duoc_ly_hoc_146

B Y T

DC L HCTP 1

(DNG CHO O TO BC S A KHOA)

M s: .01.Y.14

NH XUT BN GIO DCH NI 2007

Ch o bin son:V KHOA HC V O TO - B Y T

Ch bin:GS.TS. O VN PHAN

Nhng ngi bin son:PGS.TS. NGUYN TRN TH GING

HNG GS.TS. O VN PHAN

Page 1 of 224Dc l hc - B Y t

7/14/2011file:///C:/Windows/Temp/ugpmsddehh/duoc_ly_hoc.htm

PGS.TS. NGUYN TRNG THNG

Th k bin son:NGUYN KIU VN

Tham gia t chc bn tho:ThS. PH VN THM

TS. NGUYN MNH PHA

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

Li gii thiuThc hin mt s iu ca Lut Gio dc, B Gio dc & o to v B Y t ban hnh chng

trnh khung o to Bc s a khoa. B Y t t chc bin son ti liu dy - hc cc mn c s v chuyn mn theo chng trnh trn nhm tng bc xy dng b sch t chun chuyn mn trong cng tc o to nhn lc y t.

Sch DC L HC c bin son da trn chng trnh gio dc ca Trng i hc Y H Ni trn c s chng trnh khung c ph duyt. Sch c cc tc gi PGS.TS. Nguyn Trn th Ging Hng, GS.TS. o Vn Phan, PGS.TS. Nguyn Trng Thng bin son theo phng chm: kin thc c bn, h thng; ni dung chnh xc, khoa hc, cp nht cc tin b khoa hc, k thut hin i v thc tin Vit Nam.

Sch DC L HC c Hi ng chuyn mn thm nh sch v ti liu dy - hc chuyn ngnh Bc s a khoa ca B Y t thm nh nm 2007. B Y t quyt nh ban hnh l ti liu dy - hc t chun chuyn mn ca ngnh trong giai on hin nay. Trong thi gian t 3 n 5 nm, sch phi c chnh l, b sung v cp nht.

B Y t xin chn thnh cm n cc tc gi v Hi ng chuyn mn thm nh gip hon thnh cun sch; Cm n GS.TSKH. Hong Tch Huyn, PGS.TS. Mai Phng Mai c v phn bin cun sch sm hon thnh kp thi phc v cho cng tc o to nhn lc y t.

874 - 2007/CXB/9 - 1918/GD M s: 7K729M7 - DAI



Ln u xut bn, chng ti mong nhn c kin ng gp ca ng nghip, cc bn sinh vin v cc c gi ln xut bn sau c hon thin hn.

V KHOA HC V O TO - B Y T

LI NI UCun sch ny c bin son dng ging dy mn DC L HC cho cc Trng i hc Y,

o to Bc s a khoa nh hng cng ng.

Ngy nay, trn th trng Vit Nam c ti hn mi nghn mt hng thuc ang lu hnh. Cc thy thuc lun ng trc th thch rt ln trong vic la chn thuc cho iu tr nhm thc hin phng chm "s dng thuc an ton v hp l".

Thy thuc iu tr khng "chy" theo tng tn thuc m cn phi hiu r tc dng ca tng nhm thuc c hng s dng cho ng. Cun sch ny c bin son nhm cung cp cho sinh vin nhng kin thc c bn v c ch tc dng ca tng nhm thuc phn theo tc dng sinh l - bnh l -iu tr hc. Trn c s hiu r c ch tc dng, cc thy thuc s hiu r cc p dng lm sng ca thuc nh ch nh, chng ch nh, tc dng khng mong mun. T nhng kin thc c bn ny, trong qu trnh thc hnh, cng vi s pht trin ca cc thuc mi, ngi c hon ton c th hiu thm c im ca cc thuc c th s dng c "an ton v hp l".

Khoa hc k thut ang khng ngng pht trin. Cc loi thuc mi ang lin tc xut hin. Thm ch cn c thuc b loi tr sau vi nm c php lu hnh. V vy cc thy thuc cn lun cp nht thng tin bng cc ngun khc nhau. Cun sch gio khoa khng th lm c vic ny v sau vi nm mi ti bn mt ln.

Cc tc gi c gng bin son nhng kin thc dc l hc c bn cho sinh vin theo ng chng trnh quy nh ca B Y t. Nhng kin thc ny lm c s cho sinh vin y a khoa thc hnh v t hc sau khi ra trng.

Cc tc gi rt mong nhn c nhng kin ng gp ca ng o bn c v cc ng nghip trong ngnh y dc.

CC TC GI

KHI NIM V DC L HCDc l hc (Pharmacology) theo tu t hc l mn khoa hc v thuc. Nhng trnh ngha qu

rng ca t ny, Dc l hc ch bao hm mi nghin cu v s tng tc ca thuc vi cc h sinh hc.

Thuc l cc cht hoc hp cht c tc dng iu tr hoc d phng bnh tt cho ngi v sc vt, hoc dng trong chn on bnh lm sng, dng khi phc, iu chnh cc chc nng ca c quan trong c th.



Thuc c th c ngun gc t thc vt (cy canhkina, cy ba gc), t ng vt (insulin chit xut t ty tng b, ln), t khong vt, kim loi (kaolin, thu ngn, mui vng) hoc l t cc cht bn tng hp, tng hp ho hc (ampicilin, sulfamid).

u tin, thuc phi c nghin cu trn sc vt thc nghim xc nh c tc dng, c ch tc dng, c tnh, liu iu tr, liu c, tc dng gy t bin, gy qui thai, gy ung th... l i tng ca mn Dc l hc thc nghim (Experimental pharmacology). Nhng nghin cu ny nhm m bo an ton n mc ti a cho ngi dng thuc. Ch sau khi c s liu ng tin cy v thc nghim trn sc vt mi c p dng cho ngi.

Tuy nhin, sc vt phn ng vi thuc khng hon ton ging ngi; v vy sau giai on thc nghim trn sc vt, thuc phi c th trn nhm ngi tnh nguyn, trn cc nhm bnh nhn ti cc c s khc nhau, c so snh vi cc nhm dng thuc kinh in hoc thuc v (placebo), nhm nh gi li cc tc dng gp trong thc nghim v ng thi pht hin cc triu chng mi, nht l cc tc dng khng mong mun cha thy hoc khng th thy c trn sc vt (bun nn, chng mt, nhc u, phn ng d ng...). Nhng nghin cu ny l mc tiu ca mn Dc l hc lm sng (Clinical pharmacology).

Cun sch gio khoa ny mang tnh cht Dc l y hc (Medical pharmacology), vit cho sinh vin trng Y v thy thuc thc hnh, nhm cung cp nhng kin thc v tc dng ca thuc v nhng vn lin quan n iu tr thy thuc c th k n c an ton v hp l.

Dc l hc lun da trn nhng thnh tu mi nht ca cc ngnh khoa hc c lin quan nh sinh l, sinh ho, sinh hc, di truyn hc... ngy cng hiu su v c ch phn t ca thuc, gip cho nghin cu sn xut cc thuc mi ngy cng c tnh c hiu, khng ngng nng cao hiu qu iu tr.

Dc l hc cn chia thnh:

Dc lc hc (Pharmacodynamics) nghin cu tc ng ca thuc trn c th sng. Mi loi thuc, tu theo liu dng s c tc dng sm, c hiu trn mt m, mt c quan hay mt h thng ca c th, c s dng iu tr bnh, c gi l tc dng chnh. Ngoi ra, mi thuc li cn c th c nhiu tc dng khc, khng c dng iu tr, tri li cn gy phin h cho ngi dng thuc (bun nn, chng mt, nh trng ngc...), c gi l tc dng ph, tc dng khng mong mun hay tc dng ngoi . Tt c cc tc dng l i tng nghin cu ca Dc lc hc. Trong cun sch ny, n c vit vo mc "tc dng dc l".

Dc ng hc (Pharmacokinetics) nghin cu v tc ng ca c th n thuc, l ng hc ca s hp thu, phn phi, chuyn ho v thi tr thuc. Ngi thy thuc rt cn nhng thng tin ny bit cch chn ng a thuc vo c th (ung, tim bp, tim tnh mch...), s ln dng thuc trong ngy, liu lng thuc tu theo tng trng hp (tui, trng thi bnh, trng thi sinh l...).

Dc l thi khc (Chronopharmacology) nghin cu nh hng ca nhp sinh hc trong ngy, trong nm n tc ng ca thuc. Hot ng sinh l ca ngi v ng vt chu nh hng r rt bi cc thay i ca mi trng sng nh nh sng, nhit , m... Cc hot ng ny bin i nhp nhng, c chu k, gi l nhp sinh hc (trong ngy, trong thng, trong nm). Tc ng ca thuc cng c th thay i theo nhp ny. Ngi thy thuc cn bit chn thi im v liu lng thuc ti u.

Dc l di truyn (Pharmacogenetics) nghin cu nhng thay i v tnh cm th ca c th, ca gia nh hay chng tc vi thuc do nguyn nhn di truyn. V d ngi thiu G6PD rt d b thiu mu tan mu do dng sulfamid, thuc chng st rt... ngay c vi liu iu tr thng thng. C th ni Dc l



di truyn l mn giao thoa gia Dc l - Di truyn - Ho sinh v Dc ng hc.

Dc l cnh gic hay Cnh gic thuc (Pharmacovigilance) chuyn thu thp v nh gi mt cch c h thng cc phn ng c hi c lin quan n vic dng thuc trong cng ng. Phn ng c hi l nhng phn ng khng mong mun (ngoi ) xy ra mt cch ngu nhin vi cc liu thuc vn dng d phng, chn on hay iu tr bnh. Phenacetin l thuc h st, phi 75 nm sau khi dng ph bin mi pht hin c tc dng gy c ca thuc; sau 30 nm mi thy c chng suy gim bch cu ca amidopyrin.

Nhng mn hc trn l nhng chuyn khoa su ca Dc l hc. Ngi thy thuc cng bit r v thuc cng nm c "ngh thut" k n an ton v hp l. V iu kin thi gian v khun kh, cun sch ny ch yu cung cp nhng kin thc v dc lc hc, dc ng hc v vi mt s thuc c bit, c lu n dc l di truyn, dc l cnh gic...

Mc tiu ca mn Dc l hc l sinh vin sau khi hc xong c th:

- Trnh by v gii thch c c ch tc dng, p dng iu tr ca cc thuc i din trong tng nhm.

- Phn tch c tc dng khng mong mun v c tnh ca thuc bit cch phng v x tr.

- K c cc n thuc ng nguyn tc, ng chuyn mn, ng php l.

Ngi thy thuc nn nh rng:

Khng c thuc no v hi.

Ch dng khi tht cn, ht sc trnh lm dng thuc.

Khng phi thuc t tin lun lun l thuc tt nht.

Trong qu trnh hnh ngh, thy thuc phi lun lun hc hi nm c cc kin thc dc l ca cc thuc mi hoc nhng hiu bit mi, nhng p dng mi ca cc thuc c.

Chng IDC L HC I CNG

Bi 1I CNG V DC NG HC

MC TIU



Dc ng hc (Pharmacokinetics) nghin cu cc qu trnh chuyn vn ca thuc t lc c hp thu vo c th cho n khi b thi tr hon ton (Hnh 1.1). Cc qu trnh l:

- S hp thu (Absorption)

- S phn phi (Distribution)

- S chuyn ho (Metabolism)

- S thi tr (Excretion).

Hnh 1.1. S chuyn vn ca thuc trong c th

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

1. CC CCH VN CHUYN THUC QUA MNG SINH HC

1.1. c tnh l ho ca thuc

- Thuc l cc phn t thng c khi lng phn t PM 600. Chng u l cc acid hoc cc base

1. Phn tch c qu trnh hp thu v phn phi thuc trong c th.

2. Nu c ngha cc thng s dc ng hc ca cc qu trnh hp thu v phn phi thuc.

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

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

5. K ra c ngha thng s dc ng hc v h s thanh thi, thi gian bn thi (t1/2) v cc ng thi tr thuc khi c th.



yu.

- Kch thc phn t ca thuc c th thay i t rt nh (PM = 7 nh ion lithi) cho ti rt ln (nh alteplase - tPA - l protein c PM = 59.050). Tuy nhin, a s c PM t 100 - 1.000. gn "kht" vo mt loi receptor, phn t thuc cn t c mt kch c duy nht vi kch thc ca receptor c hiu thuc khng gn c vo cc receptor khc (mang tnh chn lc). Kinh nghim cho thy PMnh nht phi t khong 100 v khng qu 1.000, v ln qu th khng qua c cc mng sinh hc ti ni tc dng.

Mt s thuc l acid yu: l phn t trung tnh c th phn ly thun nghch thnh mt anion (in tch m) v mt proton (in tch dng).

Mt s thuc l base yu: l mt phn t trung tnh c th to thnh mt cation (in tch dng) bng cch kt hp vi mt proton:

- Cc phn t thuc c sn xut di cc dng bo ch khc nhau :

+ Tan c trong nc (dch tiu ho, dch khe), do d c hp thu.

+ Tan c trong lipid thm qua c mng t bo, gy ra c tc dng dc l v mng t bo cha nhiu phospholipid.

V vy c hp thu vo t bo thun li nht, thuc cn c mt t l tan trong nc/tan trong lipid thch hp.

- Cc phn t thuc cn c c trng bi hng s phn ly pKa

pKa c suy ra t phng trnh Henderson - Hasselbach:

Cho mt acid

Cho mt base



K l hng s phn ly ca mt acid; pKa = -logK

pKa dng cho c acid v base.

Mt acid hu c c pKa thp l mt acid mnh v ngc li. Mt base c pKa thp l mt base yu, v ngc li.

Ni mt cch khc, khi mt thuc c hng s pKa bng vi pH ca mi trng th 50% thuc c dng ion ho (khng khuch tn c qua mng) v 50% dng khng ion ho (c th khuch tn c). V khi , nng phn t/nng ion = 1 v log1 = 0.

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

+ C trng lng phn t thp.

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

+ D tan trong dch tiu ho (tan trong nc).

+ Tan c trong lipid ca mng t bo.

1.2. Vn chuyn thuc bng cch lc

Nhng thuc c khi lng phn t thp (100 - 200), tan c trong nc nhng khng tan c trong lipid s chui qua cc ng dn (d = 4 - 40) ca mng sinh hc do s chnh lch p lc thu tnh. ng dn ca mao mch c vn c ng knh l 30, ca mao mch no l 7 - 9, v th nhiu thuc khng vo c thn kinh trung ng.

1.3. Vn chuyn bng khuch tn th ng

Nhng phn t thuc tan c trong nc/lipid s chuyn qua mng t ni c nng cao sang ni c nng thp.

iu kin ca s khuch tn th ng l thuc t b ion ho v c nng cao b mt mng. Cht ion ho s d tan trong nc, cn cht khng ion ho s tan c trong lipid v d hp thu qua mng.

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

V d: khi ung 1 thuc l acid yu, c pKa = 4, gian 1 d dy c pH = 1 v gian 2 l huyt tng c pH = 7 (Hnh 1.2).



Hnh 1.2. S khuch tn qua mng

p dng phng trnh Henderson - Hasselbach, ta c:

gian 1 (d dy):

gian 2 (mu):

V ch phn khng ion ho v c nng cao mi khuch tn c qua mng cho nn acid ny s chuyn t gian 1 (d dy) sang gian 2 (huyt tng) v c hp thu.

Tr s pKa ca mt s thuc l acid yu v base yu c ghi bng 1.1. Nn nh rng base c pKa cao l base mnh v acid c pKa cao l acid yu.

Bng 1.1. Tr s pKa ca mt s thuc l acid v base yu ( nhit 250C)

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

Bng 1.2. nh hng ca pH n s ion ho ca acid salicylic c pKa = 3

Acid yu pKa Base yu pKa

Acid salicylic

Acid acetylsalicylic

Sulfadiazin

Barbital

Acid boric

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



Nh vy, acid salicylic (aspirin) c hp thu nhiu d dy v phn trn ca ng tiu ho. Qua bng ny cho thy khi b ng c thuc, mun ngn cn hp thu hoc thuc b hp thu ra ngoi, ta c th thay i pH ca mi trng.

V d phenobarbital (Luminal, Gardenal) l mt acid yu c pKa = 7,2; nc tiu bnh thng c pH cng bng 7,2 nn phenobarbital b ion ho 50%. Khi nng pH ca nc tiu ln 8, ion ho ca thuc s l 86%, do thuc khng thm c vo t bo. iu ny c dng trong iu tr nhim c phenobarbital: truyn dung dch NaHCO3 1,4% base ho nc tiu, thuc s b tng thi tr.

i vi mt cht kh (v d thuc m bay hi), s khuch tn t khng kh ti ph nang vo mu ph thuc vo p lc ring phn ca cht kh gy m c trong khng kh th vo v ho tan ca kh m trong mu.

1.4. Vn chuyn tch cc

Vn chuyn tch cc l s ti thuc t bn ny sang bn kia mng sinh hc nh mt "cht vn chuyn" (carrier) c hiu c sn trong mng sinh hc.

* c im ca s vn chuyn ny l:

- C tnh bo ho: do s lng carrier c hn.

- C tnh c hiu: mi carrier ch to phc vi vi cht c cu trc c hiu vi n.

- C tnh cnh tranh: cc thuc c cu trc gn ging nhau c th gn cnh tranh vi mt carrier, cht no c i lc mnh hn s gn c nhiu hn.

- C th b c ch: mt s thuc (nh actinomycin D) lm carrier gim kh nng gn thuc vn chuyn.

* Hnh thc vn chuyn: c hai cch

- Vn chuyn thun li: khi km theo carrier li c c s chnh lch bc thang nng , v vy s vn chuyn ny khng cn nng lng. V d vn chuyn glucose, pyramidon.

- Vn chuyn tch cc thc th: l vn chuyn i ngc bc thang nng , t ni c nng thp

pH % khng ion ho

1

2

3

4

5

6

99,0

90,9

50,0

9,09

0,99

0,10



sang ni c nng cao hn. V vy i hi phi c nng lng c cung cp do ATP thu phn, thng c gi l cc "bm", v d s vn chuyn ca Na+, K+, Ca++, I-, acid amin.

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

2. CC QU TRNH DC NG HC

2.1. S hp thu

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

- ho tan ca thuc: thuc dng di dng dung dch nc d hp thu hn dng du, dch treo hoc dng cng

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

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

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

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

T nhng yu t cho thy ng a thuc vo c th s c nh hng ln n s hp thu. Ngoi tr ng tim tnh mch, trong qu trnh hp thu vo vng tun hon, mt phn thuc s b ph hu do cc enzym ca ng tiu ho, ca t bo rut v c bit l gan, ni c i lc vi nhiu thuc. Phn thuc b ph hu trc khi vo vng tun hon c gi l "first pass metabolism" (chuyn ho do hp thu hay chuyn ho qua gan ln th nht v thng l ung thuc). Phn vo c tun hon mi pht huy tc dng dc l, c gi l sinh kh dng (bioavailability) ca thuc (xem phn sau).

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

2.1.1. Qua ng tiu ho

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



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

2.1.1.1. Qua nim mc ming: thuc ngm di li

Do thuc vo thng vng tun hon nn khng b dch v ph hu, khng b chuyn ho qua gan ln th nht.

2.1.1.2. Thuc ung

Thuc s qua d dy v qua rut vi cc c im sau:

* d dy:

- C pH = 1 - 3 nn ch hp thu cc acid yu, t b ion ho, nh aspirin, phenylbutazon, barbiturat.

- Ni chung t hp thu v nim mc t mch mu, li cha nhiu cholesterol, thi gian thuc d dy khng lu.

- Khi i hp thu nhanh hn, nhng d b kch thch.

* rut non:

L ni hp thu ch yu v c din tch hp thu rt rng (> 40 m2), li c ti mu nhiu, pH tng dn ti base (pH t 6 n 8).

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

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

- Cc anion sulfat SO42 khng c hp thu: MgSO4, Na2SO4 ch c tc dng ty.

2.1.1.3. Thuc t trc trng

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

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

2.1.2. Thuc tim

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

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

- Tim tnh mch: thuc hp thu nhanh, hon ton, c th iu chnh liu c nhanh. Dng tim cc



dung dch nc hoc cc cht kch ng khng tim bp c v lng mch t nhy cm v mu pha long thuc nhanh nu tim chm.

Thuc tan trong du, thuc lm kt ta cc thnh phn ca mu hay thuc lm tan hng cu u khng c tim mch mu.

2.1.3. Thuc dng ngoi

- Thm qua nim mc: thuc c th bi, nh git vo nim mc mi, hng, m o, bng quang iu tr ti ch. i khi, do thuc thm nhanh, li trc tip vo mu, khng b cc enzym ph hu trong qu trnh hp thu nn vn c tc dng ton thn: ADH dng bt xng mi; thuc t (lidocain, cocain) bi ti ch, c th hp thu, gy c ton thn.

- Qua da: t thuc c th thm qua c da lnh. Cc thuc dng ngoi (thuc m, thuc xoa bp, cao dn) c tc dng nng ti ch st khun, chng nm, gim au.

Tuy nhin, khi da b tn thng, vim nhim, bng... thuc c th c hp thu. Mt s cht c d tan trong lipid c th thm qua da gy c ton thn (thuc tr su ln hu c, cht c cng nghip anilin)

Gi m ni bi thuc (bng p), xoa bp, dng thuc gin mch ti ch, dng phng php ion - di (iontophoresis) u lm tng ngm thuc qua da.

Hin c dng thuc cao dn mi, lm gii phng thuc chm v u qua da, duy tr c lng thuc n nh trong mu: cao dn scopolamin, estrogen, nitrit

Da tr s sinh v tr nh, c lp sng mng manh, tnh thm mnh, d b kch ng cho nn cn thn trng khi s dng, hn ch din tch bi thuc.

- Thuc nh mt: ch yu l tc dng ti ch. Khi thuc chy qua ng mi - l xung nim mc mi, thuc c th c hp thu trc tip vo mu, gy tc dng khng mong mun.

2.1.4. Cc ng khc

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

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

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

2.1.5. Thng s dc ng hc ca s hp thu: sinh kh dng (F)

2.1.5.1. nh ngha

Sinh kh dng F (bioavailability) l t l phn trm lng thuc vo c vng tun hon dng cn hot tnh v vn tc hp thu thuc (biu hin qua Cmax v Tmax) so vi liu dng. Sinh kh dng



phn nh s hp thu thuc.

2.1.5.2. ngha

- Khi thay i t dc, cch bo ch thuc s lm thay i ho tan ca thuc (hot cht) v lm thay i F ca thuc. Nh vy, hai dng bo ch ca cng mt sn phm c th c hai sinh kh dng khc nhau. Khi nim tng ng sinh hc (bioequivalence) dng so snh cc F ca cc dng bo ch khc nhau ca mt hot cht: F1/F2.

- Khi thay i cu trc ho hc, c th lm F thay i:

Ampicilin c F = 50%

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

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

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

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

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

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

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

2.2. S phn phi

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

Qu trnh phn phi thuc ph thuc nhiu vo tun hon khu vc. Tu theo s ti mu, thng chia c th thnh 3 gian (H1.4).



Hnh 1.4. H phn phi thuc 3 gian

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

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

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

2.2.1. S gn thuc vo protein huyt tng

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

2.2.1.2. T l gn: tu theo i lc ca tng loi thuc vi protein huyt tng (bng 1.3).

Bng 1.3. T l gn thuc vo protein huyt tng

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

- S lng v tr gn thuc trn protein huyt tng.

- Nng phn t ca cc protein gn thuc.



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

2.2.1.3. ngha ca vic gn thuc vo protein huyt tng

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

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

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

- Nhiu thuc c th cng gn vo mt v tr ca protein huyt tng, gy ra s tranh chp, ph thuc vo i lc ca thuc. Thuc b y khi protein s tng tc dng, c th gy c. V d trn ngi ang dng tolbutamid iu tr i tho ng, nay v au khp, dng thm phenylbutazon, phenylbutazon s y tolbutamid ra dng t do, gy h ng huyt t ngt.

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

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

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

2.2.2. S phn phi li

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

2.2.3. Cc phn phi c bit

2.2.3.1. Vn chuyn thuc vo thn kinh trung ng

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

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

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



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

Cc yu t quyt nh tc vn chuyn thuc vo dch no tu v no th cng ging nh nguyn tc thm qua mng sinh hc, l:

- Mc gn thuc vo protein huyt tng.

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

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

Thuc ra khi dch no tu c thc hin mt phn bi c ch vn chuyn tch cc trong m ri mng mch (mt h thng vn chuyn tch cc cho cc acid yu v mt h thng khc cho cc base yu). T no, thuc ra theo c ch khuch tn th ng, ph thuc ch yu vo tan trong lipid ca thuc.

Hng ro mu - no cn ph thuc vo la tui v vo trng thi bnh l: tr s sinh v tr nh, lng myelin cn t, cu trc "hng ro" cn cha "cht ch" nn thuc d khuch tn c vo no. Penicilin khng qua c mng no bnh thng, nhng khi b vim, penicilin v nhiu thuc khc c th qua c.

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

* Kt qu ca s vn chuyn:

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

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

- C th thay i s phn phi thuc gia huyt tng v no bng cch thay i pH ca huyt tng: trong iu tr ng c phenobarbital, truyn NaHCO3 nng pH ca mu (7,6) vt ln trn pH ca dch no tu (7,3), lm cho nng dng ion ho trong huyt tng ca phenobarbital tng cao, nng dng khng ion ho gim thp s ko dng khng ion ho ca thuc t dch no tu vo mu.

2.2.3.2. Vn chuyn thuc qua nhau thai

* Phng thc vn chuyn

- Mao mch ca thai nhi nm trong nhung mao c nhng trong h mu ca m, v vy gia mu m v thai nhi c "hng ro nhau thai". Tnh thm ca mng mao mch thai nhi tng theo tui thai. S thm thuc cng theo quy lut chung:

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



- Vn chuyn tch cc: cc acid amin, cc ion Ca2+, Mg2+.

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

* Kt qu ca s vn chuyn

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

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

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

2.2.4. S tch lu thuc

Mt s thuc hoc cht c c mi lin kt rt cht ch (thng l lin kt cng ho tr) vi mt s m trong c th v c gi li rt lu, hng thng n hng chc nm sau khi dng thuc, c khi ch l mt ln: DDT gn vo m m, tetracyclin gn vo xng, mm rng, As gn vo t bo sng...

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

2.2.5. Thng s dc ng hc ca s phn phi: th tch phn phi (Vd)

2.2.5.1. nh ngha

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

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

Cp: nng thuc trong huyt tng o ngay sau khi phn phi v trc khi thi tr.

Vd: th tch khng c thc, tnh bng L (lt) hoc L/kg.

V d: mt ngi nng 60 kg, c lng nc trong c th l 36 L (60% khi lng c th), ung



0,5mg (500g) digoxin c F theo ng ung l 0,7. o nng digoxin trong huyt tng thy Cp = 0,7ng/mL (0,0007mg/mL).

Vy:

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

2.2.5.2. Nhn xt v ngha lm sng

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

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

2.3. S chuyn ho thuc

2.3.1. Mc ch ca chuyn ho thuc

thi tr cht l (thuc) ra khi c th. Nhng nh ta bit, thuc l nhng phn t tan c trong lipid, khng b ion ho, d thm qua mng t bo, gn vo protein huyt tng v gi li trong c th. Mun thi tr, c th phi chuyn ho nhng thuc ny sao cho chng tr nn cc phc hp c cc, d b ion ho, do tr nn t tan trong lipid, kh gn vo protein, kh thm vo t bo, v v th tan hn trong nc, d b thi tr (qua thn, qua phn). Nu khng c cc qu trnh sinh chuyn ho, mt s thuc rt d tan trong lipid (nh pentothal) c th b gi li trong c th hn 100 nm!

2.3.2. V tr chuyn ho v cc enzym chnh xc tc cho chuyn ho

- Nim mc rut: protease, lipase, decarboxylase

- Huyt thanh: esterase

- Phi: oxydase

- Vi khun rut: reductase, decarboxylase

- H thn kinh trung ng: mono amin oxydase, decarboxylase

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

2.3.3. Cc phn ng chuyn ho chnh

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



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

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

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

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

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

2.3.3.1. Cc phn ng pha I

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

Mt s v d:

Cc phn ng chnh pha ny gm:



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

- Phn ng kh.

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

* Phn ng oxy ho

y l phn ng ph bin nht, c xc tc bi cc enzym oxy ho (mixed - function oxydase enzym system - mfO), thy c nhiu trong microsom gan, c bit l h enzym cytochrom P450 (Cyt -P450), l cc protein mng c cha hem (hemoprotein) khu tr li ni bo nhn ca t bo gan v vi m khc. Trong c th ngi hin thy c ti 17 typ v rt nhiu di typ cytochrom P450 tham gia chuyn ho cc cht ni sinh v ngoi sinh t mi trng, thuc. Phn ng oxy ho loi ny i hi NADPH v O2 theo phc sau:

Phn ng c thc hin theo nhiu bc:

1. C cht (thuc, RH) phn ng vi dng oxy ho ca Cyt P450 (Fe3+) to thnh phc hp RH -

P450 (Fe3+)

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

2+)

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

NADPH to thnh phc hp oxy hot ho.

4. Cui cng, mt nguyn t oxy c gii phng, to H2O. Cn nguyn t oxy th 2 s oxy ho c cht (thuc): RH ROH, v Cyt.P450 c ti to.

Qu trnh phn ng c tm tt s sau:



Hnh 1.6. S oxy ho thuc ca cytochrom P450

* Phn ng kh:

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

* Phn ng thu phn

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

Bng 1.4. Cc phn ng chnh trong chuyn ho thuc pha I



2.3.3.2. Cc phn ng pha II

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

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

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

Ngoi ra, c mt s thuc hon ton khng b chuyn ho, l nhng hp cht c cc cao (nh acid, base mnh), khng thm qua c lp lipid ca microsom. Phn ln c thi tr nhanh nh



hexamethonium, methotrexat.

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

Bng 1.5. Cc phn ng chnh trong chuyn ho thuc pha II

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

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

2.3.4.1. Tui

- Tr s sinh thiu nhiu enzym chuyn ho thuc.

- Ngi cao tui enzym cng b lo ho.

2.3.4.2. Di truyn

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



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

- Ngi thiu glucose 6 phosphat dehydrogenase (G6PD) s d b thiu mu tan mu khi dng phenacetin, aspirin, quinacrin, vi loi sulfamid...

2.3.4.3. Yu t ngoi lai

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

V d: phenobarbital, meprobamat, clorpromazin, phenylbutazon, v hng trm thuc khc: khi dng nhng thuc ny vi cc thuc b chuyn ho qua cc enzym c cm ng s lm gim tc dng ca thuc c phi hp hoc ca chnh n (hin tng quen thuc).

Tri li, vi nhng thuc phi qua chuyn ho mi tr thnh c hot tnh ("tin thuc"), khi dng chung vi thuc gy cm ng s b tng c tnh (parathion paraoxon)

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

2.3.4.4. Yu t bnh l

- Cc bnh lm tn thng chc nng gan s lm suy gim sinh chuyn ho thuc ca gan: vim gan, gan nhim lipid, x gan, ung th gan... d lm tng tc dng hoc c tnh ca thuc chuyn ho qua gan nh tolbutamid, diazepam.

- Cc bnh lm gim lu lng mu ti gan nh suy tim hoc dng thuc chn giao cm ko di s lm gim h s chit xut ca gan, lm ko di thi gian bn thi (t1/2) ca cc thuc c h s chit xut cao ti gan nh lidocain, propranolol, verapamil, isoniazid.

2.4. Thi tr

Thuc c thi tr di dng nguyn cht hoc b chuyn ho.

2.4.1. Thi tr qua thn

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

2.4.1.1. Qu trnh thi tr

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

- Bi tit tch cc qua ng thn: do phi c cht vn chuyn (carrier) nn ti y c s cnh tranh



thi tr. V d dng thiazid ko di, do phi thi tr thiazid, c th gim thi acid uric, d gy bnh gut (thiazid v a.uric c cng carrier ng thn).

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

- Khuch tn th ng qua ng thn: mt phn thuc thi tr trong nc tiu ban u li c ti hp thu vo mu. l cc thuc tan trong lipid, khng b ion ho pH nc tiu (pH = 5 - 6) nh phenobarbital, salicylat. Cc base yu khng c ti hp thu.

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

2.4.1.2. ngha lm sng

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

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

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

2.4.2. Thi tr qua mt

- Sau khi chuyn ho gan, cc cht chuyn ho s thi tr qua mt theo phn ra ngoi. Phn ln sau khi b chuyn ho thm rut s c ti hp thu vo mu thi tr qua thn.

- Mt s hp cht chuyn ho glycuronid ca thuc c khi lng phn t trn 300 sau khi thi tr qua mt xung rut c th b thu phn bi glycuronidase ri li c ti hp thu v gan theo ng tnh mch ca li vo vng tun hon, c gi l thuc c chu k rut - gan. Nhng thuc ny tch lu trong c th, lm ko di tc dng (morphin, tetracyclin, digitalis tr tim...).

2.4.3. Thi tr qua phi

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

- Cc cht kh: protoxyd nit, halothan.

2.4.4. Thi tr qua sa

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

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



2.4.5. Thi tr qua cc ng khc

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

2.4.6. Thng s dc ng hc ca chuyn ho v thi tr thuc

Mc ch ca chuyn ho l lm cho thuc mt hot tnh, d tan trong nc v thi tr. V vy, qu trnh chuyn ho chnh l qu trnh thi tr thuc. C 2 thng s dc ng hc l thanh thi (CL) v thi gian bn thi (t1/2) u nh gi qu trnh chuyn ho v thi tr thuc.

2.4.6.1. thanh thi (clearance CL)

* nh ngha:

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

Clearance c biu th bng mL/pht, l s mL huyt tng c thi tr thuc hon ton trong thi gian 1 pht khi qua c quan. Hoc c khi tnh theo kg khi lng c th: mL/pht/kg.

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

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

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

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

* ngha:

- Thuc c CL ln l thuc c thi tr nhanh, v th thi gian bn thi s ngn.

- Dng CL tnh liu lng thuc c th duy tr c nng thuc n nh trong huyt tng. Nng ny t c khi tc thi tr bng tc hp thu.

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

2.4.6.2. Thi gian bn thi (half - life - t1/2)



* nh ngha:

Thi gian bn thi c phn bit lm hai loi:

- t1/2 hay t1/2 hp thu l thi gian cn thit 1/2 lng thuc dng hp thu c vo tun hon. Nu dng thuc theo ng tim bp th t1/2 khng ng k.

- t1/2 hay t1/2 thi tr l thi gian cn thit nng thuc trong huyt tng gim cn 1/2.

Trong thc hnh iu tr, hay dng t1/2 v thng ch vit l t1/2 hoc t/2.

* ngha:

- T cng thc trn ta thy t1/2 t l nghch vi CL (clearance). Khi CL thay i theo nguyn nhn sinh l hoc bnh l s lm t1/2 thay i, hiu qu ca iu tr b nh hng. Cn phi hiu chnh liu lng hoc khong cch gia cc liu.

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

Lng thuc c thi tr theo t1/2

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

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

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

S ln t1/2 Lng thuc c thi tr (%)

1

2

3

4

5

6

7

50

75

88

94

97

98

99



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

T LNG GI

1. S hp thu thuc ph thuc vo nhng yu t no?

2. Phn tch, so snh cc c im ca cc ng hp thu thuc: ng tiu ho, ng tim, ng h hp v ng qua da, nim mc.

3. Trnh by v s vn chuyn thuc vo thn kinh trung ng v qua nhau thai. ngha lm sng.

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

5. Trnh by v th tch phn phi (Vd) v ngha lm sng?

6. S gn thuc vo protein huyt tng v ngha?

7. K tn cc phn ng chnh (khng vit cng thc) ca chuyn ho thuc pha I, kt qu v ngha?

8. K tn cc phn ng chnh (khng vit cng thc) ca chuyn ho thuc pha II, kt qu v ngha?

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

10. thanh thi l g? ngha?

11. Thi gian bn thi l g? ngha?

Bi 2I CNG V DC LC HC

MC TIU

1. Trnh by c c ch tc dng ca thuc qua receptor v khng qua receptor.

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

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

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

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



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

1. C CH TC DNG CA THUC

1.1. Receptor

- Tc dng ca phn ln cc thuc l kt qu ca s tng tc gia thuc vi receptor (th th cm). Receptor l mt thnh phn i phn t (macromolcular) tn ti vi mt lng gii hn trong mt s t bo ch, c th nhn bit mt cch c hiu ch mt phn t "thng tin" t nhin (hormon, cht dn truyn thn kinh), hoc mt tc nhn ngoi lai (cht ho hc, thuc) gy ra mt tc dng sinh hc c hiu, l kt qu ca tc dng tng h .

Thnh phn i phn t ca receptor thng l protein v ch c protein mi c cu trc phc tp nhn bit c hiu ca mt phn t c cu trc 3 chiu.

Receptor c 2 chc nng:

1. Nhn bit cc phn t thng tin (hay cn gi l ligand) bng s gn c hiu cc phn t ny vo receptor theo cc lin kt ho hc:

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

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

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

Cc lc lin kt trn u l thun nghch.

- Lin kt cng ho tr: l lc lin kt gia cc nguyn t bng nhng cp in t chung. V l lc lin kt ln 50 - 150 kcal/mol nn l lin kt khng thun nghch nhit c th, khng c cht xc tc. Loi lin kt ny t gp. V d lin kt gia cht alkyl ho vi t bo ung th, cc thuc c ch enzym mono - amin oxydase (MAOI), thuc tr su ln hu c vi cholinesterase.

Mt phn t thuc c th gn vo receptor theo nhiu kiu lin kt. V d: acetylcholin gn vo receptor M - cholinergic:



Hnh 2.1. Phc hp acetylcholin - receptor M

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

2. Chuyn tc dng tng h gia ligand v receptor thnh mt tn hiu gy ra c p ng t bo. Cc receptor nm nhn t bo c hot ho bi cc ligand gn trn cc v tr c hiu ca ADN nm trong cc vng iu ho gen, gy ra s sao chp cc gen c hiu (receptor ca hormon steroid, vitamin D3...). Cc receptor nm mng t bo v xa nhn nn khng tham gia trc tip vo cc chng trnh biu hin ca gen. Khi cc ligand tc ng ln receptor s lm sn xut ra cc phn t trung gian - "ngi truyn tin th 2" (AMPv, GMPv, IP3, Ca2+, diacetyl glycerol...). Nhng cht ny s gy ra mt lot phn ng trong t bo, dn ti mt thay i chuyn ho trong t bo, cng vi hoc khng c s thay i v biu hin gen (receptor ca adrenalin, ca benzodiazepin...).

Nh vy, khi thuc gn vo receptor ca t bo th gy ra c tc dng sinh l. Nhng c khi thuc gn vo t bo m khng gy ra tc dng g, ni gn thuc c gi l ni tip nhn (acceptor) hoc receptor cm (silent receptor), nh thuc m gn vo t bo m, digitalis gn vo gan, phi, thn...

Thuc gn vo receptor ph thuc vo i lc (affinity) ca thuc vi receptor. Hai thuc c cng receptor, thuc no c i lc cao hn s y c thuc khc ra. Cn tc dng ca thuc l do hiu lc(efficacy) ca thuc trn receptor . i lc v hiu lc khng phi lc no cng i cng nhau: acetylcholin l cht dn truyn thn kinh ca h ph giao cm, khi gn vo receptor M, gy hiu lc lm tng tit nc bt, co ng t, chm nhp tim...; atropin c i lc trn receptor M mnh hn acetylcholin rt nhiu nn y c acetylcholin ra khi receptor M, nhng bn thn n li khng c hiu lc g. lm sng, tc dng ca atropin quan st c chnh l tc dng ca s thiu vng acetylcholin trn receptor M: kh ming (gim tit nc bt), gin ng t, nhp tim nhanh...

1.2. Cc c ch tc dng ca thuc

1.2.1. Tc dng ca thuc thng qua receptor

Thuc tc dng trc tip trn cc receptor ca cc cht ni sinh (hormon, cht dn truyn thn kinh): nhiu thuc tc dng trn cc receptor sinh l v thng mang tnh c hiu. Nu tc dng ca thuc ln receptor ging vi cht ni sinh, gi l cht ng vn hay cht ch vn (agonists), nh pilocarpin trn receptor M - cholinergic. Nu thuc gn vo receptor, khng gy tc dng ging cht ni sinh, tri li, ngn cn cht ni sinh gn vo receptor, gy tc dng c ch cht ng vn, c gi l cht i khng(antagonists), nh d - tubocurarin tranh chp vi acetylcholin ti receptor N ca c vn.



- Mt s thuc thng qua vic gii phng cc cht ni sinh trong c th gy tc dng: amphetamin gii phng adrenalin trn thn kinh trung ng, nitrit lm gii phng NO gy gin mch...

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

- Cc enzym chuyn ho hoc iu ho cc qu trnh sinh ho c th b thuc c ch hoc hot ho:

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

+ Thuc hot ho enzym: cc yu t vi lng nh Mg2+, Cu2+, Zn3+ hot ho nhiu enzym protein kinase, phosphokinase tc dng ln nhiu qu trnh chuyn ho ca t bo.

- Cc ion: thuc gn vo cc knh ion, lm thay i s vn chuyn ion qua mng t bo. Novocain cn tr Na+ nhp vo t bo thn kinh, ngn cn kh cc nn c tc dng gy t; benzodiazepin lm tng nhp Cl- vo t bo, gy an thn.

1.2.2. Tc dng ca thuc khng qua receptor

Mt s thuc c tc dng khng phi do kt hp vi receptor.

- Thuc c tc dng do tnh cht l ho, khng c hiu:

Cc mui cha cc ion kh hp thu qua mng sinh hc nh MgSO4, khi ung s "gi nc" thnh rut vo lng rut v gi nc trong lng rut nn c tc dng ty; khi tim vo tnh mch s ko nc t gian bo vo mu nn c dng cha ph no.

Isosorbid, mannitol dng liu tng i cao, lm tng p lc thm thu trong huyt tng. Khi lc qua cu thn, khng b ti hp thu ng thn, lm tng p lc thm thu trong ng thn, c tc dng li niu.

Nhng cht to chelat hay cn gi l cht "cng cua" do c cc nhm c cc nh -OH, -SH, -NH2, d to phc vi cc ion ho tr 2, y chng ra khi c th. Cc cht "cng cua" nh EDTA (Ethyl diamin tetra acetic acid), BAL (British anti lewisit - dimercaprol), d - penicilamin thng c dng cha ng c kim loi nng nh Cu2+, Pb2+, Hg2+ hoc thi tr Ca2+ trong ng c digital.

Than hot hp ph c cc hi, cc c t nn dng cha y hi, ng c.

Cc base yu lm trung ho dch v acid dng cha lot d dy (khng acid), nh hydroxyd nhm, magnesi oxyd.

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



2. CC CCH TC DNG CA THUC

Khi vo c th, thuc c th c 4 cch tc dng sau:

2.1. Tc dng ti ch v ton thn

- Tc dng ti ch l tc dng ngay ti ni thuc tip xc, khi thuc cha c hp thu vo mu: thuc st khun ngoi da, thuc lm sn nim mc (tanin), thuc bc nim mc ng tiu ho (kaolin, hydroxyd nhm).

- Tc dng ton thn l tc dng xy ra sau khi thuc c hp thu vo mu qua ng h hp, ng tiu ho hay ng tim: thuc m, thuc tr tim, thuc li niu. Nh vy, tc dng ton thn khng c ngha l thuc tc dng khp c th m ch l thuc vo mu "i" khp c th.

Tc dng ti ch hoc ton thn c th gy hiu qu trc tip hoc gin tip: tim d - tubocurarin vo tnh mch, thuc trc tip tc dng ln bn vn ng lm lit c vn v gin tip lm ngng th do c honh v c lin sn b lit ch khng phi thuc c ch trung tm h hp.

Mt khc, tc dng gin tip cn c th thng qua phn x: khi ngt, ngi ammoniac, cc ngn dy thn kinh trong nim mc ng h hp b kch thch, gy phn x kch thch trung tm h hp v vn mch hnh tu, lm ngi bnh hi tnh.

2.2. Tc dng chnh v tc dng ph

- Tc dng chnh l tc dng iu tr.

- Ngoi tc dng iu tr, thuc c th cn gy nhiu tc dng khc, khng c ngha trong iu tr, c gi l tc dng khng mong mun, tc dng ngoi (adverse drug reactions - ADR). Cc tc dng ngoi c th ch gy kh chu cho ngi dng (chng mt, bun nn, mt ng), gi l tc dng ph; nhng cng c th gy phn ng c hi (ngay vi liu iu tr) nh xut huyt tiu ho, gim bch cu, tt huyt p th ng...

V d: aspirin l thuc h st, gim au, chng vim (tc dng chnh), nhng gy chy mu tiu ho (tc dng c hi). Nifedipin, thuc chn knh calci dng iu tr tng huyt p (tc dng chnh), nhng c th gy nhc u, nhp tim nhanh (tc dng ph), ho, ph chn, tng enzym gan, tt huyt p (tc dng c hi).

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

2.3. Tc dng hi phc v khng hi phc

- Tc dng hi phc: sau tc dng, thuc b thi tr, chc nng ca c quan li tr v bnh thng. Sau gy m phu thut, ngi bnh li c trng thi bnh thng, tnh to.

- Tc dng khng hi phc: thuc lm mt hon ton chc nng ca t bo, c quan. V d: thuc chng ung th dit t bo ung th, bo v t bo lnh; thuc st khun bi ngoi da dit vi khun nhng khng nh hng n da; khng sinh cloramphenicol c tai bin gy suy tu xng.



2.4. Tc dng chn lc

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

Thuc c tc dng chn lc lm cho vic iu tr tr nn d dng hn, hiu qu hn, trnh c nhiu tc dng khng mong mun.

3. NHNG YU T NH HUNG N TC DNG CA THUC

3.1. V thuc

3.1.1. Thay i cu trc lm thay i dc lc hc ca thuc

Nh ta bit, thuc mun c tc dng, phi gn c vo receptor (i lc vi receptor) v sau l hot ho c receptor (c hiu lc hay tc dng dc l). Receptor mang tnh c hiu cho nn thuc cng phi c cu trc c hiu. Receptor c v nh kho v thuc l cha kho. Mt s thay i nh v cu trc ho hc (hnh dng phn t ca thuc) cng c th gy ra nhng thay i ln v tc dng.

Nh vy vic tng hp cc thuc mi thng nhm:

- Lm tng tc dng iu tr v gim tc dng khng mong mun. Khi thm F vo v tr 9 v CH3vo v tr 16 ca cortisol (hormon v thng thn), ta c betametason c tc dng chng vim gp 25 ln v khng c tc dng gi Na+ nh corticoid, trnh phi n nht.

- Lm thay i tc dng dc l: thay i cu trc ca isoniazid (thuc chng lao), ta c iproniazid, c tc dng chng trm cm, do gn vo receptor hon ton khc.

Tr thnh cht i khng tc dng: PABA l nguyn liu tng hp thc n cho vi khun. Sulfanilamid c cng thc gn ging PABA, lm vi khun s dng "nhm", khng pht trin c. V vy, sulfanilamid c tc dng km khun.



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

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

L-isoprenalin c tc dng kch thch receptor adrenergic 500 ln mnh hn D-isoprenalin.

L-quinin l thuc cha st rt, D-quinin (quinidin) l thuc cha lon nhp tim.

- Cng ngy ngi ta cng hiu r c siu cu trc ca receptor v sn xut cc thuc rt c hiu, gn c vo di typ ca receptor: receptor adrenergic 1, 2, 1, 2, 3, receptor cholinergic M1, M2, M3, receptor dopaminergic D1, D2,... D7.

3.1.2. Thay i cu trc thuc, lm thay i dc ng hc ca thuc

Khi cu trc ca thuc thay i, lm tnh cht l ho ca thuc thay i, nh hng n s ho tan ca thuc trong nc hoc trong lipid, nh hng n s gn thuc vo protein, ion ho ca thuc v tnh vng bn ca thuc. Mt s v d:

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

- Estradiol thin nhin khng ung c v b chuyn ho mnh gan. Dn xut ethinyl estradiol (-C CH gn v tr 17) rt t b chuyn ho nn ung c.

- Tolbutamid b microsom gan oxy ho gc CH3 v tr para, c t1/2 huyt tng l 4 - 8 gi. Thay gc CH3 bng Cl (Clorpropamid) s rt kh b chuyn ho, lm t1/2 ca thuc ko di ti 35 gi.

- Cc thiobarbituric t b phn ly hn barbituric pH ca ng thn nn b thi tr chm hn.

Qua y ta c th nhn thy rng, khi thuc gn vo receptor gy hiu lc, khng phi ton b phn t thuc m ch c nhng nhm chc nng gn vo receptor. Khi thay i cu trc ca nhm hoc vng chc nng, dc lc hc ca thuc s thay i. Cn khi thay i cu trc ngoi vng chc nng, c th thay i dc ng hc ca thuc.

3.2. Dng thuc



Dng thuc l hnh thc trnh by c bit ca dc cht a dc cht vo c th. Dng thuc phi c bo ch sao cho tin bo qun, vn chuyn, s dng v pht huy ti a hiu lc cha bnh ca thuc.

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

Qua s , ta thy t mt dc cht, cc nh bo ch c th a ra th trng nhiu loi bit dc (dng thuc) khc nhau, c sinh kh dng khc nhau do nh hng khc nhau ti hiu qu iu tr.

3.2.1. Trng thi ca dc cht

- tn nh: thuc cng mn, din tip xc cng tng, hp thu thuc cng nhanh.

- Dng v nh hnh v dng tinh th: thuc rn dng v nh hnh d tan, d hp thu.

3.2.2. T dc

T dc khng phi ch l "cht n" bao gi thuc m cn nh hng n ho tan, khuch tn...ca thuc. Khi thay calci sulfat (thch cao, t dc c in) bng lactose dp vin diphenylhydantoin, gy hng lot ng c diphenylhydantoin do lng thuc c hp thu nhiu hn (c, 1968). Nguyn nhn l t dc calci sulfat ch ng vai tr mt khung mang, khng tiu v xp, lm dc cht c gii phng t t trong ng tiu ho. Cn lactose li lm dc cht d tan, nn c hp thu nhanh trong thi gian ngn.

3.2.3. K thut bo ch v dng thuc

K thut bo ch l mt yu t khng km phn quan trng c tc ng trc tip n sinh kh dng ca thuc, c th kim sot c s gii phng dc cht v v tr thuc gii phng (gii phng ti ch). V vy n thng c cc nh sn xut gi b mt.

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

- Hot tnh ca thuc c vng bn.

- Dc cht c gii phng vi tc n nh.

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

- Thuc c sinh kh dng cao.

3.3. V ngi dng thuc



3.3.1. c im v tui (xem phn "dc ng hc")

3.3.1.1. Tr em

"Tr em khng phi l ngi ln thu nh li", ngha l khng phi ch gim liu thuc ca ngi ln th thnh liu ca tr em, m tr em cn c nhng c im ring ca s pht trin, l:

- S gn thuc vo protein huyt tng cn t, mt khc, mt phn protein huyt tng cn gn bilirubin, d b thuc y ra, gy ng c bilirubin.

- H enzym chuyn ho thuc cha pht trin.

- H thi tr thuc cha pht trin.

- H thn kinh cha pht trin, myelin cn t, hng ro mu - no cha bo v nn thuc d thm qua v t bo thn kinh cn d nhy cm (nh vi morphin).

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

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

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

1. Cng thc ca Young: dng cho tr em (TE) t 2 - 12 tui

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

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

3. Cng thc ca Fried: dng cho nh nhi

4. Cng thc ca Clark



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

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

1,7: BSA trung bnh ca ngi ln

3.3.1.2. Ngi cao tui

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

- Cc h enzym u km hot ng v "lo ho".

- Cc t bo t gi nc nn cng khng chu c thuc gy mt nc.

- Ngi cao tui thng mc nhiu bnh (cao huyt p, x va mch, thp khp, tiu ng...) nn phi dng nhiu thuc mt lc. Cn rt ch tng tc thuc khi k n (xem phn "tng tc thuc").

3.3.2. c im v gii

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

3.3.2.1. Thi k c kinh nguyt

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

3.3.2.2. Thi k c thai

Trong 3 thng u, thuc d gy d tt bm sinh, to ra qui thai. Trong 3 thng gia thuc c th nh hng xu n s pht trin ca bo thai, n chc nng pht trin ca cc c quan. Trong 3 thng cui, thuc c th gy sy thai, non.

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

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

3.3.2.3. Thi k cho con b



Rt nhiu thuc khi dng cho ngi m s thi tr qua sa v nh vy c th gy c hi cho con. Cc nghin cu v cc loi thuc ny ni chung cn cha c y , do tt nht l ch nn dng nhng loi thuc tht cn thit cho m. Tuyt i khng dng nhng thuc c cha thuc phin v dn xut ca thuc phin (thuc ho, codein, vin ra) v thuc thi tr qua sa v trung tm h hp ca tr rt nhy cm, c th b ngng th. Khng dng cc loi corticoid (lm suy thng thn tr), cc khng gip trng tng hp v iod (gy ri lon tuyn gip), cloramphenicol v thuc phi hp sulfametoxazol + trimethoprim (Co - trimoxazol) v c th gy suy tu xng. Cn rt thn trng khi dng cc thuc c ch thn kinh trung ng (meprobamat, diazepam), thuc chng ng kinh, u gy m mng v li b cho tr.

4. NHNG TRNG THI TC DNG C BIT CA THUC

Trong qu trnh s dng thuc, ngoi tc dng iu tr, i khi cn gp nhng tc dng "khng mong mun" do s phn ng khc nhau ca tng c th vi thuc.

4.1. Phn ng c hi ca thuc (Adverse drug reactions - ADR)

"Mt phn ng c hi ca thuc l mt phn ng c hi, khng nh c trc v xut hin liu lng thng dng cho ngi" (nh ngha ca Chng trnh gim st thuc quc t - WHO).

ADR l tn gi chung cho mi triu chng bt thng xy ra khi dng thuc ng liu. C th ch l nhng triu chng rt nh nh nhc u, bun nn... cho n nhng triu chng rt nng dn n t vong nh sc, phn v, suy tu xng. Tu theo nc v tu theo tc gi, ADR c th xy ra khong 8 -30% s ngi dng thuc.

4.2. Phn ng d ng

D ng thuc cng l 1 ADR.

Do thuc l mt protein l (insulin, thyroxin ly t sc vt), l a peptid, polysaccharid c phn t lng cao, mang tnh khng nguyn. Tuy nhin, nhng thuc c phn t lng thp hoc chnh sn phm chuyn ho ca n cng c th gy d ng, chng c gi l bn khng nguyn hay "hapten". Vo c th, hapten c kh nng gn vi mt protein ni sinh theo ng ni cng ho tr v to thnh phc hp khng nguyn.

Nhng thuc c mang nhm-NH2 v tr para, nh benzocain, procain, sulfonamid, sulfonylurea... l nhng thuc d gy mn cm v nhm-NH2 d b oxy ho v sn phm oxy ho s d gn vi nhm-SH ca protein ni sinh thnh khng nguyn.

Phn ng min dch d ng c chia thnh 4 typ da trn c s ca c ch min dch:

- Typ I hay phn ng phn v (anaphylactic reactions) do s kt hp ca khng nguyn vi khng th IgE, gn trn bch cu a base tun hon hoc cc dng bo. Phn ng lm gii phng nhiu cht ho hc trung gian nh histamin, leucotrien, prostaglandin, gy gin mch, ph v vim. Cc c quan ch ca phn ng ny l ng tiu ho (d ng thc n), da (my ay, vim da d ng), ng h hp (vim mi, hen) v h tim mch (sc phn v)

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

Cc thuc d gy phn ng typ I: thuc t procain, lidocain, khng sinh nhm lactam,



aminoglycosid, huyt thanh, globulin, vacxin, vitamin B1 tim tnh mch.

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

- Typ III hay phn ng Arthus, trung gian ch yu qua IgG c s tham gia ca b th. Phn ng gia khng nguyn v khng th to thnh phc hp min dch. Phc hp ny lng ng vo ni mc mch mu, gy tn thng vim hu hoi, c gi l bnh huyt thanh. Biu hin lm sng thng l: my ay, ban , au, vim khp, ni hch, st. Thng xy ra sau 6 - 12 ngy.

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

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

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

Cc phn ng d ng thuc khng lin quan n liu lng thuc dng, s ln dng v thng c d ng cho. V vy thy thuc cn hi k tin s d ng ca bnh nhn trc khi dng thuc. Vi nhng thuc hay gy d ng (penicilin, lidocain,...) khi dng, phi c sn thuc v phng tin cp cu (adrenalin). Sc phn v c th xy ra do ng dng thuc khc nhau: vitamin B1 dng tim tnh mch c th gy sc cht ngi, trong khi dng ung khng gy phn ng ny.

4.3. Tai bin thuc do ri lon di truyn

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

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

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

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

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

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

4.4. Quen thuc



Quen thuc l s p ng vi thuc yu hn hn so vi ngi bnh thng dng cng liu. Liu iu tr tr thnh khng c tc dng, i hi ngy cng phi tng liu cao hn.

Quen thuc c th xy ra t nhin ngay t ln u dng thuc do thuc t c hp thu, hoc b chuyn ho nhanh hoc c th km mn cm vi thuc. Thng do nguyn nhn di truyn.

Thng gp quen thuc do mc phi sau mt thi gian dng thuc, i hi phi tng dn liu.

4.4.1. Quen thuc nhanh (tachyphylaxis)

Thc nghim dng nhng liu ephedrin bng nhau, tim tnh mch cch nhau tng 15 pht, sau 4 - 6 ln, tc dng gy tng huyt p gim dn ri mt hn. Mt s thuc khc cng c hin tng quen thuc nhanh nh amphetamin, isoprenalin, adrenalin, histamin...

Nguyn nhn l:

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

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

- To cht chuyn ho c tc dng i khng vi cht m: isoprenalin (cng giao cm) qua chuyn ho gan, to ra 3 - orthomethylisoprenalin c tc dng hu .

4.4.2. Quen thuc chm

Sau mt thi gian dng thuc lin tc, tc dng ca thuc gim dn, i hi phi tng liu hoc i thuc khc. C nhiu nguyn nhn:

- Do gy cm ng enzym chuyn ho thuc, lm nhng liu thuc sau b chuyn ho nhanh, mt tc dng nhanh. Barbiturat, diazepam, tolbutamid, ru ethylic... u l nhng thuc gy cm ng enzym chuyn ho ca chnh n.

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

- Do c th phn ng bng c ch ngc li dng cc thuc li niu thi Na+ lu, c th mt nhiu Na+ s tng tit aldosteron gi li Na+, lm gim tc dng li niu.

trnh hin tng quen thuc, trong lm sng thng dng thuc ngt qung hoc lun phin thay i cc nhm thuc (s trnh by trong phn thuc c th).

4.5. Nghin thuc

Nghin thuc l mt trng thi c bit lm cho ngi nghin ph thuc c v tm l v th cht vo thuc vi cc c im sau:

- Thm thung mnh lit nn xoay s mi cch c thuc dng, k c hnh vi phm php.



- C khuynh hng tng liu.

- Thuc lm thay i tm l v th cht theo hng xu: ni iu, li lao ng, bn thu, thiu o c... gy hi cho bn thn v x hi

- Khi cai thuc s b thuc " vt" hay ln cn "i thuc": vt v, ln ln, d cm, v m hi, tiu chy... Nu li dng thuc cn "vt" s ht ngay.

Nhng thuc gy nghin u c tc dng ln thn kinh trung ng gy sng khoi lng lng, o nh, o gic ("ph" thuc) hoc trng thi hng phn mnh (thuc lc), c gi chung l "ma ty": morphin v cc cht loi thuc phin (heroin, pethidin, methadon), cocain, cn sa (cannabis, marijuana), metamphetamin, ectasy... Ru v thuc l hin cn c coi l ma ty "hp php".

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

Hin nay khng c phng php cai nghin no c hiu qu, ngoi tr ch ca ngi nghin. V vy, nghin ma tu l mt t nn x hi phi c loi tr.

T LNG GI

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

2. Trnh by cc cch tc dng ca thuc.

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

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

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

Bi 3TNG TC THUC

1. TNG TC THUC - THUC

Nhiu thuc khi cho dng cng mt lc s c tc dng qua li ln nhau, c gi l tng tc thuc.

MC TIU

1. Trnh by c tng tc dc lc hc v dc ng hc.

2. Trnh by c hiu qu v p dng ca tng tc thuc.



Trong lm sng, thy thuc mun phi hp thuc lm tng tc dng iu tr, gim cc tc dng khng mong mun. Song trong thc t, nhiu khi khng t c nh th. V vy, khi k n c t 2 thuc tr ln, thy thuc rt cn hiu r s tng tc gia chng.

1.1. Tng tc dc lc hc

L tng tc ti cc receptor, mang tnh c hiu.

1.1.1. Tng tc trn cng receptor: tng tc cnh tranh

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

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

1.1.2. Tng tc trn cc receptor khc nhau: tng tc chc nng

- C cng ch tc dng: do lm tng hiu qu iu tr.

V d: trong iu tr bnh cao huyt p, phi hp thuc gin mch, an thn v li tiu; trong iu tr lao, phi hp nhiu khng sinh (DOTS) tiu dit vi khun cc v tr v cc giai on pht trin khc nhau.

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

1.2. Tng tc dc ng hc

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

1.2.1. Thay i s hp thu ca thuc

- Do thay i ion ho ca thuc:

Nh ta bit, ch nhng phn khng ion ho ca thuc mi d dng qua c mng sinh hc v d phn tn hn trong lipid. phn ly ca thuc ph thuc vo hng s pKa ca thuc v pH ca mi trng. Cc thuc c bn cht acid yu (nh aspirin) s hp thu tt trong mi trng acid (d dy), nu ta trung ho acid ca dch v th s hp thu aspirin d dy s gim i.

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



- Vi cc thuc dng theo ng tim bp, di da: procain l thuc t, khi trn vi adrenalin l thuc co mch th procain s chm b hp thu vo mu do thi gian gy t s c ko di. Insulin trn vi protamin v km (protamin - zinc - insulin - PZI) s lm ko di thi gian hp thu insulin vo mu, ko di tc dng h ng huyt ca insulin.

- Do to phc, thuc s kh c hp thu:

Tetracyclin to phc vi Ca2+ hoc cc cation kim loi khc rut, b gim hp thu. Cholestyramin lm ta mui mt, ngn cn hp thu lipid, dng lm thuc h cholesterol mu.

- Do cn tr c hc: Sucralfat, Smecta, Maaloc (Al3+) to mng bao nim mc ng tiu ho, lm kh hp thu cc thuc khc.

trnh s to phc hoc cn tr hp thu, hai thuc nn ung cch nhau t nht 2 gi.

1.2.2. Thay i s phn b thuc

l tng tc trong qu trnh gn thuc vo protein huyt tng. Nhiu thuc, nht l thuc loi acid yu, gn thun nghch vi protein (albumin, globulin) s c s tranh chp, ph thuc vo i lc v nng ca thuc trong huyt tng. Ch c thuc dng t do mi c tc dng dc l. V vy, tng tc ny c bit c ngha vi thuc c t l gn vo protein huyt tng cao (trn 90%) v c phm vi iu tr hp nh:

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

Sulfamid h ng huyt: tolbutamid, clopropamil.

Thuc chng ung th, c bit l methotrexat.

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

1.2.3. Thay i chuyn ho

Nhiu thuc b chuyn ho gan do cc enzym chuyn ho thuc ca microsom gan (xem phn dc ng hc). Nhng enzym ny li c th c tng hot tnh (gy cm ng) hoc b c ch bi cc thuc khc. Do s lm gim t1/2, gim hiu lc (nu l thuc gy cm ng enzym) hoc lm tng t1/2, tng hiu lc (nu l thuc c ch enzym) ca thuc dng cng.

- Cc thuc gy cm ng (inductor) enzym gan: phenobarbital, phenytoin, carbamazepin, griseofulvin, rifampicin...

- Cc thuc c ch (inhibitor) enzym gan: allopurinol, cloramphenicol, cimetidin, MAOI, erythromycin, isoniazid, dicumarol.

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

Ph n ang dng thuc trnh thai ung, nu b lao dng thm rifampicin, hoc b ng kinh dng



phenytoin, c th s b "v k hoch" do estrogen trong thuc trnh thai b gim hiu qu v b chuyn ho nhanh, hm lng tr nn thp.

1.2.4. Thay i thi tr thuc

Thi tr (elimination) thuc gm hai qu trnh l chuyn ho thuc gan ( ni phn trn) v bi xut (excretion) thuc qua thn. Nu thuc bi xut qua thn dng cn hot tnh th s tng/gim bi xut s c nh hng n tc dng ca thuc.

- Thay i pH ca nc tiu: khi mt thuc lm thay i pH ca nc tiu, s lm thay i ion ho ca thuc dng km, lm thay i bi xut ca thuc. V d barbital c pKa = 7,5; pH = 7,5 th 50% thuc b ion ho; pH = 6,5 th ch c 9% b ion ho; pH = 9,5 th 91% barbital b ion ho. V vy, khi ng c cc thuc barbiturat, truyn dch NaHCO3 base ho nc tiu s tng bi xut barbiturat.

Cc thuc l acid yu (vitamin C, amoni clorid) dng liu cao, lm acid ho nc tiu s lm tng thi tr thuc loi alcaloid (quinin, morphin).

- Bi xut tranh chp ti ng thn: do hai cht cng c c ch bi xut chung ti ng thn nn tranh chp nhau, cht ny lm gim bi xut cht khc. Dng probenecid s lm chm thi tr penicilin, thiazid lm gim thi tr acid uric nn c th gy bnh gut.

1.3. Kt qu v ngha ca tng tc thuc

1.3.1. Tc dng hip ng

Thuc A c tc dng l a, thuc B c tc dng l b. Khi kt hp thuc A vi thuc B c tc dng c. Nu:

c = a + b, ta c hip ng cng (additive effect)

c > a + b, ta c hip ng tng mc (synergysm)

Hip ng cng thng khng c dng lm sng v nu cn th tng liu thuc ch khng phi hp thuc.

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

1.3.2. Tc dng i khng

Nh trong nh ngha trn, nhng khi tc dng c ca thuc A + B li nh hn tc dng cng ca tng thuc (c < a + b) ta gi l tc dng i khng. i khng c th ch mt phn (partial antagonism) khi c < a + b, nhng cng c th i khng hon ton khi a lm mt hon ton tc dng ca b.

Trong lm sng, thng dng tc dng i khng gii c.

- i khng c th xy ra ngoi c th, gi l tng k (incompatibility), mt loi tng tc thun ty l ho:



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

+ Thuc oxy ho (vitamin C, B1, penicilin) khng trn vi thuc oxy kh (vitamin B2).

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

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

- i khng xy ra trong c th:

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

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

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

+ i khng chc nng: hai cht ng vn (agonist) tc dng trn hai receptor khc nhau nhng chc nng li i khng trn cng mt c quan. Strychnin kch thch tu sng, gy co git; cura c ch dn truyn tm vn ng, gy mm c, chng c co git. Histamin kch thch receptor H1 lm co c trn kh qun, gy hen; albuterol (Ventolin), kch thch receptor 2 adrenergic lm gin c trn kh qun, dng iu tr cn hen.

1.3.3. o ngc tc dng

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

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

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

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

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

- Lm gim s quen thuc v khng thuc.

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

2. TNG TC THUC - THC N - UNG



2.1. Tng tc thuc - thc n

Thng hay gp l thc n lm thay i dc ng hc ca thuc.

2.1.1. Thc n lm thay i hp thu thuc

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

+ Ung thuc lc i, thuc ch gi li trong d dy khong 10 - 30 pht.

+ Ung thuc vo lc no, thuc b gi li trong d dy khong 1 - 4 gi, do :

Nhng thuc t tan s c thi gian tan, khi xung rut s c hp thu nhanh hn (penicilin V). Tuy nhin, nhng thuc d to phc vi nhng thnh phn ca thc n s b gim hp thu (tetracyclin to phc vi Ca2+ v mt s cation ho tr 2 khc).

Cc thuc km bn trong mi trng acid (ampicilin, erythromycin) nu b gi lu d dy s b ph hu nhiu.

Vin bao tan trong rut s b v (cn ung trc ba n 0,5 - 1h hoc sau ba n 1 - 2 gi)

Nhng thuc d kch ng ng tiu ho, nn ung vo lc no.

- S hp thu cn ph thuc vo dng bo ch: aspirin vin nn ung sau khi n s gim hp thu 50%, trong khi vin si bt li c hp thu hon ton.

2.1.2. Thc n lm thay i chuyn ho v thi tr thuc

Thc n c th nh hng n enzym chuyn ho thuc ca gan, nh hng n pH ca nc tiu v qua nh hng n chuyn ho v bi xut thuc. Tuy nhin, nh hng khng ln.

Ngc li, thuc c th nh hng n chuyn ho mt s cht trong thc n. Thuc c ch enzym mono - amin - oxydase (MAOI) nh iproniazid - l enzym kh amin - oxy ho ca nhiu amin ni, ngoi sinh - c th gy cn tng huyt p kch pht khi n cc thc n c nhiu tyramin (nh phomat), do khng c chuyn ho kp, tyramin lm gii phng nhiu noradrenalin ca h giao cm trong thi gian ngn.

2.2. Tng tc thc n ung

2.2.1. Nc

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

- Nc l phng tin dn thuc (dng vin) vo d dy - rut, lm tng tan r v ho tan hot cht, gip hp thu d dng. V vy, cn ung nc (100 - 200 mL cho mi ln ung thuc) trnh ng vin thuc ti thc qun, c th gy kch ng, lot.



- c bit cn ch :

+ Ung nhiu nc trong qu trnh dng thuc (1,5 - 2 L/ngy) lm tng tc dng ca thuc (cc loi thuc ty), lm tng thi tr v lm tan cc dn xut chuyn ho ca thuc (sulfamid, cyclophosphamid).

+ Ung t nc hn bnh thng duy tr nng thuc cao trong rut khi ung thuc ty sn, ty giun (niclosamid, mebendazol).

+ Trnh dng nc qu, nc khong base hoc cc loi nc ngt ng hp c gas v cc loi nc ny c th lm hng thuc hoc gy hp thu qu nhanh.

2.2.2. Sa

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

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

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

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

2.2.3. C ph, ch

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

- Tanin trong ch gy ta cc thuc c Fe hoc alcaloid

- Cafein cng gy ta aminazin, haloperidol, lm gim hp thu; nhng li lm tng ho tan ergotamin, lm d hp thu.

2.2.4. Ru ethylic

Ru c rt nhiu nh hng n thn kinh trung ng, h tim mch, s hp thu ca ng tiu ho. Ngi nghin ru cn b gim protein huyt tng, suy gim chc nng gan, nhng li gy cm ng enzym chuyn ho thuc ca gan (xem bi "ru"), v th ru c tng tc vi rt nhiu thuc v cc tng tc ny u l bt li. Do khi dng thuc th khng ung ru. Vi ngi nghin ru cn phi dng thuc, thy thuc cn kim tra chc nng gan, tnh trng tm thn... chn thuc v dng liu lng thch hp, trong thi gian dng thuc cng phi ngng ung ru.

3. THI IM UNG THUC

Sau khi nhn r c tng tc gia thuc - thc n - ung, vic chn thi im ung thuc hp l t c nng cao trong mu, t c hiu qu mong mun cao v gim c tc dng ph l rt cn thit.

Nn nh rng: ung thuc vo lc i, thuc ch b gi li d dy 10 - 30 pht, vi pH khong 1;



ung lc no (sau n), thuc b gi li 1 - 4 gi vi pH khong 3,5. Nh vy, tu theo tnh cht ca thuc, mc ch ca iu tr, c mt s gi chn thi im ung thuc nh sau:

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

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

- Cc thuc khng nn gi li lu trong d dy nh: cc thuc km bn vng trong mi trng acid (ampicilin, erythromycin), cc loi vin bao tan trong rut hoc cc thuc gii phng chm.

3.2. Thuc nn ung vo lc no (trong hoc ngay sau ba n)

- Thuc kch thch bi tit dch v (ru khai v), cc enzym tiu ho (pancreatin) chng i tho ng loi c ch gluconidase nn ung trc ba n 10 - 15 pht.

- Thuc kch thch d dy, d gy vim lot ng tiu ho: cc thuc chng vim phi steroid, mui kali, quinin.

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

- Nhng thuc c hp thu qu nhanh lc i, d gy tc dng ph: levodopa, thuc khng histamin H1.

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

3.4. Thuc nn ung vo bui sng, ban ngy

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

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

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

- Cc thuc an thn, thuc ng

- Cc thuc khng acid, chng lot d dy. Dch v acid thng tit nhiu vo ban m, cho nn ngoi vic dng thuc theo ba n, cc thuc khng acid dng cha lot d dy nn c ung mt liu vo trc khi i ng.

Cn nh rng khng nn nm ngay sau khi ung thuc, m cn ngi 15 - 20 pht v ung nc (100 - 200 mL nc) thuc xung c d dy.

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

T LNG GI



1. Trnh by tng tc dc ng hc ca thuc.

2. Trnh by tng tc dc lc hc.

3. Trnh by ngha v p dng lm sng ca tng tc thuc.

4. Trnh by tng tc thuc vi thc n v ung.

Chng IITHUC TC DNG

TRN H THN KINH THC VTBi 4

I CNG V PHN LOI

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

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

H thng thn kinh thc vt c chia thnh hai h giao cm v ph giao cm khc nhau v c gii phu v chc nng sinh l.

1. PHN LOI THEO GII PHU

1.1. im xut pht

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

MC TIU

1. Phn bit c v gii phu, sinh l v dc l cc h giao cm, ph giao cm, adrenergic, cholinergic

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



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

- H ph giao cm xut pht t no gia, hnh no v tu cng. no gia v hnh no, cc si ph giao cm i cng vi cc dy thn kinh trung ng: dy III vo mt; dy VII vo cc tuyn nc bt; dy IX vo c mi, cc tuyn tit nc mt, nc bt, tuyn tit nim mc mi, ming, hu; dy X vo cc tng trong ngc v bng. tu cng, xut pht t cc t sng cng th 2 n th 4 (S2 - S4) chi phi cc c quan trong h chu.

1.2. Hch

- H giao cm c ba nhm hch:

+ Chui hch cnh ct sng nm hai bn ct sng.

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

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

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

1.3. Si thn kinh

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

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

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

2. CHC NNG SINH L

2.1. Chc nng sinh l

Chc nng sinh l ca hai h giao cm v ph giao cm trn cc c quan ni chung l i khng nhau (bng 4.1).



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

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

C quanKch thch giao cm Kch thch ph giao cm

Loi receptor p ng p ng



Mt

C nan hoa

C co ng t

1 Co (gin ng t) ++

Co (co ng t) +++

Tim

Nt nh - tht

Tm nh

1 (2)

1 (2)

Tng tn s ++

Tng bin ++

Gim tn s ngng tim

Gim bin ++

Mao ng mch

Mch vnh

C vn

Da, nim mc

No

Tng

Thn

1, 2, 2

, 2

1, 2

1

1, 2

1, 2, 1, 2

Co +; gin ++

Co ++; gin ++

Co +++

Co nh

Co +++; Gin +

Co +++; gin +

Gin +

Gin +

duoc_ly_hoc_146

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