TRNG I HC Y H NI B MN DC L

DC L HC(SCH DNG CHO SINH VIN H BC S A KHOA)

NH XUT BN Y HCH NI - 2007

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TRNG I HC Y H NIB MN DC L

DC L HC(SCH DNG CHO SINH VIN H BC S A KHOA)

NH XUT BN Y HCH Ni - 2007

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CH BINGS.TS. O VN PHAN

THAM GIA BIN SON

PGS.TS. NGUYN TRN TH GING HNG

GS.TS. O VN PHAN

TS. V TH NGC THANH

PGS.TS. NGUYN TRNG THNG

TH K BIN SON

NGUYN KIU VN

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LI NI U

Cun sch ny dng ging dy mn DC L HC cho Trng i hc Y oto Bc s a khoa nh hng cng ng.Ngy nay, trn th trng Vit Nam c ti 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 trnhm 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 catng nhm thuc c hng s dng cho ng. Cun sch ny nhm cung cp chosinh vin nhng kin thc c bn v c ch tc dng ca tng nhm thuc phn theotc dng sinh l- bnh l- iu tr hc. Trn c s hiu r c ch tc dng, ngi cs hiu r cc p dng lm sng ca thuc nh ch nh, chng ch nh, tc dngkhng mong mun. T nhng kin thc c bn ny, trong qu trnh thc hnh, cngvi s pht trin ca cc thuc mi, ngi c hon ton c th hiu thm c imca cc thuc c th s dng c an ton v hp l.Khoa hc k thut ang khng ngng pht trin. Cc thuc mi ang lin tc xuthin. Thm ch cn c thuc b loi tr sau vi nm c php lu hnh. V vy ccthy thuc cn lun cp nht thng tin bng cc ngun khc nhau. Cun sch giokhoa khng th lm c vic ny v sau vi nm mi ti bn mt ln.Cc tc gi c gng trnh by nhng kin thc dc l hc c bn cho sinh vin theong chng trnh quy nh ca B Y t. Nhng kin thc ny lm c s choSinh vin Y a khoa thc hnh v t hc sau khi ra trng.Cc tc gi rt mong nhn c nhng kin ng gp, ch bo ca ngi c v ccng nghip y dc.

Cc tc gi

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MC LC

BI TC GI TRANG

KHI NIM V DC L HC 6

PHN I: DC L HC I CNG 8

Bi 1: i cng v dc ng hc o Vn Phan 9Bi 2: i cng v dc lc hc o Vn Phan 31Bi 3: Tng tc thuc o Vn Phan 44

PHN II: THUC TC DNG TRN H THN KINH THC VT 51

Bi 4: i cng v phn loi o Vn Phan 52

Bi 5: Thuc tc dng trn hcholinnergic

o Vn Phan 59

Bi 6: Thuc tc dng trn h adrenergic o Vn Phan 73

PHN III: THUC TC DNG TRN H THN KINH TRUNG NG 92

Bi 7: Thuc t o Vn Phan 93Bi 8: Thuc ng v ru Nguyn Trn Th Ging Hng 100

Bi 9: Thuc gim au loi morphin Nguyn Trn Th Ging Hng 108Bi 10: Thuc h st -gim au- chng

vimo Vn Phan 123

Bi 11: Thuc cha gut o Vn Phan 140Bi 12: Thuc an thn kinh, thuc bnh

thno Vn Phan 144

Bi 13: Thuc cha ng kinh o Vn Phan 153PHN IV: HA HC TR LIU 159

Bi 14: Thuc khng sinh khng khun o Vn Phan 160

Bi 15: Thuc khng virus (nhm khngvirus sao chp ngc)

o Vn Phan 186

Bi 16: Thuc khng nm o Vn Phan 193

Bi 17: Thuc chng lao - Thuc iu trphong

Nguyn Trng Thng 198

Bi 18: Thuc iu tr st rt Nguyn Trn Th Ging Hng 209Bi 19: Thuc chng giun sn Nguyn Trn Th Ging Hng 222Bi 20: Thuc chng amip - Trichomonas Nguyn Trn Th Ging Hng 230

Bi 21: Thuc st khun - Thuc ty u o Vn Phan 237

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BI TC GI TRANG

PHN V: THUC TC DNG TRN C QUAN V TRN MU 242

Bi 22: Thuc tr tim o Vn Phan 243

Bi 23: Thuc iu tr cn au tht ngc o Vn Phan 252Bi 24: Thuc iu tr tng huyt p o Vn Phan 259

Bi 25: Thuc li niu o Vn Phan 271Bi 26: Cc cht in gii chnh v cc

dch truyno Vn Phan 261

Bi 27: Thuc iu chnh ri lon tiu ha V Th Ngc Thanh 294Bi 28: Thuc iu chnh ri lon h hp V Th Ngc Thanh 315Bi 29: Thuc iu tr thiu mu Nguyn Trng Thng 329

Bi 30: Thuc tc dng trn qu trnhng mu v tiu fibrin Nguyn Trng Thng

337

PHN VI: THUC TC DNG TRN CHUYN HA V M 351

Bi 31: Thuc iu tr ri lon lipoproteinmu

Nguyn Trng Thng 352

Bi 32: Thuc h glucose mu Nguyn Trng Thng 359

Bi 33: Histamin v thuc khng histamin Nguyn Trng Thng 367Bi 34: Vitamin Nguyn Trng Thng 374

PHN VII: HORMON V CC THUC IU CHNH RI LON NITIT

383

Bi 40935: Hormon v cc thuc khnghormon

o Vn Phan 384

PHN VIII: IU TR NG C THUC CP TNH 413

Bi 36: iu tr ng c thuc cp tnh o Vn Phan 414

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KHI NIM V DC L HC

Dc l hc (Pharmacology) theo tu t hc l mn khoa hc v thuc. Nhng trnh ngha qu rng ca t ny, Dc l hc ch bao hm mi nghin cu v s tng tc cathuc 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 scvt, hoc dng trong chn on bnh lm sng, dng khi phc, iu chnh cc chcphn ca c quan.Thuc c th c ngun gc t thc vt (cy Canhkina, cy Ba gc), t ng vt (insulin chitxut t ty tng b, ln), t khong vt, kim loi (kaolin, thu ngn, mui vng) hoc l cccht bn tng hp, tng hp ha hc (ampicilin, sulfamid).

u tin, thuc phi c nghin cu trn sc vt thc nghim xc nh c tc dng, cch tc dng, c tnh, liu iu tr, liu c, tc dng gy t bin, gy qui thai, gy ungth... 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 saukhi 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 onthc nghim trn sc vt, thuc phi c th trn nhm ngi tnh nguyn, trn cc nhmbnh nhn ti cc c s khc nhau, c so snh vi cc nhm dng thuc kinh in hoc thucv (placebo), nhm nh gi li cc tc dng gp trong thc nghim v ng thi pht hincc triu chng mi, nht l cc tc dng khng mong mun cha thy hoc khng th thyc trn sc vt (bun nn, chng mt, nhc u, phn ng d ng v.v....). Nhng nghincu 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 choSinh vin trng Y v thy thuc thc hnh, nhm cung cp nhng kin thc v tc dng cathuc v nhng vn lin quan n iu tr thy thuc c th k n c an ton v hpl.Dc l hc lun da trn nhng thnh tu mi nht ca cc ngnh khoa hc c lin quannh sinh l, sinh ha, sinh hc, di truyn hc... ngy cng hiu su v c ch phn t cathuc, gip cho nghin cu sn xut cc thuc mi ngy cng c tnh c hiu, khng ngngnng 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. Mithuc, tu theo liu dng s c tc dng sm, c hiu trn mt m, mt c quan hay mt hthng ca c th, c s dng iu tr bnh, c gi l tc dng chnh. Ngoi ra, mithuc cn c th c nhiu tc dng khc, khng c dng iu tr, tri li cn gy phinh 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 nghincu 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 nghc ca s hp thu, phn phi, chuyn ha v thi tr thuc. Ngi thy thuc rt cn nhngthng tin ny bit cch chn ng a thuc vo c th (ung, tim bp, tim tnhmch...), s ln dng thuc trong ngy, liu lng thuc tu theo tng trng hp (tui, trngthi bnh, trng thi sinh l...).

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Dc l thi khc (Chronopharmacology) nghin cu nh hng ca nhp sinh hc trongngy, trong nm n tc ng ca thuc. Hot ng sinh l ca ngi v ng vt chu nhhng r rt ca cc thay i ca mi trng sng nh nh sng, nhit , m ... Cc hotng ny bin i nhp nhng, c chu k, gi l nhp sinh hc (trong ngy, trong thng, trongnm). 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 rtd b thiu mu tan mu do dng sulfamid, thuc chng st rt... ngay c vi liu iu trthng thng. C th ni Dc l di truyn l mn giao thoa gia Dc l - Di truyn - Hasinh v Dc ng hc.

Dc l cnh gic hay Cnh gic thuc (Pharmacovigilance) chuyn thu thp v nh gi mtcch 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 nhinvi cc liu thuc vn dng d phng, chn on hay iu tr bnh. Phenacetin l thuc hst, phi 75 nm sau khi dng ph bin mi pht hin c tc dng gy c ca thuc; sau30 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 bitr v thuc cng nm c "ngh thut" k n an ton v hp l. V iu kin thi gian vkhun kh, cun sch ny ch yu cung cp nhng kin thc v dc lc hc, dc ng hcv 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 trongtng nhm.- Phn tch c tc dng khng mong mun v c tnh ca thuc bit cch phng v xtr.- 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 thcdc l ca cc thuc mi, hoc nhng hiu bit mi, nhng p dng mi ca cc thuc c.

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PHN I

DC L HC I CNG

Bi 1: I CNG V DC 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

tr thuc khi c th.

Dc ng hc (Pharmacokinetics) nghin cu cc qu trnh chuyn vn ca thuc t lc

c hp thu vo c th cho n khi b thi tr hon ton (H1). Cc qu trnh l:

- S hp thu (Absorption)

- S phn phi (Distribution)

- S chuyn ha (Metabolism)

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- S thi tr (Excretion)

Mu M

Hp thu

(ung, bi...)

THUC

t/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

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 ha ca thuc v mng sinh hc c nh hng n cc qu trnh vn chuyn

.

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1. CC CCH VN CHUYN THUC QUA MNG SINH HC

1.1. c tnh l ha ca thuc

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

cc base 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

ca receptor c hiu thuc khng gn c vo cc receptor khc (mang tnh chn lc).

Kinh nghim cho thy PM nh nht phi t khong 100 v khng qu 1000, v ln qu th

khng qua c cc mng sinh hc ti ni tc dng.

Mt s thuc l acid yu: l phn t trung tnh c th phn ly thun nghch thnh mt anion

(in tch (-)) v mt proton (H+).

C8H7O2COOH C8H7O2COO- + H+

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 :

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Tan c trong nc (dch tiu ha, dch khe), do d c hp thu. Tan c trong m thm qua c mng t bo gy ra c tc dng dc l v mng

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

trong m thch hp.

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

pKa c suy ra t phng trnh Henderson- HasselbACh:

dng ion ha

pH = pKa + log

dng khng ion ha

Cho 1 acid:

nng phn t

pKa = pH + log

nng ion

Cho 1 base:

nng ion

pKa = pH + log

nng phn t

K l hng s phn ly ca 1 acid; pKa = - logKa

pKa dng cho c acid v base. pKa +pKb=14

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Mt acid hu c c pKa thp l 1 acid mnh v ngc li. Mt base c pKa thp l 1 base

yu, v ngc li.

Ni mt cch khc, khi mt thuc c hng s pKa bng vi pH ca mi trng th 50% thuc

c dng ion ha (khng khuch tn c qua mng) v 50% dng khng ion ha (c th

khuch tn c). V khi , nng phn t/ nng ion= 1 v log 1 = 0.

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

C trng lng phn t thp

t b ion ha: ph thuc vo hng s phn ly (pKa) ca thuc v pH ca mi trng. D tan trong dch tiu ha (tan trong nc)

ho tan trong lipid cao d qua mng ca t bo

1.2. Vn chuyn thuc bng cch lc

Nhng thuc c trng lng phn t thp (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 thu tnh. ng dn ca mao mch c vn c ng knh l 30 , ca mao mch no l 7-

9, v th nhiu thuc khng vo c thn kinh trung ng.

1.3. Vn chuyn bng khuch tn th ng (theo bc thang nng ).

Nhng phn t thuc tan c trong nc/ m s chuyn qua mng t ni c nng cao

sang ni c nng thp.

iu kin ca s khuch tn th ng l thuc t b ion ho v c nng cao b mt mng.

Cht ion ha s d tan trong nc, cn cht khng ion ha s tan c trong m v d hp thu

qua mng.

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

mi trng.

Th d: khi ung 1 thuc l acid yu, c pKa = 4, gian 1 d dy c pH= 1 v gian 2 l huyt

tng c pH = 7 (H.1)

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Gian 2

pH = 7

1000 R- COO- + H+

1 R- COOH

Gian 1

pH = 1

pKa = 4

R- 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- ]

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V ch phn khng ion ha v c nng cao mi khuch tn c qua mng cho nn acid

ny s chuyn t gian 1 (d dy) sang gian 2 (mu) v c hp thu.

Tr s pKa ca mt s thuc l acid yu v base yu c ghi bng1. Nn nh rng base c

pKa cao l base mnh v acid c pKa cao l acid yu.

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

( nhit 250C)

Acid yu 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.

Bng 1.2: nh hng ca pH n s ion ha ca salicylic acid

c pKa = 3

pH % khng ion ha

1

2

3

99,0

90,9

50,0

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4

5

6

9,09

0,99

0,10

Nh vy, salicylic acid (aspirin) uc hp thu nhiu d dy v phn trn ca ng tiu ha.

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.

Th d phenobarbital (Luminal, Gardenal) l mt acid yu c pKa = 7,2; nc tiu bnh

thng c pH cng bng 7,2 nn phenobarbital b ion ha 50%. Khi nng pH ca nc tiu

ln 8, ion ha ca thuc s l 86%, do thuc khng thm c vo t bo. iu ny

c dng trong iu tr nhim c phenobarbital: truyn dung dch NaHCO3 1,4% base

ha nc tiu, thuc s b tng thi tr.

i vi mt cht kh (th d thuc m bay hi), s khuch tn t khng kh ph nang vo mu

ph thuc vo p lc ring phn ca cht kh gy m c trong khng kh th vo v ha

tan ca kh m trong mu.

1.4. Vn chuyn tch cc

Vn chuyn tch cc l s ti thuc t bn ny sang bn kia mng sinh hc nh mt "cht vn

chuyn" (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.

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

vn chuyn.

* Hnh thc vn chuyn: c hai cch

- Vn chuyn thun li (Vn chuyn tch cc th pht) : khi km theo carrier li c c s

chnh lch bc thang nng , v vy s vn chuyn ny khng cn nng lng. Th d vn

chuyn glucose, pyramidon theo bc thang nng ca Na+

- Vn chuyn tch cc thc th (Vn chuyn tch cc nguyn pht): l vn chuyn i ngc

bc thang nng , t ni c nng thp sang ni c nng cao hn. V vy i hi phi

c nng lng c cung cp do ATP thu phn, thng c gi l cc "bm", th d s vn

chuyn ca Na+, K+, Ca++,I-, acid amin.

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

2. CC QU TRNH DC NG HC

2.1. S hp thu

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Hp thu l s vn chuyn thuc t ni dng thuc (ung, tim) vo mu ri i khp c th,

ti ni tc dng. Nh vy s hp thu s ph thuc vo:

- ha tan ca 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 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

s b ph hu do cc enzym ca ng tiu ha, ca t bo rut v c bit l gan, ni c i

lc vi nhiu thuc. Phn thuc b ph hu trc khi vo vng tun hon c gi l "first

pass metabolism" (chuyn ha do hp thu hay chuyn ha qua gan ln th nht v thng l

ung thuc). Phn vo c tun hon mi pht huy tc dng dc l, c gi l sinh kh

dng (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

gan ln th nht

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2.1.1.2. Thuc ung

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

* d dy:

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

barbiturat.

- Ni chung t hp thu v nim mc t mch mu, li cha nhiu cholesterol, thi gian thuc

d dy khng lu.

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

* rut non:

L ni hp thu ch yu v c din tch hp thu rt rng (> 40 m2), li c ti mu nhiu,

pH tng dn ti base (pH t 6 n 8).

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

t c hp thu.

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

- Cc anion sulfat SO4- - 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 ha ph hu, khong 50% thuc hp thu qua trc trng s

qua gan, chu chuyn ha ban u.

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

2.1.2. Thuc tim

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

chm

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- 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 m c th thm qua da gy c ton thn (thuc tr su ln hu c, cht c

cng nghip anilin)

Gi m ni bi thuc (bng p), xoa bp, dng thuc gin mch ti ch, dng phng php

ion- di (iontophoresis) u lm tng ngm thuc qua da.

Hin c dng thuc cao dn mi, lm gii phng thuc chm v u qua da, duy tr c

lng thuc n nh trong mu: cao dn scopolamin, estrogen, nitrit

Da tr s sinh v tr nh, c lp sng mng manh, tnh thm mnh, d b kch ng cho nn

cn thn trng khi s dng, hn ch din tch bi thuc.

20 | P a g e

- 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- 100 m2) nn hp thu nhanh. y l

ng hp thu v thi tr chnh ca thuc m hi. S hp thu ph thuc vo nng thuc

m trong khng kh th vo, s thng kh h hp, ha tan ca thuc m trong mu (hay h

s phn ly mu: kh l)

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 ha tan ca thuc (hot cht) v

lm thay i F ca thuc. Nh vy, 2 dng bo ch ca cng mt sn phm c th c 2 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 1 hot cht: F1/F2.

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

21 | P a g e

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 (first

pass metabolism) lm gim sinh kh dng ca thuc. Song i khi v thuc qua gan li c th

c chuyn ha 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. Th d propranolol c sinh kh

dng theo ng ung l 30% nhng gan n c chuyn ha 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 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,

phn ly ca nhau.

2.2. S phn phiSau 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 ha ri thi tr (H1). Gia nng thuc t do (T) v phc hp protein - thuc (P- T)

lun c s cn bng ng:

T + P P - T

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 (H2)

Gian II Gian I Gian III

22 | P a g e

C quan c ti Huyt C quan c ti

mu 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

mi trng.

- 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.

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 a1

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)

Bng 1.3: T l gn thuc vo protein huyt tng

T l gn thuc vi protein huyt tng

Thuc l acid yu Thuc l base yu

75-100%:

Phenylbutazon,

75- 100%:

Diazepam

23 | P a g e

Warfarin

Phenytoin

Aspirin

25- 75%:

Benzylpenicilin

Methotrexat

Khng gn:

Ethosuximid

Digitoxin

Clopromazin

Erythromycin

25- 75%:

Cloroquin

Morphin

Khng 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

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 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 cn bng.

24 | P a g e

- 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 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 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 dng

thuc theo ng tnh mch. Th d in hnh ca hin tng ny l gy m bng thiopental,

mt thuc tan nhiu trong m. 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 xung 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"

25 | P a g e

- 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 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 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.

26 | P a g e

Kt qu ca s vn chuyn

- Cc thuc tan nhiu trong m s thm rt nhanh vo no, nhng li khng li c lu

(xin xem "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,

ion ha 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 NaHCO3 nng pH ca mu (7,6) vt

ln trn pH ca dch no ty (7,3), lm cho nng dng ion ha trong huyt tng ca

phenobarbital tng cao nng dng khng ion ha gim thp s ko dng khng ion ha

ca thuc t dch no tu vo 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 mng mao mch thai nhi tng theo

tui thai. 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

amin bc 4 (galanin, neostigmin) khng qua c rau thai, rt nhiu thuc c th vo c

27 | P a g e

mu thai nhi, 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 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

ra a con vn cn thc.

- Ngoi ra, rau thai cn c nhiu enzym nh cholinesterase, monoamin oxydase, hydroxylase

c th 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

mt s m trong c th v c gi li rt lu, hng thng n hng chc nm sau dng thuc,

c khi ch l 1 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

(xin 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

28 | P a g e

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

Vd = lit

Cp

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.

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 mg) digoxin c F theo ng ung l 0,7. o nng digoxin trong

huyt tng thy Cp= 0,7 ng/ mL (0,0007 mg/ mL).

Vy: 0,5 0,7

Vd = = 500L hoc 8,3 L/ kg

0,0007

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 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

29 | P a g e

2.3. S chuyn ha thuc2.3.1. 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

c trong m, khng b ion ha, d thm qua mng t bo, gn vo protein huyt tng v

gi li trong 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 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 ha, mt s thuc rt tan trong m (nh pentothal) c th

b gi li trong c th hn 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

30 | P a g e

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 ha loi B hoc C.

Hp thu Sinh chuyn ha Thi tr

Pha I Pha II

AB

A B Tan trong

Tan trong C C ncm D D

Hnh 1.5. Cc phn ng chuyn ha thuc c phn 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 trongnc hn. Nhng v mt tc dng sinh hc, thuc c th mt hot tnh, hoc ch gim hottnh, hoc i 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)

31 | P a g e

Cc phn ng chnh pha ny gm:

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

- Phn ng thu phn do cc enzym esterase, amidase, protease... Ngoi gan, huyt thanh vcc m 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- functionoxydase enzym system- mfO), thy c nhiu trong microsom gan, c bit l h enzymcytochrom P450 (Cyt- P450), l cc protein mng c cha hem (hemoprotein) khu tr li nibo nhn ca t bo gan v vi m khc. Trong c th ngi hin thy c ti 17 typ v rtnhiu di typ cytochrom P450 tham gia chuyn ha cc cht ni sinh v ngoi sinh t mitrng, thuc. Phn ng oxy ha loi ny i hi NADPH v O2 theo phc sau:

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

Cytochrom P450O2 H2O

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 (Fe2+)

3) Sau , phc hp RH- P450 (Fe2+) phn ng vi 1 phn t oxy v 1 electron th 2 tNADPH to thnh phc hp oxy hot ha.

4) Cui cng, 1 nguyn t oxy c gii phng, to H2O. Cn nguyn t oxy th 2 s oxyha c cht (thuc): RH ROH, v Cyt.P450 c ti to.Qu trnh phn ng c tm tt s sau:

32 | P a g e

Hnh 1.6: S oxy ha thuc ca cytocrom P450

Phn ng kh

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

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

33 | P a g e

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

- Cc amid

RNHCH3 R- NH2 + CH2O

R- NH2 R - NHOH OH

R- CHCH3 R- C- CH3 R- C- CH3 NH2 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

RCONHR1 RCOOH + R1NH2

Imipramin, diazepam,morphin, codein,

Clorpheniramin,dapson

Diazepam,amphetamin

Tolbutamid,ibuprofen,cyclosporin,midazolam

Prontosil, tartrazin

Nitrobenzen,chloramphenicol,clorazepam,dantrolen

Methadon, naloxon

Procain,succinylcholin,aspirin, clofibrat

Procainamid,lidocain,indomethacin

34 | P a g e

2.3.3.2. Cc phn ng pha IICc cht i qua pha ny tr thnh cc phc hp khng cn hot tnh, tan d trong nc vb thi tr. Tuy vy, pha ny, sulfanilamid b acetyl ha li tr nn kh tan trong nc, ktthnh 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 ha hc ca thuc to thnh ccphc hp tan mnh trong nc. Thng thng, cc phn ng pha I s to ra cc nhm chcphn 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 (chyu l glycin), phn ng acetyl ha, methyl ha. Cc phn ng ny i hi nng lng v ccht ni sinh, l c im ca pha II.Bng 1.5: Cc phn ng chnh trong 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

-Methyl- ha

Acid UDPglucuronic

Glutathion

Glycin

Phosphoadenosylphosphosulfat

S- adenosyl methionin

UDPglucuronosyltransferase(microsom)

GSH- S-transferase (dchbo tng,microsom)

Acyl- CoA transferase (tyth)

Sulfotransferase(dch bo tng)

Transmethylase(dch bo tng)

Phenol, alcol,acidcarboxylic,sulfonamid

Epoxid, nhmnitrohydroxylamin

Dn xut acyl-CoA ca acidcarboxylic

Phenol, alcol,cc amin vngthm

Catecholamin,phenol amin, histamin

Morphin,diazepam,digitoxin,acetaminophen,sulfathiazol

Acid ethacrynicbromobenzen

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

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

Dopamin,adrenalin,pyridin,histamin

Sulfonamid,isoniazid,clonazepam,

35 | P a g e

- Acetyl- ha Acetyl- CoAN-acetyltrasferase

(dch bo tng)

Cc amin

dapson.

Ngoi ra, c mt s thuc hon ton khng b chuyn ha, l nhng hp cht c cc cao(nh acid, base mnh), khng thm qua c lp m ca microsom. Phn ln c thi trnhanh nh hexamethonium, 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.Th d paracetamol b glucuro- hp v sulfo- hp cng mt lc; chlorpromazin b chuyn ha nhn phenothiazin qua nhiu phn ng, sau l nhnh bn cng qua mt lot phn ng cui cng cho ti hn 30 cht chuyn ha khc nhau.

2.3.4. Cc yu t lm thay i tc chuyn ha thuc2.3.4.1. Tui- Tr s sinh thiu nhiu enzym chuyn ha thuc

- Ngi cao tui enzym cng b lo ho2.3.4.2. 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 ny.

- 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 mg/ mL, nhm khcch l 2,5mg/ mL. Nhm u l nhm acetyl ha chm, cn gim liu v d c vi TKT. Vdi truyn, thuc nhm acetyl ha chm, thy 60% l ngi da trng, 40% l da en v 20% lda vng. 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 (G6PD) s d b thiu mu tan mu khi dngphenacetin, aspirin, quinacrin, vi loi sulfamid...2.3.4.3. Yu t ngoi lai

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

Th d: phenobarbital, meprobamat, clorpromazin, phenylbutazon, v hng trm thuc khc:khi dng nhng thuc ny vi cc thuc b chuyn ha qua cc enzym c cm ng s lmgim tc dng ca thuc c phi hp, hoc ca chnh n (hin tng quen thuc).Tri li, vi nhng thuc phi qua chuyn ha mi tr thnh c hot tnh ("tin thuc"), khidng chung vi thuc gy cm ng s b tng c tnh (parathion paraoxon)

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

2.3.4.4. Yu t bnh l

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

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

2.4. Thi trThuc c thi tr di dng nguyn cht hoc b chuyn ha2.4.1. Thi tr qua thny l ng thi tr quan trng nht ca cc thuc tan trong nc, c trng 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 cnhtranh thi tr. Th d dng thiazid ko di, do phi thi tr thiazid, c th gim thi aciduric, 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, mth cho cc anion (cc acid carboxylic nh penicilin, thiazid, cc cht glucuro- 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 lic ti 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 ratrong qu trnh ti hp thu nc cng Na+ v cc ion v c khc. Qu trnh ti hp thu thng y ph thuc nhiu vo pH nc tiu. Khi base ha nc tiu, th cc acid yu (acidbarbituric) s b thi tr nhanh hn v b ion ha nhiu nn ti hp thu gim. Ngc li, khiacid ha nc tiu nhiu hn th cc base (amphetamin) s b thi tr nhiu hn. iu nyc 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 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

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- Sau khi chuyn ha gan, cc cht chuyn ha s thi tr qua mt theo phn ra ngoi.

Phn ln 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 khithi tr qua mt xung rut c th b thu phn bi b glycuronidase ri li c ti hp thu vgan theo 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 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 saCc cht tan mnh trong lipid (barbiturat, chng vim phi steroid, tetracyclin, cc alcaloid), c

trng 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 sahi cao hn huyt tng v cc thuc l acid yu th c nng thp hn.

2.4.5. Thi tr qua cc ng khcThuc 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 gytc 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 caNapoleon sau 150 nm!

2.4.6. Thng s dc ng hc ca chuyn ha v thi tr thucMc ch ca chuyn ha l lm cho thuc mt hot tnh, d tan trong nc v thi tr. Vvy, qu trnh chuyn ha 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 ha v thi trthuc.

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 .

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

V

CL = (mL/ pht)Cp

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

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

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Clearance cng l mt tr s o, mang tnh l thuyt v s tun hon ca mu qua c quanc lin tc lp i lp li. Trong thc t, thuc c coi l lc sch khi huyt tng saumt khong thi gian l 7 t1/2.Hai c quan chnh thamgia thi tr thuc khi c th l gan (lng thuc b chuyn ha vthi 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 (t1/2) s ngn.- Dng CL tnh liu lng thuc c th duy tr c nng thuc n nh trong huyttng. 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 t1/2 c phn bit lm 2 loi :

- t1/2 a hay t1/2 hp thu l thi gian cn thit 1/2 lng thuc dng hp thu c vo tunhon. nu dng thuc theo ng tim bp th t1/2 a 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 clearance. Khi CL thay i theo nguyn nhnsinh l hoc bnh l s lm t1/2thay i, hiu qu ca iu tr b nh hng. Cn phi hiuchnh liu lng hoc khong cch gia cc liu (xem phn Nhng bin i ca dc nghc).- 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 lnt1/2 th coi nh thuc b thi tr hon ton khi c th (xem bng).

Lng thuc c thi tr theo t/2

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

12

34

56

7

5075

8894

9798

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 thuctrong huyt tng. Nu khng th cho c liu cao (nh heparin, insulin) th truyn tnhmch lin tc hoc sn xut dng thuc gii phng chm.

39 | P a g e

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

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

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 rau 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 ha thuc pha I,

kt qu v ngha?8. K tn cc phn ng chnh (khng vit cng thc) ca chuyn ha 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?

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Bi 2: I CNG V DC 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

(l ha, 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 tcdng sinh ha v sinh l ca thuc. Phn tch cng y c cc tc dng, cng cung cpc nhng c s cho vic dng thuc hp l trong iu tr. y l nhim v c bn nht vcng l kh khn ln nht ca dc lc hc.1. C CH TC DNG CA THUC1.1. 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 lng giihn 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 ha 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 phctp 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 tny vo receptor theo cc lin kt ha hc:- Lin kt ion: cc cht ha hc mang in tch (nh nhm amoni bc 4 cu acetylcholin cin tch dng), s gn vo vng mang in tch tri du ca receptor theo lin kt ny, vilc 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 ktgia nguyn t hydro vi cc nguyn t c in tch m cao nh oxy, nit v fluor. Lc linkt khong 2- 5 kcal/ mol- Lin kt Van- der- Waals: l lc lin kt ca mi tng h gia cc electron vi cc nhnca cc phn t st bn. Lc lin kt ph thuc vo khong cch gia cc phn t, lc nytng i yu, khong 0,5 kcal/ mol. Cc thuc c vng benzen, c mt electron phn bng u thng c mi lin kt ny.Cc lc lin kt trn u l thun nghch.- Lin kt cng ha tr: l lc lin kt gia cc nguyn t bng nhng cp in t chung. V llc lin kt ln 50- 150 kcal/ mol nn l lin kt khng thun nghch nhit c th, khng

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c cht xc 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 mono- amin oxydase (MAOI), thuc tr su ln hu c vicholinesterase.

Mt phn t thuc c th gn vo receptor theo nhiu kiu lin kt. Th d: acetylcholin gnvo 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 png t bo. Cc receptor nm nhn t bo c hot ha bi cc ligand gn trn cc v trc hiu ca ADN nm trong cc vng iu ha gen, gy ra s sao chp cc gen c hiu(receptor ca hormon steroid, vitamin D3...). Cc receptor nm mng t bo v xa nhnnn khng tham gia trc tip vo cc chng trnh biu hin ca gen. Khi cc ligand tc ngln 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 tbo, dn ti mt thay i chuyn ha trong t bo, cng vi hoc khng c s thay i vbiu 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 ckhi 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 gnvo gan, phi, thn...Thuc gn vo receptor ph thuc vo i lc (affinity) ca thuc vi receptor. Hai thuc ccng receptor, thuc no c i lc cao hn s y c thuc khc ra. Cn tc dng ca thucl do hiu lc (efficacy) ca thuc trn receptor . i lc v hiu lc khng phi lc nocng i cng nhau: acetylcholin l cht dn truyn thn kinh ca h ph giao cm, khi gn voreceptor M, gy hiu lc lm tng tit nc bt, co ng t, chm nhp tim...; atropin c i lctrn receptor M mnh hn acetylcholin rt nhiu nn y c acetylcholin ra khi receptorM, nhng bn thn n li khng c hiu lc g. lm sng, tc dng ca atropin quan stc chnh l tc dng ca s thiu vng acetylcholin trn receptor M: kh ming (gim titnc bt), gin ng t, nhp tim nhanh...

1.2. Cc c ch tc dng ca thuc

42 | P a g e

1.2.1. Tc dng ca thuc thng qua receptorThuc 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 tcdng 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, khnggy tc dng ging cht ni sinh, tri li, ngn cn cht ni sinh gn vo receptor, gy tcdng c ch cht ng vn, c gi l cht i khng (antagonists), nh d- tubocurarin tranhchp 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 gygin mch...

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

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

. 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; thuctr tim digitalis c ch Na+- K+ ATPase...

. Thuc hot ha enzym: cc yu t vi lng nh Mg2+, Cu2+, Zn2+ hot ha nhiu enzymprotein kinase, phosphokinase tc dng ln nhiu qu trnh chuyn 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 receptorMt 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 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 tnhmch 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 ngthn, c tc dng li niu.

Nhng cht to chelat hay cn gi l cht "cng cua" do c cc nhm c cc nh -OH, -SH, -NH2, d to phc vi cc ion ha tr 2, y chng ra khi c th. Cc cht "cng cua" nhEDTA (ethyl diamin tetra acetic acid), BAL (British anti lewisit- dimercaprol), d- penicilaminthng 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 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, ging

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pyrimidin, nhp vo acid nucleic, dng chng ung th, chng virus. Sulfamid gn gingparaamino 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 vomu: thuc st khun ngoi da, thuc lm sn nim mc (tanin), thuc bc nim mc ngtiu 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, tcdng 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 gintip lm ngng th do c honh v c lin sn b lit ch khng phi thuc c ch trung tmh hp.Mt khc, tc dng gin tip cn c th thng qua phn x: khi ngt, ngi ammoniac, ccngn dy thn kinh trong nim mc ng h hp b kch thch, gy phn x kch thch trungtm h hp v vn mch hnh ty, lm ngi bnh hi tnh.

2.2. Tc dng chnh v tc dng ph- Tc dng chnh l tc dng iu tr

- Ngoi tc dng iu tr, thuc c th cn gy nhiu tc dng khc, khng c ngha trongiu tr, c gi l tc dng khng mong mun, tc dng dng ngoi (adverse drugreactions- 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 viliu iu tr) nh xut huyt tiu ha, gim bch cu, tt huyt p th ng...Th d: aspirin l thuc h st, gim au, chng vim (tc dng chnh), nhng gy chy mutiu ha (tc dng c hi). Nifedipin, thuc chn knh calci dng iu tr tng huyt p (tcdng chnh), nhng c th gy nhc u, nhp tim nhanh (tc dng ph), ho, ph chn, tngenzym gan, tt huyt p (tc dng c hi).Trong iu tr, thng phi hp thuc lm tng tc dng chnh v gim tc dng khngmong mun. Th d ung thuc chn b giao cm cng vi nifedipin s lm gim c tcdng lm tng nhp tim, nhc u ca nifedipin. Cng c th thay i ng dng thuc nhdng 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 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 phn 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 ditvi khun nhng khng nh hng n da; khng sinh cloramphenicol c tai bin gy suy tyxng.

2.4. Tc dng chn lcTc dng chn lc l tc dng iu tr xy ra sm nht, r rt nht. Th d aspirin ung liu 1-2 g/ ngy c tc dng h st v gim au, ung liu 4- 6 g/ ngy c c tc dng chng vim;

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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 b2 adrenergic...Thuc c tc dng chn lc lm cho vic iu tr tr nn d dng hn, hiu qu hn, trnhc nhiu tc dng khng mong mun.

3. NHNG YU T NH HUNG N TC DNG CA THUC:3.1. V thuc3.1.1. 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) vsau l hot ha c receptor (c hiu lc hay tc dng dc l). Receptor mang tnhc hiu cho nn thuc cng phi c cu trc c hiu. Receptor c v nh kha v thucl cha kha. Mt s thay i nh v cu trc ha hc (hnh dng phn t ca thuc) cng cth 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 vCH3 vo v tr 16 ca corticoid (hormon v thng thn), ta c betametason c tc dngchng 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 ciproniazid, c tc dng chng trm cm, do gn vo receptor hon ton khc.

Sulfanilamid PABA (para amino benzoic acid)Khng histamin H1 c cng thc gn ging vi histamin, tranh chp vi histamin ti receptorH1.- 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 b adrenergic 500 ln mnh hn d. isoprenalin.

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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 rtc hiu, gn c vo di typ ca receptor: receptor adrenergic a1, a2, b1, b2, b3, receptorcholinergic M1, M2, M3, receptor dopaminergic D1, D2, ... D7.

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

- Dopamin khng qua c hng ro mu no, nhng l. dopamin (Levodopa), cht tin thnca dopamin th qua c.

- Estradiol thin nhin khng ung c v b chuyn ha mnh gan. dn xut ethinylestradiol (-C CH gn v tr 17) rt t b chuyn ha nn ung c.- Tolbutamid b microsom gan oxy ha gc CH3 v tr para, c t/2 huyt tng l 4- 8 h.Thay gc CH3 bng Cl (Clorpropamid) s rt kh b chuyn ha, lm t/2 ca thuc ko di ti35 h.- Cc thiobarbituric t b phn ly hn barbituric pH ca ng thn nn b thi tr chm hn.

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

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

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

Dc cht

K thut bo ch ng dng thucDng 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 dngQua s , ta thy t 1 dc cht, cc nh bo ch c th a ra th trng nhiu loi bitdc (dng thuc) khc nhau, c sinh kh dng khc nhau do c nh hng khc nhau tihiu 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.

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

3.2.3. K thut bo ch v dng thucK 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(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 saocho:

- 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 thuc3.3.1. c im v tui (xin xem phn "dc ng hc")3.3.1.1. Tr em:"Tr em khng phi l ngi ln thu nh li", ngha l khng phi ch gim liu thuc cangi 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 cngn bilirubin, d b thuc y ra, gy ng c bilirubin.

- H enzym chuyn ha thuc cha pht trin- H thi tr thuc cha pht trin

- H thn kinh cha pht trin, myelin cn t, hng ro mu- no cha bo v nn thuc 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

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Tui TE + 1

Liu ngi ln 24

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

4 + 1

2,0 g = 0,41 g 24

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)

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 ln3.3.1.2. Ngi cao tuiNgi cao tui cng c nhng c im ring cn lu :- Cc h enzym u km hot ng v "lo ha"

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- 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, tiung...) nn phi dng nhiu thuc mt lc. Cn rt ch tng tc thuc khi k n (xinxem phn "tng tc thuc")

3.3.2. c im v giiNhn 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 nguytKhng cm hn thuc. Nu phi dng thuc di ngy, c tng t ngng thuc th nn spxp vo lc c kinh.3.3.2.2. Thi k c thaiTrong 3 thng u, thuc d gy d tt bm sinh, to ra qui thai. Trong 3 thng gia thuc cth nh hng xu n s pht trin ca bo thai, n chc phn pht trin ca cc c quan.Trong 3 thng cui, thuc c th gy xy thai, non.V vy, khi cn ch nh thuc cho ph n c thai, cn cn nhc tht k gia li ch cho ngim v mc nguy hi cho bo thai. Ni chung, trong 3 thng u, tuyt i trnh dng mi loithuc.

i vi ngi m, khi c thai, lng nc gi li trong c th tng, th tch mu tng, hmlng protein huyt tng c th gim, lng lipid c th tng... lm nh hng n ng hcca thuc.3.3.2.3. Thi k cho con bRt nhiu thuc khi dng cho ngi m s thi tr qua sa v nh vy c th gy c hi chocon. Cc nghin cu v cc loi thuc ny ni chung cn cha c y , do tt nht lch nn dng nhng loi thuc tht cn thit cho m. Tuyt i khng dng nhng thuc ccha thuc phin v dn xut ca thuc phin (thuc ho, codein, vin ra) v thuc thi trqua sa v trung tm h hp ca tr rt nhy cm, c th b ngng th. Khng dng cc loicorticoid (lm suy thng thn tr), cc khng gip trng tng hp v iod (gy ri lon tuyngip), cloramphenicol v thuc phi hp sulfametoxazol + trimethoprim (Co- trimoxazol) vc 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 THUCTrong 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 thch l nhng triu chng rt nh nh nhc u, bun nn... cho n nhng triu chng rtnng 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 ngD ng thuc cng l 1 ADR.

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Do thuc l 1 protein l (insulin, thyroxin ly t sc vt), l a peptid, polysaccharid c phnt lng cao, mang tnh khng nguyn. Tuy nhin, nhng thuc c phn t lng thp hocchnh sn phm chuyn ha ca n cng c th gy d ng, chng c gi l bn khngnguyn hay "hapten". Vo c th, hapten c kh nng gn vi mt protein ni sinh theong ni cng ha 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 ha v sn phm oxyha 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 vikhng th IgE, gn trn bch cu a base tun hon hoc cc dng bo. Phn ng lm giiphng nhiu cht ha hc trung gian nh histamin, leucotrien, prostaglandin, gy gin mch,ph v vim. Cc c quan ch ca phn ng ny l ng tiu ha (d ng thc n), da (myay, 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 b lactam,aminoglycosid, huyt thanh, g globulin, vaccin, vitamin B1 tim tnh mch.- Typ II hay phn ng hu t bo (cytolytic reactions) xy ra khi c s kt hp khng nguynvi khng th IgG v IgM ng thi c s hot ha h b th. M ch ca phn ng ny lcc t bo ca h tun hon. Th d: thiu mu tan mu do penicilin, thiu mu tan mu tmin do methyl dopa, ban xut huyt gim tiu cu do quinidin, gim bch cu ht dosulfamid, 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. Phnng gia khng nguyn v khng th to thnh phc hp min dch. Phc hp ny lng ngvo ni mc mch, gy tn thng vim hu hoi, c gi l bnh huyt thanh. Biu hinlm sng thng l: my ay, ban , au, vim khp, ni hch, st. Thng xy ra sau 6- 12ngy.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 vi thc bo. Khi cc t bo mn cm tip xc vi khng nguyn, s gii phng cclymphokin 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 thngc d ng cho. V vy cn hi tin s d ng ca bnh nhn trc khi dng thuc. Vi nhngthuc hay gy d ng (penicilin, lidocain,...) khi dng, phi c sn thuc v phng tin cpcu (adrenalin). Sc phn v c th xy ra do ng dng thuc khc nhau: vitamin B1 dngtim 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 truynThng 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 reductased b thiu mu tan mu khi dng primaquin, quinin, pamaquin (xin xem bi "Thuc chngst rt"), sulfamid, nitrofuran...

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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 ngida 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 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 sthiu ht di truyn 1 enzym no .

4.4. Quen thucQuen 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, hocb chuyn ha nhanh, hoc c th km mn cm vi thuc. Thng do nguyn nhn di truyn.

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

4.4.1. Quen thuc nhanh (tAChyphylaxis)Thc nghim dng nhng liu 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 chin 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 nisinh. 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 cht m: isoprenalin (cng b giao cm) quachuyn ha gan, to ra 3- orthomethylisoprenalin c tc dng hu b.4.4.2. Quen thuc chmSau mt thi gian dng thuc lin tc, tc dng ca thuc gim dn, i hi phi tng liuhoc i thuc khc. C nhiu nguyn nhn:- Do gy cm ng enzym chuyn ha thuc, lm nhng liu thuc sau b chuyn ha nhanh,mt tc dng nhanh. Barbiturat, diazepam, tolbutamid, ru ethylic... u l nhng thuc gycm ng enzym chuyn ha ca chnh n.

- Do gim s lng receptor cm ng vi thuc mng t bo (iu ha gim- downregulation): khi dng thuc cng giao cm, ph giao cm ko di... Tri li, khi dng ccthuc phong to ko di s lm tng s lng receptor (iu ha tng- up regulation) nhdng thuc hu b giao cm, thuc an thn c ch h dopaminergic. Khi ngng thuc d gyhin tng hi ng (rebound)

- Do c th phn ng bng c ch ngc li dng cc thuc li niu thi Na+ lu, c th mtnhiu 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 lunphin thay i cc nhm thuc (s trnh by trong phn thuc c th)

4.5. Nghin thuc

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Nghin thuc l mt trng thi c bit lm cho ngi nghin ph thuc c v tm l v thcht 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 maty "hp php".

C ch nghin cn cha c hon ton bit r, c nhiu gi thuyt gii thch: do c thkhng sn xut morphin ni sinh; lm ri lon chc phn ca nron, gy phn ng b tr cac 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 nginghin. V vy, nghin ma tu l mt t nn x hi phi c loi tr.

CU HI T LNG GI

1. Trnh by cc c ch tc dng ca thuc.2. Trnh by cc cch tc dng ca thuc.3. Phn tch nhng yu t v thuc c nh hng n tc dng ca thuc.4. Phn tch nhng yu t ca ngi dng thuc c nh hng n tc dng ca thuc.5. Trnh by nhng tai bin khi dng thuc: phn ng c hi, phn ng d ng, ri lon

do di truyn, nghin thuc.

Bi 3: TNG TC THUC

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MC TIU HC TP: Sau khi hc xong bi ny, sinh vin c kh nng:

1. Trnh by c tng tc dc lc hc v dc ng hc.2. Trnh by c hiu qu v p dng ca tng tc thuc.

1.TNG TC THUC- 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, gimcc tc dng khng mong mun. Song trong thc t, nhiu khi khng t c nh th. Vvy, 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 hcL tng tc ti cc receptor, mang tnh c hiu

1.1.1. Tng tc trn cng receptor: tng tc cnh tranhThng 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: atropinkhng acetylcholin v pilocarpin ti receptor M; nalorphin khng morphin ti receptor camorphin; cimetidin khng histamin ti receptor H2.Thuc cng nhm c cng c ch tc dng, khi dng chung tc dng khng tng bng tngliu ca mt thuc m c tnh li tng hn: CVKS, aminosid vi dy VIII.

1.1.2. Tng tc trn cc receptor khc nhau: tng tc chc phn.- C cng ch tc dng: do lm tng hiu qu iu tr.Th d: trong iu tr bnh cao huyt p, phi hp thuc gin mch, an thn v li tiu; trongiu tr lao, phi hp nhiu khng sinh (DOTS) tiu dit vi khun cc v tr v cc giaion pht trin khc nhau.

- C ch tc dng i lp, gy ra c chc phn i lp, dng iu tr nhim c:strychnin liu cao, kch thch ty sng gy co cng c, cura do c ch dn truyn tm vnng, lm mm c; histamin tc ng trn receptor H1 gy gin mch, tt huyt p, trong khinoradrenalin tc ng ln receptor a1 gy co mch, tng huyt p.1.2. Tng tc dc ng hcL cc tng tc nh hng ln nhau thng qua cc qu trnh hp thu, phn phi, chuyn hav thi 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 hcv d phn tn hn trong lipid. phn ly ca thuc ph thuc vo hng s pKa ca thuc vpH ca mi trng. Cc thuc c bn cht acid yu (nh aspirin) s hp thu tt trong mitrng acid (d dy), nu ta trung ha acid ca dch v th s hp thu aspirin d dy s gimi.

- 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

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cc thuc d tan trong lipid, khi dng cng vi parafin (hoc thc n c m) s lm tng hpthu.- Vi cc thuc dng theo ng tim bp, di da: procain l thuc t, khi trn vi adrenalinl thuc co mch th procain s chm b hp thu vo mu do thi gian gy t s c kodi. Insulin trn vi protamin v km (protemin- zinc- insulin- PZI) s lm ko di thi gianhp thu insulin vo mu, ko di tc dng h ng huyt ca insulin.- Do to phc, thuc s kh c hp thu:

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

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

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

1.2.2. Thay i s phn b thuc l tng tc trong qu trnh gn 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 huyttng 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 thgy nhim c.

1.2.3. Thay i chuyn haNhiu thuc b chuyn ha gan do cc enzym chuyn ha thuc ca microsom gan (xin xemphn dc ng hc). Nhng enzym ny li c th c tng hot tnh (gy cm ng) hoc bc ch bi cc thuc khc. Do s lm gim t/2, gim hiu lc (nu l thuc gy cm ngenzym) hoc lm tng t/2, tng hiu lc (nu l thuc c ch enzym) 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.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 hiuqu v b chuyn ha nhanh, hm lng tr nn thp.

1.2.4. Thay i thi tr thucThi tr (elimination) thuc gm 2 qu trnh l chuyn ha thuc gan ( ni phn trn)v bi xut (excretion) thuc qua thn. Nu thuc bi xut qua thn dng cn hot tnh ths tng/ gim bi xut s c nh hng n tc dng ca thuc.

- Thay i pH ca nc tiu: khi mt thuc lm thay i pH ca nc tiu, s lm thay i ion ha ca thuc dng km, lm thay i bi xut ca thuc. Th d barbital c pKa = 7,5;

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pH = 7,5 th 50% thuc b ion ha; pH = 6,5 th ch c 9% b ion ha pH = 9,5 th 91%barbital b ion ha. V vy, khi ng c cc thuc barbiturat, truyn dch NaHCO3 base hanc tiu s tng bi xut barbiturat.

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

- Bi xut tranh chp ti ng thn: do 2 cht cng c c ch bi xut chung ti ng thn nntranh chp 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 thuc1.3.1. Tc dng hip ngThuc A c tc dng l a, thuc B c tc dng l b. Khi kt hp thuc A vi thuc B c tcdng c. Nuc = 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 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 khngNh trong nh ngha trn, nhng khi tc dng c ca thuc A + B li nh hn tc dng cngca tng 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 tontc 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 tcthun ty l ha:

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

+ Thuc oxy ha (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 kimloi (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 gimtc 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.Th d: acetylcholin v atropin ti receptor M- cholinergic; histamin v cimetidin trnreceptor H2 d dy.

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+ 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 thchreceptor H1 lm co c trn kh qun, gy hen; albuterol (Ventolin), kch thch receptor b2adrenergic lm gin c trn kh qun, dng iu tr cn hen.

1.3.3. o ngc tc dng

Adrenalin va c tc dng kch tch receptor a adrenergic (co mch, tng huyt p), va ctc dng kch thch receptor b adrenergic (gin mch, h huyt p). Khi dng mt mnh, dotc dng a mnh hn b nn adrenelin gy tng huyt p. Khi dng phentolamin (Regitin) lthuc c ch chn lc receptor a ri mi tim adrenalin th do ch kch thch c receptor bnn adrenelin gy 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 thucTuy 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 mctng tc 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:- S hp thu ph thuc vo thi gian rng ca d dy. D dy khng phi l ni c chc nnghp thu ca b my tiu ha. Tuy nhin, do pH rt acid (khi i, pH 1; khi no pH 3) chonn 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 bgim 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 dys b ph hu nhiu.

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

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

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

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

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Thc n c th nh hng n enzym chuyn 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 khngln.

Ngc li, thuc c th nh hng n chuyn ha mt s cht trong thc n. Thuc c chenzym mono- amin- 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 nhiutyramin (nh khng c chuyn ha kp, lm gii phng nhiu noradrenalin ca h giao cmtrong thi gian ngn.

2.2. Tng tc thc n ung2.2.1. Nc- 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 tanhot cht, gip hp thu d dng. V vy cn ung nc (100 - 200 mL cho mi ln ungthuc) 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 ha ca thuc(sulfamid, cyclophosphamid).

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

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

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

2.2.4. Ru ethylicRu c rt nhiu nh hng n thn kinh trung ng, h tim mch, s hp thu ca ngtiu ha. Ngi nghin ru cn b gim protein huyt tng, suy gim chc nng gan, nhngli gy cm ng enzym chuyn ha thuc ca gan (xin xem bo "ru"), v th ru c tngtc vi rt nhiu thuc v cc tng tc ny u l bt li. Do khi dng thuc th khngung ru. Vi ngi nghin ru cn phi dng thuc, thy thuc cn kim tra chc nng

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gan, tnh trng tm thn... chn thuc v dng liu lng thch hp, trong thi gian dngthuc cng phi ngng ung ru.3. THI IM UNG THUCSau khi nhn r c tng tc gia thuc- thc n- ung, vic chn thi im ung thuchp l t c nng cao trong mu, t c hiu qu mong mun cao v gim ctc dng ph l rt cn thit.

Nn nh rng: ung thuc vo lc i, thuc ch b gi li d dy 10- 30 pht, vi pH 1;ung lc no (sau n), thuc b gi li 1- 4 gi vi pH 3,5. Nh vy, tu theo tnh cht cathuc, 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 phngchm.

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 itho ng loi c ch gluconidase nn ung trc ba n 10- 15 pht.- Thuc kch thch d dy, d gy vim lot ng tiu ha: cc thuc chng vim phi steroid,mui kali, quinin.- 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 khnghistamin 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 gicng.- Cc corticoid: thng ung 1 liu vo 8 gi sng duy tr c nng n nh trongmu.

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, chonn ngoi vic dng thuc theo ba n, cc thuc khng acid dng cha lot d dy nn cung 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 ctnh thay i theo nhp ngy m. Tuy nhin, trong iu tr, vic cho thuc cn tu thuc vothi gian xut hin triu chng.

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CU HI 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.

PHN IITHUC TC DNG TRN H

THN KINH THC VT

Bi 4: I CNG 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 ngngoi mun, c vai tr iu ha chc phn ca nhiu c quan, h thng cho gii hnsng 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 phtnhng si thn kinh ti cc tng, mch mu v c nhn. Trc khi ti c quan thu nhn, ccsi ny u dng mt xinap ti hch, v vy c si trc hch (hay tin hch) v si sauhch (hay hu hch). Khc vi nhng b phn do h thn kinh trung ng iu khin, cc cquan do h thn kinh thc vt chi phi vn c th hot ng t ng khi ct t nhng sithn kinh n chng.H thng thn kinh thc vt c chia thnh 2 h giao cm v ph giao cm khc nhau v cgii phu v chc phn sinh l.1. PHN LOI THEO GII PHU1.1. im xut pht

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- H giao cm xut pht t nhng t bo thn kinh sng bn ca tu sng t t sng ngcth 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, ccsi ph giao cm i cng vi cc dy thn kinh trung ng: dy III vo mt; dy VII vo cctuyn nc bt; dy IX vo c mi, cc tuyn tit nc mt, nc bt, tuyn tit nim mcmi, ming, hu; dy X vo cc tng trong ngc v bng. tu cng, xut pht t cc tsng cng th 2 n 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 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 kchthch 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 xungtc 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 vikhong 8000 si hu hch.

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

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Hnh 4.1. Cu to gii phu ca h thn kinh thc vt2. CHC PHN SINH L2.1. Chc phn sinh lChc phn sinh l ca hai h giao cm v ph giao cm trn cc c quan ni chung l ikhng nhau (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 cm

Loi receptor p ng p ng

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Mt

C nan h