Sach Duoc Ly Hoc y Hn

7/29/2019 Sach Duoc Ly Hoc y Hn

1/439

dc l hc 2007 - i hc Y H ni

(sch dng cho sinh vin h bc s a khoa)

Bi 1: i c-ng v d-c ng hc

Mc tiu hc tp: Sau khi hc xong bi ny, sinh vin c kh nng:1. Phn tch c qu trnh hp thu v phn phi thuc trong c th.2. Nu c ngha ca cc thng s dc ng hc ca cc qu trnh hp thu v phn

phi thuc.

3. Nu c ngha ca vic gn thuc vo protein huyt tng.

4. Trnh by c nhng qu trnh v ngha ca s chuyn ha thuc trong c th.

5. K ra c ngha thng s dc ng hc v h s thanh thi, t/2 v cc ng thi trthuc khi c th.

Dc ng hc (Pharmacokinetics) nghin cu cc qu trnh chuyn vn ca thuc t lc chp thu vo c th cho n khi b thi tr hon ton (H 1). Cc qu trnh l:

- S hp thu (Absorption)

- S phn phi (Distribution)

- S chuyn ha (Metabolism)

- S thi tr (Excretion)

Mu M

Hp thu(ung, bi...)

Thuct/m

Thuc - protein

Protein

+thuc(T)

M

D tr

T T - Rec

Chuyn ha

Cht chuyn ha (M)

Tc dng

Thi tr

Hnh 1.1. S chuyn vn ca thuc trong c th

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


2/439



1. Cc cch vn chuyn thuc qua mng sinh hc1.1. c tnh l ha ca thuc

- Thuc l cc phn t thng c trng lng phn t PM 600. Chng u l cc acid hoc ccbase yu.

- Kch thc phn t ca thuc c th thay i t rt nh (PM = 7 nh ion lithi) cho ti rt ln(nh alteplase- tPA- l protein c PM = 59.050). Tuy nhin, a s c PM t 100- 1000. gn"kht" vo 1 loi receptor, phn t thuc cn t c mt kch c duy nht vi kch thc careceptor c hiu thuc khng gn c vo cc receptor khc (mang tnh chn lc). Kinhnghim cho thy PM nh nht phi t khong 100 v khng qu 1000, v ln qu th khng qua

c cc mng sinh hc ti ni tc dng.Mt s thuc l acid yu: l phn t trung tnh c th phn ly thun nghch thnh mt anion (intch (-)) v mt proton (H +).

C8H7O2COOH C8H7O2COO- + H+

Aspirin 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 tbo cha nhiu phospholipid.

V vy c hp thu vo t bo thun li nht, thuc cn c mt t l tan trong nc/ tan trongm 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:dng ion ha

pH = pKa + logdng khng ion ha

Cho 1 acid:nng phn t

pKa = pH + lognng ion


3/439



Cho 1 base:

nng ionpKa = pH + lognng phn t

K l hng s phn ly ca 1 acid; pKa = - logKapKa 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, vngc 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 khuchtn c). V khi , nng phn t/ nng ion= 1 v log 1 = 0.

Ni chung, mt thuc phn tn tt, d c hp thu khi

C trng lng phn t thp

t b ion ha: ph thuc vo hng s phn ly (pKa) ca thuc v pH ca mi trng.

D tan trong dch tiu ha (tan trong nc)

ho tan trong lipid cao d qua mng ca t bo

1.2. Vn chuyn thuc bng cch lc

Nhng thuc c trng lng phn t thp (100- 200), tan c trong nc nhng khng tan c

trong m s chui qua cc ng dn (d= 4 - 40

) ca mng sinh hc do s chnh lch p lc thutnh. ng dn ca mao mch c vn c ng knh l 30 , ca mao mch no l 7- 9, v thnhiu 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 sangni 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 thuqua mng.

S khuch tn ca acid v base yu ph thuc vo hng s phn ly pKa ca thuc v pH ca mitrng.

Th d: khi ung 1 thuc l acid yu, c pKa = 4, gian 1 d dy c pH= 1 v gian 2 l huyttng c pH = 7 (H.1)


4/439



Gian 2pH = 7

1000 R- COO- + H+

1 R- COOH

Gian 1pH = 1

pKa = 4R- COO- + H+ 1

R- COOH 1000

Hnh 1.2: S khuch tn qua mng

p dng phng trnh Henderson- Hasselbach, ta c:

gian 1 (d dy):

[ R- COOH ]log = 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 schuyn 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 pKacao l base mnh v acid c pKa cao l acid yu.

Bng 1.1: Tr s pKa ca mt s thuc l acid v base yu

( nhit 250C)

Acid yu pKa Base yu pKa

Salicylic acid

Acetylsalicylic acid

Sulfadiazin

Barbital

Boric acid

3.00

3.49

6.48

7.91

9.24

Reserpin

Codein

Quinin

Procain

Atropin

6.6

7.9

8.4

8.8

9.65

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


5/439



Bng 1.2: nh h-ng ca pH n s ion ha ca salicylic acidc pKa = 3

pH % khng ion ha

1

2

3

4

5

6

99,0

90,9

50,0

9,09

0,99

0,10

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 rangoi, 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 thngc pH cng bng 7,2 nn phenobarbital b ion ha 50%. Khi nng pH ca nc tiu ln 8, ionha ca thuc s l 86%, do thuc khng thm c vo t b o. iu ny c dng trongiu tr nhim c phenobarbital: truyn dung dch NaHCO 3 1,4% base ha nc tiu, thucs b tng thi tr.

i vi mt cht kh (th d thuc m bay hi), s khuch tn t khng kh ph nang vo muph thuc vo p lc ring phn ca cht kh gy m c trong khng kh th vo v ha tanca 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 vnchuyn" (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


6/439



- Vn chuyn thun li (Vn chuyn tch cc th pht) : khi km theo carrier li c c s chnhlch bc thang nng , v vy s vn chuyn ny khng cn nng lng. Th d vn chuynglucose, 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 nnglng c cung cp do ATP thu phn, thng c gi l cc "bm", th d s vn chuyn caNa+, K+, Ca++,I-, acid amin.

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

2. Cc qu trnh d-c ng hc2.1. S hp thu

Hp thu l s vn chuyn thuc t ni dng thuc (ung, tim) vo mu ri i khp c th, tini tc dng. Nh vy s hp thu s ph thuc vo:

- ha tan ca thuc. Thuc dng di dng dung dch nc d hp thu hn dng du, dchtreo hoc dng cng

- pH ti ch hp thu v c nh hng n ion ha v tan ca thuc.

- Nng ca thuc. Nng cng cao cng hp thu nhanh.

- Tun hon ti vng hp thu: cng nhiu mch, cng hp thu nhanh.

- Din tch vng hp thu. Phi, nim mc rut c din tch ln, hp thu nhanh.

T nhng yu t cho thy ng a thuc vo c th s c nh hng ln n s hp thu.Ngoi tr ng tim tnh mch, trong qu trnh hp thu vo vng tun hon, mt phn thuc sb ph hu do cc enzym ca ng tiu ha, ca t bo rut v c bit l gan, ni c i lcvi nhiu thuc. Phn thuc b ph hu trc khi vo vng tun hon c gi l "first pass


7/439



metabolism" (chuyn ha do hp thu hay chuyn ha qua gan ln th nht v thng l ungthuc). Phn vo c tun hon mi pht huy tc dng dc l, c gi l sinh kh dng(bioavailability) ca thuc (xin xem phn sau)

Sau y s im qua cc ng dng thuc thng thng v cc c im ca chng.

2.1.1. Qua -ng tiu ha

u im l d dng v l ng hp thu t nhin.

Nhc im l b cc enzym tiu ha ph hu hoc thuc to phc vi thc n lm chm hp thu.i khi thuc kch thch nim mc tiu ha, gy vim lot

2.1.1.1. Qua nim mc ming: thuc ngm di li

Do thuc vo thng vng tun hon nn khng b dch v ph hu, khng b chuyn ha qua ganln 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 ddy 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, pHtng dn ti base (pH t 6 n 8).

- Thuc t b ion ha nhng nu t hoc khng tan trong lipid (sulfaguanidin, streptomycin) th tc hp thu.

- Thuc mang amin bc 4 s b ion ha mnh kh hp thu, th d cc loi cura.

- Cc anion sulfat SO4- - khng c hp thu: MgSO 4, Na2SO4 ch c tc dng ty.

2.1.1.3. Thuc t trc trng

Khi khng dng ng ung c (do nn, do hn m, hoc tr em) th c d ng thuc t vohu mn. Khng b enzym tiu ha ph hu, khong 50% thuc hp thu qua trc trng s quagan, chu chuyn ha ban u.

Nhc im l hp thu khng hon ton v c th gy kch ng nim mc hu mn.2.1.2. Thuc tim

- Tim di da: do c nhiu si thn kinh cm gic nn au, t mch mu nn thuc hp thu chm

- Tim bp: khc phc c hai nhc im trn ca tim di da - mt s thuc c th gy hoit c nh ouabain, calci clorid th khng c tim bp.


8/439



- Tim tnh mch: thuc hp thu n hanh, hon ton, c th iu chnh liu c nhanh. Dng timcc dung dch nc hoc cc cht kch ng khng tim bp c v lng mch t nhy cm vmu 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 phhu 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 cd tan trong m c th thm qua da gy c ton thn (thuc tr su ln hu c, cht c cngnghip 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 lngthuc 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 cnthn 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 nimmc 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 phnang, nim mc ng h hp. V din tch rng (80 - 100 m2) nn hp thu nhanh. y l nghp thu v thi tr chnh ca thuc m hi. S hp thu ph thuc vo nng thuc m trongkhng kh th vo, s thng kh h hp, ha tan ca thuc m trong mu ( hay h s phn lymu: kh)

Mt s thuc c th dng di dng phun sng iu tr ti ch (hen ph qun).

- Tim tu sng: thng tim vo khoang di nhn hoc ngoi mng cng gy t vng thp(chi di, khung chu) bng dung dch c t trng cao (hyperbaric solution) hn dch no tu.

2.1.5. Thng s d-c 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 dngcn hot tnh v vn tc hp thu thuc (biu hin qua Cmaxv Tmax) so vi liu dng. Sinh khdng phn nh s hp thu thuc.

2.1.5.2. ngha


9/439



- Khi thay i t dc, cch bo ch thuc s lm thay i ha tan ca thuc (hot cht) vlm thay i F ca thuc. Nh vy, 2 dng bo ch ca cng mt sn phm c th c 2 sinh khdng khc nhau. Khi nim tng ng sinh hc (bioequivalence) dng so snh cc F cacc dng bo ch khc nhau ca 1 hot cht: F 1/F2.

- Khi thay i cu trc ha hc, c th lm F thay i:Ampicilin c F = 50%

Amoxicilin (gn thm nhm OH) c F = 95%

- S chuyn ha thuc khi qua gan ln th nht, hay chuyn ha trc khi vo tun hon (firstpass metabolism) lm gim sinh kh dng ca thuc. Song i khi v thuc qua gan li c thc chuyn ha thnh cht c hot tnh nn tuy sinh kh dng ca ng ung l thp nhng tcdng dc l li khng km ng tim chch tnh mch. Th d propranolol c sinh kh dngtheo ng ung l 30% nhng gan n c chuyn ha thnh 4 - OH propranolol vn c hottnh nh propranolol.

- Cc yu t lm thay i F do ngi dng thuc:

. Thc n lm thay i pH hoc nhu ng ca ng tiu ha.

. Tui (tr em, ngi gi): thay i hot ng ca cc enzym.

. Tnh trng bnh l: to bn, tiu chy, suy gan.

. Tng tc thuc: hai thuc c th tranh chp ti ni hp thu hoc lm thay i tan, phnly ca nhau.

2.2. S phn phi

Sau khi c hp thu vo mu, mt phn thuc s gn vo protein ca huyt tng (cc proteintrong t bo cng gn thuc), phn thuc t do khng g n vo protein s qua c thnh mch

chuyn vo cc m, vo ni tc dng (cc receptor), vo m d tr, hoc b chuyn ha ri thitr (H1). Gia nng thuc t do (T) v phc hp protein - thuc (P- T) lun c s cn bngng:

T + P P - T

Qu trnh phn phi thuc ph thuc nhiu vo tun hon khu vc. Tu theo s ti mu, thngchia c th thnh 3 gian (H 2)

Gian II Gian I Gian III

C quan c ti Huyt C quan c timu nhiu: tim, thn, tng mu t hn: m m,

gan, no, phi da, c

Hnh 1.4. H phn phi thuc 3 gian

Hai loi yu t c nh hng n s phn phi thuc trong c th:

- V pha c th: tnh cht mng t bo, mng mao mch, s lng v tr gn thuc v pH ca mitrng.

- V pha thuc: trng lng phn t, t l tan trong nc v trong lipid, tnh acid hay base, ion ha, i lc ca thuc vi receptor.


10/439



2.2.1. S gn thuc vo protein huyt t-ng

2.2.1.1. V tr gn: phn ln gn vo albumin huyt tng (cc thuc l acid yu) v vo 1glycoprotein (cc thuc l base yu) theo cch gn thun nghch .

2.2.1.2. T l gn: tu theo i lc ca tng loi thuc vi protein huyt tng(bng 1)

Bng 1.3: T l gn thuc vo protein huyt t-ng

T l gn thuc vi protein huyt t-ng

Thuc l acid yu Thuc l base yu75-100%:

Phenylbutazon,

Warfarin

Phenytoin

Aspirin

25- 75%:

Benzylpenicilin

Methotrexat

Khng gn:

Ethosuximid

75- 100%:

Diazepam

Digitoxin

Clopromazin

Erythromycin

25- 75%:

Cloroquin

MorphinKhng gn:

Isoniasid

Ouabain

S gn thuc vo protein huyt tng ph thuc vo 3 yu t:

- S lng v tr gn thuc trn protein huyt tng

- Nng phn t ca cc protein gn thuc

- Hng s gn thuc hoc hng s i lc gn thuc

2.2.1.3. ngha ca vic gn thuc vo protein huyt tng

- Lm d hp thu, chm thi tr v protein mu cao nn ti ni hp thu, thuc s c ko nhanhvo mch.

- Protein huyt tng l cht m, l kho d tr thuc, sau khi gn thuc, s gii phng t tthuc ra dng t do v ch c dng t do mi qua c cc mng sinh hc pht huy tc dngdc l.


11/439



- Nng thuc t do trong huyt tng v ngoi dch k lun trng thi cn bng. Khi nng thuc dch k gim, thuc huyt tng s i ra, protein gn thuc s nh thuc gi c nbng.

- Nhiu thuc c th cng gn vo 1 v tr ca protein huyt tng, gy ra s tranh chp, ph

thuc vo i lc ca thuc. Thuc b y khi protein s tng tc dng, c th gy c. Th dtrn ngi ang dng tolbutamid iu tr i tho ng , nay v au khp, dng thmphenylbutazon, phenylbutazon s y tolbutamid ra dng t do, gy h ng huyt t ngt.

C khi thuc y c cht ni sinh, gy tnh trng nhim c cht ni sinh: salicylat y bilirubin,sulfamid h ng huyt y insulin ra khi v tr gn vi protein.

- Trong iu tr, lc u dng liu tn cng bo ha cc v tr gn, sau cho liu duy tr n nh tc dng.

- Trong cc trng hp bnh l lm tng - gim lng protein huyt tng (nh suy dinh dng,x gan, thn h, ngi gi...), cn hiu chnh liu thuc.

2.2.2. S phn phi li

Thng gp vi cc thuc tan nhiu trong m, c tc dng trn thn kinh trung ng v dngthuc theo ng tnh mch. Th d in hnh ca hin tng ny l gy m bng thiopental, mtthuc tan nhiu trong m. V no c ti mu nhiu, nng thuc t c ti a trong nort nhanh. Khi ngng tim, nng thiopental trong huyt tng gim nhanh v thuc khuch tnvo cc m, c bit l m m. Nng thuc trong no gim theo n ng thuc trong huyttng. V vy khi m nhanh, nhng tc dng m khng lu . Khi cho cc liu thuc b xung duy tr m, thuc tch ly nhiu m m. T y thuc li c gii phng li vo mu tino khi ngng cho thuc, lm cho tc dng c a thuc tr nn ko di.

2.2.3. Cc phn phi c bit

2.2.3.1. Vn chuyn thuc vo thn kinh trung ng

Phng thc vn chuyn: thuc phi vt qua 3 "hng ro"

- T mao mch no vo m thn kinh (hng ro mu - no): thuc tan nhiu trong lipid th dthm, thuc tan trong nc rt kh vt qua v c c t bo thn kinh m (astrocyte - t bo hnhsao) nm rt st nhau, ngay ti mng y, ngoi ni m mao mch.

- T m ri mng mch vo dch no tu (hng ro mu - mng no hoc mu- dch no tu):nh hng ro trn; thuc cn tan mnh trong lipid.

- T dch no tu vo m thn kinh (hng ro dch no tu - no), thc hin bng khuch tn thng.

Cc yu t quyt nh tc vn chuyn thuc vo dch no tu v no th cng ging nh

nguyn tc thm qua mng sinh hc, l:- Mc gn thuc vo protein huyt tng

- Mc ion ha ca phn thuc t do (ph thuc vo pH v pKa)

- H s phn b lipid/ nc ca phn thuc t do khng ion ha ( tan trong lipid)

Thuc ra khi dch no tu c thc hin m t phn bi c ch vn chuyn tch cc trong mri mng mch (mt h thng vn chuyn tch cc cho cc acid yu v mt h thng khc cho


12/439



cc base yu). T no, thuc ra theo c ch khuch tn th ng, ph thuc ch yu vo tantrong lipid ca thuc.

Hng ro mu - no cn ph thuc vo la tui v vo trng thi bnh l: tr s sinh v tr nh,lng myelin cn t, cu trc "hng ro" cn cha "cht ch" nn thuc d khuch tn c

vo no. Penicilin khng qua c mng no bnh thng, nhng kh i b vim, penicilin v nhiuthuc khc c th qua c.

Hng ro mu no mang tnh cht mt hng ro lipid khng c ng dn, v vy, i vi nhngcht tan mnh trong lipid, coi nh khng c hng ro. Mt s vng nh ca no nh cc nhn bnca vng di i, sn no tht 4, tuyn tng v thu sau tuyn yn cng khng c hng ro.

Kt qu ca s vn chuyn

- Cc thuc tan nhiu trong m s thm rt nhanh vo no, nhng li khng li c lu (xinxem "s phn phi li").

Thuc b ion ha nhiu, kh tan trong m, kh thm vo thn kinh trung ng: atropin sulfat,mang amin bc 3, t ion ha, vo c TKT; cn atropin methyl bromid, mang amin bc 4, ionha mnh, khng vo c TKT.

- C th thay i s phn phi thuc gia huyt tng v no bng thay i pH ca huyt tng:trong iu tr ng c phenobarbital, truyn NaHCO 3 nng pH ca mu (7,6) vt ln trn pHca dch no ty (7,3), lm cho nng dng ion ha trong huyt tng ca phenobarbital tngcao nng dng khng ion ha gim thp s ko dng khng ion ha ca thuc t dch no tuvo mu.

2.2.3.2. Vn chuyn thuc qua rau thai

Phng thc

- Mao mch ca thai nhi nm trong nhung mao c nhng trong h mu ca m, v vy gia

mu m v thai nhi c "hng ro rau thai". Tnh thm ca m ng mao mch thai nhi tng theo tuithai. S thm thuc cng theo quy lut chung:

- Cc thuc tan trong m s khuch tn th ng: thuc m hi, (protoxyd nit, halothan,cyclopropan), thiopental.

- Vn chuyn tch cc: cc acid amin, cc ion Ca ++, Mg++.

- Thm bo (pinocytosis) vi cc git huyt tng ca m

Kt qu

- Tr cc thuc tan trong nc c trng lng phn t ln trn 1000 (nh dextran) v cc aminbc 4 (galanin, neostigmin) khng qua c rau thai, rt nhiu thuc c th vo c mu thainhi, gy nguy him cho thai (phenobarbital, sulfamid, morphin), v vy, khng nn coi l c"hng ro rau thai".

- Lng thuc gn vo protein- huyt tng mu m cao th nng thuc t do thp, ch cthuc t do ny mi sang c mu con, ti y mt phn thuc ny li gn vo protein huyttng mu con, v vy nng thuc t do trong mu con cng thp. t c nng thuct do tng ng nh mu m, cn khong thi gian ti 40 pht. V d tim thiopental cho mtrong thi gian chuyn d, v sau 10 pht m c th nng thiopental trong mu con vn


13/439



cha t c mc m, iu gii thch v sao b m ng m li c th ra a con vn cnthc.

- Ngoi ra, rau thai cn c nhiu enzym nh cholinesterase, monoamin oxydase, hydroxylase cth chuyn ha thuc, lm gim tc dng bo v thai nhi.

2.2.4. S tch lu thuc

Mt s thuc hoc cht c c mi lin kt rt cht ch (thng l lin kt cng ha tr) vi mts m trong c th v c gi li rt lu, hng thng n hng chc n m sau dng thuc, c khich l 1 ln: DDT gn vo m m, tetracyclin gn vo xng, mm rng, As gn vo t bosng...

Mt s thuc tch ly trong c vn v cc t bo ca m khc vi nng cao hn trong mu.Nu s gn thuc l thun nghch th thuc s li c gii phng t "kho d tr" vo mu (xinxem "s phn phi li"). Nng quinacrin trong t bo gan khi dng thuc di ngy c th caohn nng huyt tng vi trm ln do t bo gan c qu trnh vn chuyn tch cc koquinacrin vo trong t bo.

2.2.5. Thng s d-c ng hc ca s phn phi: th tch phn phi (Vd)

2.2.5.1. nh ngha

Th tch phn phi biu th mt th tch biu kin (khng c thc) cha ton b lng thuc c a vo c th c nng bng nng thuc trong huy t tng.

DVd = lit

Cp

D: liu lng thuc a vo c th (mg) theo ng tnh mch. Nu theo ng khc th phi tnhn sinh kh dng : D F

Cp: nng thuc trong huyt tng o ngay sau khi phn phi v trc khi thi tr.Vd: th tch khng c thc, tnh bng L (lt) hoc L/ kg.

Th d: mt ngi nng 60 kg, c lng nc trong c th l 36 L (60% trng lng c th), ung 0,5 mg (500 g) digoxin c F theo ng ung l 0,7. o nng digoxin trong huyttng thy Cp= 0,7 ng/ mL (0,0007 mg/ mL).Vy: 0,5 0,7

Vd = = 500L hoc 8,3 L/ kg0,0007

Vd = 500L , ln bng gn 14 ln lng nc trong c th nn l th tch biu kin.

2.2.5.2. Nhn xt v ngha lm sng

- Vd nh nht l bng th tch huyt tng (3L hoc 0,04L/ kg). Khng c gii hn trn cho Vd.Vd cng ln chng t thuc cng gn nhiu vo m: iu tr nhim khun xng khp nn chnkhng sinh thch hp c Vd ln.

- Khi bit Vd ca thuc, c th tnh c liu cn dng t nn g huyt tng mong mun:D = Vd Cp

2.3. S chuyn ha thuc


14/439



2.3.1. Mc ch ca chuyn ha thuc:

thi tr cht l (thuc) ra khi c th. Nhng nh ta bit, thuc l nhng phn t tan ctrong m, khng b ion ha, d thm qua mng t bo, gn vo prot ein huyt tng v gi litrong c th. Mun thi tr, c th phi chuyn ha nhng thuc ny sao cho chng tr nn cc

phc hp c cc, d b ion ha, do tr nn t tan trong m, kh gn vo protein, kh thm vot bo, v v th, tan hn trong nc, d b thi tr (qua thn, qua phn). Nu khng c cc qutrnh sinh chuyn ha, mt s thuc rt tan trong m (nh pentothal) c th b gi li trong c thhn 100 nm !

2.3.2. Ni chuyn ha v cc enzym chnh xc tc cho chuyn ha:

- Nim mc rut: protease, lipase, decarboxylase

- Huyt thanh: esterase

- Phi: oxydase

- Vi khun rut: reductase, decarboxylase

- H thn kinh trung ng: monoaminoxydase, decarboxylase

- Gan: l ni chuyn ha chnh, cha hu ht cc enzym tham gia chuyn ha thuc, s trnh by di y

2.3.3. Cc phn ng chuyn ha chnh

Mt cht A c a vo c th s i theo 1 hoc cc con ng sau:

- c hp thu v thi tr khng bin : bromid, lithi, saccharin.

- Chuyn ha thnh cht B (pha I), ri cht C (pha II) v thi tr

- Chuyn ha thnh cht D ( pha II) ri thi tr

Cht A c th c hoc khng c hot tnh, sinh ra cht B khng c hoc c hot tnh. Cht C v Dlun l cht khng c hot tnh sinh hc. Mt cht m A c th sinh ra nhiu cht chuyn haloi B hoc C.

Hp thu Sinh chuyn ha Thi tr

Pha I Pha II

AB

A B Tan trongTan trong C C n- cm D D


15/439



Hnh 1.5. Cc phn ng chuyn ha thuc c ph n lm 2 pha

2.3.3.1. Cc phn ng pha I

Qua pha ny, thuc ang dng tan c trong m s tr nn c cc hn, d tan trong nchn. Nhng v mt tc dng sinh hc, thuc c th mt hot tnh, hoc ch gim hot tnh, hoci khi l tng hot tnh, tr nn c hot tnh.

Mt s th d:Oxy kh

+ Prontosil Sulfanilamid(khng hot tnh (c hot tnh)"tin thuc")

oxy ha

+ Phenylbutazon oxyphenbutazon(c hot tnh) (cn hot tnh)

thu phn+ Acetylcholin Cholin + A.acetic

(c hot tnh) (mt hot tnh)

Cc phn ng chnh pha ny gm:

- Phn ng oxy ha: l phn ng rt thng gp, c xc tc bi cc enzym ca microsom gan,c bit l hemoprotein, cytocrom P450.

- Phn ng thu phn do cc enzym esterase, amidase, protease... Ngoi gan, huyt thanh v ccm khc (phi, thn...) cng c cc enzym ny.

- Phn ng kh.

Phn ng oxy ha

y l phn ng ph bin nht, c xc tc bi cc enzym oxy ha (mixed - function oxydaseenzym system- mfO), thy c nhiu trong microsom gan, c bit l h enzym cytochrom P450(Cyt- P450), l cc protein mng c cha hem (hemoprotein) khu tr li ni bo nhn ca tbo gan v vi m khc. Trong c th ngi hin thy c ti 17 typ v rt nhiu di typ

cytochrom P450 tham gia chuyn ha cc cht ni sinh v ngoi sinh t mi trng, thuc. Phnng oxy ha loi ny i hi NADPH v O 2 theo phc sau:

C cht C cht (R- OH)(RH) oxy ha

Cytochrom P450O2 H2O


16/439



NADPH + H+ NADP+

Phn ng c thc hin theo nhiu bc:

1) C cht (thuc , RH) phn ng vi dng oxy ha ca Cyt P450 (Fe3+

) to thnh phc hp RH-P450 (Fe3+)

2) Phc hp RH- P450 (Fe3+) nhn 1 electron t NADPH, b kh thnh RH- P450 (Fe

2+)

3) Sau , phc hp RH- P450 (Fe2+) phn ng vi 1 phn t oxy v 1 electron th 2 t NADPH

to thnh phc hp oxy hot ha.

4) Cui cng, 1 nguyn t oxy c gii phng, to H 2O. Cn nguyn t oxy th 2 s oxy hac cht (thuc): RH ROH, v Cyt.P450 c ti to.

Qu trnh phn ng c tm tt s sau:

Hnh 1.6: S oxy ha thuc ca cytocrom P450

Phn ng khKh cc dn xut nitro, cc aldehyd, carbonyl bi cc enzym nitroreductase, azoreductase,dehydrogenase... (bng 1.4)

Phn ng thu phn

Cc ng ni este v amid b thu phn bi cc enzym esterase, amidase c trong huyt tng,gan, thnh rut v cc m khc (bng 1.4)


17/439



Bng 1.4: Cc phn ng chnh trong chuyn ha thuc pha I

Loi phn ng Phn ng Th d cc thuc

1. Phn ng oxyha

- N- mt alkyl

- N- oxy ha

-Mt amin oxy ha

Hydroxy ha mchthng

2. Phn ng kh

- Azo- kh

- Nitro- kh

- Carbonyl- kh

3. Phn ng thyphn

- Cc este

RNHCH3 R- NH2 + CH2O

R- NH2 R - NHOH

OH

R- CHCH3 R- C- CH3 R- C- CH3NH2 NH2 O + NH2

R- CH2- CH3 R- CH2- CH3

OH

RN=NR1RNH- NHR1RNH2+R1NH2

RNO2 RNO RNHOH R-NH2

R- CR' R- CHR'

O OH

R1COOR2 R1COOH + R2OH

Imipramin, diazepam,morphin, codein,

Clorpheniramin,dapson

Diazepam,amphetamin

Tolbutamid,

ibuprofen,cyclosporin,midazolam

Prontosil, tartrazin

Nitrobenzen,chloramphenicol,clorazepam, dantrolen

Methadon, naloxon

Procain,succinylcholin,aspirin, clofibrat


18/439



- Cc amid

RCONHR1 RCOOH + R1NH2

lidocain,indomethacin

2.3.3.2. Cc phn ng pha II

Cc cht i qua pha ny tr thnh cc phc hp khng cn hot tnh, tan d trong nc v bthi tr. Tuy vy, pha ny, sulfanilamid b acetyl ha li tr nn kh tan trong nc, kt thnhtinh th trong ng thn, gy i mu hoc v niu.

Cc phn ng pha II u l cc phn ng lin hp: mt phn t ni sinh (acid glucuronic,glutathion, sulfat, glycin, acetyl) s ghp vi mt nhm ha hc ca thuc to thnh cc phchp tan mnh trong nc. Thng thng, cc phn ng pha I s to ra cc nhm chc phn cnthit cho cc phn ng pha II, l cc nhm - OH, -COOH, -NH2, -SH...

Cc phn ng chnh: cc phn ng lin hp vi acid glucuronic, acid sulfuric, acid amin (ch yul glycin), phn ng acetyl ha, methyl ha. Cc phn ng ny i hi nng lng v c cht nisinh, l c im ca pha II.

Bng 1.5: Cc phn ng chnh tr ong chuyn ha thuc pha II

Loi phnng

C cht nisinh

Enym chuyn (vtr)

Loi c cht Th d ccthuc

- Glucuro- hp

- Glutathion-hp

- Glycin- hp

- Sulfo- hp

Acid UDPglucuronic

Glutathion

Glycin

Phosphoadenosylphosphosulfat

UDP glucuronosyltransferase(microsom)

GSH- S-transferase (dchbo tng,microsom)

Acyl- CoA

transferase (tyth)

Sulfotransferase(dch bo tng)

Phenol, alcol,acidcarboxylic,sulfonamid

Epoxid, nhmnitrohydroxylamin

Dn xut acyl-CoA ca acid

carboxylic

Phenol, alcol,cc amin vngthm

Morphin,diazepam,digitoxin,acetaminophen,sulfathiazol

Acid ethacrynicbromobenzen

Acid salicylic,a.benzoic,a.nicotinic,a.cholic

Estron, anilin,methyldopa, 3-OH cumarin,acetaminophen

Dopamin,


19/439



-Methyl- ha

- Acetyl- ha

S- adenosyl

methionin

Acetyl- CoA

Transmethylase

(dch bo tng)

N-acetyltrasferase

(dch bo tng)

Catecholamin,phenol amin,

histamin

Cc amin

adrenalin,pyridin,histamin

Sulfonamid,isoniazid,clonazepam,dapson.

Ngoi ra, c mt s thuc hon ton khng b chuyn ha, l nhng hp cht c cc cao (nhacid, base mnh), khng thm qua c lp m ca microsom. Phn ln c thi tr nhanh nhhexamethonium, methotrexat.

Mt s hot cht khng c cc cng c th khng b chuyn ha: barbital, ether, halothan,dieldrin.

Mt thuc c th b chuyn ha qua nhiu phn ng xy ra cng mt lc hoc tip ni nhau. Thd paracetamol b glucuro- hp v sulfo- hp cng mt lc; chlorpromazin b chuyn ha nhnphenothiazin qua nhiu phn ng, sau l nhnh bn cng qua mt lot phn ng cuicng cho ti hn 30 cht chuyn ha khc nhau.

2.3.4. Cc yu t lm thay i tc chuyn ha thuc

2.3.4.1. Tui

- Tr s sinh thiu nhiu enzym chuyn ha thuc

- Ngi cao tui enzym cng b lo ho

2.3.4.2. Di truyn

- Do xut hin enzym khng in hnh khong 1: 3000 ngi c enzym cholinesterase khngin hnh, thu phn rt chm suxamethonium nn lm ko di tc dng ca thuc n y.

- Isoniazid (INH) b mt tc dng do acetyl ha. Trong mt nghin cu, cho ung 10 mg/ kgisoniazid, sau 6 gi thy lng isoniazid trong mu mt nhm l 3 - 6 g/ mL, nhm khc chl 2,5g/ mL. Nhm u l nhm acetyl ha chm, cn gim liu v d c vi TKT. V ditruyn, thuc nhm acetyl ha chm, thy 60% l ngi da trng, 40% l da en v 20% l davng. Nhm sau l nhm acetyl ha nhanh, cn phi tng liu, nhng sn phm chuyn haacetyl isoniazid li c vi gan.

- Ngi thiu glucose 6 phosphat dehydrogenase (G 6PD) s d b thiu mu tan mu khi dngphenacetin, aspirin, quinacrin, vi loi sulfamid...

2.3.4.3. Yu t ngoi lai


20/439



- Cht gy cm ng enzym chuyn ha: c tc dng lm tng sinh cc enzym microsom gan,lm tng hot tnh cc enzym ny.

Th d: phenobarbital, meprobamat, clorpromazin, phenylbutazon, v hng trm thuc khc: khidng nhng thuc ny vi cc thuc b chuyn ha qua cc enzym c cm ng s lm gim tc

dng ca thuc c phi hp, hoc ca chnh n (hin t ng quen thuc).Tri li, vi nhng thuc phi qua chuyn ha mi tr thnh c hot tnh ("tin thuc"), khi dngchung vi thuc gy cm ng s b tng c tnh (parathion paraoxon)

- Cht c ch enzym chuyn ha: mt s thuc khc nh cloramphenicol, d icumarol, isoniazid,quinin, cimetidin... li c tc dng c ch, lm gim hot tnh chuyn ha thuc ca enzym, do lm tng tc dng ca thuc phi hp.

2.3.4.4. Yu t bnh l

- Cc bnh lm tn thng chc phn gan s lm suy gim sinh chuyn ha thu c ca gan: vimgan, gan nhim m, x gan, ung th gan... d lm tng tc dng hoc c tnh ca thuc chuynha qua gan nh tolbutamid, diazepam.

- Cc bnh lm gim lu lng mu ti gan nh suy tim, hoc dng thuc chn giao cm kodi s lm gim h s chit xut ca gan, lm ko di t/2 ca cc thuc c h s chit xut cao tigan nh lidocain, propranolol, verapamil, isoniazid.

2.4. Thi tr

Thuc -c thi tr d-i dng nguyn cht hoc b chuyn ha

2.4.1. Thi tr qua thn

y l ng thi tr quan trng nht ca cc thuc tan trong nc, c trng lng phn t nhhn 300.

2.4.1.1. Qu trnh thi tr- Lc th ng qua cu thn: dng thuc t do, khng gn vo protein huyt tng.

- Bi tit tch cc qua ng thn: do phi c cht vn chuy n (carrier) nn ti y c s cnh tranh thi tr. Th d dng thiazid ko di, do phi thi tr thiazid, c th gim thi acid uric, d gybnh gut (thiazid v a.uric c cng carrier ng thn).

Qu trnh bi tit tch cc xy ra ch yu ng ln gn, c 2 h vn chuyn khc nhau, mt hcho cc anion (cc acid carboxylic nh penicilin, thiazid, cc cht glucuro - v sulfo- hp), v mth cho cc cation (cc base hu c nh morphin, thiamin).

- Khuch tn th ng qua ng thn: mt phn thuc th i tr trong nc tiu ban u li cti hp thu vo mu. l cc thuc tan trong lipid, khng b ion ha pH nc tiu (pH = 5 -6)

nh phenobarbital, salicylat. Cc base yu khng c ti hp thu.

Qu trnh ny xy ra ng ln gn v c ng ln xa do bc thang nng c to ra trongqu trnh ti hp thu nc cng Na + v cc ion v c khc. Qu trnh ti hp thu th ng yph thuc nhiu vo pH nc tiu. Khi base ha nc tiu, th cc acid yu (acid barbituric) s bthi tr nhanh hn v b ion ha nhiu nn ti hp thu gim. Ngc li, khi acid ha nc tiunhiu hn th cc base (amphetamin) s b thi tr nhiu hn. iu ny c ng dng trong iutr nhim c thuc.


21/439



2.4.1.2. ngha lm sng

- Lm gim thi tr tit kim thu c: penicilin v probenecid c chung h vn chuyn ti ngthn. Thn thi probenecid (r tin, t tc dng iu tr) v gi li penicilin (t tin hn, c tcdng iu tr).

- Lm tng thi tr iu tr nhim c: base ha nc tiu, lm tng ion ha caphenobarbital, tng thi tr khi b nhim c phenobarbital (xin xem"khuch tn th ng").

- Trong trng hp suy thn, cn gim liu thuc dng

2.4.2. Thi tr qua mt

- Sau khi chuyn ha gan, cc cht chuyn ha s thi tr qua mt theo p hn ra ngoi. Phnln sau khi b chuyn ha thm rut s c ti hp thu vo mu thi tr qua thn.

- Mt s hp cht chuyn ha glycuronid ca thuc c trng lng phn t trn 300 sau khi thitr qua mt xung rut c th b thu phn bi glycuronidase ri li c ti hp thu v gantheo ng tnh mch gnh li vo vng tun hon, c gi l thuc c chu k rut - gan.

Nhng thuc ny tch lu trong c th, lm ko di tc dng (morphin, tetracyclin, digitalis trtim...).

2.4.3. Thi tr qua phi

- Cc cht bay hi nh ru, tinh du (eucalyptol, menthol)

- Cc cht kh: protoxyd nit, halothan

2.4.4. Thi tr qua sa

Cc cht tan mnh trong lipid (barbiturat, chng vim phi steroid, tetracyclin, cc alcaloid), ctrng lng phn t di 200 thng d dng thi tr qua sa.

V sa c pH hi acid hn huyt tng nn cc thuc l base yu c th c nng trong sa hicao hn huyt tng v cc thuc l acid yu th c nng thp hn.

2.4.5. Thi tr qua cc -ng khc

Thuc c th cn c thi tr qua m hi, qua nc mt, qua t bo sng (lng, tc, mng),tuyn nc bt. S lng khng ng k nn t c ngha v mt iu tr. Thng c th gy tcdng khng mong mun (diphenyl hydantoin gy tng sn li khi b bi tit qua nc bt) . Hocdng pht hin cht c (c gi tr v mt php y): pht hin asen trong tc ca Napoleon sau 150nm!

2.4.6. Thng s d-c ng hc ca chuyn ha v thi tr thuc

Mc ch ca chuyn ha l lm cho thuc mt hot tnh, d tan trong nc v thi tr. V vy,

qu trnh chuyn ha chnh l qu trnh thi tr thuc. C 2 thng s dc ng hc l thanhthi (CL) v thi gian bn thi (t 1/2) u nh gi qu trnh chuyn ha v thi tr thuc.

2.4.6.1. thanh thi (clearance CL )

nh ngha

thanh thi (CL) biu th kh nng ca 1 c quan (gan, thn) trong c th thi tr hon tonmt thuc (hay mt cht) ra khi huyt tng khi mu tun hon qua c quan .


22/439



Clearance c biu th bng mL/ pht, l s mL huyt tng c thi tr thuc ho n ton trongthi gian 1 pht khi qua c quan. Hoc c khi tnh theo kg thn trng: mL/ pht/ kg.

VCL = (mL/ pht)

CpV: tc thi tr ca thuc qua c quan (mg/ pht)

Cp: nng thuc trong huyt tng (mg/ L)

Clearance cng l mt tr s o, mang tnh l thuyt v s tun hon ca mu qua c quan clin tc lp i lp li. Trong thc t, thuc c coi l lc sch khi huyt tng sau mt khongthi gian l 7 t1/2.

Hai c quan chnh thamgia thi tr thuc khi c th l gan (lng thuc b chuyn ha v thitr nguyn cht qua mt) v thn, v vy, CL ton b c coi l CL gan + CL thn.

ngha

- Thuc c CL ln l thuc c thi tr nhanh, v th thi gian bn thi (t 1/2) s ngn.- Dng CL tnh liu lng thuc c th duy t r c nng thuc n nh trong huyt tng.Nng ny t c khi tc thi tr bng tc hp thu.

- Bit CL hiu chnh liu trong trng hp bnh l suy gan, suy thn.

2.4.6.2. Thi gian b n thi (half - l i fe- t1/2 )

nh ngha

Thi gian bn thi t1/2 c phn bit lm 2 loi :

- t1/2 hay t1/2 hp thu l thi gian cn thit 1/2 lng thuc dng hp thu c vo tun

hon. nu dng thuc theo ng tim bp th t 1/2 khng ng k.- t1/2 hay t1/2 thi tr l thi gian cn thit nng thuc trong huyt tng gim cn 1/2.

Trong thc hnh iu tr, hay dng t 1/2 v thng ch vit l t 1/2 hoc t/2.

ngha

- T cng thc trn ta thy t 1/2 t l nghch vi clearance. Khi CL thay i theo nguyn nhn sinhl hoc bnh l s lm t 1/2thay i, hiu qu ca iu tr b nh hng. Cn phi hiu chnh liulng hoc khong cch gia cc liu (xem phn Nhng bin i ca dc ng hc).

- Trong thc hnh iu tr, thng coi thi gian 5 l n t1/2 (5 ln dng thuc cch u) th nng thuc trong mu t c trng thi n nh (Css), v sau khi ngng thuc khong 7 ln t 1/2 th

coi nh thuc b thi tr hon ton khi c th (xem bng).

L-ng thuc -c thi tr theo t/2

S ln t1/2 L-ng thuc -c thi tr (%)

1 50


23/439



2

3

4

5

6

7

75

88

94

97

98

99

- i vi mi thuc, thi gian bn thi l ging nhau cho mi liu dng. Do c th suy rakhong cch dng thuc:

. Khi t1/2 < 6h: nu thuc t c, cho liu cao ko di c nng hiu dng ca thuc tronghuyt tng. Nu khng th cho c liu cao (nh heparin, insulin) th truyn tnh mch lin tchoc sn xut dng thuc gii phng chm.

. Khi t1/2 t 6 n 24h: dng liu thuc vi khong cch ng bng t 1/2.

. Khi t1/2 > 24h: dng liu duy nht 1 ln mi ngy.

cu hi t l-ng gi1. S hp thu thuc ph thuc vo nhng yu t no?

2. Phn tch, so s nh c c c im ca c c ng hp thu thuc: ng ti u ha, ngti m, ng h hp v ng qua da, ni m m c.

3. Tr nh by vs vn chuyn thuc vo thn kinh trung ng v qua r au thai. ngha lmsng.

4. Sinh kh dng ca thuc l g? ngha.

5. Tr nh by vt htch phn phi (V d) v ngha l m sng?

6. S gn thuc vo pr otein huyt t ng v ngha?

7. K t n c c phn ng chnh (khng vit cng thc) ca chuyn ha thuc pha I, kt quv ngha?

8. K t n c c phn ng chnh (khng vit cng t hc) ca chuyn ha thuc pha II , kt quv ngha?

9. Tr nh by c c c ch thi tr thuc qua thn, qua gan, qua sa v ngha lm sng.

10. thanh thi l g? ngha?

11. Thi gian b n thi l g? ngha?


24/439



Bi 2: i c-ng v D-c lc hc

Mc tiu hc tp: Sau khi hc xong bi ny, sinh vin c kh nng:1. Trnh by c c ch tc dng ca thuc qua receptor v khng qua receptor.

2. Phn bit c cc cch tc dng ca thuc.

3. Trnh by c nhng yu t thuc v bn thn thuc quyt nh tc dng ca thuc (lha, cu trc, dng bo ch).

4. Nu c nhng yu t chnh v pha ngi bnh c nh hng n tc d ng ca thuc(tui, quen thuc).

5. Trnh by c 5 trng thi tc dng c bit ca thuc.

Dc lc hc nghin cu tc dng ca thuc ln c th sng, gii thch c ch ca cc tc dngsinh ha v sinh l ca thuc. Phn tch cng y c cc tc dng, cng cung cp cnhng c s cho vic dng thuc hp l trong iu tr. y l nhim v c bn nht v cng lkh khn ln nht ca dc lc hc.

1. C ch tc dng ca thuc

1.1. Receptor

- Tc dng ca phn ln cc thuc l kt qu ca s tng tc gia thuc vi receptor (th thcm). Receptor l mt thnh phn i phn t (macromolcular) tn ti vi mt l ng gii hntrong mt s t bo ch, c th nhn bit mt cch c hiu ch mt phn t "thng tin" t nhin

(hormon, cht dn truyn thn kinh), hoc mt tc nhn ngoi lai (cht ha hc, thuc) gyra 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 nyvo receptor theo cc lin kt ha hc:

- Lin kt ion: cc cht ha hc mang in tch (nh nhm amoni bc 4 cu acetylcholin c intch dng), s gn vo vng mang in tch tr i du ca receptor theo lin kt ny, vi lc linkt khong 5- 10 kcal/ mol.

- Lin kt hydro: do s phn b khng ng u electron trong phn t nn c mi lin kt gianguyn t hydro vi cc nguyn t c in tch m cao nh oxy, nit v fluor. Lc lin ktkhong 2- 5 kcal/ mol

- Lin kt Van- der- Waals: l lc lin kt ca mi tng h gia cc electron vi cc nhn cacc phn t st bn. Lc lin kt ph thuc vo khong cch gia cc phn t, lc ny tng iyu, khong 0,5 kcal/ mol. Cc thuc c vng benzen, c mt electron phn b ng uthng c mi lin kt ny.


25/439



Cc lc lin kt trn u l thun nghch.

- Lin kt cng ha tr: l lc lin kt gia cc nguyn t bng nhng cp in t chung. V l lclin kt ln 50- 150 kcal/ mol nn l lin kt khng thun nghch nhit c th, khng c chtxc tc. Loi lin kt ny t gp. Th d lin kt gia cht alkyl ha vi t bo ung th, cc thuc

c ch enzym monoamin 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 voreceptor 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 lcVan- der- Waals

2) Chuyn tc dng tng h gia ligand v receptor thnh mt tn hiu gy ra c p ngt bo. Cc receptor nm nhn t bo c hot ha bi cc ligand gn trn cc v tr c hiuca ADN nm trong cc vng iu ha gen, gy ra s sao chp cc gen c hiu (receptor cahormon steroid, vitamin D 3...). Cc receptor nm mng t bo v xa nhn nn khng tham giatrc tip vo cc chng trnh biu hin ca gen. Khi cc ligand tc ng ln receptor s lm snxut ra cc phn t trung gian- "ngi truyn tin th 2" (AMPv, GMPv, IP3, Ca

2+, diacetylglycerol...)- Nhng cht ny s gy ra mt lot phn ng trong t bo, dn ti mt thay ichuyn 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 khithuc 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 vogan, phi, thn...

Thuc gn vo receptor ph thuc vo i lc (affinity) ca thuc vi receptor. Hai thuc c cngreceptor, thuc no c i lc cao hn s y c thuc khc ra. Cn tc dng ca thuc l do


26/439



hiu lc (efficacy) ca thuc trn receptor . i lc v hiu lc khng phi lc no cng i cngnhau: acetylcholin l cht dn truyn thn kinh ca h ph giao cm, khi gn vo receptor M, gyhiu lc lm tng tit nc bt, co ng t, chm nhp tim...; atropin c i lc trn receptor Mmnh hn acetylcholin rt nhiu nn y c acetylcholin ra kh i receptor M, nhng bn thn

n li khng c hiu lc g. lm sng, tc dng ca atropin quan st c chnh l tc dng cas thiu vng acetylcholin trn receptor M: kh ming (gim tit nc bt), gin ng t, nhptim nhanh...

1.2. Cc c ch tc dng ca thuc

1.2.1. Tc dng ca thuc thng qua receptor

Thuc tc dng trc tip trn cc receptor ca cc cht ni sinh (hormon, cht dn truyn thnkinh): nhiu thuc tc dng trn cc receptor sinh l v thng mang tnh c hiu. Nu tc dngca thuc ln receptor ging vi cht ni sinh, gi l cht ng vn hay cht ch vn (agonists),nh pilocarpin trn receptor M- cholinergic. Nu thuc gn vo receptor, khng gy tc dngging 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 viacetylcholin 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 adrenalin trn thn kinh trung ng, nitrit lm gii phng NO gy ginmch...

Xt trn nhiu mt, protein l mt nhm quan trng ca receptor - thuc. Do , ngoi receptor tbo, cc receptor ca thuc cn l:

- Cc enzym chuyn ha hoc iu ha cc qu trn h sinh ha c th b thuc c ch hoc hotha:

. Thuc c ch enzym: captopril c ch enzym chuyn angiotensin I khng hot tnh thnhangiotensin II c hot tnh dng cha cao huyt p; cc thuc chng vim phi steroid c chcyclooxygenase, lm gim tng hp prostaglandin nn c tc dng h st, chng vim; thuc trtim digitalis c ch Na +- K+ ATPase...

. Thuc hot ha enzym: cc yu t vi lng nh Mg 2+, Cu2+, Zn2+ hot ha nhiu enzym proteinkinase, 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;benzodiazepin lm tng nhp Cl - vo t bo, gy an thn.

1.2.2. Tc dng ca thuc khng qua receptor

Mt s thuc c tc dng khng phi do kt hp vi receptor.- Thuc c tc dng do tnh cht l ha, khng c hiu:

Cc 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 mchs ko nc t gian bo vo mu nn c dng cha ph no.


27/439



Isosorbid, mannitol dng liu tng i cao, lm tng p lc thm thu trong huyt tng. Khilc qua cu thn, khng b ti hp thu ng thn, lm tng p lc thm thu trong ng thn, ctc 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 cua" nh EDTA(ethyl diamin tetra acetic acid), BAL (British anti lewisit - dimercaprol), d- penicilamin thngc dng cha ng c kim loi nng nh Cu 2+, Pb2+, Hg2+ hoc thi tr Ca2+ trong ng cdigital.

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 hydroxydnhm, magnesi oxyd.

- Thuc c cu trc tng t nh nhng cht sinh ha bnh thng, c th thm nhp vo ccthnh phn cu trc ca t bo, lm thay i chc phn ca t bo. Thuc ging purin, gingpyrimidin, nhp vo acid nucleic, dng chng ung th, chng virus. Sulfamid gn ging

paraamino benzoic acid (PABA), lm vi khun dng "nhm", khng pht trin c.

2. Cc cch tc dng ca thucKhi 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 qua ng hhp, ng tiu ha hay ng tim: thuc m, thuc tr tim, thuc li niu. Nh vy, tc dng

ton thn khng c ngha l thuc tc dng khp c th m ch l thuc vo mu "i" khpc 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 tiplm ngng th do c honh v c lin sn b lit ch khng phi thuc c ch trung tm h hp.

Mt khc, tc dng gin tip cn c th thng qua phn x: khi ngt, ngi ammoniac, cc ngndy thn kinh trong nim mc ng h hp b kch thch, gy phn x kch thch trung tm hhp 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 iutr, c gi l tc dng khng mong mun, tc dng dng ngoi (adverse drug reactions -ADR). Cc tc dng ngoi c th ch gy kh chu cho ngi dng (chng mt, bun nn, mtng), gi l tc dng ph; nhng cng c th gy ph n ng c hi (ngay vi liu iu tr) nhxut 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 tiuha (tc dng c hi). Nifedipin, thuc chn knh calci dng iu tr tng huyt p (tc dng


28/439



chnh), nhng c th gy nhc u, nhp tim nhanh (tc dng ph), ho, ph chn, tng enzymgan, tt huyt p (tc dng c hi).

Trong iu tr, thng phi hp thuc lm tng tc dng chnh v gim tc dng khng mongmun. Th d ung thuc chn giao cm cng vi nifedipin s lm gim c tc dng lmtng nhp tim, nhc u ca nifedipin. Cng c th thay i ng dng thuc nh dng thuct hu mn trnh tc dng kh ung, gy bun nn.

2.3. Tc dng hi phc v khng hi phc

- Tc dng hi phc: sau tc dng, thuc b thi tr, chc phn ca c quan li tr v bnhthng. 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 vikhun nhng khng nh hng n da; khng sinh cloramphenicol c tai bin gy suy ty xng.

2.4. Tc dng chn lc

Tc dng chn lc l tc dng iu tr xy ra sm nht, r rt nht. Th d aspirin ung liu 1 - 2g/ ngy c tc dng h st v gim au, ung liu 4 - 6 g/ ngy c c tc dng chng vim;digitalis gn vo tim, no, gan, thn... nhng vi liu iu tr, ch c tc dng trn tim; albuterol(Salbutamol- Ventolin) kch thch chn lc receptor 2 adrenergic...

Thuc c tc dng chn lc lm cho vic iu tr tr nn d dng hn, hiu qu hn, trnh cnhiu 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 d-c lc hc ca thuc.

Nh ta bit, thuc mun c tc dng, phi gn c vo receptor (i lc vi receptor) v sau l hot ha c receptor (c hiu lc hay tc dng dc l). Receptor mang tnh c hiucho 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 nhngthay 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 vimgp 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.


29/439



Sulfanilamid PABA (para amino benzoic acid)

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

- Cc ng phn quang hc hoc ng phn hnh hc ca thuc cng lm thay i cng tcdng, hoc lm thay i hon ton tc dng ca thuc.

l. isoprenalin c tc dng kch thch receptor adrenergic 500 ln mnh hn d. isoprenalin.

l. quinin l thuc cha st rt, d. quinin (quinidin) l thuc cha lon nhp tim.

- Cng ngy ngi ta cng hiu r c siu cu trc ca receptor v sn xut cc thuc rt chiu, gn c vo di typ ca receptor: receptor adrenergic 1, 2, 1, 2, 3, receptorcholinergic M1, M2, M3, receptor dopaminergic D 1, D2, ... D7.

3.1.2. Thay i cu trc thuc, lm thay i d-c ng hc ca thuc

Khi cu trc ca thuc thay i, lm tnh cht l ha ca thuc thay i, nh hng n s hatan ca thuc trong nc hoc trong lipid, nh hng n s gn thuc vo protein, ion haca 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 ethinyl 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. Thaygc 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.


30/439



Qua y ta c th nhn thy rng, khi thuc gn vo receptor gy hiu lc, khng phi ton bphn t thuc m ch c nhng nhm chc phn gn vo receptor. Khi thay i cu trc canhm 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 thucphi c bo ch sao cho tin bo qun, vn chuyn, s dng v pht huy ti a hiu lc chabnh ca thuc.

C th tm tt qu trnh hnh thnh v pht huy tc dng ca mt dng thuc trong c th nhsau:

Dc chtK thut bo ch ng dng thuc

Dng thuc

T dc

Dng thuc Gii phng dc Dc cht ti ni Hiu qutrong c th vo mu iu tr

cht v hp thu (sinh kh dng) tc dng

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 quiu tr.

3.2.1. Trng thi ca d-c 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 d-c

T dc khng phi ch l "cht n" bao gi thuc m cn nh hng n ha tan, khuchtn...ca thuc. Khi thay calci sulfat (thch cao, t dc c in) bng lactose dp vindiphenylhydantoin, gy hng lot ng c diphenylhydantoin do lng thuc c hp thunhiu hn (c, 1968). Nguyn nhn l t dc calci sulfat ch ng vai tr mt khung mang,khng tiu v xp, lm dc cht c gii phng t t trong ng tiu ha. Cn lactose li lmdc 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 khdng ca thuc, c th kim sot c s gii phng dc cht v v tr thuc gii phng ( giiphng ti ch). V vy n thng c cc nh sn xut gi b mt.

Hin c rt nhiu dng thuc khc nhau c sn xut theo cc k thut khc nhau sao cho:

- Hot tnh ca thuc c vng bn

- Dc cht c gii phng vi tc n nh

- Dc cht c gii phng ti ni cn tc ng (gii phng ti ch, targetting medication)


31/439



- Thuc c sinh kh dng cao.

3.3. V ngi dng thuc

3.3.1. c im v tui (xin xem phn "d-c 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 ngiln th thnh liu ca tr em, m tr em cn c nhng c im ring ca s pht trin, l:

- S gn thuc vo protein huyt tng cn t, mt khc, mt phn protein huyt tng cn gnbilirubin, 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 dthm qua v t bo thn kinh cn d nhy cm (nh vi morphin)

- T bo cha nhiu nc, khng chu c thuc gy mt nc.

- Mi m v c quan ang pht trin, ht sc thn trng khi dng cc loi hormon.

Mt s tc gi a ra cc cng thc tnh liu lng cho tr em:

1. Cng thc ca Young: dng cho tr t 2- 12 tui

Tui TE Liu ngi ln

Tui TE + 12

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

Tui TE + 1 Liu ngi ln

24

Th d: liu cho ngi ln l 2,0. Liu cho tr 4 tui l4 + 1

2,0 g = 0,41 g24

3. Cng thc ca Fried: dng cho nh nhi

Tui TE (thng) Liu ngi ln

150 (Trng lng trung bnh ca ngi ln)

4. Cng thc ca ClarkTrng lng TE (pounds)


32/439



Liu ngi ln150

Tuy nhin tnh liu theo din tch c th th tt hn. Khi dng cng thc:

BSA (m2) ca tr em Liu ngi ln

1.7

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

1.7: BSA trung bnh ca ngi ln

3.3.1.2. Ngi cao tui

Ngi cao tui cng c nhng c im ring cn lu :

- Cc h enzym u km hot ng v "lo ha"

- 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, tiu ng...)nn phi dng nhiu thuc mt lc. Cn rt ch tng tc thuc khi k n (xin xem phn"tng tc thuc")

3.3.2. c im v gii

Nhn chung, khng c s khc bit v tc dng v liu lng ca thuc gia nam v n. Tuynhin, vi n gii, cn ch n 3 thi k:

3.3.2.1. Thi k c kinh nguyt

Khng cm hn thuc. Nu phi dng thuc di ngy, c tng t ngng thuc th nn sp xpvo lc c kinh.

3.3.2.2. Thi k c thai

Trong 3 thng u, thuc d gy d tt bm sinh, to ra qui thai. Trong 3 thng gia thuc c thnh hng xu n s pht trin ca bo thai, n chc phn pht trin ca cc c quan. Trong 3thng cui, thuc c th gy xy thai, n on.

V vy, khi cn ch nh thuc cho ph n c thai, cn cn nhc tht k gia li ch cho ngi mv mc nguy hi cho bo thai. Ni chung, trong 3 thng u, tuyt i trnh dng mi loi thuc.

i vi ngi m, khi c thai, lng nc gi li trong c th tng, th tch mu tng, hm lngprotein huyt tng c th gim, lng lipid c th tng... lm nh hng n ng hc cathuc.

3.3.2.3. Thi k cho con b


33/439



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 nndng nhng loi thuc tht cn thit cho m. Tuyt i khng dng nhng thuc c cha thucphin v dn xut ca thuc phin (thuc ho, codein, vin ra ) v thuc thi tr qua sa v trung

tm h hp ca tr rt nhy cm, c th b ngng th. Khng dng cc loi corticoid (lm suythng thn tr), cc khng gip trng tng hp v iod (gy ri lon tuyn gip), cloramphenicolv thuc phi hp sulfametoxazol + trimethoprim (Co- trimoxazol) v c th gy suy tu xng.Cn rt thn trng khi dng cc thuc c ch thn kinh trung ng (meprobamat, diazepam),thuc chng ng kinh, u gy m mng v li b cho tr.

4. Nhng trng th i tc dng c bit ca th ucTrong qu trnh s dng thuc, ngoi tc dng iu tr, i khi cn gp nhng tc dng "khngmong 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 thch l nhng triu chng rt nh nh nhc u, bun nn... cho n nhng triu chng rt nngdn n t vong nh sc, phn v, suy tu xng. Tu theo nc v tu theo tc gi, ADR c thxy ra khong 8- 30% s ngi dng thuc.

4.2. Phn ng d ng

D ng thuc cng l 1 ADR.

Do thuc l 1 protein l (insulin, thyroxin ly t sc vt), l a peptid, polysaccharid c phn tlng cao, mang tnh khng nguyn. Tuy nhin, nhng thuc c phn t lng thp hoc chnh

sn phm chuyn ha ca n cng c th gy d ng, chng c gi l bn khng nguyn hay"hapten". Vo c th, hapten c kh nng gn vi mt protein ni sinh theo ng ni cng hatr v to thnh phc hp khng nguyn.

Nhng thuc c mang nhm NH 2 v tr para, nh benzocain, procain, sulfonamid,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 phn v (anaphylactic reactions) do s kt hp ca khng nguyn vi khngth IgE, gn trn bch cu a base tun hon hoc cc dng bo. Phn ng lm gii phng nhiucht 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, vim da d ng),ng h hp (vim mi, hen) v h tim - mch (sc phn v)

Cc phn ng ny thng xy ra ngay sau khi dng thuc.

Cc thuc d gy phn ng typ I: 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 khng nguyn vikhng th IgG v IgM ng thi c s hot ha h b th. M ch ca phn ng ny l cc t


34/439



bo ca h tun hon. Th d: thiu mu tan mu do penicilin, thiu mu tan mu t min domethyl 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 nimc mch, gy tn thng vim hu hoi, c gi l bnh huyt thanh. Biu hin lm sngthng l: my ay, ban , au, vim khp, ni hch, st. Thng xy ra sau 6 - 12 ngy.

Cc thuc c th gp l sulfonamid, penicilin, mt s thuc chng co git, iod, mui Hg, huytthanh.

Hi chng Stevens- Johnson l biu hin nng ca typ ny.

- Typ IV hay phn ng nhy cm mun, trung gian qua t bo lympho T c mn cm v ithc bo. Khi cc t bo mn cm tip xc vi khng nguyn, s gii phng cc lymphokin gyra phn ng vim. Vim da tip xc l biu hin thng gp ca typ ny.

Cc phn ng d ng thuc khng lin quan n liu lng thuc dng, s ln dng v thng cd ng cho. V vy cn hi tin s d ng ca bnh nhn trc khi dng thuc. Vi nhng thuchay 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 tnhmch c th gy sc cht ngi, trong khi dng ung khng gy phn ng ny.

4.3. Tai bin thuc do ri lon di truyn

Thng l do thiu enzym bm sinh, mang tnh di truyn trong gia nh hay chng tc.

Ngi thiu enzym glucose- 6- phosphat deshydrogenase (G-6-PD) hoc glutathion reductase db thiu mu tan mu khi dng primaquin, quinin, pamaquin (xin xem bi " Thuc chng st rt"),sulfamid, nitrofuran...

Gen kim tra vic to G- 6-PD nm trn chromosom X, v vy, tai bin thng xy ra nam.Ngi ta c lng c khong 100- 200 triu ngi mang gen ny v thng gp trn ngi daen.

Ngi thiu enzym methemoglobin reductase l nhng ngi d hp t (khong 1% dn s). Khidng thuc st rt (pamaquin, primaquin), thuc khng sinh, st khun (cloramphenicol, sulfon,nitrofurantoin), thuc h st (phenazol, paracetamol) rt d b methemoglobin.

Ngi thiu acetyl transferase s chm acetyl ha mt s thuc nh hydralazin, isoniazid,phenelzin... nn d b nhim c cc thuc ny.

Hin tng c ng (idiosyncrasy) l nhy cm c nhn bm sinh vi thuc chnh l s thiuht di truyn 1 enzym no .

4.4. Quen thuc

Quen thuc l s p ng vi thuc yu hn hn so vi ngi bnh thng dng cng liu. Liuiu 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 bchuyn 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.


35/439



4.4.1. Quen thuc nhanh (tAChyphylaxis)

Thc nghim dng nhng liu ephedrin bng nhau, tim tnh mch cch nhau tng 15 pht, sau4- 6 ln, tc dng gy tng huyt p gim dn ri mt hn. Mt s thuc khc cng c hin tngquen thuc nhanh nh amphetamin, isoprenalin, adrenalin, histamin...

Nguyn nhn l:

- Thuc tc dng gin tip qua s gii phng cht ni sinh ca c th, lm cn kit cht ni sinh.Ephedrin, amphetamin lm gii phng adrenalin d tr ca h giao cm.

- Kch thch gn nhau qu lm receptor "mt mi"

- To cht chuyn ha c tc dng i khng vi ch t m: isoprenalin (cng giao cm) quachuyn 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 tng liu hoc

i thuc khc. C nhiu nguyn nhn:- Do gy cm ng enzym chuyn ha thuc, lm nhng liu thuc sau b chuyn ha nhanh, mttc dng nhanh. Barbiturat, diazepam, tolbutamid, ru ethylic... u l nhng thuc gy cmng enzym chuyn ha ca chnh n.

- Do gim s lng receptor cm ng vi thuc mng t bo (iu ha gim - down regulation):khi dng thuc cng giao cm, ph giao cm ko di... Tri li, khi dng cc thuc phong toko di s lm tng s lng receptor (iu ha tng - up regulation) nh dng thuc hu giaocm, thuc an thn c ch h dopaminergic. Khi ngng thuc d gy hin tng hi ng(rebound)

- Do c th phn ng bng c ch ngc li dng cc thuc li niu thi Na + lu, c th mt

nhiu Na

+

s tng tit aldosteron gi li Na

+

, lm gim tc dng li niu. trnh hin tng quen thuc, trong lm sng thng dng thuc ngt qung hoc lun phinthay 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 chtvo 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, bn thu, thiu

o c... gy hi cho bn thn v x hi- Khi cai thuc s b thuc " vt" hay ln cn "i thuc" : vt v, ln ln, d cm, v m hi, tiuchy... 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, onh, o gic ("ph" thuc) hoc trng thi hng phn mnh (thuc lc), c gi chung l "maty": morphin v cc cht loi thuc phin (heroin, pethidin, methadon), cocain, cn sa (cannabis,marijuana), metamphetamin, ectasy... Ru v thuc l hin cn c coi l ma ty "hp php".


36/439



C ch nghin cn cha c hon ton bit r, c nhiu gi thuyt gii thch: do c th khngsn xut morphin ni sinh; lm ri lon chc phn ca nron, gy phn ng b tr ca c th; tora cht i khng vi ma ty nn i hi phi tng liu...

Hin nay khng c phng php cai nghin no c hiu qu, ngoi tr ch ca ngi nghin. V

vy, nghin ma tu l mt t nn x hi phi c loi tr.

Cu hi t l-ng gi

1. Trnh by cc c ch tc dng ca thuc.

2. Trnh by cc cch tc dng ca thuc.

3. Phn tch nhng yu t v thuc c nh hng n tc dng ca thuc.

4. Phn tch nhng yu t ca ngi dng thuc c nh hng n tc dng ca thuc.

5. Trnh by nhng tai bin khi dng thu c: phn ng c hi, phn ng d ng, ri lon dodi truyn, nghin thuc.


37/439



Bi 3: tng tc thuc

Mc tiu hc tp: Sau khi hc xong bi ny, sinh vin c kh nng:1. Trnh by -c t-ng tc d-c lc hc v d-c ng hc.

2. Trnh by -c hiu qu v p dng ca t-ng tc thuc.

1.Tng tc thuc- thucNhiu 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 tc dng iu tr, gim cctc dng khng mong mun. Song trong thc t, nhiu khi khng t c nh th. V vy, khik n c t 2 thuc tr ln, thy thuc rt cn hiu r s tng tc gia chng.

1.1. Tng tc dc lc hcL tng tc ti cc receptor, mang tnh c hiu

1.1.1. T-ng t c trn cng receptor: t-ng tc cnh tranh

Thng lm gim hoc mt tc dng ca cht ng vn (a gonist), do cht i khng (antagonist)c i lc vi receptor hn nn ngn cn cht ng vn gn vo receptor: atropin khngacetylcholin v pilocarpin ti receptor M; nalorphin khng morphin ti receptor ca morphin;cimetidin khng histamin ti receptor H2.

Thuc cng nhm c cng c ch tc dng, khi dng chung tc dng khng tng bng tng liuca mt thuc m c tnh li tng hn: CVKS, aminosid vi dy VIII.

1.1.2. T-ng tc trn cc receptor khc nhau: t-ng 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 iutr lao, phi hp nhiu khng sinh (DOTS) tiu dit vi khun cc v tr v cc giai on phttrin khc nhau.

- C ch tc dng i lp, gy ra c chc phn i lp, dng iu tr nhim c: strychninliu cao, kch thch ty sng gy co cng c, cura do c ch dn truyn tm vn ng, lm mmc; histamin tc ng trn receptor H1 gy gin mch, tt huyt p, trong khi noradrenalin tcng ln receptor 1 gy co mch, tng huyt p.

1.2. Tng t c dc ng hc

L cc tng tc nh hng ln nhau thng qua cc qu trnh hp thu, phn phi, chuyn ha vthi tr v th n khng mang tnh c hiu.

1.2.1. Thay i s hp thu ca thuc

- Do thay i ion ha ca thuc:

Nh ta bit, ch nhng phn khng ion ha ca thuc mi d dng qua c mng sinh hc vd phn tn hn trong lipid. phn ly ca thuc ph thuc vo hng s pKa ca thuc v pH


38/439



ca mi trng. Cc thuc c bn cht acid yu (nh aspirin) s hp thu tt trong mi trng acid(d dy), nu ta trung ha acid ca dch v th s hp thu aspirin d dy s gim i.

- Vi cc thuc dng theo ng ung: khi dng vi thuc lm thay i nhu ng rut s lmthay i thi gian lu gi thuc trong rut, thay i s hp thu ca thuc qua rut. Mt khc cc

thuc d tan trong lipid, khi dng cng vi parafin (hoc thc n c m) s lm tng hp thu.- Vi cc thuc dng theo ng tim bp, di da: procain l thuc t , khi trn vi adrenalin lthuc co mch th procain s chm b hp thu vo mu do thi gian gy t s c ko di.Insulin trn vi protamin v km (protemin - zinc- insulin- PZI) s lm ko di thi gian hp thuinsulin 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 (Al3+) to mng bao nim mc ng tiu ha, lmkh 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 thucloi acid yu, gn thun nghch vi protein (albumin, globulin) s c s tranh chp, ph thucvo i lc v nng ca thuc trong huyt tng. Ch c thuc dng t do mi c tc dngdc l. V vy, tng tc ny c bit c ngha vi thuc c t l gn vo protein huyt tngcao (trn 90%) v c phm vi iu tr hp nh:

. Thuc chng ng mu loi khng vitamin K: dicumarol, warfarin

. Sulfamid h ng huyt: tolbutamid, clopropamil

. Thuc chng ung th, c bit l methotrexat

Tt c u b cc thuc chng vim phi steroid d dng y khi protein huyt tng, c th gynhim c.

1.2.3. Thay i chuyn ha

Nhiu thuc b chuyn ha gan do cc enzym chuyn ha thuc ca microsom ga n (xin xemphn dc ng hc). Nhng enzym ny li c th c tng hot tnh (gy cm ng) hoc b cch bi cc thuc khc. Do s lm gim t/2, gim hiu lc (nu l thuc gy cm ng enzym)hoc lm tng t/2, tng hiu lc (nu l thuc c ch 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, cimetidin, MAOI,erythromycin, isoniazid, dicumarol.

Cc thuc hay phi hp vi cc loi trn thng gp l cc hormon (thyroid, corticoid, estrogen),thuc chng ng kinh, thuc h ng huyt, thuc tim mch.


39/439



Ph n ang dng thuc trnh thai ung, nu b lao dng thm rifampicin, hoc b ng kinhdng phenytoin, c th s b "v k hoch" do estrogen trong thuc trnh thai b gim hiu qu vb 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 ) vbi 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 ionha ca thuc dng km, lm thay i bi xut ca thuc. Th d barbital c pKa = 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 bion ha. V vy, khi ng c cc thuc barbiturat, truyn dch NaHCO3 base ha nc tiu stng bi xut barbiturat.

Cc thuc l acid yu (vitamin C, amoni clorid) dng liu cao, lm acid ha nc tiu s lm tngthi 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 tranhchp nhau, cht ny lm gim bi xut cht khc. Dng probenecid s lm chm thi trpenicilin, 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 dngc. 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 thuc ch khngphi hp thuc.

Hip ng tng mc thng dng trong iu tr lm tng tc dng iu tr v lm gim tcdng ph, tc dng c hi. Hai thuc c hip ng tng mc c th qua tng tc dc nghc (tng hp thu, gim thi tr) hoc tng tc dc lc hc (trc tip hoc gin tip quareceptor)

1.3.2. Tc dng i khng

Nh trong nh ngha trn, nhng khi tc dng c ca thuc A + B li nh hn tc dng cng catng thuc (c < a + b) ta gi l tc dng i khng. i khng c th ch mt phn (partialantagonism) khi c < a + b, nhng cng c th i khng hon ton khi a lm mt hon ton tcdng 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 tcthun ty l ha:

+ Acid gp base: to mui khng tan. Khng tim khng sinh loi acid (nhm lactam) vo ngdn dch truyn c tnh base.


40/439



+ Thuc oxy ha (vitamin C, B 1, penicilin) khng trn vi thuc oxy kh (vitamin B2)

+ Thuc c bn cht l protein (insulin, heparin) khi gp mui kim loi s d kt ta.

+ Than hot, tanin hp ph hoc lm kt ta nhiu alcaloid (quinin, atropin) v cc mui kim loi(Zn, Pb, Hg...)

- i khng xy ra trong c th:

Khi thuc A lm gim nng ca thuc B trong mu (qua dc ng hc) hoc lm gim tcdng ca nhau (qua dc lc hc), ta gi l i khng (antagonism)

V dc lc hc, c ch ca tc dng i khng c th l:

+ Tranh chp trc tip ti receptor: ph thuc vo i lc v nng ca thuc ti receptor. Thd: acetylcholin v atropin ti receptor M - cholinergic; histamin v cimetidin trn receptor H2 d dy.

+ i khng chc phn: hai cht ng vn (agonist) tc dng trn 2 receptor khc nhau nhngchc phn li i khng trn cng mt c quan. Strychnin kch thch tu sng, gy co git; cura

c ch dn truyn tm vn ng, gy mm c, chng c co git. Histamin kch thch receptorH1 lm co c trn kh qun, gy hen; albuterol (Ventolin), kch thch rec eptor2 adrenergic lmgin c trn kh qun, dng iu tr cn hen.

1.3.3. o ng-c t c dng

Adrenalin va c tc dng kch tch receptor adrenergic (co mch, tng huyt p), va c tcdng kch thch receptor adrenergic (gin mch, h huyt p). Khi dng mt mnh, do tc dng mnh hn nn adrenelin gy tng huyt p. Khi dng phentolamin (Regitin) l thuc c chchn lc receptor ri mi tim adrenalin th do ch kch thch c receptor nn adrenelingy h huyt p, tc dng b o ngc.

ngha ca tng tc thucTrong lm sng, thy thuc dng thuc phi hp vi mc ch:

- Lm tng tc dng ca thuc chnh (hip ng tng mc)

- Lm gim tc dng khng mong mun ca thuc iu tr

- Gii c (thuc i khng, thuc lm tng thi tr, gim hp thu, trung ha...)

- Lm gim s quen thuc v khng thuc

Tuy nhin, nu khng hiu r tc dng phi hp, thy thuc c th lm gim tc dng iu trhoc tng tc dng c ca thuc. Trong cc sch hng dn dng thuc, thng c mc tngtc ca tng thuc.

2. Tng tc thuc- thc n- ung2.1. 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:


41/439



- S hp thu ph thuc vo thi gian rng ca d dy. D dy khng phi l ni c ch c nng hpthu ca b my tiu ha. Tuy nhin, do pH rt acid (khi i, pH 1; khi no pH 3) cho nn cnlu :

+ 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 (penicilinV). Tuy nhin, nhng thuc d to phc vi nhng thnh phn ca thc n s b gim hp thu(tetracyclin to phc vi Ca++ v mt s cation ho tr 2 khc).

. Cc thuc km bn trong mi trng acid (ampicilin, erythromycin) nu b gi lu d dy sb 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 gim hp thu50%, 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 nctiu, 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 chenzym monoamin- oxydase (MAOI) nh iproniazid- l enzym kh amin- oxy ha ca nhiuamin 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 cm trong thigian ngn.

2.2. Tng tc thc n ung2.2.1. N-c

- Nc l ung (dung mi) thch hp nht cho mi loi thuc v khng xy ra tng k khiha tan thuc.

- Nc l phng tin dn thuc (dng vin) vo d dy - rut, lm tng tan r v ha tan hotcht, 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 :

+ Ung 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 gas v cc loinc ny c th lm hng thuc hoc gy hp thu qu nhanh.

2.2.2. Sa


42/439



Sa cha calci caseinat. Nhiu thuc to phc vi calci ca sa s khng c hp thu(tetracyclin, lincomycin, mui Fe...)

Nhng thuc d tan trong lipid s tan trong lipid ca sa chm c hp thu.

Protein ca sa cng gn thuc, lm cn tr hp thu.

Sa c pH kh cao nn lm gim s kch ng d dy ca cc thuc acid.

2.2.3. C ph, ch

- Hot cht cafein trong c ph, nc ch lm tng tc dng ca thuc h st gim au aspirin,paracetamol; nhng li lm tng tc dng ph nh nhc u, tng nhp tim, tng huyt p nhng bnh nhn ang dng thuc loi MAOI.

- Tanin trong ch gy ta cc thuc c Fe hoc al caloid

- Cafein cng gy ta aminazin, haloperidol, lm gim hp thu; nhng li lm tng ha tanergotamin, lm d hp thu.

2.2.4. R-u ethylicRu c rt nhiu nh hng n thn kinh trung ng, h tim mch, s hp thu ca ng tiuha. Ngi nghin ru cn b gim protein huyt tng, suy gim chc nng gan, nhng li gycm ng enzym chuyn ha thuc ca gan (xin xem bo "ru"), v th ru c tng tc vi rtnhiu thuc v cc tng tc ny u l bt li. Do khi dng thuc th khng ung ru.Vi ngi nghin ru cn phi dng thuc, thy thuc cn kim tra chc nng gan, tnh trngtm thn... chn thuc v dng liu lng thch hp, trong thi gian dng thuc cng phingng ung ru.

3. Thi im ung thucSau 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 gim c tc dngph l rt cn thit.

Nn nh rng: ung thuc vo lc i, thuc ch b gi li d dy 10 - 30 pht, vi pH 1;ung lc no (sau n), thuc b gi li 1 - 4 gi vi pH 3,5. Nh vy, tu theo tnh cht ca thuc,mc ch ca iu tr, c mt s gi chn thi im ung thuc nh sau:

3.1.Thuc nn ung vo lc i (trc ba n 1/2 - 1 gi)

- Thuc "bc" d dy cha lot trc khi thc n c mt, nh sucralfat.

- Cc thuc khng nn gi li lu trong d dy nh: cc thuc km bn vng trong mi trngacid (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 (pancreatin) chng i thong 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,mui kali, quinin.


43/439



- Nhng thuc c thc n lm tng hp thu, hoc do thc n lm chm di chuyn thuc nnko di thi gian hp thu: cc vitamin, cc vin nang amoxicilin, cephalexin, cc vin nndigoxin, sulfamid.

- Nhng thuc c hp thu qu nhanh lc i, d gy tc dng ph: levodopa, thuc khng

histamin H1.3.3. Thuc t b nh hng bi thc n, ung lc no cng c: prednisolon, theophylin,augmentin, digoxin.

3.4. Thuc nn ung vo bui sng, ban ngy

- Cc thuc kch thch thn kinh trung ng, cc thuc li niu trnh nh hng n gic ng.

- Cc corticoid: thng ung 1 liu vo 8 gi sng duy tr c nng n nh trong mu.

3.5. Thuc nn ung vo bui ti, trc khi i ng.

- Cc thuc an thn, thuc ng

- Cc thuc khng acid, chng lot d dy. Dch v acid thng tit nhiu vo ban m, cho nnngoi vic dng thuc theo ba n, cc thuc khng acid dng cha lot d dy nn c ungmt 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.

D-c l thi khc (chronopharmacology) cho thy c nhiu thuc c hiu lc hoc c tnhthay i theo nhp ngy m. Tuy nhin, trong iu tr, vic cho thuc cn tu thuc vo thigian xut hin triu chng.

cu hi t lng gi

1. Trnh by t-ng tc d-c ng hc ca thuc.

2. Trnh by t-ng tc d-c lc hc.

3. Trnh by ngha v p dng lm sng ca t-ng tc th uc.

4. Trnh by t-ng tc thuc vi thc n v ung.


44/439



Bi 4: i c-ng v phn loi

Mc tiu hc tp: Sau khi hc xong bi ny, sinh vin c kh nng:1. Phn bit c v gii phu, sinh l v dc l cc h giao cm, ph giao cm,adrenergic, cholinergic

2. Phn bit c cc tc dng sinh l ca h M - N- cholinergic

H thn kinh thc vt (cn gi l h thn kinh t ng) chuyn iu khin cc hot ng ngoi mun, c vai tr iu ha chc phn ca nhiu c quan, h thng cho gii hn sng ca c thgi c s n nh trong mi trng sng lun lun thay i.

H thng thn kinh thc vt hnh thnh t nhng trung tm trong no v tu sng, xut phtnhng si thn kinh ti cc tng, mch mu v c nhn. Trc khi ti c quan thu nhn, cc siny u dng mt xinap ti hch, v vy c si trc hch (hay tin hch) v si sau hch (hayhu hch). Khc vi nhng b phn do h thn kinh trung ng iu khin, cc c quan do hthn kinh thc vt chi phi vn c th hot ng t ng khi ct t nhng si thn kinh nchng.

H thng thn kinh thc vt c chia thnh 2 h giao cm v ph giao cm khc nhau v c giiphu v chc phn sinh l.

1. Phn loi theo gii phu1.1. im xut pht

- H giao cm xut pht t nhng t bo thn kinh sng bn ca tu sng t t sng ngc th

nht n t sng tht lng th 3 (T1- L3).

- H ph giao cm xut pht t no gia, hnh no v tu cng. no gia v hnh no, cc siph giao cm i cng vi cc dy thn kinh trung ng: dy III vo mt; dy VII vo cc tuynnc bt; dy IX vo c mi, cc tuyn tit nc mt, n c bt, tuyn tit nim mc mi, ming,

hu; dy X vo cc tng trong ngc v bng. tu cng, xut pht t cc t sng cng th 2n th 4 (S2- S4) chi phi cc c quan trong h chu.

1.2. Hch

- H giao cm c 3 nhm hch:

. Chui hch cnh ct sng nm hai bn ct sng

. Nhm hch trc ct sng, gm hch tng, hch mc treo v hch h v, u nm trong bng.

. Nhm hch tn cng gm nhng hch nm cnh trc trng v bng quang.

- H ph giao cm: cc hch nm ngay cnh hoc ngay trong thnh c qua n.

1.3. Si thn kinh

- H giao cm: mt si tin hch thng tip ni vi khong 20 si hu hch cho nn khi kchthch giao cm, nh hng thng lan rng.


45/439



- H ph giao cm: mt si tin hch thng ch tip ni vi mt si hu hch, cho nn xung tcthn kinh thng khu tr hn so vi xung tc giao cm. Tuy nhin, i vi dy X th m riAuerbACh v m ri Meissner (c coi l hch) th mt si tin hch tip ni vi khong 8000si hu hch.

V hch nm ngay cnh c quan, cho nn cc si hu hch ph giao cm rt ngn.


46/439



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

2. Chc phn sinh l2.1. Chc phn sinh l

Chc phn sinh l ca hai h giao cm v ph giao cm trn cc c quan ni chung l i khngnhau (bng 4.1)

Bng 4.1: p ng ca c quan vi h thn kinh thc vt

C quan Kch thch giao cm Kch thch ph giao cmLoi receptor p ng p ng

MtC nan hoaC co ng t

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

Tim

Nt nh- thtTm nh1 (2)1(2)

Tng tn s ++Tng bin ++ Gim tn s ngng tim

Gim bin ++Mao ng mch

Mch vnhC vnDa, nim mcNoTngThn

1, 2, 2, 21, 211, , 21, 2, 1, 2

Co +; gin ++Co ++; gin ++Co +++Co nhCo +++; Gin +Co +++; gin +

Gin +Gin +GinGin--

Tnh mch 1, 2 Co ++; gin ++ -Ph qun

2

Gin + Co ++Rut

Nhu ngC thtBi tit

1, 2, 212

Gim +Co +c ch

Tng +++Gin +Tng +++

ThnTit renin 1, 1 Gim +; tng ++ -

T cung 1, 2 Cha: co (1); gin (2)Khng cha; gin (2)

Thay i theo chu kkinh...

C quan sinhdc nam

1 Phng tinh +++ Cng +++

Bng quangC bng quangC trn

21

Gin +Co ++

Co +++Gin ++

Gan 1, 2 Hu glycogen v tn toglucose +++

-


47/439



TyAciniT bo

12

Gim tit +Gim tit +++tng tit ++

Tng tit ++--

T bo m 2, 1 (3) Hu lipid +++ -Ghi ch: - Cc receptor ca h ph giao cm u l cc loi receptor M

- Mc p ng t thp (+) n cao (+++)

2.2. Xinap v cht dn truyn thn kinh

Khi ta kch thch cc dy thn kinh (trung ng v thc vt) th u mt ca cc dy s titra nhng cht ha hc lm trung gian cho s dn truyn gia cc dy tin hch vi hu hch,hoc gia dy thn kinh vi cc c quan thu nhn. Cht ha hc lm trung gian cho s dn truyn gi l cht dn truyn thn kinh.

H thng thn kinh ca ngi c hng chc t nron. S thng tin gia cc nron cng davo cc cht dn truyn thn kinh. Cc thuc nh hng n chc phn thn kinh thng l thngqua cc cht dn truyn thn kinh .

Cht dn truyn thn kinh hch giao cm, ph giao cm v hu hch ph giao cm u lacetylcholin, cn hu hch giao cm l noradrenalin, adrenalin v dopamin (gi chung lcatecholamin). Cc cht dn truyn thn kinh tc ng n mng sau xinap lm thay i tnhthm ca mng vi ion Na+, K+ hoc Cl- do gy ra hin tng bin cc (kh cc hoc u ccha). Ion Ca++ ng vai tr quan trng trong s gii phng cht dn truyn thn kinh.


48/439



2.3. Cc cht dn truyn khc

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

Ngi ta tm thy trong tu thng thn, trong cc si thn kinh, trong hch thn kinh thc vthoc trong cc cu trc do h thn kinh thc vt chi phi mt lot cc peptid sau: e nkephalin,cht P, somatostatin, hormon gii phng gonadotropin, cholecystokinin, vasoactive intestinalpeptide (VIP), neuropeptid Y (NPY)... Vai tr dn truyn ca ATP, VIP v NPY trong h thnkinh thc vt dng nh c coi l nhng cht iu bin t c dng ca NA v ACh. Nh vy,bn cnh h thn kinh thc

vt vi s dn truyn bng ACh v NA cn tn ti mt h thng dn truyn khc c gi l dntruyn khng adrenergic, khng cholinergic [Nonadrenergic, non cholinergic (NANC)transmission].

Burnstock (1969, 1986) thy c cc si thn kinh purinergic chi phi c trn ng tiu ha,ng sinh dc- tit niu v mt s mch mu. Adenosin, ATP l cht dn truyn, cc receptorgm receptor adenosin (A hoc P1) v receptor ATP (P2). Cc di typ receptor u hot ngthng qua protein G, cn receptor P2x li thng qua knh ion (Fredholm v cs, 1994).Methylxantin (cafein, theophylin) l cht c ch cc receptor ny.

Nitric oxyd cng l mt cht dn truyn ca h NANC c tc dng lm gin mch, gin phqun. Nitric oxyd c ni m thnh mch, khi c gii phng s hot ha guanylyl cyclase,lm tng tng hp GMPv, gy gin c trn thnh mch.

Cc cht dn truyn thn kinh c tng hp ngay ti t bo thn kinh, sau c lu tr dith phc hp trong cc ht c bit nm ngn dy thn kinh trnh b ph hu. Di tc dngca nhng lung

Sach Duoc Ly Hoc y Hn

Documents

Transcript of Sach Duoc Ly Hoc y Hn