DC L LM SNG

BI 1. KHI NIM V THUC 1.1. Khi nim v thuc :

Thuc l nhng sn phm c ngun gc t ng vt, thc vt, khong vt, ha dc hay sinh hm : + Phng bnh, cha bnh. + Phc hi, iu chnh chc nng c th. + Lm gim triu chng bnh. + Chn on bnh. + Phc hi hoc nng cao sc khe. + Lm mt cm gic mt b phn c th hay ton thn. + Lm nh hng n qu trnh sinh sn. + Lm thay i hnh dng c th 1.2. Tn thuc : 1.2.1. Tn ha hc : nu hot cht ca thuc l cht ha hc. 1.2.2. M s : c s dng trong qu trnh thuc cn ang c th nghim tin lm sng v lm sng. V d dch chit t l Bch qu ( Ginkgo biloba L. ) trong qu trnh th nghim mang m s EGb 761. 1.2.3. Tn chung ( nonproprietary name ), cn c gi l tn gc ( generic name ; nom generique ). Tng ng vi mi thuc nht nh, mi nc c mt tn chung c chp thun s dng trong nc . V d Php, tn chung cc thuc c ghi trong Dc in quc gia. Cn M, tn chung ca thuc do mt hi ng xem xt la chn. 1.2.4. Tn chung quc t ( INN = international nonproprietary name hay DCI = De-nomination commune internationale ). Nm 1953, WHO ngh nn chn cho mi dc cht mt tn chung c quc t tha nhn da trn cc nguyn tc : ngn gn, d c, d vit, kh nhm ln, tin s dng, phn nh nhm tc dng dc l{ cng nh i din cu trc ha hc.

1.2.5. Tn bit dc hay tn c ch ( trade mark name; brand name; nom de marque; sp cialit pharmaceutique; tn thng mi ). Sau tn bit dc c th c du hiu chng t tn thuc c ng k{ ti Vn phng sng ch ( M ) hoc

cu chng ti Ta n ( Php ). WHO khuyn co cc nc khng nn dng tn chung quc t lm tn bi?t dc.

* V d cc tn thuc : paracetamol. + Tn chung quc t ( INN, DCI ) : paracetamol. + Tn chung M : ac-etaminophen. Tn chung Php : paracetamol. + Tn ha hc : N-acetyl p-aminophenol; P.acetamidophenol; 4-hydroxyacetanilid. + Tn bit dc : algo-tropin, cetamol, datril, efferalgan, panadol, paradon 1.3. Hn dng : + Hn dng thuc l khong thi gian c n nh cho mt loi thuc m trong thi gian ny thuc c bo qun trong iu kin quy nh phi m bo t cht lng theo tiu chun ng k{. + Hn dng thuc thng c ghi bng s hoc bng ch trn nhn thuc nhm ch r sau thi hn ny, thuc khng cn gi tr s dng.

+ Mt s k hiu v hn dng : HD ( Vit Nam ), expiry date, EXP. date, EXP., EXD., E.D.; Exp., use by, best before ( Anh ) + Cc k hiu tng t : validity, shelf-life ( tui th ca thuc ).1.4. Tiu chun cht lng thuc: 1.4.1. Tiu chun GMP ( good pharmaceutical manufacturing practice ) : do WHO quy nh. K hiu : GMP

1.4.2. Tiu chun cc Dc in quc t hoc quc gia c uy tn :

+ Dc in M ( USP = The United states pharmacopoeia ). c USP 24 ( USP XXIV 2000 ) + Dc in Anh ( BP = British pharmacopoeia ). + Dc in Chu u ( EP = European pharmacopoeia ). + Dc in Hn Quc ( KP = Korean pharmacopoeia )

1.4.3. Tiu chun FDA ( Food and drug administration - C quan qun l thc phm v thuc ):

- KFDA = Korea food and drug administration. - US-FDA = The United states food and drug administration.

1.4.4. Cc cp tiu chun Vit Nam v thuc : a- Tiu chun Dc in Vit Nam ( DVN ): l tiu chun cp nh nc v thuc. C DVN III ( 2002 ).b- Tiu chun c s : + L tiu chun do c s sn xut thuc bin son, p dng i vi cc sn phm do c s sn xut ra. Vit tt : TCCS.

+ C 2 loi tiu chun c s : - TCCS ca nhng sn phm lu hnh th trng : phi ng k{ vi c quan c thm quyn. Cc mc tiu chun cht lng khng c thp hn cc mc quy nh trong tiu chun DVN. - TCCS ca cc thuc pha ch trong n v (khng lu hnh trn th trng): do th trng n v xt duyt v ban hnh

1.4.5. Tiu chun ca cc nh sn xut nc ngoi + l tiu chun do nh sn xut t t ra cho cc sn phm ca mnh. Tiu chun ny thng tng ng vi tiu chun ca cc Dc in quc gia hoc quc t c uy tn cao ( BP, USP, EP, KP ).

+ K hiu : home standard, in-house, munufacturers ( standard, specification )

BI 2. CHUYN HA THUC 1. Hu qu ca chuyn ha thuc

2. Ni chuyn ha v cc enzym chnh xc tc + Nim mc rut : protease, lipase, decarboxylase. + Huyt thanh : esterase. + Phi : oxydase. + Vi khun rut : reductase, decarboxylase. + H TKT : MAO, decarboxylase. + Gan : l ni chuyn ha chnh, cha hu ht cc enzym tham gia chuyn ha thuc. 3. Cc pha chuyn ha Thng thng cc thuc c chuyn ha qua 2 pha. 3.1. Pha I: bao gm cc phn ng: oxy ho, oxy kh v phn ng thu phn. 3.1.1. Phn ng oxy ho: L phn ng ph bin nht, cxc tc bi cc enzym oxy ho (mixed function oxydase enzym - mfO) c nhiu trong microsom g?an - h enzym cytochrom P450

(Cyt P450). Phn ng c thc hin theo nhiu bc: a.C cht (thuc, RH) phn ng vi dng oxy ho ca Cyt - P450(Fe3+) to thnh phc hp RH - P450 (Fe3+). b.Phc hp RH - P450 (Fe3+) nhn 1 electron t NADPH, b kh thnh RH - P450 (Fe2+). c.Sau , phc hp RH - P450 (Fe2+) phn ng vi 1 phn t oxy v 1 electron th 2 t NADPH to thnh phc hp oxy hot ho. d.Cui cng, 1 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. Phn ng cho s oxy ha thuc c tm tt nh sau :R-H + 2e- + 2H+ + O2 R-OH + H2O* Nhng phn ng oxy ho khc: MAO nm ti np th gan, thn, h thn kinh trung ng, xc tc cho ging ho catecholamin v serotonin h thn kinh, lm mt tc dng ca nhiu thuc c cha amin. 3.1.2. Phn ng kh: kh cc dn xut nitro, cc aldehyd, bi enzym nitro reduc-tase, dehydrogenase. RNO2 RNO RNHOH RNH2 (Nitrobenzen, Cloramphenicol, Clorazepam) 3.1.3. Phn ng thu phn: Cc ester (procain, aspirin, succinylcholin, clofibrat) : R1COOR2 RCOOH + R2OH Cc amid (procainamid, lidocain, indomethacin) : RCONHR1 R- COOH + R1NH2 Mt s thuc v mt s cht l este hoc amid c thy phn nh esterase hoc amidase gan, rut, huyt tng, no Sau khi thy phn, cc cht ny l ra cc nhm chc OH hoc NH2 v d dng lin hp vi acid glucuronic hoc acid acetic hay acid sulfuric. Amidase hot tnh yu hn esterase nn Procainamid kh chuyn ha hn Procain. Do vy, Procainamid tc dng k o di hn Procain. Acetylcholin l cht trung gian ha hc ca h thn kinh cng b thu phn thnh acid acetic v cholin di s xc tc ca cholinesterase. *a s cc thuc c chuyn ho pha I; Cc thuc sau khi c chuyn ho s: Gim tc dng hoc mt c tnh. Hoc s to ra mt s nhm chc trong cu trc phn t: - OH, - COOH, - NH2, - SHtham gia vo phn ng lin hp pha II *Tuy nhin

: + Mt s cht phi qua chuyn ha mi c tc dng : - Levo dopa chuyn ha thnh Dopamin - Aldomet chuyn ha thnh a- metyl noradrenalin + Mt s t cht qua chuyn ha c tc dng bng hoc mnh hn cht m VD: - Phenacetin Paracetamol - Diazepam Oxazepam - Digitoxin Digoxin - Prednisolon Prednison (C th s dng cht con sn xut thuc). + Mt s t qua chuyn ha lm tng c tnh : - Parathion Paraoxon (dit cn trng) - Carbon tetraclorid CCl- Carbon tetraclorid CCl (Cl - gy hoi t gan) 3.2. Pha II : Sau khi ging ho pha I, cht chuyn ho va to thnh lin hp vi mt phn t ni sinh: acid acetic, acid glucuronic, acid sulfuric, acid amin (glycin). . . cui cng cho cht lin hp t tan trong lipid, d b ion ho, khng hp thu, khng cn hot tnh, d tan trong nc v b thi tr - l qu trnh kh c: iu kin: cc phn ng ny i hinng lng v c cht ni sinh Cc phn ng lin hp chnh:

3.2.1. Vi acid glucuronic : C nhiu cht lin hp vi acid glucuronic : cc acid mch thng hoc acid c nhn thm (acid salicylic, acid nicotinic) cho dn xut N-glucuronid. Nhng ch xc tt c S khi glucuro - hp s to dn xut S - glucuronid. Phn ng c th tm tt nh sau : Dng glucuronid ca thuc va c to thnh s c tnh acid, ion ho c PH sinh l, rt tan trong nc, cho nn s thi nhanh qua nc tiu hoc qua mt. Nh vy phn ng glucuro lin hp r rng l mt qu trnh gii c ca thuc. 3.2.2. Lin hp vi acid sulfuric Cc cht c nhm chc ru hoc phenol, v d Cloramphenicol, Estrol, Butanol s lin hp vi acid sulfuric trong cytosol ca t bo di s xc tc ca en-zym sulfotransferase. PAPS + R-OH R-SO4 + PAP H C6H5OH + H2SO4 SO4

3.2.3. Vi acid acetic Nhng thuc c cha amin bc nht (nh histamin), cc sulfamid, cc hydrazin (nh isoniazid), u c th acetyl ho; sulfanilamid sau khi aceto hp s cho nhng tinh th sc cnh kh tan, gy tn thng b my tit niu. Trong c th cc phn ng chuyn ha thuc pha I, II xy ra ch yu gan, ngoi ra cn xy ra mt s c quan nh thn, nim mc rut, phi, da t bo, phn ng chuyn ha xy ra li ni bo, cytosol, ty lp th, nhn v mng bo tng. 4. c ch enzym v cm ng enzym chuyn ha thuc, hu qu 4.1. c ch enzym microsom Vi thuc no mt tc dng sau khi b oxy ha microsom gan, sau khi enzym chuyn ha b c ch, thuc s tng tc dng, tng c tnh. Mt vi v d ngi : 4.2. Cm ng enzym microsom : Hin tng lm tng tng hp cc protein - enzym gi l cm ng enzym. (Induc-tion); cht gy c hin tng cm ng enzym l cht gy cm ng. (Inductor). n nay tm thy trn trn 200 cht gy c cm ng enzym oxy ha thuc microsom gan, gip thuc chuyn ha nhanh hn bnh thng, mt tc dng nhanh (hoc mt c tnh nhanh). Sau y l danh mc mt vi cht gy cm ng enzym m ta thng gp : Glutethimid, Barbiturat, Diphenylhydantoin, Meprobamat, Diazepam, Chlorpro-mazin, Promazin, Iproniazid, Imipramin, Nikethamid, Phenylbutazon, Tolbutamid, Carbutamid, Diphenhydramin, Rifampycin Nhn xt :khi kt hp thuc cng mt lc - Nu cht chuyn ho t tc dng hn cht m, th qua cm ng enzym, thuc s gim nhanh tc dng v gim c tnh nh vi Meprobamat, Barbiturat, Tolbu-tamid v.v.. - Nu phi qua chuyn ho th thuc mi c tc dng hoc tng tc dng, th cm ng enzym, ngc li, i k o theo tng mnh tc dng dc l{ (v c tnh) ca thuc , v d Parathion CCl4, Primaquin, Imipramin v.v.. - Nu thuc khng chuyn ho qua miorosom gan, th bt c loi cht gy cm ng no cng chng lm thay i dc ng hc v tc dng ca thuc , v d vi Acetazolamid, Aspirin, Barbital, khng sinh loi Aminoglycosid, Lithium v.v. - C thuc dng lin tc dn n gy cm ng enzym chuyn ho ca chnh thuc : Rifampycin, Carbamazepin, mt s Barbiturat, Meprobamat, Diphenylhydantoin, Phenylbutazon, Corticoid

5. ngha thc tin ca chuyn ho thuc qua gan 5.1. Qua chuyn ho nh hng n tc dng ca thuc : 5.1.1. Qua chuyn ho mt tc dng : + a s cc thuc qua chuyn ho to thnh cht t tan trong lipid, d lin hp, d ion ho pH sinh l, mt tc dng v d thi tr ra ngoi. V d : Clopromazin, cc Barbiturat, Phenytoin v.v.. + Nhiu cht chuyn ho qu nhanh, nn mt tc dng nhanh. Do vy, ko di tc dng ca thuc c th thay i cu trc bng cch thay i cc nhm chc d b chuyn ho hoc bao vy cc nhm chc bng cch to ra cc lin kt khc. V d : - Thay nhm methyl ca Tolbutamid bng Cl ta c Clopropamid c t/2 ko di 12 - 24 h, trong khi Tolbutamid c t/2 = 4 - 7 h. - Procain b esterase thu phn mt tc dng nhanh. Khi thay i cu trc to thnh Procainamid b chuyn ho chm hn nn tc dng k o di hn. 5.1.2. Qua chuyn ho mi c tc dng :

+ Mt s tin thuc (prodrugs bn thn cha c tc dng dc l{. Sau khi vo c th, cc thuc ny b chuyn ho to ra cht chuyn ho c tc dng dc l. V d : Cyclophosphamid Aldophosphamid + Vi nhng thuc thng qua chuyn ho mi c tc dng, khi phi hp vi cc cht gy cm ng enzym s lm tng tc dng ca thuc. Ngc li dng km vi cc cht c ch s lm gim tc dng. 5.1.3. Qua chuyn ho vn gi nguyn tc dng : Mt s cht sau khi chuyn ho sinh ra cht chuyn ho c tc dng nh cht m, thm ch c cht t tc dng ph hn cht m. VD: Phenacetin Paracetamol 5.2. Qua chuyn ho tng c tnh * Carbontetraclorid sau khi chuyn ho qua gan to thnh gc t do CCl3. Chnh gc t do triclomethyl gy c vi gan. Khi kt hp cc cht gy cm ng enzym oxy ho cng lm tng c tnh ca CCl4 . * Parathion l cht dit cn trng, bn thn n khng c ch cholinesterase ca cn trng, vt ch, nhng trong c th cn trng v ngi parathion b chuyn ho qua MFO to ra cht paraoxon c tc dng c ch cholinesterase ca cn trng v ngi, gy c cho ngi v cn trng. * Primaquin l thuc chng st r t khi vo c th b chuyn ho thnh demethylprimaquin, 5 - OH - primaquin v 5 - OH - demethylprimaquin.

Chnh 3 cht chuyn ho ny gy met-Hb hoc thiu mu tan mu. Isoniasid (Rimifon) nh phn ng lin hp vi acid acetic to ra cc acetyliso-niasid. Acetylisoniasid b thy phn tip tc to ra acetylhydrazin v cht chuyn ha ny b chuyn ha qua MFO to ra cht chuyn ha c vi t bo gan. Trong iu tr lao, phi hp INH vi Rifampycin (mt cht gy cm ng enzym microsom gam) s lm tng tn thng gan. PHN PHI THUC

Gn thuc vo protein huyt tngSau khi thuc hp thu, thuc qua mu chuyn n ni c tc dng, ti mu, thuc c chia lm 2 dng : - Dng kt hp vi protein huyt tng - Dng t do * Kh nng gn vo protein huyt tng tuz theo tng loi thuc : Gn mnh 75 - 98% : Sulfamid chm, Quinin, Rifampicin, Digoxin, Lincomycin, in-domethaxin, Dicumarol. . . Gn yu : 1 - 8% : Sulfaguanidin, Barbital Mt s t cht khng gn c vo protein huyt tng, l nhng phn t nh, tan nhiu trong nc : Ure, ouabain, Glucocorticoid ngha : - Mt khi dng kt hp th thuc cha thm qua mng, cha c hot tnh ch dng t do mi c tc dng v c tnh ( phc hp thuc - protein ). Protein huyt tng l kho d tr thuc phc hp ( thuc- protein ) ko di s c mt ca thuc mu, khng ging ho, khng khuych tn qua mng sinh vt, khng thi. Phc hp l ngun cung cp thng xuyn dng t do, ko di tc d?ng ca thuc. - Do c gn vo protein huyt tng tnh ho tan ca thuc trong nc cng tng theo ( Dicoumarol t tan trong nc s tr nn d tan trong huyt tng ). - Nu hai thuc cng c i lc vi nhng ni ging nhau protein huyt tng, chng s i khng cnh tranh, phn t do ca thuc tng, tc dng v c tnh tng theo, do cn lu { phi hp thuc trong iu tr : ngi b bnh dng Tolbutamid v Phenlbutazon ( y Tolbutamid b y, bnh nhn d b chong do gim ng huyt t ngt). - Tr em : kh nng gn thuc km, d nhy cm vi thuc. * Trong qu trnh iu tr bnh nhng liu u tin ca thuc gn mnh vo protein huyt tng bao gi cng phi cao ( liu tn cng ) bo ho

v tr gn, lm cho nhng liu tip tc ( liu duy tr ) c th t hiu lc. * Nu thuc cng gn mnh vo protein huyt tng v vo t chc khc ( tc dng chn lc ) th iu trn khng cn ng. V d : Digital gn vo protein, nhng cn gn mnh vo t chc tim ( Gp 5 ln protein huyt tng ) tc dng r tim.

BI 3. I CNG V DC NG HC 1. CC CCH VN CHUYN THUC QUA MNG SINH HC

1.1. c tnh l ha ca thuc - Thuc l cc phn t thng c trng lng phn t P M 600. Chng u l cc acid hoc cc base yu. - Kch thc phn t ca thuc c th thay i t rt nh (P M = 7 nh ion lithi) cho ti rt ln (nh alteplase- tPA- l protein c P M = 59.050). Tuy nhin, a s c P M t 100- 1000. gn kht vo 1 loi receptor, phn t thuc cn t c mt kch c duy nht vi kch thc ca receptor c hiu thuc khng gn c vo cc receptor khc (mang tnh chn lc). Kinh nghim cho thy P M nh nht phi t khong 100 v khng qu 1000, v ln qu th khng qua c cc mng sinh hc ti ni tc dng. Mt s thuc l acid yu: l phn t trung tnh c th phn ly thun nghch thnh mt anion (in tch (-)) v mt proton (H +). C8H7O2COOH C8H7O2COO + H+ Apirin trung tnh Aspirin anion Proton Mt s thuc l base yu : l mt phn t trung tnh c th to thnh mt cation (in tch (+)) bng cch kt hp vi 1 proton: C12H11ClN3NH3 C12H11ClN3NH2 + H + Pyrimethamin cation Pyrimethamin Proton trung tnh - Cc phn t thuc c sn xut di cc dng bo ch khc nhau : Tan c trong nc (dch tiu ha, dch khe), do d c hp thu. Tan c trong m thm qua c mng t bo gy ra c tc dng dc l v mng t bo cha nhiu phospholipid . V vy c hp thu vo t bo thun li nht, thuc cn c mt t l tan trong nc/ tan trong m thch hp. - Cc phn t thuc cn c c trng bi hng s phn ly pKa pKa c suy ra t phng trnh Hend erson-HasselbACh:

K l hng s phn ly ca 1 acid; pKa = - logKa pKa dng cho c acid v base. pKa +pKb=14 Mt acid hu c c pKa thp l 1 acid mnh v ngc li. Mt base c pKa thp l 1 base yu, v ngc li. Ni mt cch khc, khi mt thuc c hng s pKa bng vi pH ca mi trng th 50% thuc c dng ion ha (khng khuch tn c? qua mng) v 50% dng khng ion ha (c th khuch tn c). V khi , nng phn t/ nng ion= 1 v log 1 = 0. Ni chung, mt thuc phn tn tt, d c hp thu khi C trng lng phn t thp t b ion ha: ph thuc vo hng s phn ly (pKa) ca thuc v pH ca mi trng. D tan trong dch tiu ha (tan trong nc) ho tan trong lipid cao d qua mng ca t bo 1.2. Vn chuyn thuc bng cch lc Nhng thuc c trng lng phn t thp (1 00- 200), tan c trong nc nhng khng tan c trong m s chui qua cc ng dn (d= 4 - 40 ) ca mng sinh hc do s chnh lch p lc thu 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 (theo bc thang nng ). Nhng phn t thuc tan c trong nc/ m s chuyn qua mng t ni c nng cao sang ni c nng thp. iu kin ca s khuch tn th ng l thuc t b ion ho v c nng cao b mt mng . Cht ion ha s d tan trong nc, cn cht khng ion ha s tan c trong m v d hp thu qua mng. S khuch tn ca acid v base yu ph thuc vo hng s phn ly pKa ca thuc v pH ca mi trng. Th d: khi ung 1 thuc l acid yu, c pKa = 4, gian 1 d dy c pH= 1 v gi-an 2 l huyt tng c pH = 7 (H.1)

p dng phng trnh Henderson - Hasselbach, ta c:

gian 1 (d dy):

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

[ R - COO- ] gian 2 (mu):

[ R- COOH ] log = 4 - 7 = - 3; Log ca - 3 = 1/1000 [ R - COO- ] V ch phn khng ion ha v c nng cao mi khuch tn c qua mng cho nn acid ny s chuyn t gian 1 (d dy) sang gian 2 (mu) v c hp thu. Tr s pKa ca mt s thuc l acid yu v base yu c g hi bng1. Nn nh rng base c pKa cao l base mnh v acid c pKa cao l acid yu.

cid yu pKa Base yu pKa Salicylic acid

Acetylsalicylic acid Sulfadiazin Barbital Boric acid Reserpin 6.6 Codein 7.9 Quinin 8.4 Procain 8.8 Atropin 9.

Bng 1.1: Tr s pKa ca mt s thuc l acid v base yu ( nhit 250C) Nh vy, salicylic acid (aspirin) uc hp thu nhiu d dy v phn trn ca ng tiu ha. Quabng 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 t rng. Th d phenobarbital (Luminal, Gardenal) l mt acid yu c pKa = 7,2; nc tiu bnh thng c pH cng bng 7,2 nn phenobarbital b ion ha 50%. Khi nng pH ca nc tiu ln 8, ion ha ca thuc s l 86%, do thuc khng thm c vo t b o. iu ny c dng trong iu tr nhim c phenobarbital: truyn dung dch NaHCO 3 1,4% base ha nc tiu, thuc s b tng thi tr. i vi mt cht kh (th d thuc m bay hi), s khuch tn t khng kh ph nang vo mu ph thuc vo p lc ring phn ca cht kh gy m c trong khng kh th vo v ha tan ca kh m trong mu. 1.4. Vn chuyn tch cc Vn chuyn tch cc l s ti thuc t bn ny sang bn kia mng sinh hc nh mt cht vn ch?uyn (carrier) c hiu c sn trong mng sinh hc. * c im ca s vn chuyn ny l: - C tnh bo ha: do s lng carrier c hn

- C tnh c hiu: 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 1 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 (Vn chuyn tch cc th pht) : khi km theo carrier li c c s chnh lch bc thang nng , v vy s vn chuyn ny khng cn nng lng. Th d vn chuyn glucose, pyramidon theo bc thang nng ca Na +Vn chuyn tch cc thc th (Vn chuyn tch cc nguyn pht): l vn chuyn i ngc bc thang nng , t ni c nng thp sang ni c nng cao hn. V vy i hi phi c nng lng c cung cp do ATP thu phn, thng c gi l cc bm, th d s vn chuyn ca Na+, K+, Ca++,I-, acid amin.

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

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

Hp thu l s vn chuyn thuc t ni dng thuc (ung, tim) vo mu ri i khp c th, ti ni tc dng. Nh vy s hp thu s ph thuc vo: - ha tan ca t huc. Thuc dng di dng dung dch nc d hp thu hn dng du, dch treo hoc dng cng - pH ti ch hp thu v c nh hng n ion ha v tan ca thuc. - Nng ca thuc. Nng cng cao cng hp thu nhanh. - Tun hon ti vng hp thu: cn g 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 ha, ca t bo rut v c bit l gan, ni c i lc vi nhiu thuc. Phn thuc b ph hu trc khi vo vng tun hon c gi l first pass metabolism (chuyn ha do hp thu hay

chuyn ha qua gan ln th nht v thng l ung thuc). Phn vo c tun hon mi pht huy tc dng dc l{, c gi l sinh kh dng (bioavail-ability) ca thuc (xin xem phn sau) Sau y s im qua cc ng dng thuc thng thng v cc c im ca chng. 2.1.1. Qua ng tiu ha u im l d dng v l ng hp thu t nhin. Nhc im l b cc enzym tiu ha ph hu hoc thuc to phc vi thc n lm chm hp thu. i khi thuc kch thch nim mc tiu ha, gy vim lot 2.1.1.1. Qua nim mc ming: thuc ngm di li Do thuc vo thng vng tun hon nn khng b dch v ph hu, khng b chuyn ha qua gan ln th nht 2.1.1.2. Thuc ung Thuc s qua d dy v qua rut vi cc c im sau: * d dy: - C pH = 1- 3 nn ch hp thu cc acid yu, t b ion ha, nh aspirin, phenylbutazon, barbiturat?. - Ni chung t hp thu v nim mc t mch mu, li cha nhiu cholesterol, thi gian thuc d dy khng lu. - Khi i hp thu nhanh hn, nhng d b kch thch * rut non: L ni hp thu ch yu v c din tch hp thu rt rng (> 40 m 2), li c ti mu nhiu, pH tng dn ti base (pH t 6 n 8). - Thuc t b ion ha nhng nu t hoc khng tan trong lipid (sulfaguanidin, streptomycin) th t c hp thu. - Thuc mang amin bc 4 s b ion ha mnh kh hp thu, th d cc loi cu-ra. - Cc anion sulfat SO 4 khng c hp thu: MgSO 4, Na2SO4 ch c tc dng ty.2.1.1.3. Thuc t trc trngKhi khng dng ng ung c (do nn, do hn m, hoc tr em) th c d ng thuc t vo hu mn. Khng b enzym tiu ha ph hu, khong 50% thuc hp thu qua trc trng s qua gan, chu chuyn ha ban u. Nhc im l hp thu khng hon ton v c th gy kch ng nim mc hu

mn. 2.1.2. Thuc tim

- Tim di da: do c n hiu 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 n hanh, hon ton, c th iu chnh liu c nhanh. Dng tim cc dung dch nc hoc cc cht kch ng khng tim bp c v lng mch t nhy cm v mu pha long thuc nhanh nu tim chm.Thuc tan trong du, thuc lm kt ta cc thnh phn ca mu h ay 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 c c 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, thu c xoa bp, cao dn) c tc dng nng ti ch st khun, chng nm, gim au. Tuy nhin, khi da b tn thng, vim nhim, bng thuc c th c hp thu. Mt s cht c d tan trong m c th thm qua da gy c ton thn (thuc tr su ln hu c, cht c cng nghip anilin) Gi m ni bi thuc (bng p), xoa bp, dng thuc gin mch ti ch, dng phng php ion -di (iontophoresis) u lm tng ngm thuc qua da. Hin c dng thuc cao dn mi, lm gii phng thuc chm v u qua da, duy tr c lng thuc n nh trong mu: cao dn scopolamin, estrogen, nitrit Da tr s sinh v tr nh, c lp sng 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 t i ch. Khi thuc chy qua ng mi - l xung nim mc mi, thuc c th c hp thu trc tip vo mu, gy

tc dng khng mong mun. 2.1.4. Cc ng khc

- Qua phi: cc cht kh v cc thuc bay hi c th c hp thu qua cc t bo biu m ph nang, nim mc ng h hp. V din tch rng (80 - 100 m2?) nn hp thu nhanh. y l ng hp thu v thi tr chnh ca thuc m hi. S hp thu ph thuc vo nng thuc m trong khng kh th vo, s thng kh h hp, ha tan ca thuc m trong mu ( hay h s phn ly

mu: kh ) 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 (hy-perbaric 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 t huc (biu hin qua C max v Tmax) so vi liu dng . Sinh kh dng phn nh s hp thu thuc. 2.1.5.2. ngha

BI 4. KHI NIM TNG TC THUC 1. Mt s khi nim c bn

Tng tc thuc l hin tng xy ra khi hai thuc tr ln c s dng ng thi. S phi hp lm thay i tc dng hoc c tnh ca mt trong nhng th thuc . Khi phi hp thuc nhm li dng tng tc thuc theo hng c li tng hiu qu iu tr, gim tc dng ph hoc gii c thuc. Th nhng, trong thc t iu tr c nhng tnh hung hon ton bt ng: cng mt thuc mc liu iu tr m khi phi hp vi thuc ny li gim hoc mt tc dng, ngc li, dng vi thuc kia th li xy ra ng c.

T l tng tc thuc tng theo cp s nhn vi s loi thuc phi hp, c ngha l nguy c ri ro, tht bi cng tng theo. Do vic cho thuc v phi hp thuc trong iu tr l 1 vn phc tp, lun t ra cho ngi thy thuc phi cn nhc v lun phi quan tm n hin tng tng tc thuc c th xy ra. Nhn nh v tng tc thuc hng dn cho bnh nhn khi s dng thuc v c nhng li khuyn vi bc s khi gp nhng n thuc phi hp khng ng. Cc tnh hung c th xy ra khi phi hp thuc c tm tt nh sau:

2. S phi hp thuc dn ti tng tc dng - tng tc c tnh hip ng S phi hp thuc lm tng hiu qu tc dng l mc tiu trong iu tr.

l s tng tc mang tnh hip ng thuc, n xy ra ti cc receptor khc nhau, nhng c cng ch tc dng l: lm tng hiu qu iu tr. Cc kh nng c th xy ra vi loi tng tc ny l: 2.1.Hip ng cng (Additive) * Khi phi hp hai hay nhiu thuc vi nhau m tc dng thu c bng tng tc dng ca cc cht thnh phn, ta c hp ng cng. Th d: Nh c s phi hp ny m Olcandomycin ni rng c ph tc dng, cn Tetraxyclin th gim c liu, do gim c c tnh. * Nhng tng tc c th xy ra ti cc receptor khc nhau nhng c cng ch tc dng rt ph bin trong iu tr. V d: Phi hp thuc li tiu - an thn vi cc thuc chng tng huyt p iu tr bnh huyt p cao. Phi hp khng sinh vi cc thuc gim tit HCL iu tr vin lo t ng tiu ho. Phi hp? khng sinh c c ch tc dng khc nhau trong iu tr lao * Cc phi hp ny thng c p dng ph bin trong iu tr, tuy nhin cng hay gp nhng tng tc bt li do bc s v tnh phi hp cc thuc c tn bit dc khc nhau, nhng thc t li l cng mt hot cht . V d: Phi hp cc khng sinh nhm Aminoglycozid: Gentamycin + Strepto-mycin > lm tng suy thn v ic khng hi phc. 2.2. Hip ng tng cng (Potencial) * Khi tc dng phi hp vt tng tc dng ca cc cht thnh phn, ta c hip ng tng cng. Loi hip ng ny thng xy ra khi cc cht thnh phn tc dng ln nhng khu khc nhau trn cng mt chui phn ng:

V d: P.A.BA FH2 FH4

(-) (-) Sulffamid Trimethoprim Pyrimetamin Acid Folic l Coenzym gip vi khun to nn cc base purin, thymin v cc acid amin cn tng hp ADN, ARN vi khun pht trin. Sunfamid do cnh tranh vi P.A.B lm gim lng FH2, cn cc dn cht Pir-imidin (trimethoprim, pirimethamin) li c ch enzym DHFR xc tc cho qu trnh chuyn FH2 thnh FH4, lm gim lng FH4. Kt qu cui cng l thiu acid Folic, v vy c ch s pht trin vi khun. Hai loi thuc dng chung s c tc dng hip ng vt mc (ch khng phi mt php cng thng thng), mnh hn hn khi dng n c tng loi, l nguyn tc to nn cng thc thuc khng khun hoc thuc chng st rt c hiu lc cao. * Khi phi hp li hai thuc tc dng km khun nh trong ch phm : Co tri-moxazol (Bactrim) gm: Sulfamethoxazol + Trimethoprim) , ta li thu c tc dng dit khun. Ch phm ny c tc dng rt tt vi nhng vi khun khng cc khng sinh khc. Ch phm Fansidar: (Sulfadoxin + Pyrimethamin). Hip ng vt mc cn c to nn khi cht chnh - cht ch vn, c tng tim lc nh cht phi hp c th khng tc dng ln mt c quan ch vi cht chnh. V d: Clofibrat dng chung vi thuc khng Vitamin K lm tng tc dng chng ng mu, mc d Clofibrat khng c tc dng chng ng. Thuc co mch adrenalin s lm tng tc dng gy t tng vng ca novocain khi dng phi hp . Khi iu tr cao huyt p thng phi hp thuc li tiu vi thuc gin mch, thuc li tiu lm gim lu lng tun hon v thuc gin mch c tc dng h huyt p tt hn. Tt c nhng tng tc hip ng k trn, u thuc loi tng tc v mt dc lc, ngha l hip ng v mt tc dng.

3. S phi hp thuc dn ti gim tc dng - tng tc c tnh i khng.

* Khi phi hp thuc ngi ta c gng trnh nhng phi hp lm gim tc dng ca nhau. Tuy nhin, nhiu lc tng tc ny li c s dng nh mt v kh li hi gii c thuc hoc lm gim nhng tc dng ph ca cht ch vn. C nhng kh nng i khng sau i khng

Ho hc Dc l Vt l Dc ng hc Dc lc hc Hp thu Phn b Chuyn ho Thi tr Cnh tranh Khng cnh 3.1. i khng ho hc * Tng tc ho hc c th gp vi tt c cc loi phn ng ho hc m ta bit. Khi trn chung cc thuc ngoi c th nu xy ra hin tng ta, c khi chuyn thnh dng kh bay ln, hoc dung dch i ?mu ta c th d dng nhn bit v trnh c. V d: Cc mui ca kim hu c v acid hu c, khi trn chung s xy ra phn ng trao i, dn n gim tan: Streptomycin sulfat trn vi natri benzyl penicilin, dimedrol clohydrat vi barbital natri (ta dimedrrol v bar-bital). iu ng ch { l c nhng phn ng ta khng nhn thy c nhng n li to ra cc sn phm khng c hot tnh hoc c vi c th. V d: - Khng nn trn vitamin B12 vi bt kz mt vitamin no trong syrine v coban s ph hu cc vitamin. Khi trn B12 vi B1, sn phm to thnh s gy d ng do tc ng ca B12 n B1. - Glucose l mt cht c tnh kh, v vy vic pha mt thuc nh morphin, no-radrenalin, glycozid tr tim vo dung dch ny truyn nh git hoc tht trc trng l khng nn. Nhng tng tc xy ra ngoi c th gi l tng k (incompatility), cn tnh n c kh nng phn ng khi thuc vo c th. Cc alcaloit b ta bi thuc cha tanin, tetraxyclin to chelate vi cc ion kim loi ho tr II.III lc thuc s khng c hp thu. Hin tng gi l tng tc thuc (inter-action). - Nhng tng tc i lp rt cn trnh v lm gim tc dng ca thuc V d: Khng ung vitamin B1 cng mt lc vi cc penicilin hoc streptomycin v vitamin B1 ph hu cc khng sinh ny. Nu ng thi dng vitamin B1 vi vitamin B6 th pyridoxin s ngn cn qu

trnh photphorin ho ca vitamin B1, tc l cn tr vitamin B1 chuyn thnh dng c hot tnh sinh hc. Khng ung acid nicotinic (vitamin PP) vi vitamin B6 v vitamin PP s ph hu vitamin B6 (vitamin PP l cofactor ca enzym NADP). - Nn nh rng vitamin B6 l ng yu t hot ho ca enzym vn chuyn nhm NH2 v kh carboxyl ca cc acid amin; Do khi iu tr bnh Parkinson khng nn phi hp Levodopa vi vitamin B6 liu cao. 3.2. i khng vt l Cc thuc bc : albumin (lng trng trng), tinh bt s gim tc dng ca mt s thuc kch ng (corticoid). Than hot l cht hp ph tt nhiu thuc khi ng c. 3.3. i khng dc l: bao gm i khng dc lc hc v i khng dc ng hc.

3.3.i khng dc lc hc L i khng do i lp v tc dng v c ch tc dng. C 2 loi i khng: 3.3.1. i khng cnh tranh: 2 thuc tc dng ln cng mt receptor (Rp), thuc no c i lc mnh hn vi Rp s pht huy c tc dng. Ni mt cch khc: cht ch vn (agonist) v cht i khng (antagonist) cnh tranh vi nhau cng mt ni ca receptor, thuc no c i lc mnh hn vi receptor s pht huy tc dng. V d: Nalorxon - morphin Atropin - Pilocarpin (Rp M) Histamin - phenergan (Rp H1) Histamin - cimetidin (Rp H2) Acetylcholin - piperazin (Rp N ca c giun) Isoproterenol - propranolon (Rp b) 3.3.2. i khng khng cnh tranh Cht i khng c th tc ng ln Rp v tr khc vi cht ch vn; cht i khng lm cho Rp bin dng, qua Rp s gim i lc vi cht ch vn v nu c tng liu cht ch vn cng khng t c hiu lc ti a. V d: mt s cht khng histamin Rp H1 : terfenadin ,astemizol Cc thuc lm mt tc dng ca nhau do tc dng i lp nhau: + Strychnin hn?g phn tu sng, lm tng cng kin c, cn thuc t hoc

cura i khng khng cnh tranh vi tc dng ny ca strychnin. + Acetylcholin - cura + Atropin lm mt tc dng co c vng ca Morphin do thng c phi hp vi Morphin gim au do co tht ng mt, ng niu + Ephedrin c tc dng cng ph giao cm s b cn tr nu dng cng Pilo-cacpin - cht cng giao cm. + Cc khng sinh nhm Beta - lactam s b gim tc dng nu dng cng vi Tetraxtyclin v tc dng gim tng hp protein trong t bo vi khun ca Tetraxyclin s lm chm s phn bo v do lm Penicilin kh ph v v vi khun hn. 3.4. i khng dc ng hc

* Loi tng tc ny xy ra trong sut qu trnh tun hon ca thuc trong c th, k t khi bt u thm nhp n lc o thi. 3.4.1. Tng tc lc hp thu (Absorption = A) * Do thay i ion ho ca thuc S vn chuyn thuc qua mng sinh hc ch yu theo c ch khuch tn th ng v do ph thuc vo h s phn b m / nc ca thuc. Ch nhng cht khng ion ho mi phn tn tt trong m v d qua mng theo c ch ny. Theo phng trnh trn ta nhn thy: Cc cht c bn cht acid yu s hp thu tt trong mi trng acid: Phenylbu-tazon, cc Barbiturat, Aspirin hp thu tt d dy. Cc cht c bn cht base yu s hp thu tt trong mi trng kim: Quinin, Ephedrin, Atropin, Morphin hp thu tt rut. Vic thay i mi trng ca mt thuc c th do cc thuc dng km gy nn, cng c th do thc n v cc cht lng dng ung thuc to ra. + Khi iu tr bng Levodopa, nn trnh dng nhng ch phm m thu phn v Levodopa s b gim hp thu, cc cht m khi vo c th s phn hu thnh acid amin v cnh tranh carrier vi levodopa khi hp thu. + Thuc chng toan d dy lm tng pH ng tiu ho, ngn cn hp thu thuc l acid yu ( aspirin, barbiturat, sulfamid, cumarin) . + Hydroxyd AL cn tr hp thu INH, Doxycyclin. + Khi ung Tetraxyclin nn trnh dng nhng ch phm cha kim loi nng nh Fe, Al, Mg v Tetraxyclin r to chelate vi kim loi nng do khng hp thu c. + Cholestyramin - mt cht lm ta mui mt, dng ngn cn qu trnh

hp thu cc cht bo, gy h mc cholesterol/ mu, cng c th to phc vi mt s thuc v cn tr hp thu. + Cholestyramin lm gim hp thu cc vitamin tan trontg du (A.D.E.K) acid folic, vitamin B12. Nu dng cholestyramin ko di, cn b cung cc vitamin trn. + INH iu tr lao, nn b xung vitamin B6 (20 mg - 25 mg/ ngy) v INH to phc vi B6 c th gy ri lon chc phn thn kinh do thiu B6 (Pyridoxin). 3.4.2. Tng tc trong qu trnh phn b: (Ditribution = D) * Khi tun hon trong mu, thuc thng dng lin kt vi Protein ca huyt tng. Dng ny khng c tc dng dc l{ v cng khng b chuyn ho. Tuy nhin lun tn ti mt cn bng ng gia dng thuc lin kt v thuc t do. Dng t do l dng c tc dng dc l. Nu s dng hai thuc c cng mt im gn trn phn t protein, thuc no c i lc mnh s y thuc kia ra khi v tr v chim ly protein. V d: Tolbutamid + Phenylbuta-zon ( y tolbutamid b y), d b chong do gim ng huyt t ngn kit. y l loi tng tc bt li gp nhiu trong k n bi v thng xy ra bt ng trong sut qu trnh tun hon ca thuc trong c th. 3.4.3. Tng tc giai on chuyn ho: (Metabolism = M) Gan l c quan chuyn ho thuc quan trng nht ca c th. S suy gim chc nng gan k o theo nhng thay i cc thng s dc ng hc ca thuc: * Nhng thuc c tc dng tng cm ng enzym s lm tng tc chuyn ho ca cc thuc dng phi hp hoc ngay c chnh n khi dng lp li, do lm gim tc dng. Cc thuc thng gp l: Phenobarbital, Rifampicin, Doxycyclin, Spironolacton * Nhng thuc c tc dng c ch enzym microsom gan: Cloramphenicol, Cimetidin. Quercetin, Levodopa, INH lm cho nhiu thuc khc ko di tc dng v tng c tnh. V d: Cimetidin lm chm chuyn ho qua gan ca Diazepam, DPH, Theophilin, Carbamazepin, Lidocain, Metromidazol Cc thuc cn lu { khi phi hp vi cc cht trong bng trn l cc hormon (thyroid, corticoid, estrogen), theophylin, thuc chng ng kinh, thuc chng ng mu dng ung, thuc h ng huyt, thuc tim mch chuyn ho qua gan 3.4.4.Tng tc thuc giai on thi tr: (Elimination = E) Cc cht kim s lm tng tc o thi cc thuc c tnh acid nh Barbitu-rat, Aspirin do vy lm gim tc dng ca cc cht ny. Ngc li cc cht c tnh acid nh vitamin c, dch p hoa qu s tng o thi cc alcaloid.

Vic gim tc dng do nhng tng tc dc ng hc gy ra thng rt kh trnh v n bt ng; hu qu rt phc tp. Trc y nhiu trng hp xy ra khi phi hp thuc khng gii thch c . Ti sao cng mt thuc liu iu tr nhng lc th khng hiu lc, lc th c nguy c ng c. Ngy nay nh s pht trin ca dc ng hc, nhiu vn c sng t. Chnh v vy trong bn hng dn s dng thuc by gi thng c thm mc dc ng hc (pharmacokinetics) v tng tc thuc (interactions). iu gip cho ngi s dng nh hng tt hn, trnh c nhng tai bin v nng cao hiu qu iu tr. Cc thuc b nh hng nhiu l thuc bi xut ch yu qua thn dng cn hot tnh. Thuc phi hp c th lm qu trnh bi xut ca thuc dng km theo c ch: Thay i pH ca nc tiu: * Cc antacid nh NaHCO3, Maalox, Kavet gy kim ho nc tiu, do lm tng thi tr cc thuc c bn cht acid yu nh barbiturat, salicylat; Ngc li, vi cc thuc l alcaloid (th d: quinidin, theophylin) th tc bi xut li c nguy c b gim, dn n tng tc dng. * Vitamin C liu cao (>2 g) gy acid ho nc tiu, lm tng thi tr cc thuc c bn cht alcaloid dn n gim tc dng, nhng li ko di thi gian tn ti ca cc salicylat gy tng nguy c chy mu. nh hng n c ch trao i cht ng thn: V d: Probenecid s cnh tranh carrier bi xut ca nhiu loi thuc (cc penicilin, cephalosporin) v lm chm qu trnh bi xut ca cc thuc ny. Corticoid cn tr tc dng ca cc thuc li tiu do i lp v c ch bi xut mui - nc. { ngha ca tng tc thuc: Li dng - Ci thin tc dng dc l - Ci thin dc ng? hc ca thuc - Gii c Trnh - Phi hp lm tng c tnh v tc dng ph - Phi hp lm gim tc dng dc l v hiu qu iu tr.

BI 5. CC LOI 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 tcthuc. Trong lm sng, thy thuc mun phi hp thuc lm tng t c dng iu tr, gim cctc dng khng mong mun. Song trong thc t, nhiu k hi 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 (a gonist), do cht i kh ng (antagonist) c i lc vi receptor hn nn ngn cn cht ng vn gn vo receptor: atropin khng acetylcholin v pilocarpin ti receptor M; nalor-phin 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 b ng tng liu ca mt thuc m c tnh li tng hn: CVKS, aminosid vi dy VIII. 1.1.2. Tng tc trn cc receptor khc nhau: tng tc chc phn. - C cng ch tc dng: do lm tng hiu qu iu tr. Th d: trong iu tr bnh cao huyt p, phi hp thuc gin mch, an thn v li tiu; trong iu tr lao, phi hp nhiu khng sinh (DOTS) tiu dit vi khun cc v tr v cc gi ai on pht trin khc nhau. - C ch tc dng i lp, gy ra c chc phn i lp, dng iu tr nhim c: strychnin liu cao, kch thch ty sng gy co cng c, cura do c ch dn truyn tm vn ng, lm mm c; histamin tc ng trn receptor H 1 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 ha v thi tr v th n khng mang tnh c hiu.

1.2.1. Thay i s hp thu c a thuc - Do thay i ion ha ca thuc: Nh ta bit, ch nhng phn khng ion ha ca thuc mi d dng qua c m ng sinh hc v d phn tn hn trong lipid. phn ly ca thuc ph thuc vo hng s pKa ca thuc v pH ca mi trng. Cc thuc c bn cht acid yu (nh aspirin) s hp thu tt trong mi trng acid (d dy), nu ta trung ha acid ca dch v th s hp thu as-pirin d dy s gim i. -

Vi cc thuc dng theo ng ung: khi dng vi thuc lm thay i nhu ng r ut s lm thay i thi gian lu gi thuc trong rut, thay i s hp thu ca thuc qua ru t. Mt khc cc thuc d tan trong lipid, khi dng cng vi parafin (hoc thc n c m) s lm tng hp thu. -

Vi cc thuc dng theo ng tim bp, di da: procain l thuc t , khi trn v i 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 v?i protamin v km (protemin - zinc- insulin-PZI) s lm ko di thi gian hp thu insulin vo mu, ko di tc dng h ng

huyt ca insulin. - Do to phc, thuc s kh c hp thu: Tetracyclin to phc vi Ca ++ hoc cc cation kim loi khc rut, b gim hp thu. Cholestyramin lm ta mui mt, ngn cn hp thu lipid, dng lm thuc h cholesterol mu. - Do cn tr c hc: Sucralfat, smecta, maaloc (Al 3+) to mng bao nim mc ng tiu ha, lm kh hp thu cc thuc khc. trnh s to phc hoc cn tr hp thu, 2 thuc nn ung cch nhau t nht 2 gi. 1.2.2. Thay i s phn b thuc

l tng tc trong qu trnh g n 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 protei n huyt tng cao (trn 90%) v c phm vi iu tr hp nh: . Thuc chng ng mu loi khng vitamin K: dicumarol, warfarin . Sul-famid 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 ha Nhiu thuc b chuyn ha gan do cc enzym chuyn ha thuc ca micro-som g a n (xin xem phn dc ng hc). Nhng enzym ny li c th c tng hot tnh (gy cm ng) hoc b c ch bi cc thuc khc. Do s lm gim t/2, gim hiu lc (nu l thuc gy c m ng enzym) hoc lm tng t/2, tng hiu lc (nu l thuc c ch enzy m) ca thucdng cng. - Cc thuc gy cm ng (inductor) enzym gan: phenobarbital, phenytoin, carbamazepin, griseofulvin, rifampicin - Cc thuc c ch (inhibitor) enzym gan: allopurinol, cloramphenicol, cime-tidin, MAOI, erythromycin, isoniazid, dicuma rol. Cc thuc hay phi hp vi cc loi trn thng gp l cc hormon (thyroid, cortic oid, 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 ri-fampicin, hoc b

ng kinh dng phenytoin, c th s b v k hoch do estrogen trong thuc trnh thai

b gim hiu qu v b chuyn ha nhanh, hm lng tr nn thp. 1.2.4. Thay i thi tr thuc Thi tr (elimination) thuc gm 2 qu trnh l chuyn ha thuc gan ( ni phn trn ) v bi xut (excretion) thuc qua thn. Nu thuc bi xut qua thn dng cn hot tnh th s tng/ gim bi xut s c nh hng n tc dng ca thuc. - Thay i pH ca nc tiu: khi mt thuc lm thay i pH ca nc tiu, s lm thay i ion ha ca thuc dng km, lm thay i bi xut ca thuc. Th d barbital c pK a = 7,5; pH = 7,5 th 50% thuc b ion ha; pH = 6,5 th ch c 9% b ion ha pH = 9,5 th 91% barbital b ion ha. V vy, khi ng c cc thuc barbiturat, truyn dch NaHCO3 base ha nc tiu s tng bi xut barbiturat. Cc thuc l acid yu (vitamin C, amoni clorid) dng liu? cao, lm acid ha nc tiu s lm tng thi tr thuc loi alcaloid (quinin, morphin). - Bi xut tranh chp ti ng thn: do 2 cht cng c c ch bi xut chung ti ng thn nn tranh chp nhau, cht ny lm gim bi xut cht khc. Dng probenecid s lm chm thi tr penicilin, thiazid lm gim thi tr acid uric nn c th gy bnh gut. 1.3. Kt qu v ngha ca tng tc thuc 1.3.1. Tc dng hip ng Thuc A c tc dng l a, thuc B c tc dng l b. Khi kt hp thuc A vi thuc B

c tc dng c. Nu c = a + b, ta c hip ng cng (additive effect) c > a + b, ta c hip ng tng mc (synergysm) Hip ng cng thng khng c dng lm s ng v nu cn th tng liu thu c ch khng phi hp thuc. Hip ng tng mc thng dng trong iu tr lm tng tc dng iu tr v l m gim tc dng ph, tc dng c hi. Hai thuc c hip ng tng mc c th qua tng t c 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 d ng 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 h on 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 t ng k (incompatibility), mt loi tng tc thun ty l ha: + 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 ha (vitamin C, B 1, penicilin) khng trn vi thuc oxy kh (vi-tamin 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 l m gim tc dng ca nhau (qua dc lc hc), ta gi l i khng (an-tagonism) V dc lc hc, c ch ca tc dng i khng c th l: + Tranh chp trc tip ti receptor: ph thuc vo i lc v nng ca thuc ti receptor. Th d: acetylcholin v atropin ti receptor M

cholinergic; histamin v cimetidin trn receptor H 2 d dy. + i khng chc phn: hai cht ng vn (agonist) tc dng trn 2 receptor khc nhau nhng chc phn li i khng trn cng mt c quan. Strychnin kch thch tu sng, gy co git; cura c ch dn truyn tm vn ng, gy mm c, chng c co git. Histamin

kc h thch receptor H1 lm co c trn kh qun, gy hen; albuterol (Ventolin), kch thch rec eptor 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 tch 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 tuyng 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 ha) - Lm gim s quen thuc v khng thuc Tuy nhin, nu khng hiu r tc dng phi hp, thy thuc c th lm gim tc d ng iu trhoc tng tc dng c ca thuc. Trong cc sch hng dn dng thu c, thng c mc tngtc ca tng thuc.

2. TNG TC THUC - THC N- UNG 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 ch c nng hp thu ca b my tiu ha. Tuy nhin, do pH rt acid (khi i, pH 1; khi no pH 3) cho nn cn lu : + Ung thuc lc i, thuc ch gi li trong d dy khong 10 - 30 pht. + Ung thuc vo lc no, thuc b gi li trong d dy khong 1 - 4 gi, do : . Nhng thuc t tan s c thi gian tan, khi xung rut s c hp thu nhanh hn (penicilin V). Tuy nhin, nhng thuc d to phc vi nhng thnh phn ca thc n s

b gi m hp thu (tetracyclin to phc vi Ca ++ v mt s cation ho tr 2 khc). . Cc thuc km bn trong mi trng acid (ampicilin, erythromycin) nu b gi l u d dy s b ph hu nhiu. . Vin bao tan trong rut s b v (cn ung trc ba n 0,5 - 1h hoc sau ba n 1 - 2 gi) . Nhng thuc d kch ng ng tiu ha, n n ung vo lc no. - S hp thu cn ph thuc vo dng bo ch: aspirin vin nn ung sau khi n s g im hp thu 50%, trong khi vin si bt li c hp thu hon ton. 2.1.2. Thc n lm thay i chuyn ha v thi tr thuc Thc n c th nh hng n enzym c huyn ha thuc ca gan, nh hng n pH ca nc tiu, v qua nh hng n chuyn ha v bi xut thuc. Tuy nhin, nh hng khng ln. Ngc li, thuc c th nh hng n chuyn ha mt s cht trong thc n. Thuc c ch enzym mono- amin- oxydase (MAOI) nh iproniazid - l enzym kh amin - oxy ha ca nhiu amin ni, ngoi sinh c th gy cn tng huyt p kch pht khi n cc thc n c nhiu tyramin (nh khng c chuyn ha kp, lm gii phng nhiu noradrenalin ca h giao c m 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 t ng k khi ha tan thuc. - Nc l phng tin dn thuc (dng vin) vo d dy rut, lm tng tan r v ha tan hot cht, gip hp thu d dng. V vy cn ung nc (100 200 mL cho mi ln ung thuc) trnh ng vin thuc ti thc qun, c th gy kch ng, lot. - c bit cn ch : + Un?g nhiu nc trong qu trnh dng thuc (1,5 2 l/ ngy) lm tng tc dng ca thu c (cc loi thuc ty), lm tng thi tr v lm tan cc dn xut chuyn ha ca thuc (sulfamid, cyclophosphamid). + Ung t nc hn bnh thng duy tr nng thuc cao trong rut khi

ung thuc ty sn, ty giun (niclosamid, mebendazol). + Trnh dng nc qu, nc khong base hoc cc loi nc ngt ng hp c g as 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, lincomyc in, mui Fe) Nhng thuc d tan trong lipid s tan trong lipid ca sa chm c hp thu. Protein ca sa cng gn thuc, lm cn tr hp thu. Sa c pH kh cao nn lm gim s kch ng d dy ca cc thuc acid. 2.2.3. C ph, ch - Hot cht cafein tr ong 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 al caloid - Cafein cng gy ta aminazin, haloperidol, lm gim hp thu; nhng li lm tng ha tan ergotamin, lm d hp thu. 2.2.4. Ru ethylic Ru c rt nhiu nh hng n thn kinh trung ng, h tim mch, s hp thu ca ng tiu ha. Ngi nghin ru cn b gim protein huyt tng, suy gim chc nng gan, nhng li gy cm ng enzym chuyn ha thuc ca gan (xin xem bo ru), v th ru c t ng tc vi rt nhiu thuc v cc tng tc ny u l bt li. Do khi dng thuc th khn g ung ru. Vi ngi nghin ru cn phi dng thuc, thy thuc cn kim tra chc nng g an, tnh trng tm thn chn thuc v dng liu lng thch hp, trong thi gian dng thu c cng phi ngng ung ru. 3. THI IM UNG THUC Sau khi nhn r c tng tc g ia 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 gi m c tc dng ph l rt cn thit.

Nn nh rng: ung thuc vo lc i, thuc ch b gi li d dy 10 30 pht, vi pH 1; ung lc no (sau n), thuc b gi li 1 - 4 gi vi pH 3,5. Nh vy, tuz 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 lo t 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 ch m. 3.2. Thuc nn ung vo lc no (trong hoc ngay sau ba n) - Thuc kch thch bi tit dch v (ru khai v), cc enzym tiu ha (pancre-atin) ch ng i tho ng loi c ch gluconidase nn ung trc ba n 10 - 15 pht. - Thuc kch thch d dy, d gy vim lot ng tiu ha: cc thuc chng vim phi steroid, mu?i kali, quinin

- Nhng thuc c thc n lm tng hp thu, hoc do thc n lm chm di

chuy n thuc nn ko di thi gian hp thu: cc vitamin, cc vin nang amox-icilin, cephalexin, cc vin nn digoxin, sulfamid. - Nhng thuc c hp thu qu nhanh lc i, d gy tc dng ph: lev-odopa, 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 v o 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 n n 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 ng y m. Tuy nhin, trong iu tr, vic cho thuc cn tuz th uc vo thi gian xut hin triu chng.

BI 6. IU TR NG C THUC CP TNH 1. I CNG 1.1. Nguyn nhn ng c thuc cp tnh :

+ Do nhm ln : ca thy thuc hoc ca bnh nhn + Do nhm ln : - Loi thuc, - Liu lng - ng dng - Thi gian dng + Do c : - Ca bnh nhn : t t - Ca ngi khc : uc

1.2. Triu chng ng c thuc cp tnh : Khng c hiu : + Ri lon thn kinh : ng li b, hn m hoc kch ng, co git + Ri lon tim mch : ri lon nhp tim, gim hoc tng huyt p + Ri lon h hp : kh th, tng tit m ri, ri lon h hp chu kz + Ri lon tiu ha : au bng d di, nn ma, xut huyt tiu ha + Ri lon thn - tit niu : b i, thiu niu, v niu ( suy thn cp ).

1.3. Nguyn tc iu tr : + Nhanh chng loi tr cht c ra khi c th. + Trung ha cht c c hp thu vo c th. + iu tr triu chng v hi sc cho bnh nhn.

2. CC BIN PHP IU TR : 2.1. Loi tr cht c ra khi c th :

2.1.1. Qua ng tiu ha : a- Gy nn : + Siro ipeca 15 - 20 ml, pha long trong 250 ml nccho bnh nhn ung. Nu sau 15 ph bnh nhn khng nn c th dng nhc li. + Trng hp khng c thuc, bnh nhn cn tnh, c th ngoy hng, cho ung mn tht, hoc ung 250 ml dung dch natri clorid ( NaCl ) u trng. + CC : bnh nhn hn m, ng c cc acid, base mnh. b- Ra d dy :bng dung dch thuc tm ( KMnO4 ) 0,1 %, tanin ( acid tanic ) 5% hoc nc m cho ti khi nc ra tr thnh trong. + Vi cc thuc hp thu nhanh nh aspirin, cloroquin, meprobamat, thuc ng barbiturat, colchicin th ra d dy v gy nn ch c tc dng trong vng 6 h u, khi cht c cn d dy. + i v?i nhim c cc loi thuc ng BZD, cc thuc c chu kz gan-rut?, nhim c hn hp hoc nhim c cc cht khng r th nn ra d dy trong vng 24 h ( nu khng c chng ch nh ) + BZD : benzodiazepin, + Cc thuc c chu kz gan-rut : morphin, strychnin, cloramphenicol, chlor-promazin,tetracyclin, quinin, sulfamid chm, cc hormon sinh dc, digitoxin, imipramin + CC : bnh nhn hn m ( v d a nhm ng cao su vo kh qun hoc cht nn quay ngc ng vo phi, gy t vong ), ng c cc cht n mn ( nh acid, base mnh v ng cao su c th lm rch thc qun ). c- Dng cc cht hp ph : Sau khi ra d dy, cho ung than hot 30 - 40 g/ln, cch 4 h/ln ( u im ? ). + C nhiu u im : - Hon ton khng c, - R tin, - S dng n gin, thun tin - Ngn cn c chu kz gan - rut ca cc thuc thi theo ng mt. + Cht thay th ? Cht thay th :kaolin hoc bt than ci, bt go, bt ng rang chy tn nh. 2.1.2. Qua ng h hp : + Ch nh :ng c cc thuc thi qua ng h hp nh cc thuc m th kh ( ether, halothan), ru, kh t, xng, carbon monoxyd ( CO ), ace-

ton + Cc thuc hay dng : - Pentetrazol ( BD : cardiazol, corazol, tetracor.. ), ng 1 - 5 - 10 ml dd 10 %. Tim SIV, IM 0,5 -1,0 g tuz BN. L 10 - 30 ml dd 10 % : ung 20 git/ln x 2 - 3 ln/24 h. Vin nn 0,10 : ung 1 - 2 vin/ln x 2 - 3 ln/24 h. - Lobelin : ng 3 - 10 mg/1 ml. Tim IM, SC 10 mg hoc tim IV chm 3 mg + H hp nhn to. 2.1.3. Qua ng tit niu :

a- Thuc li niu thm thu : + Mannitol ( BD : mannidex, osmitrol, osmos-al ). L 100 - 250 - 500 - 1.000 ml dd 10 - 20 %. Truyn IV 1 - 2 g/kg, tc 10 - 20 ml/1 ph ( tuz bnh nhn ). + Glucose u trng 10 - 20 - 30 % + Ringer lactat ( 1 l dd cha 3,1 g natri lactat; 6 g NaCl; 0,4 g KCl; 0,4 g CaCl2 ). t dng. * Chng ch nh chung: suy thn nng, suy tim nng, ph phi cp, tng huyt p, try tim mch nng * Ch : ch nn dng cc thuc li niu thm thu khi chc chn chc nng thn cn tt. Khi dng cc thuc ny s lm tng thi tr cc khng sinh nn cn phi tng liu khng sinh. b- Kim ha nc tiu :p dng khi iu tr ng c cp cc thuc c bn cht l acid yu ( thuc ng barbiturat, NSAID ( aspirin, diclofenac, indomethacin, phenylbutazon )). Thng dng 2 loi sau : + Natri hydrocarbonat ( NaHCO3 ). L 500 ml dd ng trng 1,4 %. Truyn nh git IV 2 - 3 l/24 h. - Nhc im : a thm Na+ vo c th, do d gy tai bin ph no khi chc nng thn khng tt ( 1 g NaHCO3 c 0,273 g Na ). + Trometamol ( THAM, trihydroxymetylaminmetan ). - Bit dc : alcaphor, talatrol, thamac tat, tham E - L 250 ml dd tim truyn 9,15 g km 1,5 g acid acetic kt tinh v pH 8,6. Ngi ln truyn IV 1 g/3 kg/24 h ( 250 - 500 ml ). c- Acid ha nc tiu : p dng khi iu tr ng c cc thuc c bn cht base hu c : quinin, cloroquin, dn xut quinolein, imipramin, mecamy-

lamin, quinacrin, nicotin, procain, phenothiazin Hay dng : + Amoni clorid ( TK : amchlor, acid-amon ). Dng bt, ung 3,0 - 6,0 g/24 h ( c th 10,0 - 12,0 g/24 h ), chia lm 2 - 3 ln. + Acid phosphoric : ung 15 - 100 git/24 h ( pha vi nc ). Vic acid ha kh thc hin hn vic kim ha nc tiu, ng thi c th chu ?ng tnh trng nhim toan k m hn tnh trng nhim kim nn cng d gy nguy him cho c th.

2.2. Trung ho cht c : Trong lm sng thng hay dng cc cht tng k ha hc ngn cn hp thu cc cht c, lm mt hot tnh hoc i khng vi tc dng ca cht c. 2.2.1. Cc cht tng k ha hc ti d dy : ngn cn hp thu cht c vo c th, sau khi ra d dy c th cho bnh nhn ung cc thuc : + Tanin 1 - 2 %, 100 - 200 ml ( tanin 5 % ra d dy ) + C th thay bng nc ch xanh, l i, sim, b gic Tanin c tc dng lm kt ta nhiu alcaloid nh strychnin, quinin, quinidin, apomorphin, morphin, cocain, cc kim loi nng ( mui km, coban, ng, ch, thy ngn ). + Sa, lng trng trng ( 6 qu trng/1 l nc ) : ngn cn hp thu cc mui thy ngn, phenol. + Than hot ( BD : carbolenum, ostacol, medicoal ). C dng bt, vin nn 0,25 0,50 g , nh dch 2 %. Ung 30 - 40 g bt/ln, ngy 3 - 4 ln, cch nhau 4 h. C th thay bng bt go, bt ng rang chy, kaolin. Than hot c tc dng hp ph mnh trong cc trng hp nhim c cc alcaloid ( morphin, strychnin ), cc mui kim loi nng ( sublime - HgCl2 ), cc cht mang in tch (+) v (-) cho nn c th p dng c trong hu ht cc trng hp nhim c qua ng tiu ha. 2.2.2. Cc cht tng k ha hc dng ng ton thn : To Met-Hb : khi iu tr ng c acid cyanhydric - HCN ( Sn ). + Natri nitrit 3 % ( l 0,3 g/10 ml ) Tim IV 1 l trong 3, sau 5 tim IV 50 ml dd natri thiosulfat 50 % ( cn c ng natri thiosulfat 0,5 g/5 ml, 2 g/10 ml ). + Dimercaprol ( BAL = British anti Lewisit ). ( BD : antoxol, dicaptol, dithioglycerin ), ng 100 mg/1 ml v 200 mg/2 ml. - iu tr ng c cc kim loi nng ( arsen, vng, thu ngn ).

Lewisit = yperit : cht c gy ngt Tim IM 2 - 3 mg/kg/ln : - Ngy N1, 2 : cch 4 h tim 1 ln, - Ngy N3 : cch 6 h tim 1 ln. - Cc ngy sau : 2 ln/24h. + EDTA ( ethylen diamino tetraacetic acid ) hoc cc mui Na v Ca ca acid ny ( EDTA calci dinatri v EDTA dinatri ( Na2EDTA ) iu tr ng c cc ion ha tr 2 nh Pb2+, Fe2+, Cr2+, Cu2+ v digitalis ( thi tr Ca2+ ). - EDTA dinatri ng 0,5 g/10 ml. Pha vo dung dch glucose hoc NaCl ng trng, truyn IV rt chm 1 - 2 ng/24h ( trong 2h ) ( trnh cn tetani ). t iu tr 5 ngy, ngh 7 ngy mi c iu tr t tip theo. - EDTA calci dinatri ng 0,5 g/10 ml. Cch dng : ng IV : pha 1 ng trong 250 - 500 ml dd glucose 5 %, truyn IV chm trong 2 h, chia lm 2 ln/ngy. Liu trung bnh : 15 - 25 mg/kg/24 h, ti a 50 mg/kg/24 h. t iu tr 5 ngy, ngh 2 ngy gia 2 t iu tr. ng tim IM : dd 20 %. Liu lng : 12,5 mg/kg/ln, cch 4 - 6 h tim 1 ln, ti a 50 mg/kg/24 h. Ha thm dd procain 1 % tim IM. 2.2.3. S dng cc thuc i khng dc l c hiu : + V d : naloxon ( BD : nalon, narcan ), ng 0,4 mg/1 ml; tim IV, tim IM iu tr ng c morphin v cc thuc gim au gy nghin. Tuy phng php ny iu tr c hiu qu nhanh v tt, nhng do c rt t thuc c tc dng i khng c l{ c hiu, cho nn phn ln phi iu tr theo triu chng.

2.3. iu tr triu chng v iu tr hi sc cho bnh nhn : 2.3.1. S dng cc thuc i khng sinh l : + Dng cc thuc kch thch TKTW iu tr ng c cc thuc c ch TK-TW v ngc li. - Thuc kch thch TKTW: bemegrid, cafein, amphetamin, long no, pentetra-zol - Thuc c ch TKTW : thuc ng barbiturat, thuc an thn, thuc m.. + Dng thuc gin c cura iu tr ng c cc thuc gy co git ( pentetra-zol, strychnin ). * Nhc im : phi dng thuc i khng vi liu cao, thng l liu c cho

nn c hi cho bnh nhn. 2.3.2. Hi sc tng hp : a- Hi sc tim mch : dng cc thuc tr tim gi n nh huyt p, chng try tim mch. + VD : dng nordrenalin ng 1 mg/1 ml. Pha 1-4 ng trong 500 - 1000 ml dd glucose 5 %, truyn SIV ( tc 2 - 4 mg/1 ph ). + DOCA ( desoxycorticosteron acetat ), ng 5 - 10 mg, vin t di li 5 mg. Tim IM 1 2 ng/24 h. Nu nh cho ngm di li 1 - 2 vin/24 h. b- Hi sc h hp : dng cc thuc kch thch h hp : + Pentetrazol ( BD : cardiazol, corazol ) ng 0,10 g/1 ml. Tim IM, SC, IV ti 6 - 8 ng/24 h. + Cafein ng 0,07 - 0,25 - 0,40 g/1 ml. Tim SC 0,07 - 1,5 g/24 h. + H hp nhn to, th oxy. c- Thm phn phc mc hoc chy thn nhn to: + Ch nh : - Cc trng hp nhim c nng ( ng c cc kim loi nng, sulfamid, bar-biturat liu cao ) - Khi thn suy, cc phng php iu tr thng thng khng mang li kt qu. - Khi c chng ch nh dng cc thuc li niu thm thu. d- Thay mu :ch nh : + Ng c phospho trng : phi lm sm trc 8 h k t khi ng c mi c kh nng cu c nn nhn. + Ng c cc thuc vi liu cht : cc thuc chng st rt, cht c t bo ( cc thuc chng ung th ), isoniazid, dn xut salicylat ( nht l tr em ) + Cc cht lm tan mu : saponin, sulfon + Cc cht gy Met-Hb : anilin, thuc gim au h st dn xut anilin ( phenacetin, paracetamol ), nitrit, cloroquin Giai on u c th iu tr bng xanh methylen ng 0,10 g/ 5 ml. Pha 10 ml vo 500 ml dd glucose 5%, truyn IV. Hoc tim IV vitamin C 4,0 - 6,0g/24h. Nu khng c kt qu th phi thay mu. * Ch : bin php thay mu cn phi lm sm v khi lng mu thay

th phi ln ( 7 l ) th mi c kt qu. Nu ngy hm sau mu cn cha nhiu Met-Hb th c th phi truyn li.

2.3.3. Cng tc chm sc ngi bnh : a- Ch dinh dng :cho n cc thc n nh ( cho, sp, ph ), d tiu, ca-lo. Nu bnh nhn khng n c phi t sonde d dy hoc truyn hu mn khi c tn thng thc qun ( ng c acid, base mnh ) Cn b sung thm nhiu vitamin, nht l vitamin nhm B, C. B sung thm insulin khi truyn nhiu glucose. b- Chng bi nhim ( ph qun, phi, ng tit niu ) : khng sinh. c- Cng tc h l : gi v sinh thn th sch s, chng lo t, ht m ri

BI 7. I CNG V DC LC HC Dc lc hc nghin cu tc dng ca thuc ln c th sng, gii thch c

ch ca cc tc dng sinh ha v sinh l ca thuc. Phn tch cng y c cc tc dng, cng cung cp c nhng c s cho vic dng thuc hp l trong iu tr. y l nhim v c? bn nh t 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 recep tor (th th cm). Receptor l mt thnh phn i phn t (macromolcular) tn ti vi mt l ng gii hn trong mt s t bo ch, c th nhn bit mt cch c hiu ch mt phn t th ng tin t nhin (hormon, cht dn truyn thn kinh), hoc mt tc nhn ngoi lai (cht ha hc, t huc) gy ra mt tc dng sinh hc c hiu, l kt qu ca tc dng tng h . Thnh phn i phn t ca receptor thng l protein v ch c protein mi c cu trc phc tp

nhn bit c hiu ca mt phn t c cu trc 3 chiu. Receptor c 2 chc phn: 1) Nhn bit cc phn t thng tin (hay cn gi l ligand) bng s gn c hiu cc phn t ny vo receptor theo cc lin kt ha hc: - Lin kt ion: cc cht ha hc mang in tch (nh nhm amoni bc 4 cu acetylc holin 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 ha tr: l lc lin kt gia cc nguyn t bng nhng cp in t c hung. 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. Th d lin kt gia cht alkyl ha vi t bo ung t h, cc thuc c ch enzym mono - amin oxydase (MAOI), thuc tr su ln hu c vi cholinesterase. Mt phn t thuc c th gn vo receptor theo nhiu kiu lin kt. Th d: acetylcholin gn vo receptor M- cholinergic:

Hnh 2.1. Phc hp acetylcholin - receptor M

Acetylcholin gn vo receptor M theo ng ni sau: - Hai O ca chc ester to lin kt hydro vi receptor

- Nhm CH2- CH2 gn vi receptor bng lin kt phn t (lc Van - der- Waals) - Hai gc CH3 ca amin bc 4 gn vo cc khoang ca v tr anion cng bng lc Van- der- Waals 2) Chuyn tc dng tng h gia ligand v receptor thnh mt tn hiu gy ra c p ng t bo. Cc receptor nm nhn t bo c hot ha bi cc ligand gn trn cc v tr c hiu ca ADN nm trong cc vng iu ha gen, gy ra s sao chp cc gen c hiu (r eceptor ca hormon steroid, vitamin D 3). 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 rece ptor s lm sn 2+xut ra cc phn t trung gi?an - ngi truyn tin th 2 (AMPv, GMPv, IP 3, Ca, diacetyl glycerol)- Nhng cht ny s gy ra mt lot phn ng trong t bo, dn ti mt thay i chuyn ha trong t bo, cng vi hoc khng c s thay i v biu hin gen (receptor ca adrenalin, ca benzodiazepin). Nh vy, khi thuc gn vo receptor ca t bo th gy ra c tc dng sinh l. Nhng c khi thuc gn vo t bo m khng gy ra tc dng g, ni gn thuc c gi l ni tip nhn (acceptor) hoc receptor cm, (silent receptor) nh thuc m gn vo t bo m, digitalis gn vo gan, 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 c a 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 r eceptor M, gy hiu lc lm tng tit nc bt, co ng t, chm nhp tim; atropin c i lc tr n receptor M mnh hn acetylcholin rt nhiu nn y c acetylcholin ra kh i receptor M, n hng 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 c a 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 d n truyn thn kinh): nhiu thuc tc dng trn cc receptor sinh l v thng mang tnh c hiu. Nu tc dng ca thuc ln rec eptor ging vi cht ni sinh, gi l cht ng vn hay cht ch vn (agonists), nh pilocarpin trn receptor M cholin-ergic. 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 dn g c ch cht ng vn, c gi l cht i khng (antagonists), nh d tubocurarin tranh chp vi acetylcholin ti receptor N ca c vn. - Mt s thuc thng qua vic gii phng cc cht ni sinh trong c th gy tc dng: amphetamin gii phng adren alin trn thn kinh trung ng, nitrit lm gii phng NO gy gin mch Xt trn nhiu mt, protein l mt nhm quan trng ca receptor thuc. Do , ngoi receptor t bo, cc receptor ca thuc cn l: - Cc enzym chuyn ha hoc iu ha cc qu trn h sinh ha c th b thuc c c h hoc hot ha: . Thuc c ch enzym: captopril c ch enzym chuyn angiotensin I khng hot tnh thnh angiotensin II c hot tnh dng cha cao huyt p; cc thuc chng vim phi steroid c ch cyclooxygenase, lm gim t ng hp prostaglandin nn c tc dng h st, chng vim; thuc tr tim digitalis c ch Na +- K+ ATPase . Thuc hot ha enzym: cc yu t vi lng nh Mg 2+, Cu2+, Zn2+ hot ha nhiu enzym protein kinase, phosphokinase tc dng ln nhiu qu trnh chuy n ha ca t bo. - Cc ion: thuc gn vo cc knh ion, lm thay i s vn chuyn ion qua mng t bo. Novocain cn tr Na + nhp vo t bo thn kinh, ngn cn kh cc nn c tc dng gy t; benzodiazepi?n lm tng nhp Cl - vo t bo, gy an thn. 1.2.2. Tc dng ca thuc khng qua receptor Mt s thuc c tc dng khng phi do kt hp vi receptor. - Thuc c tc dng do tnh cht l ha, khng c hiu: Cc mui cha cc ion kh hp thu qua mng sinh hc nh MgSO 4, 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 huy t tng. Khi lc qua cu thn, kh ng b ti hp thu ng thn, lm tng p lc thm thu tron g ng thn, c tc dng li niu. Nhng cht to chelat hay cn gi l cht cng cua do c cc nhm c cc nh OH, -SH, NH2, d to phc vi cc ion ha tr 2, y chng ra khi c th. Cc c ht cng c ua nh EDTA (ethyl diamin tetra acetic acid), BAL (British anti lewisit

dimercaprol), d- penicilamin thng c dng cha ng c kim loi nng nh Cu 2+, Pb2+, Hg2+ hoc thi tr Ca 2+ trong ng c digital. Than hot hp ph c cc hi, cc c t nn dng cha y hi, ng c. Cc base yu lm trung ha dch v acid dng cha lot d dy (khng acid), nh hydroxyd nhm, magnesi oxyd.

Thuc c cu trc tng t nh nhng cht sinh ha bnh thng, c th thm n hp vo cc thnh phn cu trc ca t bo, lm thay i chc phn ca t bo. Thuc ging purin, ging pyrimidin, nhp vo acid nucleic, dng chng ung th, chng virus. Sul-famid gn ging paraamino benzoic acid (PABA), lm vi khun dng nhm, khng pht trin c.

2. CC CCH TC DNG CA THUC Khi vo c th, thuc c th c 4 cch tc dng sau: 2.1. Tc dng ti ch v ton thn: - Tc dng ti ch l tc dng ngay ti ni thuc tip xc, khi thuc cha c hp thu vo mu: thuc st khun ngoi da, thuc lm sn nim mc (tani n), thuc bc nim mc ng tiu ha (kaolin, hydroxyd nhm).

- Tc dng ton thn l tc dng xy ra sau khi thuc c hp thu vo mu qu a ng h hp, ng tiu ha hay ng tim: thuc m, thuc tr tim, thuc li niu. Nh vy, tc dng ton thn khng c ngha l thuc tc dng khp c th m ch l thuc vo m u 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 ammoni ac, cc ngn dy thn kinh trong nim mc ng h hp b kch thch, gy phn x kch thch trung tm h hp v vn mch hnh ty, lm ngi bnh 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 dng ngoi (adverse drug reactions ADR). Cc tc dng ngo?i c th ch gy kh chu cho ngi dng (chng mt, bu n nn, mt ng), gi l tc dng ph; nhng cng c th gy ph n ng c hi (ngay vi liu iu tr) nh xut huyt tiu ha, gim bch cu, tt huyt p th ng Th d: aspirin l thuc h st, gim au, chng vim (tc dng chnh), nhng gy chy mu tiu ha (tc dng c hi). Nifedipin, thuc chn knh calci dng iu tr tng huyt p (tc dng chnh), nhng c th gy nhc u, nhp tim nhanh (tc dng ph), ho, ph chn, 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 dn g khng mong mun. Th 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 ph c v khng hi phc

- Tc dng hi phc: sau tc dng, thuc b thi tr, chc phn ca c quan li tr v bnh thng. Sau gy m phu thut, ngi bnh li c trng thi bnh thng, tnh to. - Tc dng khng hi phc: thuc lm mt hon ton chc ph n ca t bo, c quan. Th d: thuc chng ung th dit t bo ung th, bo v t bo lnh; thuc st khun bi ngoi da dit vi khun nhng khng nh hng n da; khng sinh clo-ramphenicol c tai bin gy suy ty xng. 2.4. Tc dng chn lc Tc dng chn l c l tc dng iu tr xy ra sm nht, r rt nht. Th 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 h n, 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 re ceptor) v sau l hot ha c receptor (c hiu lc hay tc dng dc l). Receptor ma ng tnh c hiu cho nn thuc cng phi c cu trc c hiu. Receptor c v nh kha v thuc l cha kha. Mt s thay i nh v cu trc ha hc (hnh dng phn t ca thuc) cng c th gy ra nhng thay i ln v tc dng. Nh vy vic tng hp cc thuc mi thng nhm: - Lm tng tc dng iu tr v gim tc dng khng mong mun. Khi thm F vo v tr 9 v CH 3vo v tr 16 ca corticoid (hormon v thng thn), ta c betametason c tc dng chng vim gp 25 ln v khng c tc dng gi Na + nh corticoid, trnh phi n nht. - Lm thay i tc dng dc l{: thay i cu trc ca isoniazid (thuc chng

lao), ta c iproniazid, c tc dng chng trm cm, do gn vo receptor hon ton khc.

Sulfanilamid PABA (para amino benzoic acid)

Khng histamin H1 c cng thc gn ?ging vi histamin, tranh chp vi his-tamin ti receptor H 1. -

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 dn g 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 t huc rt c hiu, gn c vo di typ ca receptor: receptor adrenergic 1, 2, 1, 2, 3, receptor cholinergic M1, M2, M3, receptor dopaminergic D 1, D2, D7.

3.1.2. Thay i cu trc thuc, lm thay i dc ng hc ca thuc Khi cu trc ca thuc thay i, lm tnh cht l ha ca thuc thay i, nh hng n s ha tan ca thuc trong nc hoc trong lipid, nh hng n s gn thuc vo prote in, ion ha ca thuc v tnh vng bn ca thuc. Mt s v d: -

Dopamin khng qua c hng ro mu no, nhng l. dopamin (Levo dopa), cht tin thn ca dopamin th qua c. -

Estradiol thin nhin khng ung c v b chuyn ha mnh gan. dn xut et hinyl estradiol (-C CH gn v tr 17) rt t b chuyn ha nn ung c. -

Tolbutamid b microsom gan oxy ha gc CH 3 v tr para, c t/2 huyt tng l 4 - 8 h. Thay gc CH3 bng Cl (Clorpropamid) s rt kh b chuyn ha, lm t/2 ca thuc ko di ti 35 h. - Cc thiobarbituric t b phn ly hn barbituric pH ca ng thn nn b thi tr chm hn.

Qua y ta c th nhn th y rng, khi thuc gn vo receptor gy hiu lc, kh ng phi ton b phn t thuc m ch c nhng nhm chc phn gn vo receptor. Khi thay i cu trc ca nhm hoc vng chc phn, dc lc hc ca thuc s thay i. Cn khi thay i cu trc ngoi vng chc phn, c th thay i dc ng hc ca thuc. 3.2. Dng thuc Dng thuc l hnh thc trnh by c bit ca dc cht a dc cht vo c th. Dng thuc phi c bo ch sao cho tin bo qun, vn chuyn, s dng v pht huy ti a hiu lc cha bnh ca thuc. C th tm tt qu trnh hnh thnh v pht huy tc dng ca mt dng thuc tro ng c th nh sau:

Qua s , ta thy t 1 dc cht, cc nh bo ch c th a ra th trng

nhiu loi bit dc (dng thuc) khc nhau, c sinh kh dng khc nhau do c nh hng khc nhau ti hiu qu iu tr. 3.2.1. Trng thi ca dc cht - tn nh: thuc cng mn, din tip xc cng tng, hp thu thuc cng nhanh. - Dng v nh hnh v dng tinh th: thuc rn dng v nh hnh d tan, d hp thu. 3.2.2. T dc T dc khng phi ch l cht n bao gi thuc m cn nh hng n ha tan, khuch tnca thuc. Khi thay calci sul-fat (thch cao, t dc c in) bng lactose dp vin diphenylhydantoin, gy

hng lot ng c diphenylhydantoin do lng thuc c hp thu nhiu hn (c, 1968). Nguyn nhn l t dc calci sulfat ch ng vai tr mt khung mang, khng tiu v xp, lm dc cht ?c gii phng t t trong ng tiu ha. Cn la ctose 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, target-ting medication) - Thuc c sinh kh dng cao. 3.3. V ngi dng thuc 3.3.1. c im v tui (xin xem phn dc ng hc) 3.3.1.1. Tr em: Tr em khng phi l ngi ln thu nh li, ngha l khng phi ch gim liu thuc ca ngi ln th thnh liu ca tr em, m tr em cn c nhng c im ring ca s pht trin, l: - S gn thuc vo protein huyt tng cn t, mt khc, mt phn protein huyt t ng cn gn bilirubin, d b thuc y ra, gy ng c bilirubin. - H enzym chuyn ha thuc cha pht trin - H thi tr thuc cha pht trin - H thn kinh cha pht trin, myelin cn t, hng ro mu no cha bo v nn thuc d thm qua v t bo thn kinh cn d nhy

cm (nh vi morphin) - T bo cha nhiu nc, khng chu c thuc gy mt nc. - Mi m v c quan ang pht trin, ht sc thn trng khi dng cc loi hormon. Mt s tc gi a ra cc cng thc tnh liu lng cho tr em:

BSA: Body Surface Area -Din tch c th (tra monogram)

1.7: BSA trung bnh ca ngi ln 3.3.1.2. Ngi cao tui Ngi cao tui cng c nhng c im ring cn lu {: - Cc h enzym u km hot ng v lo ha - Cc t bo t gi nc nn cng khng chu c thuc gy mt n c - Ngi cao tui thng mc nhiu bnh (cao huyt p, x va mch, thp khp, ti u ng) nn phi dng nhiu thuc mt lc. Cn rt ch tng tc thuc khi k n (xin xem phn tng tc thuc) 3.3.2. c im v gii Nhn chung, khng c s kh c bit v tc dng v liu lng ca thuc gia nam v n. Tuy nhin, vi n gii, cn ch n 3 thi kz: 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 gi a thuc c th nh hng xu n s pht trin ca bo thai, n chc phn pht trin ca cc c quan. Trong 3 thng cui, thuc c th gy xy thai, non. V vy, khi cn ch nh thuc cho ph n c thai, cn cn nhc tht k gia li ch cho ngi m v mc nguy hi cho bo thai. Ni

chung, trong 3 thng u, tuy?t i trnh dng mi loi thuc. i vi ngi m, khi c thai, lng nc gi li trong c th tng, th tch mu t ng, hm lng protein huyt tng c th gim, lng lipid c th tng lm nh hng n ng hc ca thuc. 3.3.2.3. Thi k cho con b Rt nhiu thuc khi dng cho ngi m s thi tr qua sa v nh vy c th gy c hi c ho 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 q ua sa v trung tm h hp ca tr rt nhy cm, c th b ngng th. Khng dng cc loi cortico id (lm suythng thn tr), cc khng gip trng tng hp v iod (gy ri lon tuy n gip), cloramphenicol v thuc phi hp sulfametoxa zol + 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 TH UC 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 p hn 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 tri u 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. Tuz theo nc v tuz 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 AD R. Do thuc l 1 protein l (insulin, thyroxin ly t sc vt), l a peptid, polysacchari d c phn t lng cao, mang tnh khng nguyn. Tuy nhin, nhng thuc c phn t lng th p hoc chnh sn phm chuyn ha 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 n g ni cng ha tr v to thnh phc hp khng nguyn. Nhng thuc c mang nhm NH 2 v tr para, nh benzocain, procain, sul-fonamid, sulfonylurea l nhng thuc d gy mn cm v nhm NH 2 d b oxy ha v sn phm oxy ha 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 ph n v (anaphylactic reactions) do s kt hp ca khng ng uyn vi khng th IgE, gn trn bch cu a base tun hon hoc cc dng bo. Phn ng lm gii phng nhiu cht ha hc trung gian nh histamin, leucotrien, prostaglandin, gy gin mch, ph v vi m. Cc c quan ch ca phn ng ny l ng tiu ha? (d ng thc n), da (my ay, v im 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: thu c t procain, lidocain, khng sinh

nhm lactam, aminoglycosid, huyt thanh, globulin, vaccin, vitamin B 1 tim tnh mch. -

Typ II hay phn ng hu t bo (cytolytic reactions) xy ra khi c s kt hp khn g nguyn vi khng th IgG v IgM ng thi c s hot ha h b th. M ch ca phn ng ny l cc t bo ca h tun hon. Th d: thiu mu tan mu do penicilin, thiu mu tan mu t min do methyl dopa, ban xut huyt gim tiu cu do quinidin, gim bch cu ht do sulfamid, luput ban h thng do procainamid. -

Typ III hay phn ng Arthus, trung gian ch yu qua IgG c s tham gia ca b th . Phn ng gia khng nguyn v khng th to thnh phc hp min dch. Phc hp ny lng ng vo ni mc mch, gy tn thng vim hu hoi, c gi l bnh huyt thanh. Biu hin lm sng thng l: my ay, ban , au, vim khp, 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, mu i 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 m n cm v i thc bo. Khi cc t bo mn cm tip xc vi khng nguyn, s gii phng cc ly mphokin 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 dn g v thng c d ng cho. V vy cn hi tin s d ng ca bnh nhn trc khi dng thuc. V i 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 B 1 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. tc. PD) hoc glutathion reductase d b thiu mu tan mu khi dng primaquin, quinin, pamaquin (xin xem bi Thuc chng st rt), sulfamid, nitrofu-ran quinin, pamaquin (xin xem bi Thuc chng st rt), sulfamid, nitro-furan PD nm trn chromosom X, v vy, tai bin thng xy ra nam. Ngi ta c lng c khong 100

200 triu ngi mang gen ny v thng gp trn ngi da en. Ngi thiu enzym methe moglobin reductase l nhng ngi d hp t (khong 1% dn s). Khi dng thuc st rt (pamaquin, primaquin), thuc khng sinh, st khun (clo-ramph enicol, sulfon, nitrofurantoin), thuc h st (phenazol, paracetamol) rt d b methemoglobin. Ngi thiu ac etyl transferase s chm acetyl ha mt s thuc nh hy-dralazin, isoniazid, phenelzin nn d b nhim c cc thuc ny. Hin tng c ng (idiosyncrasy) l nhy cm c nhn bm sinh vi thuc ch nh l s thiu ht di truyn 1 enzym no . 4.4. Quen thuc Quen thuc l s p ng vi thuc yu hn hn so vi ngi bnh thng dng c? ng 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 ha nhanh, hoc c th km mn cm vi thuc. Thng do nguyn nhn di truyn. Thng gp quen thuc do mc phi sau mt thi gian dng thuc, i hi phi tng dn liu. 4.4.1. Quen thuc nhanh (tAChyphylaxis) Thc nghim dng nhng liu Thc nghim dng nhng liu

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, isopre-nalin, 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 ha c tc dng i khng vi ch t m: isoprenalin (cng giao cm) qua chuyn ha 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 t ng liu hoc i thuc khc. C nhiu nguyn nhn: -

Do gy cm ng enzym chuyn ha thuc, lm nhng liu thuc sau b chuyn h a nhanh, mt tc dng nhanh. Barbiturat, diazepam, tolbutamid, ru ethylic u l nhng thuc gy cm ng enzym chuyn ha ca chnh n. - Do gim s lng receptor c m ng vi thuc mng t bo (iu ha gim

down regulation): khi dng thuc cng giao cm, ph giao cm ko di Tri li, khi dng cc thu c phong to ko di s lm tng s lng receptor (iu ha 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 h oc 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 t m 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 - C khuynh hng tng liu -

Thuc lm thay i tm l v th cht theo hng xu: ni iu, li lao ng, b n 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 tr ung ng gy sng khoi

lng lng, o nh, o gic (ph thuc) hoc trng thi hng phn mnh (thuc lc), c gi c hung l ma ty: morphin v cc cht loi thuc phin (heroin, pethidin, methadon), co-cain, cn sa (cannabis, marijuana), metamphetamin, ectasy Ru v thuc l hin cn c coi l ma ty h?p 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 phn ca nron, gy phn ng b tr ca c th; to ra cht i khng vi ma ty nn i hi phi tng liu Hin nay khng c phng php cai nghin no c hiu qu, ngoi tr ch ca ng i nghin. V vy, nghin ma tu l mt t nn x hi phi c loi tr.

BI 8. THUC TC DNG TRN H ADRENERGIC H adrenergic l h hu hch giao cm, gii phng cht trung gian ha hc

gi chung l catecholamin v u mang nhn catechol (vng benzen c hai nhm OH v tr ortho v mt gc amin chui bn. Cc catecholamin gm c adrenalin (c sn xut ch yu tu thn g thn)

noradrenalin ( u tn cng cc si giao cm) v dopamin ( mt s vng trn th n kinh trung ng).

Hnh 6.1. Sinh tng hp catecholamin

CHUYN HA CA CATECHOLAMIN Catecholamin c sinh tng hp t tyrosin di tc dng ca mt s en-

zym trong t bo a crm tu thng thn, cc nron hu hch giao cm v mt s nron ca thn kinh trung ng theo s trn (hnh 6.2)

Hnh 6.2. Chuyn vn ca catecholamin ti tn cng dy giao cm

Tyrosin c vn chuyn vo u tn cng dy giao cm nh c ht vn chuyn ph thuc Na +(A). Tyrosin c chuyn ha thnh dopamin (DA) ri c cht vn c huyn (B) a vo cc ti d tr (cc ht). Cht vn chuyn ny cng vn chuyn c noradrenalin (NA) v v i amin khc. Trong ti d tr, DA c chuyn ha thn h NA. in th hot ng lm m kn h calci, Ca 2+ vo t bo, gii phng NA t ti d tr. Sau khi c tng hp, mt phn catecholamin s kt hp vi ATP hoc vi mt dng protein ha tan l chromogranin tr thnh dng khng c hot tnh, khng b cc e nzym p h 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. Gi a 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 ha ngc chiu: khi nora-drenalin tng th hot tnh ca enzym gim, v ngc li. Mt khc, cc cht cng re ceptor 2 lm gim gii phng noradrenalin ra khe xinap v do tr lng ca nora-

drenalin trong bo tng s tng ln. Theo gi thit ca Burn v Rand (1959

1962) di nh hng ca xung tc thn kinh, ngn dy giao cm lc u tit ra acetylcholin, l m thay i tnh thm ca mng t bo, do Ca ++ t ngoi t bo thm nhp c vo trong t bo, ng vai tr nh mt enzym lm v lin kt ATP - catecholamin, gii phng catecholamin ra dng t do. Sau khi c gii phng, mt phn noradrenalin s tc n g ln cc receptor (sau

v trc xinap), mt phn chuyn vo mu tun hon tc dng xa hn ri b ging ha, cn p hn ln (trn 80%) s c thu hi li, phn nh khc b mt hot tnh ngay? trong bo tng. Hnh 6.3. S phn ca n oradrenalin 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 ha bi COMT 4. Chuyn ha trong bo tng bi MAO Catecholamin b mt hot tnh bi qu trnh oxy ha 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 ti th (mitochondria), v vy n ng vai tr ging ha catecholamin trong t bo hn l tun hon. Phong to MAO th lm tng catecholamin trong m nhng khng nh hng n tc dng ca cat-echolamin ngoi lai. COMT l enzym ging ha catecholamin ngoi t bo, c mng xinap v nhi u 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 c c 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 sau). 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 ha m) v nhm 2 (lm gin mch, gin kh o v chuyn ha ng). 2 trc xinap kch thch lm tng gii phng NA, c vai tr iu ha ngc vi 2. 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 ha, khi kch thch s lm gim gii phng norad renalin ra khe xinap, ng thi lm gim tit r enin, 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 re ceptor c hiu i vi n gi l cc receptor dopaminergic (receptor delta - )

Bng 6.1: Cc receptor adrenergic Iso*: Isoproterenol Adr: adrenalin NA: noradrenalin Ghi ch ca bng 3: - Mi receptor u kch thch adenylcyclase thng qua protein G S v lm tng AMPv, ngoi ra cn lm knh calci cm ng vi in th ca c vn v ctim.Receptor 2, tri li, c ch adenylcyclase thng qua protein G i, ng thi hot ha 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 (IP 3).

THUC CNG H ADRENERGIC L nhng thuc c tc dng ging adrenalin v noradrenalin , kch thch

hu hch giao cm nn cn gi l thuc cng giao cm. Theo c ch tc dng c th chia cc thuc ny lm hai loi:

- Loi tc dng trc tip trn cc receptor adrenergic sau xinap nh adrenalin, noradrenalin, isoproterenol, phenylephrin - Loi tc dng gin tip do kch thch cc receptor trc xi?nap, lm gii phng cate cholamin 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 h on ton bit r (nh ephedrin, amphetamin), reserpin khng nh hng n tc dng ny; ho c c ch mono - amin- oxydase (MAOI), lm vng bn catecholamin. 2.1.Thuc cng receptor alpha v beta 2.1.1.Adrenalin c, bng A L hormon ca tu thng thn, ly ng vt hoc tng hp. Cht t nhin l ng phn t tuyn c tc dng mnh nht. 2.1.1.1.Tc dng Adrenalin tc dng c trn v receptor. - Trn tim mch: 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 methyla tropin) trc ct phn x ny th adrenalin ch lm tim p nhanh mnh v hu yt 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 tru ng bnh khng tng hoc ch t ng 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 d ng trong iu tr co tht mch vnh v tc dng ny li km theo lm tng cng nng v chuyn ha ca c tim. Di tc dng ca adrenalin, mch mu mt s vng co li s y mu ra nhng khu vc t chu nh hng hn, gy gin mch th ng nhng ni (nh mch no, mch phi) do d gy cc bin chng t 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 ad renalin lm gin rt mnh, km theo l co mch nim mc ph qun, lm gim ph cho nn nh h ng rt tt ti tnh trng bnh. Son g adrenalin b mt tc dng rt nhanh vi nhng ln dng sa u, v vy khng nn dng ct cn hen. - Trn chuyn ha: Adrenalin lm tng hu glycogen gan, lm tng glucose mu, lm tng acid bo t do trong mu, tng chuyn ha c bn, tng s dng oxy c a m. Cc c ch tc dng ca adrenalin hay catecholamin ni chung l lm tng tng h p adenosin 3 - 5- monophosphat (AMP - vng) t ATP do hot ha

adenylcyclase (xem s ) S tc ng ca catecholamin ln chuyn ha ng v m

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 a drenalin 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 hydro-clorid. Liu ti a: mi ln 1 mL; 24 gi : 5 mL ng 1 mL = 0,001g adrenalin hydro-clorid 2.1.2. Noradrenalin (arterenol) c, bng A L cht dn truyn thn kinh ca cc si hu hch giao cm. Tc dng mn h 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 nn tc dng c hung 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 ha thn nhit ph thuc vo s cn bng gia NA, serotoni