide) Lng phan t nho o ion hoa yeu trong huyet tng Moi noi long leo vi proteines Hang rao mau nao khong tham cac thuoc Gan ket vi proteine Ions Dang thuoc tan hoan toan trong nc Hau qua thuoc tham vao nao : Nhng thuoc tham vao nao nhanh la thuoc de tan trong lipide : Barbiturates, benzodiazepines, thiopental, methaqualone. Catecholamines b ion hoa pH huyet tng, khong qua c hang rao mau nao. Nhng Dopamine, nor-adrenaline va GABA (Gamma-amino-butirique-acide) lai c tong hp ngay tai nao
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(tr acide amine : phenylalamine, acide glutamique do tham t mau vao). Atropine (amine bac 3), qua c hang rao mau-nao, nen co the gay ao giac atropinique; trong luc o methyl-atropine co kha nang ion hoa hn, th khong qua c hang rao mau-nao (Buscopan). nhng tre sinh non hoac s sinh, do cau truc hang rao maunao cua cac chau cha hoan chnh, khi s dung nhng thuoc (ngay ca bilirubine na) co the qua hang rao mau-nao, gay vang da do tan huyet Trong ieu tr viem mang nao, nen chon dung nhng loai khang sinh co the qua hang rao mau-nao (Sulfamides, Chloramphenicol, Colimycine), ngay ca tiem vao tuy song (IR). Mot so tnh trang benh ly, lam cho hang rao mau-nao tr nen de tham hn (viem mang nao, cao huyet ap nang, thieu mau nao cuc bo, hon me kem theo nhiem toan acidose). Penicilline G tiem bap (IM) qua hang rao mau- nao co the gay co giat ong kinh. Aldomet qua c hang rao mau-nao, kch thch Receptor 2 trung ng gay lu lan (confusion) Clonidine kch thch Receptor 2 trung ng gay ha huyet ap, nhng neu khong qua c hang rao mau nao, chonidine se la chat kch thch Receptor 2 ngoai bien, gay co mach tang huyet ap Nhng chat phong toa ( bloquants), qua c hang rao mau nao, gay nen hien tng mong du (Onirisme)

Hang rao nhau thai (barriere foeto-placentaire) Thuoc qua nhau thai, chu yeu bang khuech tan. Thc ra ay nh mot tram trung chuyen (intermediaire de transfert), ca truc khoi soang mach mau, cho phep nhieu c che thong qua. Khuech tan thu ong cho cac chat tan trong lipide nh kh gay me (N 2 O, Halothane, Cyclopropane), thiopental Chuyen ch chu ong cho cac acide amine (histidine), ion Ca + + , Mg + + . Khuech tan gian d cho glucose.
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Am bao (huyet tng cua me) Thc bao : Khi mang thai, s tham cac chat t soang mau sang mao mach (nhng mao mach nay nhung mao cua thai va tam mnh trong soang mau), se tang len. Nhng chat tan trong nc co trong lng phan t tren 1000 (dextran), NH 4 (nh Gleamine, Neostigmine) thc te khong qua c hang rao nhau thai. Tat ca nhng thuoc qua c hang rao nhau thai, eu gay t nhieu nguy hiem cho thai nhi. ang chu y la nhng thuoc Sulfamides, tetraciclines, morphine, phenobarbitales Nhau con thieu kha nhieu men (Cholinesterase, MAO, Hydrolase ) e phan huy thuoc, nh o co phan han che, ngan chan tac ong cua thuoc len thai nhi. V. CHUYEN HOA THUOC 5.1. MUC CH CUA S CHUYEN HOA Bien nhng chat tan trong lipides, khong the thai tr trc tiep, thanh nhng chat tan c trong nc, de dang cho thai tr qua nc tieu vi mot lng nhieu nhat. (Cac thuoc kh trung nc tieu, aminosides). e cho nhng chat chuyen hoa co the hoat ong manh hn : methyl dopa > methyl nor-adrenaline (Ha huyet ap) DOPA Dopamine (chong Parkinson) Imipramine Desmethyl imipramine (chong tram cam) Phenylbutazone Oxy phenylbutazone (khang viem) Benzodiazepine Oxazepam (an than, gay ngu) Phenacetine Paracetamol (ha nhiet) Lam cho a so cac thuoc tr nen vo hoat: Chlopromazine 30 chat chuyen hoa Thalidomide 100 chat chuyen hoa 5.2.NI THC HIEN CHUYEN HOA SINH HOC : GAN : Bi cac Enzymes cua vi the (Cytochrome P450) hay enzyme cua bao tng. NAO : L-DOPA Dopamine (do DOPA Decarboxylase) ONG TIEU HOA : Bi cac enzymes : Protease, lipase, va vi trung ng ruot. HUYET THANH MAU : bi esterase
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(Proparacetamol Paracetamol; Aspirine salicylique) NHAU : THAN : Vitamine D PHOI : Prostaglandines (PG) 5.3. S O CHUYEN HOA SINH HOC :

a.

Chuyen hoa sinh hoc trai qua 2 pha : pha I va pha II PHA II PHA I Gom cac phan ng ket hp vi : Gom cac phan ng o Acide glycuronique o Oxy hoa o Kh o H 2 SO4 o Thuy phan o Acide amine o Kh carbone (C) o Methyl hoa Hap thu chuyen hoa sinh hoc Thai tr Pha I Pha II
B A Chat chuyen hoa C A B C D

Tan trong Lipide nc B : Hoat ong hay khong hoat ong C, D : Vo hoat 5.4. C CHE CHUYEN HOA SINH HOC :

Tan

trong

PHA I : Oxy hoa :la phan ng chung nhat c x dung e bien oi cac chat hu c nh Oxyd hoa : Alcool, aldehydes, nhom alkyl va Sulfidryl Hydroxy hoa cac vong Kh alkyl-oxyde hoa
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Kh halogene a so phan ng oxy hoa c cac enzymes cua vi the gan, nhat la Cytochrome P 450 xuc tac, de sinh thanh nhng dan xuat co hydroxyde (OH) V du : Phenobarbital p OH-phenobarbital. Mot cach tong quat phan ng oxy hoa do Cytochrome P 450 xay ra nh sau : HNH TRANG 50

Nhng Enzymes khac khong phai cua vi the gan V du : - MAO trong cac ti the : Oxyde hoa cac Catecholamines, ethanol aldehyde acide - Peroxidases, dehydrogenases, prostaglandine synthetase Kh : nhom nitrogene Protonsil Sulfamide Sous nitrate de bismuth dan xuat nitrite (oc oi vi tre em) Cortisone hydrocortisone Sulindac dan xuat disulfure co hoat tnh chong viem Thuy phan : Penicilline G b dch v (HCl) thuy phan Acetyl Choline b cholinesterase thuy phan Insuline, ACTH, b Protease thuy phan Kh nhom Carboxyl (-COOH) : L.DOPA, b kh carboxyl bi Dopadecarboxylase Dopamine PHA II Nhng phan ng thuoc pha II, bieu lo ac tnh rieng cua loai (espece). ngi la phan ng lien ket vi acide glycuronique, H 2 SO4 , glycine. Du vi chat nao, thuoc sau khi lien ket se tr thanh dan xuat vo hoat ve sinh ly va e tan trong nc hn, e thai tr qua than. - Ket hp vi acide glycuronique tao hp chat glycuro-hp (aspirine). - Ket hp vi acide sulfurique tao hp chat sulfo- hp (steroides)

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- Acide amines ma glycine la chu yeu, de ket hp vi acide thm va acide mach thang (acide Salicylique acide Salicylurique). - Ket hp vi acide acetique tao thanh dan xuat acetyl (acetyl hoa) vo hoat (co xuc tac cua acetyl transferase va coenzyme A) V du : Cac dan xuat cua aniline, Sulfamides, INH va aminophenazone. - Ket hp methyl hoa : Methyl hoa cac nhom -OH, -SH, -NH, -NH 2 cua thuoc. V du : Nor-adrenaline Metha-nor-adrenaline (COMT = Catechol-O-methyl-transferase) Tom lai : Tat ca cac phan ng chuyen hoa thuoc, co u moi ac tnh cua nhng phan ng enzymes : - Chuyen biet : Nhieu tieu loai cua cytochrome P 450 , tng ng vi cac c chat khac nhau. - De bao hoa : trong cac trng hp qua lieu, luon luon co s bao hoa, tuy nhien oi khi cung co tnh trang bao hoa trong ieu tr (Phenytoine, Verapamil), do s chuyen hoa le thuoc vao lieu thuoc. Trng hp nay ch tang mot lieu thuoc nho cung se lam tang nong o rat ln cua thuoc ay. 5.5.NHNG YEU TO ANH HNG TOC O CHUYEN HOA Loai ong vat Co s khac nhau ve toc o chuyen hoa gia con ngi va thu vat nen thi gian tac ong cua thuoc cung khac nhau gia chung. V du : Cung mot lieu Pethidine, ngi hieu ng duy tr t 3- 4 gi, nhng cho ngan hn. Pethidine, moi gi, khoang 20% c chuyen hoa trong c the con ngi, nhng cho co e 90% Tuoi tre s sinh va sinh non : cha u enzymes e xuc tac phan ng ket hp. Nen bilirubine t do khong ket hp u vi cac acide glycuronique nen gay vang da, chloramphenicol cung vay, nong o chloramphenicol t do khong ket hp u. Do chc nang nay cua cac chau cha hoan b, nen rat de gay ngo oc ngi gia ca : thng do anh hng cua suy chc nang Gan-Than.
COMT

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Phai tnh t b anh hng, nhng khi co mang thai, s ket hp vi acide glycuronique b giam Di truyen mot so ngi do di truyen gene, nen toc o chuyen hoa thuoc co the nhanh hoac cham. V du : Mot so ngi, c cho cholinesteraes khong ien hnh vao huyet tng, thay co hien tng thuy phan suxamethonium cham hn cholinesterase bnh thng Mot so ngi acetyl hoa INH cham, nguy c tch luy thuoc ln, se gay nguy hiem. Trong luc o co mot so ngi acetyl hoa INH lai rat nhanh, nen hieu ng mat nhanh. Can xem xet ieu chnh lieu thuoc cho 2 loai ngi ke tren. Co hai nhom ngi hydroxyl hoa nhanh va cham oi vi mot so thuoc t nh debrisoquine, mephenytoine, perhexilline. Tnh trang bnh ly Benh ly cung lam bien oi hoat tnh enzymes cua gan, hoac huy te bao gan, nen lam giam toc o chuyen hoa thuoc. Cam ng enzymes Cam ng enzymes (Indution enzymatique) lien quan en loai Isoenzyme cuacytochrome P 450 . S cam ng nay can co thi gian tiep xuc vi thuoc. e bao hoa hoac cho phan ng thuan nghch khi ngng thuoc. Co 2 loai cam ng : - T cam ng (auto induction) : Thuoc kch thch chuyen hoa cua chnh no. Nen can tang dan lieu lng (chlor-promazine, meprobamte, phenobarbital, tolbutamide, chlordiazepoxide, dyphenylhyd-antoine, warfarine) - D cam ng (hetero-induction) : Thuoc kch thch s chuyen hoa cua thuoc khac. Can tang dan lieu lng cua thuoc khac o (rifamycine, thuoc nga thai loai uong, phenobarbital, diphenylhyd-antoine, griseofulvine thng gay cam ng vi thuoc khac). Thuoc la va ru dung lau ngay, cung la chat gay cam ng enzymes c che enzymes

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Ngc lai hien tng cam ng, c che enzymes lam tang ban huy t 1 / 2 va tao nguy c tch luy thuoc. V du : Nhng c che enzymes nh : T.A.O, IMAO, cimetidine, Allopurinol. S canh tranh de vo hoat hoa cua hai thuoc tren cung mot he enzymes V du : Methanol Dehydrogenase Ethanol Nen co the cho ethanol e giai oc methanol. Acetaldehyde Formol oc

5.6. TAM QUAN TRONG CUA CHUYEN HOA THUOC TRONG IEU TR Quyet nh ng cho thuoc vao c the : V du : Nhng thuoc b dch v pha huy, hoac phai chu s chuyen hoa khi qua gan (propranolol, isoprenaline, trinitrine ) co the chon ng a thuoc khac, con neu uong co the tang lieu. Quyet nh lieu lng: Toc o chuyen hoa thanh chat vo hoat nhanh hay cham, la can c tham khao e quyet nh lieu lng, so lan cho thuoc moi ngay, hoac lu lng tiem truyen tnh mach. Thay oi chuyen hoa cua mot thuoc, bang cach cho mot thuoc khac trc, hay ong thi vi thuoc ay, e gay ra s tang cng hay oi khang thuoc. VI. THAI TR THUOC Ch co thuoc trong huyet tng (ngan mach mau) c thanh thai khi i qua mot c quan (gan than). 6.1. THAI TR THAN : Than thai tr thuoc bang 3 c che sau : loc cau than, bai tiet chu ong ong than va tai hap thu thu ong ong than Loc cau than :

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- Phan t co kch thc 8 mm, nhng phan t gan ket vi proteine huyet tng va nhng phan t thuoc qua ln khong the qua than bang c che loc,(co the qua bang khuech tan thu ong). - Mot so chat khong c tai hap thu, cung khong c thai tr nh inuline, mannitol (ngoai sinh) va Creatinine (noi sinh), c dung e nh lng he so thanh thai cua cau than (130 ml/phut). Bai tiet chu ong ong than : - Nh cac he thong chuyen ch, ong than co the bai tiet mot so chat nh penicilline G va mot so Cephalosporines. Nhng s bai tiet nayb c che bi probenecide, nen lam giam thai cac chat tren Tai hap thu thu ong ong than : - Thng cac he thong chuyen ch theo hai chieu : thai ra long ong than va tai hap thu chu ong tr vao (acide urique). Dang thuoc khong ion hoa c tai hap thu ong than gan va xa bi c che khuech tan thu ong , t le vi o tan trong lipides cua dang khong ion hoa, co tuy thuoc vao pH cua nc tieu. V du : No oc Barbiturates ieu tr bang NaHNO 3 , kiem hoa nc tieu, tang thai tr (aspirine cung vay v mang tnh acide) Ngo oc Amphetamine, co the acide hoa nc tieu bang NH 4 Cl e tang thai tr Hau qua tong quat : - Mot thuoc, noi chung co the chu nhieu tac ong thai tr. Thuoc co the tng tac vi cac chat noi sinh than. V du : aspirine, phenylbutazone, thuoc li tieu thiazides lieu thap ngan chan ong than bai tiet acide urique, gay cn goutte. Nhng lieu cao lai ngan chan ong than tai hap thu acide urique, a en tnh trang tieu tien ra acide urique (effet uricosuriqua) kem theo cn au quan than do soi urate. - Thuoc co the tng tac vi cac chat khac na. V du : Probenecide lam cham bai thai Pennicilline qua ng nieu va furosemide lam cham bai thai lithium. - suy than kem theo tch luy thuoc, oc tnh thuoc co nguy c tang cao. Vay viec chon lieu thuoc sao cho benh nhan thch nghi vi he so thanh thai creatinine. - Co hai kha nang : Giam lieu, gi ung khoang cach gia cac lan cho thuoc.

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Khong giam lieu ma keo dai khoang cach gia cac lan cho thuoc 6.2. THAI TR NGOAI THAN Mat: - Thuoc c thu hoi ve gan va bai tiet qua mat. S chuyen ong o theo c che chuyen ch chu ong. - Nhng chat c bai thai qua mat chnh , gom : Digitaline, rifampine, ampicilline, acide mat, cholesterol, d-tubocurarine. - Mot so thuoc phai qua cchu trnh ruot-gan, se keo dai them thi gian nan lai trong c the nh : digitaline, morphine, chloramphenicol. He qua : - e ieu tr nhiem trung ng mat, ngi ta chon dung nhng loai khang sinh bai thai qua mat : ampicilline, tetracycline, mot so sulfamides va rifampicine. - Novobiocine canh tranh vibilirubine e c chuyen ch chu ong t mau vao gan, bilirubine t do tang, gay vang da. - Neu b tat ng dan mat, nhng thuoc bai thai qua mat se lai, co the gay oc (rifampicine). Tuyen nc bot : Spirammycine, morphine, alcaloides khac, kim loai nang (Hg, Bi) va amphetamine, la nhng thuoc c bai thai qua tuyen nc bot, nen thng gay sng nu rang (hypertropie gingivale). - e li dung iem nay, ngi ta truy tm dau vet cua cac chat kch thch (doping), (cung nh morphine strychnine) v doping tiet ra t tuyen nc bot - Nen dung spiramycine trong ieu tr viem hong Phan : Cac thuoc khang sinh va sulfamide cho qua ng ruot (Neomycine, ganidan), cung nh nhng chat bai thai qua mat ma khong c tai hap thu qua ong tieu hoa, eu c bai thai qua phan. Sa me : Hau het cac thuoc eu khuech tan trong sa me. Mo hoi : Iodura, bromure, ch, arsenic, thuy ngan, quinine, mot so khang sinh, sulfamides, c thai tr theo mo hoi. Phoi : Chat kh, dung dch boc hi, nhat la cac chat gay me va ru, bai thai qua phoi. V du : ru, eucalyptol, camphre (tinh dau) halothane N 2 O v..v. 6.3. S CO NH LAU DAI CUA MOT SO THUOC TRONG C THE (Pharmaco-thesaveis-mose)

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Cac muoi vang, polyvinylpyrolidone tren he vong mo. Arsenic tren da va long. Iode va cac dan xuat co Iode tren tuyen giap. Tetracyclines tren xng va rang ang hnh thanh Chat diet con trung (DDT) tren mo m Methotrexate tren gan. Muoi Ca 2+ tren than (hoi chng Burnet) Phenytoine tren than kinh trung ng VII. NHNG THONG SO DC ONG HOC. Nhng thong so d ong hoc, c tnh toan t nhng nong o thuoc co trong huyet tng va nc tieu. No giup ta ieu chnh c lng (Posologie) cho oi vi tng benh trang cua benh nhan. 7.1. CHO MOT LIEU THUOC TIEM NHANH QUA NG TNH MACH (IV) Thuoc phan phoi trong mot ngan trung ng : Mau

C = Ctp e ket
t
o

log C

t p

= log C

to o ( ke t ) p

- C tp = (thuoc)/huyet tng thi iem t - Ct


o o

= (thuoc)/ huyet tng thi iem t o (ngay sau khi tiem tnh

mach). - k e = Hang so thai tr

- e = He so ly trch thuoc

Log C tp 100 50 10 AUC 1 t1 2

+ thi iem t = t 1 2 + ke =
0,693 t1 2 t1 2 = 0,693 ke

log2 = ke t 1 2

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+ t1 2 la thi gian ban huy trong huyet tng : o la thi gian Cp t o


1 giam i a en C 1 2 ng vi t 2

+ Thuoc phan phoi trong hai ngan (trung ng va ngoai bien.

t p

= A e t + B e

+ A = (Thuoc)/huyet tng, ban dau cua pha phan phoi. + B = (thuoc)/ huyet tng, ban au cua pha thai tr. + = o doc ng vi pha phan phoi + = o doc ng vi pha thai tr. Moi pha ng vi : Thi gian ban huy ng vi pha phan phoi Thi gian ban huy ng vi pha thai tr Ch co ban huy cua pha thai tr c bieu dien bang t 1 2 v thi gain ban huy cua phan phoi a co thai tr. 7.2. CHO MOT LIEU DUY NHAT QUA NG MIENG: Thuoc t ong tieu hoa c hap thu vao mau : van toc hap thu > van t toc thai tr c p tang dan c e at en nong o nh trong huyet tng (Cmax). Luc nay van toc hap thu = van toc thai tr va sau o, van toc thai t tr > van toc hap thu c p giam dan d - SSC Surface sous la courbe = AUC. Tch phan nong o thuoc trong huyet tng t 0 vo cc.

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7.3. THE TCH PHAN PHOI BE MAT (VD) : Vd la the tch ly thuyet tng tng, trong o mot lng (Q) cua mot thuoc phan tan ong nhat va co nong o bang nong o thuoc o trong huyet tng cung mot thi iem Vd =
Qt Ct

Khi tiem nhanh vao tnh mach mot lng thuoc Q roi o nong o thuoc trong huyet tng nhieu lan nhng thi iem khac nhau se ve c ng bieu dien Cp theo thi gian L.

- Co ng vi t = 0 1 -C1 2 ng vi t 2 - Co nong o nh toi a, ngay sau khi tiem vao tnh mach (IV) mot lng Qo
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The tch phan phoi thi iem t = 0 Vd =

Vd nho hn (~ 6L) th nong o thuoc ch quanh quan trong huyet tng. Vd ln hn (~ 6L) thuoc phan phoi en cac mo va c (thuoc)/mo > (thuoc)/ huyet tng. 7.4. HE SO THANH THAI TONG CONG (CL). CL :Tong the tch huyet tng, c thai tr ra khoi c the trong mot n v thi gian . Co 2 cong thc tnh Cl : T ng bieu hien Cp theo t : Cl = Vd Ke t 1 2 Ke Cl T dien tch di ng bieu dien AUC (SSC) theo thi gian (t) T lng thuoc Q cho vao c the e tm Cl Q CL = AUC 7.5. O KHA DUNG SINH HOC : Dien ta ong thi ve toc o va cng o cua mot hoat cha i vao trong mau. o kha dung sinh hoc tuyet oi (F1) : La t so lng thuoc co mat trong mau, sau khi c cho va c the bang ng cho uong (per os), so vi lng thuoc tng ng c tiem qua ng tnh mach (IV) F1 =
AUC uong PO AUC tiem IV

Qt Qo = Ct Co

Lieu tiem IV Lieu cho uong

Cach tnh : - So sanh hai ng bieu dien (Thuoc)/huyet tng (Cp) theo thi gian t - Tnh dien tch di ng bieu dien ( AUC) cua cung mot lng thuoc (Q) khi cho uong va tiem tnh mach Ket qua : - Thuoc trc tiep tiem vao tnh mach, o kha dung sinh hoc cua thuoc o la 100% (F1 = 1) - Thuoc cho vao c the qua ng uong, do khong hap thu hoan toan, nen o kha dung sinh hoc cua thuoc < 100% (F <1) o kha dung sinh hoc tng oi (F2) : So sanh thuoc th vi thuoc chuan (thng dang long, dung e uong), e xac nh t le gia hai AUC
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F2 =

AUC thuoc th AUC thuoc chuan

Thong so F 2 giup so sanh nhng dang bao t cua cung mot loai thuoc F2 =
AUC ( b ) AUC ( a )

(a) va (b) : nhng dang bao che khac nhau cua cung mot loai thuoc 7.6. KHI CHO THUOC NHIEU LAN : Nhng thong so dc ong hoc tren ngi sau khi cho mot lieu duy nhat. Nhng tren thc te, benh nhan c ieu tr, can lap lai nhieu lan cho thuoc Bnh nguyen : Nong o thuoc on nh (CSS) (Steady State Concentration) Khi van toc hap thu (hay van toc tiem truyen ) = van toc thai tr. Luc o nong o thuoc se bnh on trong huyet tng va bnh nguyen xuat hien. CSS =
Tong lieu a dung CL

Lu lng vao (Q/min) = Lu lng ra (Cl.Cp) Cp = Css = Q/min 1/Cl Trng hp cho thuoc nhieu lan : Css =
Tong lieu n

1 Cl

n = khoang thi gian gia cac lieu Cho thuoc qua ng ngoai mach mau. ng uong, khong lien tuc. Css = (F lieu)/n 1/Cl) (F = kha dung sinh hoc ; n = khoang thi gian gia cac lieu; Css = nong o trung bnh gia gia nhng nh o trong huyet tng sau moi lan cho thuoc ). Trc moi lan cho trc can xac nh nong o thap nhat cua lieu cho trc.

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anh gia thi gian e at c nong o bnh nguyen (Plateau) :khoang 4 -5 t 1 V du : mot lieu A co thi gian ban huy (t1/2) = 12 gi 2 va c cach 12 gi cho lieu thuoc mot lan . Sau lieu I 12 gi : [A]p = 50% [A] ban au Sau lieu II [A]p nh = 100 + 50 = 150% 12 gi sau : [A]p = 150/2 = 75% Sau lieu III [A]p nh = 100+75 = 175% 12 gi sau : [A]p = 175/2 = 87,5% Sau lieu IV [A]p nh = 100 + 87,5 = 187,5% 12 gi sau : [A]p = 187,5/2 = 93,75% Sau lieu V [A]p nh 100 + 93,75 = 193,75% 12 gi sau : [A]p = 193,75/2 = 96,87% 1 T Vt 2 tr i, nong o thuoc trong huyet tng dao ong gia 100% va 200% so vi nong o ban au. Nong o on nh trong vung bnh nguyen phu thuoc vao nong o lieu au tien, nhng thi gian e at en o, eu nh nhau (Vt 1 2 ) bat ke lieu thap hay cao. Ta co the at nhanh en nong o can bang Css bang cach cho mot lieu nap ban au : Lieu nap = 2 lieu duy tr oi vi nhng thuoc co thi gain ban huy dai (t 1 2 ), cach dung mot lieu nap abn au cho benh nhan se ton thi gian e at ti nong o can bang. 7.7. TNG QUAN GIA NONG O THUOC TRONG HUYET TNG VA HIEU QUA IEU TR : oi vi nhng thuoc co pham vi ieu tr han hep, phai o nong o thuoc huyet tng. Nhat la nhng trng hp thuoc a c x dung en lieu chuan roi ma van khong hieu qua. V du : S dung (Barbital) nong o can bang cho benh nhan b benh ong kinh ma van c tiep tuc len cn, khi xet en viec tang lieu them trong pham vi ieu tr. VIII. TNG TAC CUA THUOC 8.1. NH NGHA : Tng tac cua thuoc la s bien oi hieu ng cua mot thuoc do co mot thuoc khac hien dien trong c the. Hau qua cua tng tac thuoc co the lam tang hay giam hieu qua cua nhng thuoc c dung.

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Tng tac thuoc xay ra trong qua trnh chuyen hoa, goi la tng tac dc ong hoc. Tng tac thuoc xay ra tai mat tac ong cua thuoc goi la tng tac dc lc hoc. Hiep ong (Synergie) : Hai chat A va B co cung mot hoat tnh dc ly, nhng khac nhau ve cng o (EA>EB). Khi dung chung A va B, se cho mot hieu ng chung la Co 3 trng hp xay ra : Hiep ong cong (S.additive) : khi = EA + EB Hiep ong mot phan (S.partielle) : khi < EA + EB Hiep ong boi tang (S. potentialisatrice) : khi > EA + EB oi khang (Antagonisme) : Hai chat A va B co cung mot hoat tnh dc ly, nhng khac nhau ve cng o. Khi A va B phoi hp nhau se cho hieu ng . Co hai trng hp xay ra : oi khang hoan toan (A.totale) : = 0 oi khang mot phan (A.partiel) : EB < EA S tang cng (Potentiallisation) Khi hai chat A va B co hoat tnh dc ly khac nhau, hieu ng chung () cua A va B ln hn mot trong hai hieu ng rieng le : > EA hoac > EB 8.2. C CHE TNG TAC THUOC : Tng tac dc lc Tng tac dc lc la tng tac xay ra ngay tai ni tac ong cua thuoc : Hiep ong : Co 4 c che giai thch ve hiep ong dc lc : Bao ve hoat chat cac receptor. Tang tnh nhay cam (hoac ai tnh) cua receptor oi vi thuoc. Tang gan thuoc vao receptor Tang tac ong len cac receptor chuyen biet khac, e cho nhng hieu ng dc lc tng ong. + Thuoc tac ong tren cung 1 receptor : - Tng tac hiep ong hay oi khang, tuy theo nong o tng oi cua thuoc c cho.

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Thuoc A lieu thap, A gan len mot phan cua receptor chuyen biet. Thuoc B (hiep ong vi A) co hoat tnh noi tai thap hn, cho cung luc vi A lieu thap, se gan phan con lai cua receptor t do. Ket qua hieu ng chung () la hiep ong cong. Neu tang nong o [B], B se canh tranh chiem phan cua A tren receptor, hieu ng cua A se giam en o triet tieu. Neu B co u so lng cang tranh lan het v tr cua A. Hiep ong cong se tr thanh hiep ong tng phan va cuoi cung B tr neen oi khang vi A + Thuoc tac ong hiep ong gian tiep tren cac receptor khac nhau : - Khi thuoc B huy mot phan hieu ng cua chat oi khang. V du : Atropine phoi hp vi Adrenaline, se keo dai hieu ng tang nhp tim va tang huyet ap cua adrenaline, bang cach huy phan xa cua day X ( von lam cham nhp tim) Hai thuoc A va B tac ong nhng v tr khac nhau tren ca receptor khac, nhng eu cho cung mot hieu nh nh nhau : V du 1 : Phoi hp hai thuoc khang sinh e diet vi trung - lactamines + aminosides se at en hieu ng hp ong boi tang ( tac ong len ca 30S ribosome cua vi trung). V du 2 : Furosemide (tac ong tai nganh len cua quai Henle) - Sprironolactone (tac ong tai ong ln xa), se at en hieu ng hiep ong cong. V du 3 : Theophylline + thuoc kch thch 2 . Se cho hieu ng hiep ong cong ATP AMP vong AMP Adenylare cyclase Phosphodiesterase

Chat kch thch 2 Theophylline oi khang : hai chat oi khang co ai tnh va hoat tnh noi tai khac nhau, canh tranh thuan nghch tren cung mot loai receptor. - Khi chat oi khang chiem het cac R va co hoat tanh noi tai = 0, oi khang hoan toan xay ra - Khi chat oi khang co hoat tnh noi tai yeu, se xay ra oi khang mot phan - Khi hai chat co ai tnh khac biet va co nong o xap x nhau, se en oi khang mot phan.
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V du : Cac chat phong toa c che cac hieu ng cua Catecholamines :


Acebutol Kch thch 1 Butoxamine Kch thch 2 - Cac antihistamimmique type H 1 va H 2 phong be hieu ng cua histaminees tren receptor H 1 va H 2
adrenaline

Promethazine Kch thch H 1 Cimetidine Kch thch H 2 - Naloxone thuoc giai oc morphine co ai tnh hn vi R cua morphine nhng co hoat tnh noi tai yeu. Khi Naloxone chiem lnh receptor cua morphine, tuy co lam giam cng o hieu ng cua morphine nhng v thi gian ban huy (1/2) cua naloxone ngan, nen khi nong o naloxone giam, morphine se tai hien va chiem lai receptor cua no.
Histamine

Tng tac dc ong hoc Tng tac thuoc, dien ra cac giai oan chuyen hoa thuoc, nh nhng c che sau : Trc va trong hap thu : Tng tac thuoc xay ra rat nhieu ong tieu hoa, sau khi cho thuoc qua ng uong : Phc hp hoa (complexation) trong long ruot. + Cac tetracyclines, va cac muoi nh : + Cholestyramine hap thu nhieu thuoc va giam hoat tnh cua chung. Nhat la digitale, khang vitamine K loai uong va vitamines tan trong dau Ion hoa : tang ion hoa, se lam giam hap thu thuoc. + Nhng chat kiem hoa, lam giam hap thu cac thuoc co tnh acide yeu nh cac thuoc chong viem khong Steroides, khang vitamine K loai uong, cac Sulfamides. Thay oi thi gian tiep xuc vi niem mac ng tieu hoa : + Cac thuoc nhuan trang, lam tang van toc chuyen van qua ruot, giam hap thu thuoc, nhat la cac thuoc dang tac dung cham, dang tac dung dai. + Cac anticholinegiques (atropine, hyoscyamine) tr hoan lam chong da day, nen tang hap thu cac thuoc o + Cac thuoc che ch ng tieu hoa phu len be mat, ngan chan thuoc tiep xuc vi niem mac, lam giam tai hap thu. S bien oi cua vi trung ng ruot :
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+ Cac thuoc khang sinh dung qua ng uong, co the giam hoac bien oi vi trung ng ruot, do o bien oi tac dung cua thuoc. + V du : Bnh nhan ieu tr bang khang vitamine K loai uong, co the b xuat huyet v nhng vi trung tong hp vitamine K ruot b giam. S hien dien Lipide (dau ricin, olive) : + Se lam tang hap thu qua ang oi vi mot so thuoc (griseofulvine) S canh tranh cac chat chuyen ch cua niem mac ng tieu hoa : lam cho hang rao tiau hoa b khiem khuyet, gay tang hap thu qua ang. S thng ton nang ne niem mac tieu hoa : lam cho hang rao tieu hoa b khiem khuyet, gay tang hap thu qua ang. Lien quan en cac ng cho thuoc khac, co the xay ra : + Tng k (incompatibilites) lam ket tua hay vo hoat cac chat ngay trong vat ng tiem truyen ( Lactamine trong dung dch Glucose) + Cac chat tan trong lipide se lam tang s khuech tan qua da cua cac thuoc dung ngoai da Khi khuech tan : S khuech tan cua thuoc tiem bap (IM) se tang, neu co cho them hyaluronidase, ngc lai, s khuech tan cua thuoc te se b giam neu co mat thuoc co mach. Chuyen van trong mau : co nguy c canh tranh tai ni gan ket tren proteine cua mau nhat la albumine. Albumine la ni gan ket cua cac thuoc co tnh acide, thuoc khang vitamine K loai uong, thuoc chong viem khong Steroides, penicilline, thuoc ha ng huyet loai uong, tetracycline va Sulfamides Nhng thuoc c phong thch dang t do, ma v tr cu cua no a b thuoc khac chiem c cung lai tang cng hieu ng cua chung. Ngay trong chuyen hoa sinh hoc : Tng tac xay ra thng xuyen. Thuoc co the cam ng (induction) vi cac enzymes chuyen hoa thuoc Cytochrome P450), gia toc chuyen hoa thuoc thanh mot chat vo hoat, chat co oc tnh hoac mot chat co hoat tnh cao hn. Thuoc cung co the c che cac enzymes chuyen hoa keo da hieu ng cua thuoc khac. Thuoc A, gan chat Thuoc B, gan trung Nguy c do tng tac vao proteine bnh vao proteine (b A chiem v tr) Phenyl-butazone Acenocoumarol Xuat huyet Ph enytoine Tolbutamide Ha ng huyet Salicylates Methotrexate Tang oc tnh Methotrexate
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Chat gay cam ng enzymes Phenobarbital Phenytoine Rifampicine Griseofulvine Carbamazepine Mot so hydrocarbure co Cl Hut thuoc la kinh nien Hydrocarbure a vong gay ung th Ru

Thuoc dung chung b tng tac 1. c vo hoat nhanh hn Thuoc chong dong khang vitamine K [Estrogenest] thap, uong thuoc nga thai Digoxine Theophylline Cyclosporine 2. B bien the thanh dang : Hoat ong : Cyclophosphamide oc tnh : INH Thuoc c bao ve trc nguy c b pha huy va tang hieu ng. Thuoc chong ong khang vitamine K Sulfamides ha ng huyet Benzodiazepine Estrogenes, bloquants Lidocaine, theophylline, Phenytoine Mercaptopurine

Nhng thuoc c che enzymes Cimetidine Troleandomycine Miconazole Ketoconazole I.M.A.O Allopurinol

Trong ton tr : Nhng chat co tnh acide, gan chat vao proteine cua mo, ton tr o va phong thch dan. V du : Tolbutamide khi dung chung vi Sulfamides khang sinh, tolbutamide tuy b canh tranh thay the noi ket tren albumine huyet tng. Nhng tolbutamide van keo dai tac ong ha ng huyet mot cach khac thng, la v do tolbutamide lien tuc gan chac mo va t o phong thch lien tuc Trong thai tr than : + Loc va tai hap thu : Nhng chat lam thay oi pH cua nc tieu, (thuoc li tieu NH 4 OH. NaHCO 3 ), se lam tang o ion hoa cua thuoc mang

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tnh acide yeu hoac base. Tang ion hoa se tang bai thai chung ra ngoai c the. + Tien trnh bai thai chu ong cua ong than : nhng thuoc co tnh acide (cac Salicylate, acetazolamide, probennecide, phenylbutazone, indomethacine, chlorpromide, penicilline G) hoac cac chuyen hoa chat lien hp hay khong lien hp, eu c ong than bai thai chu ong nh enzymes chuyen ch. Co hien tng hai phan t khac nhau canh tranh tren cung mot chat chuyen ch, ket qua mot chat c gi lai, con chat kia b thai ra. V du : Probenecide giam van toc bai thai cua penicilline G, penicilline G c gi lai, nen tac dung c keo dai them, Indomethacine cung vay, nen co nguy c gay oc Indomethacine. T TM GIAI AP Thuoc la nhng chat co anh hng en qua trnh song. Vay nhng thuoc co lng phan t nho (<1000), nhng thuoc co cau truc tap the va ngay ca tnh chat ly hoa cua chung a anh hng nh the nao tren qua trnh song ay ? Phan biet, biet dc va tac dung ac hieu cua thuoc ? Can nam vng cach at ten thuoc da tren c s tiep au hoac tiep v ng. Dc lc hoc : 5 c che tong quat. Moi c che neu len c hai v du minh hoa. Chat noi (Ligands) la nhng chat co the noi ket vao R, gom ca nhng chat noi sinh va chat a t ben ngoai vao. Hay neu v du moi loai. Moi noi e gan ket chat noi (Ligands) vi receptor (R), co the thuan nghch. Hay minh hoa moi loai bang nhng v du cu the. Ban chat cua Receptor la proteines, gluco-proteine, AND va polysaccharides cua he thong song gom ca enzymes. Hay neu vai v du minh hoa. Chat ong van (agonistes) cua mot receptor la nhng chat va co ai tnh va co hoat tnh noi tai. Ve s o chng minh. Chat oi van (antagonistes) gom chat oi van canh tranh va khong canh tranh, ve s o chng minh. Neu vai v du chng minh rang receptor co tnh ieu chnh. Dc ong hoc : ve s o tong quat, minh hoa 4 giai oan noi tiep va an xen nhau gia thuoc va he thong song.

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o kha dung sinh hoc (bio-availability) phan anh ty suat cua lng thuoc c cho qua ng uong va lng thuoc thc te co mat trong tuan hoan mau, tnh bang AUC. Ve s o minh hoa. 5 c che xuyen mang te bao. Ap dung phng trnh Henderson Hasselbalch e chng minh s hap thu cac chat acide yeu va base yeu. Trnh bay 5 ac tnh cua chuyen ch chu ong (transport actif). S hap thu cua acid yeu va base yeu moi trng pH da day. Do ac tnh cua ruot, nen s hap thu thuoc tai o co nhng thay oi tng oan hay neu v du chng minh. Li hai trong tiem di da, tiem bap va tnh mach. Li hai khi a thuoc qua trc trang Ve s o tong quat ve phan phoi thuoc trong giai oan huyet tng Neu v du minh hoa s canh tranh tren cung mot moi noi cua thuoc giai oan huyet tng Phan biet bm va kenh mang te bao. Phan biet ai tnh va hoat tnh noi tai cua thuoc tren receptor ac hieu. Phan biet pH va pK Nhng ac iem hap thu thuoc ng tieu hoa va ngoai ng tieu hoa Nhng ac iem cua noi gan ket thuan nghch va khong thuan nghch gia thuoc va proteine trong huyet tng va trong mo Tnh hng ti (tropisme) ac tnh cua thuoc oi vi mot so mo. Phan phoi thuoc trong nc va trong m. S khuech tan cua thuoc qua hang rao mau nao va hang rao mau nhau. Trnh bay 2 pha bien oi sinh hoc trong chuyen hoa thuoc va nhng yeu to anh hng. Hien tng cam ng men va c che men trong chuyen hoa thuoc. Trnh bay 3 c che thai tr thuoc qua than. Tham khao nhng thong so dc ong hoc va dc lc cua thuoc. Phan biet tng tac dc ong va dc lc cua thuoc.

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