1. Duoc Ly Dai Cuong

8/14/2019 1. Duoc Ly Dai Cuong

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DC LY HOC AI CNGMUC TIEU, YEU CAU :- Nam vng nhng khai niem c ban ve dc ly hoc ai cng va biet vandung nhng khai niem ay trong cac chng muc dc ly chuyen e.- Nam vng 2 qua trnh c ban dc ly hoc : Dc lc va dc ong, biets dung thuoc mot cach hp ly, an toan va co hieu qua.

I. NHNG KHAI NIEM C BAN :1.1. DC LC HOC :La mon khoa hoc nghien cu ve tng tac (interaction) gia thuoc (D)

va he thong song (R) .

Tng tac co ngha la tac ong qua lai : Thuoc tac ong len he thongsong (D R), thuoc pham tru nghien cu cua dc l hoc(Pharmacodynamics), con he thong song tac ong tr lai oi vi thuoc (R

D), thuoc pham tru nghien cu cua dc ong hoc (Pharmacokinetics).Dc lc va dc ong la 2 qua trnh c ban cua dc ly hoc, chung vanong, an xen vao nhau, tao ra nhng hieu ng dc ly. Van dung toi anhng hieu ng mong muon vao muc ch ieu tr va han che het mc hieung khong mong muon cua thuoc, nham nang cao hieu qua ieu tr, giamthieu tai bien, gop phan bao ve sc khoe cua nhan dan, la muc tieu yeucau chung cua dc ly hoc

Dc ly hoc la mon khoa hoc ban le, noi lien gia c s va lamsang, gia ly luan va thc tien, lien he rat mat thiet en cac mon khoa hocc ban, y hoc c s, toan hoc, thong ke sinh hoc, hoa hoc, y hoc ien t,phap y, luan ly va xa hoi hoc cac mon hoc lien he o, thuc ay dc lyhoc phat trien va s phat trien cua dc ly hoc tr lai ap ng ngay cangtot hn, mang lai hieu qua ieu tr cao hn cho thc tien lam sang.

Dc ly hoc van dung phng phap phan tch va tong hp, ket hpchat che gia nguyen ly thc nghiem lam sang va ket qua lam sang,luon luon la ni kiem nghiem mot cach chnh xac toan bo cong tac nghiencu cua chung ta.

e am bao at en hieu qua chung cuoc trong ieu tr, ngi thaythuoc phai nam vng s bien oi cua thuoc qua 4 giai oan sau :

1. Giai oan kha dung sinh hoc (Bioavailability) : Chon la thuoc,xac nh lieu lng, dang thuoc va con ng a thuoc vao cthe.

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2. Giai oan dc ong (Pharmacokinetics) : Nam vng so phancua thuoc trong c the.

3. Giai oan dc lc (Pharmacodynamics) : Nam vng tac ongva c che tac ong cua thuoc

4. Giai oan van dung hieu ng dc ly vao ieu tr : Ch nh,chong ch nh, anh gia ket dieu tr

1.2. THUOC :La nhng chat hoac hon hp cac chat, c dung e cha benh, phong

benh va chan oan, nham phuc hoi chc nang von co cua n v song.

Cac ac tnh cua thuoc : Phan t : Nhng thuoc co lng phan t t 100 en 1000, de hap thu

v de khuech tan va thuan li cho viec chuyen ch thuoc qua mang te bao. Hnh khoi cau truc lap the : a so cac thuoc, tng tac vi nhng

v tr chuyen biet c goi la thu the R (Receptor). o la cau truc khonggian 3 chieu cua ai phan t. Cau truc lap the hnh khoi cua thuoc phai ankhp va van vi hnh khoi cua thu the ay. Co khoang 25% so thuoc cs dung, la nhng chat ong phan lap the. Chung thng rat khac biet vecac hieu ng, cung cach thai tr thuoc ra ngoai c the, cung nh ve octnh.

V du : L-quinin (chong sot ret) va D-quinidine (chong loan nhp tim);

R (-) prilocain, thuy phan rat nhanh thanh O-toluidine, gay mathemoglobin,con S (+) prilocain thuu phan rat cham, t gay methemoglobine hn. Ca haidang ong phan thalidomide, eu co tac dung an than gay ngu, nhng chco dang L (-) co tng gay quai thai cho va loai ong vat v.v..

Hoa tnh : Co nhng thuoc phan ng rat manh nh nhng chat Alkylhoa (mechlorethamine), trong khi o, cung co nhng chat tr, Xenon changhan, co tac dung gay me.

Thuoc co the la carbohydrate, lipide hay proteine, co tnh acideyeu hay base yeu.

o ion hoa cua thuoc, tuy thuoc pH cua moi trng tng khuvc hoac v tr cua c the

Nguon goc :Thien nhien : Khoang chat, ong vat, thc vat. V du : Kaolin t at

set trang. Emetine t re cay ipeca. Insuline t tuy tang. Penicilline t nampenicillium.

Ban tong hp : T chat t nhien vo hoat, qua s bien oi trong phong

th nghiem, co the tr thanh thuoc co hoat tnh. V du : Penicilline ban tong

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hp, c hnh thanh t 6-amino-penicillanic, chat t nhien ly trch tPenicillium.

Tong hp toan phan : Chloramphenicol, Ephedrine, Phenylephrineco the tong hp toan phan, gia thuoc re hn chat t nhien, ma oc tnh lai

t hn.Phan loai thuoc :Thuoc chuan (Produits officinaux) : La nhng thuoc co ac tnh ly-

hoa va dc ly, c ghi trong dc ien quoc gia. Thuoc bao che theo toa Bac s (Preparations magistrales) : Nhng

thuoc bao che danh rieng cho mot benh nhan theo ch nh cua Bac s.Dang thuoc nay nay a loi thi

Biet dc (Specialites pharmaceutique) : Nhng thuoc c bao che

san, trnh bay di dang bao b, ong goi ac biet. c ac ten riengva c bay ban th trng sau khi Bo Y te kiem nh va cho phep.

Thuoc chu yeu (Medicaments essentiels) : Co khoang 200 hoat chatcan thiet, khong the mien tr ma moi Bac si phai co, e ieu tr nhngbeng thong thong.

Thuoc n le (Medicaments orphelins) : La nhng thuoc c sanxuat mot lng t oi, e cha cho mot so ngi mac benh hiem hoi, dokhong co li nhuan cao, nen t c cac nha cong nghe dc pham quan

tam.at ten thuoc : Ten khoa hoc (Denomination Scientifique) : Nhng hoa chat phai

tuan thu cac qui luat at ten theo danh phap quoc te IUP (UnionInternational de chimie pure et appliquee), nhng ten khoa hoc thng quadai va phc tap cho ngi ke toa dung thuoc.

V du : Acide acetyl salicylique - (3,4 dihydroxyphenyl) -methylamino ethanol.

Ten thng mai (Denomination commerciale) : Ten kieu cach nhanhieu, cau chng (Registereo trade mark name) cua cac biet dc, co thecha mot hay nhieu chat ma cac nha bao che san xuat ra bang nhieu tenthng mai khac nhau. V du : acide acetyl salicylique c bay ban dinhieu ten biet dc nh Aspirine Bayer, Aspirine du Rhone 500, Aspro,Aspan pH8.

Ten thong thng (denomination commun) : e khac phuc nhciem gay phien toai t ten khoa hoc, ten thng mai. To chc Y te the gii

co hng dan cach at ten thuoc chung cho tat ca cac nc, da tren c s

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nhng tiep au ng (prefix) hay tiep v ng (suffixe) can he en cac nhomthuoc, tat nhien cung co mot so ngoai le :- ctide Polypeptides tong hp t cac corticotrophine ong vat- ac Cac chat chong viem nhom Ubufenac

- andro Steroides androgenes- arol Cac chat ong mau nhom dicoumarol- astine Cac thuoc khang histamine- azepam Cac chat nhom diazepam- bol Cac steroides ong hoa (anabolisants)- caine Cac thuoc te- cef Cac thuoc khang sinh t acide Cephalosporanique- cilline Cac thuoc khang sinh t acid 6 amino-penicillanique

- cycline Cac thuoc khang sinh nhom tetracyclines- dipine Cac chat dan mach ngoai bien nhom nifedipine- estr Cac chat Estrogenes- fibrate Cac chat nhom clofibrate- formine Cac chat ha ng huyet nhom Phenformine- gest Cac Steoides Progestogenese- gly Cac Sulfamides ha ng huyet- Io Cac chat co Iode

- ium Cac ammonium bac IV- metacine Cac chat khang viem nhom Indomethacine- mycine Cac thuoc khang sinh t cac chung Streptomyces- nidazol Cac chat cha nguyen sinh ong vat cua nhom

metronidazol- olol Cac chat phong toa nhom propranolol- onide Steroides dung tai cho cha nhom Acetal- orex Cac chat gay thieu Oxy dan xuat t phenethylamine

- pramine Cac chat trong nhom imipramine- pride Cac chat thuoc nhom Sulpiride- profene Cac chat khang viem nhom ibuprofene- reline Cac Peptides kch thch phong thch hormones tuyen yen- sulfa Cac Sulfamides- terol Cac chat dan phe quan t phenethylamine- tidine Cac chat oi khang recepteur H 2- trexate Cac chat oi khang acide folique

- verine Cac chat chong co that nhu papaverine- vin Cac alcaloides Vinca

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Nguyen tac ke toa thuoc : Toa thuoc c xem nh c lieu phap y Ch viet tren toa, phai

chan phng de oc, ro rang khong gay nham lan cho ngi thc hien.

Khong c ke toa bang but ch, de tay xoa. Noi dung ke toa phai hp ly,chnh xac va gay gon. Moi toa thuoc c cho, gom 6 muc theo th t sau :

Ho ten, hoc v, chc danh a ch cua ngi ke toa, nhat la chky va ngay thang nam ke toa, o la nhng c lieu quan trong eco c s truy cu ve sau.

Ho ten, tuoi, phai tnh cua benh nhan. Nham xac nh nhngthuoc c ke cho benh nhan nay ch khong phai benh nhankhac.

Ten thuoc : Co the dung ten thuoc thong thng, hay ten bietdc va khong c viet tac cac ten thuoc. Neu trong 1 toa kenhieu loai thuoc, thuoc tien ghi trc, cac thuoc ho tr ghi tieptheo, co the ghi ham lng cung hang vi ten thuoc.

Lieu lng : Ghi ro lieu lng va so lan cho thuoc (uong, tiem,dung tai cho) trong moi ngay. Tong so ngay ieu tr va tong sothuoc c yeu cau

Cach dung :o ng mieng : nuot, nhai nhuyen.?o ng tiem : Tiem bap, tiem tnh mach?o Thuoc ac vao hau mon, am ao?o Khoang cach lan cho thuoc trong ngay ?o Uong luc bung trong hay sau khi an ?o Co lac chai trc khi uong ?

Tai cap : Toa thuoc sau khi dung xong, con c tai cap ? oi vi nhng thuoc co oc tnh (A,B)

Thuoc oc bang A : Tat ca viet bang ch cac ham lng, lieulng. Trng hp do yeu cau bat buoc cho thuoc qua lieu, thaythuoc ghi cau toi cho lieu nay va ky ten chu trach nhiem

Toa thuoc co thuoc oc bang A va B c dung < 10 ngay, lieulng thuoc ghi bang ch va thuoc ngu ch c dung toi a 3ngay

1.3. DC ONG HOC (PHARMACOKINETICS):La mot phan cua dc ly hoc, nham nghien cu qua trnh hap thu,

phan phoi, chuyen hoa va thai tr cua thuoc.

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Dc ong hoc c ban : Nham xac nh nhng tham so dc ongtren vat th nghiem va tren ngi khoe manh.

Dc ong hoc lam sang : Nghien cu ve s bien oi dc ong trenbenh nhan va tren cac phe ieu tr phoi hp, e xac nh lieu cho

(Posologie) thch hp.- Nhng thong so dc ong o lng c t xac nh nong o thuoc

(hoac chuyen hoa cua chung) huyet tng, hoac nc tieu, sau khi chothuoc vao c the bang cac con ng khac nhau

1.4. DC LC HOC (PHARMACODYNAMICS)La mot phan cua dc ly hoc, nham nghien cu nhng hieu ng sinh

hoa-sinh ly cua thuoc tren hng c quan, nhng he thong (quan sat s bienoi ve hnh thai va sinh ly, sinh hoa) cua c the.

- Co gang chng minh c che tac dung cua thuoc

II. C CHE TAC ONG CUA THUOC :2.1.CAC CACH TAC ONG CUA THUOC :Tac ong vat ly hoa hoc :- Thuoc khang toan, lam tang pH dch v (pH bnh thng da day :

(1,2 3,5)) bao ve niem mac da day.- Thuoc hap phu (adsorbants), nh than hoat, hut cac oc to, thuoc.

- Resine trao oi Ion nh cho Lestyramine (Questran), trao oi Ion vicac acides beo, nh o c che s hap thu cholesterol.Tac ong tren Enzymes chuyen hoa :- Aspirine hoac cac chat khang viem khong steroides, c che men

Cyclo oxygenase- Cac chat c che men MAO (Inhibiteur de la Mono oxydase)- Theophylline c che men Phosphodiesterase, duy tr AMP vong.Tac ong len s chuyen van (Transport) :

- Digitaline ngan chan Na-K / ATPase cua mang te bao.- (Ca ) noi bao tang gay tang co bop c tim++

- Thuoc li tieu nhom Thiazides, c che trao oi Na / K ong lnxa.

+ +

- Nhng thuoc phong toa kenh Calcium, ngan chan Ca tham vao ctim va thanh ong mach, nen lam giam co bop c tim.

++

Tac ong len s tong hp ai phan t : Proteine, AND, ARN- Sulfamides, gay bien oi s tong hp ARN cua vi trung.

- Aminosides, c che s tong hp proteine cua vi trungTac ong len cac v tr thu the chuyen biet R (Receptor)

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- a so cac thuoc, noi ket vao R t nhien trong c the (von la cho noiket cuaq cac chat noi sinh, e am bao cac chc nang bnh thng vamot so tnh trang bnh ly)

Hnh 1: thu the chuyen biet S noi ket nay, se dan ti nhng phan ng tng t nh nhng chat noisinh. Ve mat nay, ngi ta quan niem thuoc la chat ong van (agoniste)cua R. Va ngc lai, neu no ngan chan tac ong cua chat noi sinh, ngi tagoi thuoc o la chat oi van (antagoniste) cua R.

2.2. CHAT NOI KET (LIGANDS) Chat noi la tat ca nhng chat co the noi ket vao R. Nh the chat noi

gom co : Chat noi sinh va nhng chat ong van hoac oi van vi chat noisinh cua R.- Nhng chat noi sinh : La nhng chat t nhien c tao ra trong c

the, nh chat trung gian than kinh (neuromediateurs), co nhieu tac dungtren cac c va cac tuyen : Nor-adrenaline, Acetyl choline nh cac kchthch to (hormones), c phong thch vao mau, tac ong len mo ch vanh cac autacoides noi sinh, chung tac ong va nh chat trung gian trongqua trnh benh ly, gay d ng, gay viem, au, sot: histamine, serotonine,prostaglandines, PAF (Platelet-Activating-Factor), Angiotensine,Neuropeptides

- Nhng chat ong van, oi van cua R : la nhng chat noi nhan tao.Cau truc lap the cua cac chat noi rat quan trong, chnh ieu o tao ra cacchat ong phan lap the, co hieu ng chnh, hieu ng ngoai y muon, octnh rat khac biet nhau.

Gan ket gia chat noi va R :Chat noi co the gan ket vi R mot cach thuan nghch va khong thuan

nghch.

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- Gan ket thuan nghch (Liasion resersible) :La loai gan ket khong benvng, phan ng xay ra thuan nghch hai chieu : D + R DR. ay D vaR noi ket vi nhau bang nhieu ng noi khac nhau

- Noi ion : Hai phan t cha hai loai ion mang ien tch trai dau (anion,

cation) chung se hut nhau. Phan ng nay phu thuoc vao o phan ly (P )cua phc hp DR cua moi trng (v pH anh hng en o phan ly P cuaphc hp DR)

K

K

- Noi hydrogen : Protone H nhan ien t t nguyen t cho khac, taothanh cau noi dai 3A O (g = 2 5 Kcal/mol)

+

- Noi Van der Waals : Trong hay gia phan t cua D va R co s tngtac gia hai cc tch ien trai dau, gia vung ien dng va ien am (g < 1Kcal/mol).

- Tng tac k nc (interation hydrophobe) : la tng tac gia phankhong phan cc cua cac phan t (g = 1 Kcal/mol).

Mc o va thi gian e gan ket D va R, phu thuoc vao tnh chat vakieu noi thuan nghch tng ng

- Gan ket khong thuan nghch (Liason irreversible): La kieu noi benchat, phan ng ch xay ra mot chieu : D + R DR. D va R la hai phan tdung chung cap ien t vi ng noi cong hoa tr, phong thch, thu vao,mot nang lng ang ke (g = 100 Kcal/mol), nen hieu ng cua D keo dai.

V du : Hp chat phosphore hu c gan ket khong thuan nghch vi mencholinesterase.

2.3. RECEPTOR R- Ban chat cua R : R la cau truc khong gian 3 chieu cua ai phan t,

khi chat noi gan vao se cho nhng ap ng sinh ly, sinh hoa chuyen biet.Ban chat cua R la Proteine : Glycoproteine, acide desoxyribonuclei-que(AND) va polysaccharides

Nh o, R co kha nang nhan dien va gan ket cac thuoc hoac chat noi

sinh thch hp vi no V tr, phan bo phan loai cac R:- R co nhieu nhat mang te bao Receptor ACTH, receptor cac

catecholamines, co trong bao tng (kch thch to tuyen giap) va co trongnhan te bao (receptor cua actinomycine, cua kch thch to tuyen giap).

- Cung mot loai R co the phan bo : cung mot loai mo phan bo nhieuni nh c trn. V du : receptor Muscarinic M khi b kch thch se apng duy nhat : co c trn phe quan va c trn tieu hoa. nhieu loai mo

khac nhau. V du : R-

3

1 cua nor-adrenaline, gay ap ng tren c tim (tang

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nhp va tang co bop), tren tieu ong mach (co mach) va tren mo m (tieum).

- Cung mot chat noi, co the co nhieu loai receptor va cho nhau loaihieu ng khac nhau. V du : nor-adrenaline t nhat co hai loai receptor

va .- Nh kham pha ra cac chat ong van, oi van, ngi ta phan loai

c cac receptor khac nhau cua cung mot chat noi. V du : mot chat noisinh histamine cho nhieu ap ng tren c trn kh quan, ruot, t cung vatren niem mac da day.

- Cromoglycate la chat c che chuyen biet tac ong histamine tren khquan. Cimetidine c che chuyen biet tac ong cua histamin tren tang tietdch da day. Nh o ngi ta hieu c rang histamine co t nhat hai loai

receptor H 1 va H . Cromoglycate la chat oi van H1 con Cimetidine lachat oi van H .

2

2

Hnh 2: Thu the alpha va beta

2.4. CHAT ONG VAN CHAT OI VAN:CHAT ONG VAN

Chat ong van la chat va co ai tnh (affinite) va co hoat tnh(activete) cua mot receptor. Khi tat ca cac receptor eu gan ket vi chatong van (tat ca eu c hoat hoa) se cho mot hieu ng toi a E max (Effet

maximal).Hnh 3: chat ong van tren thu the chuyen biet cung kch hoat protein

Gq.

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Vi 4 chat oi van A, B, C, D, do hoat tnh noi tai (activite

intrinseque) cua chung khac nhau, nen ng bieu hien hieu ng theo Lognong o cung nh cho ap ng E cua chung cung khac nhaumax

= 1 oi vi AB = 0,5 oi vi C = 0,4 oi vi D

V A va B at hieu ng toi a E max = 100%. Nong o C at 50% E .Nong o D at 40% E

max

max

Hoat tnh noi tai () cua mot chat ong van bang t so cua hieu ngtoi a ma no at c, tren hieu ng toi a cua mot chat ong van khac Ai tnh cua chat ong van D nghch ao cua hang so phan ly (Ka)

phc hp DR, hoac bang hang so phc hp DR : D + R DR tai iemcan bang nong o DR.

Theo nh luat tac ong khoi lng (action de mass)[ ] [ ][ ]DR

RD . = K a

[ ]D Nong o chat ong van t do[ ]R Nong o R t doKa : Hang so phan ly cua phc hp DR

Nghch ao cua Ka = hang so phc hp DR (ai tnh cua D), c dienta bang pD.

LogKa

1 = Log Ka = pD

Tnh gia tr cua ai tnh trong thc te la xac nh nong o chat ong van(D) sao cho u e tao ra hieu ng bang 21 E va thi iem o, so R t

do bang so R a gan ket vi D. Hay

max

[ ]D = [ ]DR . Trong bieu thc 1 co theviet:Ka = [ ] [ ]

[ ]DRRD . = [ ][ ]

[ ]DRDRD . = D

c biet [ ]D = Ka pD = - Log Ka = - Log [ ]D PD Ai tnh : la am logarithme nong o phan t cua mot chat ong van,

cho mot ap ng bang 50% ap ng toi a co the co c. Chat ong van toan phan va tng phan :

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

- Co hoat tnh noi tai thap hn A va B (( = 0,5), nhng ai tnh cua Ccao hn cua B (-Log D > -Log D ) ta goi C la mot chat ong van tngphan.

50

C

50

B

Hnh 4: Cac mc o hieu qua do chat ong van tac ong len thuthe.

CHAT OI VANHnh 5 ng bieu dien hoat tnh cua thuoc; chat ong van va chat oi

van.

- Chat oi van canh tranhB gan ket thuan nghch vi R, ay ng bieu dien cua chat ong van

A sang phai, ta goi o la chat oi van canh tranh.Giam ai tnh cua chat ong vanBao ton hoat tnh noi tai cua chat ong vanPhai tang lieu chat ong van mi at c hieu qua toi a- Chat oi van khong canh tranh:

C gan ket khong thuan nghch vi R.Chat oi van khong canh tranh:Bao ton hoat tinh cua chat ong van AGiam hoat tnh noi tai cua chat ong van ADu co tang lieu cho A, cung khong canh tranh noi vi C.Khong phuc hoi c hieu qua toi a.

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2.5. S IEU HOA RECEPTOR:- Trong thc nghiem, neu kch thch nhieu lan R, bang mot chat ong

van vi tan so ln hoac lieu cao, ta se thay s ap ng dc ly se giam bthoac mat dan. Neu s kien xay ra mot cach nhanh chong, ta goi o la s

giam mien nhanh .(Tachyphylaxis), neu xay ra t t cham rai, ta goi la sdung nhan (Tolerance) ma khong nen goi la giam nhay cam mac phai(Hyposensibilite acquise), hay mat nhay cam (desensibilite) nh trong dng. S giam ap ng nay c phat hien trong thc nghiem bang nhngchat ong van cua Receptor kh phe quan, hoac serotonine tren hoitrang co lap

- o la do so R di chuyen t mang te bao qua hien tng nhap bao (+)R c ieu chnh xuong thap (down regulation); Do thay oi hoa tr cua

R, hoac do cac R b tieu huy nh trong benh nhao c, tieu ng, khanginsuline. Hien tng o, giup ta hieu c dung nhan thng xay ra vaphat trien tang lieu nhng chat gay nghien.

- So R cung tang hay giam trong tnh trang sinh ly hoac benh ly nh bhoan (castration), R cua androgene se b giam. Ngc lai trong thi ongduc, R progesterone tang va R oestrogene giam.

- S gia tang tong hp cac R, hoac s dung dai han cac chat oi van,co the lam tang tnh nhay cam, tang tnh hoat ong cua chat ong van oi

vi cac R cua no, gay ra hieu ng doi ngc, hoac giam ngng kch thchR cua ca chat kch thch ong van. V du s dung propranolol dai han, neungng thuoc ot ngot, se b hien tng doi ngc lam cho huyet ap tangvot, vt mc bnh thng.

- ac biet, s tong hp cac R d thng co the do gene sinh ung bu(oncogeneux) hoac do cac hormones cua c the, dan ti s bien oi cac tebao thng thanh te bao ac tnh

III. S HAP THU THUOC TRONG C THE : So phan cua thuoc trong c the trai qua 4 giai oan noi tiep sau ay :- Hap thu : - T ni tiep xuc vi c the, thuoc vao tuan hoan (tr tiem

thang vao mach mau).- Phan phoi : T mau, thuoc en cac mo.- Chuyen hoa : Thuoc bien oi sinh hoc chu yeu tai gan.- Thai tr : Thuoc bai thai ra ngoai c the chu yeu qua gan va than.

Hnh 6 :S o bieu dien s hap thu chuyen hoa va thai tr thuoc cua hethong song.

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3.1. O KHA DUNG SINH HOC CUA THUOC:(BIO-AVAILABILITY)

- Trc khi c hap thu, mot t le hoat chat c phong thch ri khoidc pham D (hoat chat X va ta dc E) e cho hieu ng. o kha dungsinh hoc la t so gia lng thuoc cho vao va lng thuoc thc te co mattrong tuan hoan

- o kha dung sinh hoc, phan anh t suat (%) cua lng thuoc cho qua

ng uong va lng thuoc thc te co mat trong tuan hoan sau khi qua ruotva gan. T suat o c tnh bang AUC

- AUC (Area under concentration time-curve)- AUC la dien tch di ng bieu dien nong o cua thuoc trong mau

theo thi gian.

- o kha dung sinh hoc ky hieu bang F. Thuoc tiem trc tiep vaotnh mach co o kha dung sinh hoc 100%. F = 1. Neu s dung thuoc quang uong, v du propranolol uong, o kha dung sinh hoc ch at 30%, F =0,3 v phai qua chuyen hoa thuoc bc au ruot va gan.

- CHUYEN HOA BC AU (First pass metabolism)Trc khi thuoc uong c hap thu, thuoc phai qua chuyen hoa trc

tuan hoan (Presystemic metabolism), ruot gan, nen lng thuoc thc teco mat trong tuan hoan thng giam so vi lieu thuoc uong ban au.

3.2. S CHUYEN VAN CUA THUOC :

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T ni tiep xuc vi c the, thuoc phai vt qua nhieu vat can e vao

mau. o la mang te bao mot lp (te bao thng b ruot) va nhieu lp (tebao thng b da). Co nhieu c che xuyen mac khac nhau:

Khuyech tan thu ong : pho thong nhat oi vi thuoc.Khuyech tan gian d (can cha tai)Chuyen ch thu ong. (can chat tai)LocAm bao va xuat bao.

Hnh 8 hien tng nhap bao (endocytosis-am bao)Mang te bao va mang sinh vat

Ben ngoai cua tat ca cac loai te bao, eu co mang bao boc xungquanh, c goi la mang te bao (cell membrane), v chat cha ng bentrong la bao tng (cytoplasma), nen con c goi la mang bao tng(Plasma membrane, plasmalemma). Mang te bao, khong ch la mang loc,

la ranh gii gia cac te bao ma con la ni trao oi chat (vat chat, chat dinhdng), la dien tiep xuc vi tn hieu hoan canh ben ngoai.Khai niem mang te bao noi tren c m rong va hieu sau hn o la

mang sinh hoc. No bao gom ca cac mang trong noi bao : Mang hat, mangmen, mang he noi vong, nhat la mang ti the.

Mang bao tng co tnh ban tham, day o 7,5 mm (7,5 A ), laa motcau truc kham gom tap hp nhng phan t, sap xep thanh 3 lp, 2 lplipide va 1 lp protein xen gia

O

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- Hai lp lipide cha nhieu phospholipde, mot au la phosphate hu ca nc, hng ra ngoai hai ben mang, con au k nc hng vao bentrong.

- Mot lp proteine gom 5 loai phan t, co phan hu cc a nc hng

ra mat ngoai mang, phan vo cc k nc nam trong mang. Nhng proteinecua mang co the la:

Bm (pump) : e ay cac ion qua mang ( Na va Ca ) ngckhuynh o nong o, can nang lng.

+ ++

Kenh (channels) : e cho cac ion vao mang ( Na va Ca ) theokhuyng o nong o va khong can nang lng.

+ ++

Enzymes cua mang.Proteine cau truc cua mangReceptor cua chat noi sinh va thuoc

Nhng c che chuyen van thuoc qua mang Khuech tan thu ong (diffusion passive) Nhng chat khong ien ly, nhng chat kem ien ly va nhng chat

khong ion hoa, chuyen van qua mang bang c che khuech tan thu ong,tc theo chieu khuynh o nong o (nh luat Fick)

)(..12 CCe

SKD

dt

dQ=

dt

dQ = Toc o khuech tan cua thuoc D

D = He so khech tan cua thuoc DK1 = He so phan ly cua thuoc D (Lipid/

nc)S = Dien tch cua mangE = Be day cua mang

C > C 1 2

Mng

DD

Mang te bao cha nhieu lipide. Thuoc khuech tan qua mang rat phuthuoc vao tnh hoa tan trong lipide cua no va he so phan ly lipide/ nc.

Tnh hoa tan trong lipide cua thuoc phu thuoc vao o ion hoa cua D,ma o ion hoa cua D lai phu thuoc vao pH cua moi trng va hang so phanly cua D.

Cac chat khong ien ly : khong ion hoa trong moi trng, de tantrong lipide, thuoc khuech tan t le vi khuyng o nong o va o tan tronglipide.

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Cac chat ien ly manh (ion hoa moi pH) : Chat muoi cua cac acidemanh va base manh rat tan trong nc, rat kho xuyen mang (CaCl 2 ,MgSO , NH , Neomycine SO , Streptomycine SO )4 +4 4 4

Cac chat ien ly yeu : La cac acide va base hu c t nhieu ion hoatrong moi trng: phan ion hoa [ ]Ci se tan trong nc, phan khong ion hoa

se tan trong lipide. T le ion hoa theo pH cua moi trng va theo hangso phan ly cua acide hay base yeu. Phng trnh Henderson Hasselbalchxac nh:

[Cni]

- oi vi acide yeu :

AH A + H [ ][ ][ ] A

KAH

HA=

++ .

Ci = A = Nong o phan ion hoaC = = Nong o phan khong ion hoani [AH]K = Hang so phan ly cua acide yeuAKhi [ ] [ ] ApKAHA = = pHpK =A +

Ci

CnipH log

Ngha la, khi acide yeu t ion hoa trong moi trng pH acides se chap thu nhieu hn.

- oi vi base yeu :

BH [ ][ ][ ] B

KBH

HBHB =+

+++

+=Cin

CipHpKB log

Ngha la, khi cac base yeu t ion hoa trong moi trng pH base se chap thu nhieu hn.

Anh hng cua he so phan ly lipide/ nc (K 1 trong cong thc Fick).

Do hang so phan ly (K hay K ) co nh, yeu to K khong oi, nen

o tan trong lipide tr nen quan trong. Neu K 1 bang vo nh thuoc tan hoantrong lipide, se khong vao c pha nc trong c the, th khong c hapthu (Vaseline). Ngc lai, thuoc (cac phan t cua D) hoan toan tan hettrong nc, cung se nh vay.

A B A

Cho nen gia tnh tan trong lipide va tnh tan trong nc phai c canbang.

Mot thuoc tot phai la thuoc va hoa tan c trong lipide va tan ctrong nc.

Khuech tan gian d (diffusion facilitee)

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S xuyen mang te bao cua thuoc qua trung gian cua chat tai theokhuynh o nong o ma khong can en nang lng.

V du : S hap thu Ca ta trang, s xuyen vao au tan cung sicholineergic cua choline, cung nh s hap thu tetracyclines, pralidoxime,

hexamethonium.

+2

Chuyen ch thu ong (transport actif)Mot chat khong tan trong te bao, nhng co the xuyen mang vao trong

te bao, nh tao thanh phc chat tam thi vi mot phan t dung lam chattai (transporteur). S chuyen ch chu ong nay can nang lng (t ATPc thuy phan do ATPase) va ngc chieu vi khuynh o nong o.

- Chuyen ch chu ong co 5 ac tnh :

I

X(C1)

MANG TE BAO

XP XPP

II

X(C2)

C2 > C1

- Tnh bao hoa (so chat tai co nh).- Tnh chuyen biet (theo cau truc hoa hoc).

- Tnh co the b c che (neu thuoc va chat tai gan ket khong thuannghch).

- Tnh co the b giam chat tai (neu co hai loai phan t cung canh tranhmot chat tai)

- Co gia tr oi vi cac phan t sinh ly hoac thuoc can (Penicilline,acide amines, Vitamines K, Na , glucose), va nhng cau truc hoa hoctng t (base hu c Purine va Pyrimidine).

+

Loc : La phng thc xuyen mang cua nhng phan t tan trong nc

qua lo cua mang te bao (khong co he than kinh trung ng). Nh vay kchthc cua cac phan t xuyen mang nay phai nho ( 1000 (a so la polipeptides)tham nhap vao noi bao bang cach nay

Xuat bao (Exocytose) : la hien tng te bao phong thch ra ngoai

nhng chat noi sinh tch luy trong boc (Acetylcholine, Catecholamines).3.3. HAP THU T NG RUOT (VOIE ENTERALE)

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DA DAYpH cua da day vao khoang 1-3,5Nhng chat tan trong lipide, se c khuech tan thu ong qua niem

mac da day.Nhng chat ien ly manh (rat phan ly), thc te khong c hap thu.Nhng chat ien ly yeu : acide yeu : c hap thu tot tren ly thuyet.

V du :Aspirine (pK

Ci

CnipHpKAA log)3 +==

CCi

CniCini log13100 +==

Base quinin (pK = 8,4) ( pH = 1,4 rat t c hap

thu

B = CiCni

710

Nhng chat ien ly rat yeu : Hau nh khong ion hoa, du pH cua moitrng ra sao (cafeine, barbiturates). Le ra nhng chat nay, c hap thunhieu hn, nhng do s khong tan trong nc cua dang ion hoa, nen se cophan nho khong c khuech tan co the gay nen phan ng phu (Digoxinetren ng tieu hoa).

Nhng yeu to anh hng en mc o hap thu :- Da day trong, (1- 1/2 gi trc khi an hoac 2 gi sau o) se hap thu

tot hn v khong b thc an can tr.- Thc an la chat beo, tat nhien de dang hap thu nhng thuoc tan trong

lipide. (griseofulvine, vitamine K ). Khoi lng thc an cung lam chams hap thu thuoc, v se phai keo dai thi gian ay thc an xuong ruot.

- Nhng chat co kch ng da day, cung nh nhng thuoc gay danmach, co the lam cham hoac lam tang s hap thu.

- Kiem hoa cac chat trong da day, se lam giam hap thu cac chat toanyeu (aspirine), nhng lai lam tang hap thu cac chat kiem yeu. Nhng noichung, do han hep cua niem mac da day, nen mc o hap thu da day cohan che.

RUOT Nhng ac tnh cua ruot- S phan phoi day ac cac mach mau cung nh dien tch mao mach

ruot rat rong, nen se hap thu thuoc tot hn da day.- pH long ruot cao hn (pH 6 7), nhng pH mao mach hi

acide (pH = 5,3-5,5), nhng acide co pK > 3 va nhng base co pK < 7,8c hap thu tot ruot non.

a B

S hap thu thay oi tng oan ruot.

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- Ta trang (doudenum) : Ca , Fe.+2

- hong trang (jejunum) : lipide (de hap thu bi muoi mat tao thanhdang micelles, xuyen qua bieu mo bang c the am bao).

- Hoi trang (Ileon) : Hap thu thu ong Ca , vitamine B12 (nh yeu to

noi tai)

+2

- Ket trang (colon) : Thc te khong hap thu, tr H O va Na (chuyench chu ong) Ca , Cl va K (khuech tan thu ong).

2

+

+2 +

Nhng c che hap thu ruot- Khuech tan thu ong : cac chat tan trong lipide, nh vitamine tan

trong dau, (A, D, E, K) va cac ion Ca , Cl va K ( hong trang).+2 +

- Chuyen ch chu ong : a so cac glucides, acide amine, vitamineB1, H O, Na , Ca ta trang2 + +2

Nhng nhan to anh hng en hap thu.- Mot so chat can tr s hap thu (Ca va tetracylines tao nen phc

hp kho hap thu)

+2

- Cung co mot so chat tao de dang cho ruot hap thu cac chat khac(Vitamine B gan ket vi yeu to noi tai cua da day, nen hap thu Ca da day > hong trang).

12

+2

- Vitamine D giup c the hap thu Calcium tot hn. Nhng thuoc luon luon c hap thu : Sulfamides, digitoxine,

aspirine, benzodiazepine. Nhng thuoc luc nao cung t c hap thu : Aminosides.

(Streptomycine, Neomycine, Kanamycine) va cac muoiNH (Neostigmine)4

Nhng thuoc c hap thu mot phan roi thay oi : CacPenicilline, mot so glucoside, digitaques.

Li va bat li cua cach cho thuoc qua ng uong

Li iem :

- Cach cho thuoc qua ng uong, (per os) se cho thuoc vao ngtieu hoa mot cach chac chan, vi ieu kien thuoc c tieu hoa thc s.

- De ap dung va de c benh nhan chap nhan chap nhan.- Kinh te nhat- t nguy hiem nhat, neu l co qua lieu, co the lay ra bang cach cho oi

hoac suc ra da day.Bat li:- Khong thch hp cho nhng thuoc co mui v kho chu, nhng thuoc

kch ng hay de bi phan huy bi dch v (polypeptides insuline), hoac

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nhng thuc khong ben vng trong moi trng pH acide cua da day(penicilline G)

- Kho x dung cho tre em, v cac chau khong chu nuot- Khong dung cho benh nhan hon me.Mc o hap thu khong ong eu v :- Toc o tang khi da day rong- Nhu ong ruot- Tuan hoan mau trong ong tieu hoa thay oi, khi lo lang.- Khong tiet dch do benh ly (Mat)- ac tnh cua ta dc, toc o tan, thi gian phan ra (Desintegration)Cac dang bao che cua thuoc qua ng uong- Dang ac : Thuoc phai c phong thch va hoa tan trong ong tieu

hoa di nhng hnh thc thuoc goi (Cachet), vien nang (gelule), viennhong (capsules), vien tron (pilule), hat nho (granule), vien nen(comprime), vien boc ng (dragee).

- Lp ao boc vien thuoc, c ieu chnh sau cho en c ni canmi tan ra. Ta dc phai thch hp cho bao hanh, giup de hap thu, giambt kch ng niem mac da day va ruot non.

- Dang long : Hoat chat c hoa tan hay treo l lng trong dung moi :sirop, potion, dung dch treo (suspension), nhu tng (emulsion) hay dung

dch trong ru (ru thuoc quinquina)- Dang co tac dung dai : e tranh phien phc phai dung thuoc nhieu

lan trong ngay, mot so thuoc c :- Bao che di dang vien nen hay boc ng, co nhieu lp theo o,

hoat tnh c phong ra dan dan. Can lu y dang nay, neu c hap thuqua nhanh se co nguy c trung oc. Neu c hap thu qua cham se khongat hieu qua. Ngoai ra con co nhng khac biet ca nhan ve o lam trong daday, co khi benh nhan uong thuoc, c tong ra nguyen trang.

- Thuoc c nghien cu mc o phan t, e at c tnh thai trcham nh doxycycline, flagentil.3.4. HAP THU THUOC THEO NG NGOAI RUOT VA TIEM

CHCHTiem di da (Voie sous cutanee SC)

- Nhng thuoc khuech tan trong chat nen c ban, tham c vao noimac cua mach mau va mach bach huyet (loc qua khe h gia cac te baonoi mac; s hoa nhap, khuech tan) c dung e tiem di da. Trong

trng hp b choang, tuan hoan ngoai vi suy giam, tiem di da se khongco hieu qua. Neu kem theo mot chat co mach vao dung dch tiem di da

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(thuoc gay te loai tiem), hoac mot dung dch treo dung e tiem chch nh.Hon hp insuline + protamine + zine th hap thu thuoc se cham lai.

- Ni tiem chch di da thng mat sau canh tay hay mat ngoai ui.Tiem bap (Voi intramusculaire)

C bap co nhieu mach mau va co rat t si than kinh cam giac, nen toco hap thu thuoc nhanh hn va t au hn tiem di da.

- Sau khi tiem bap, ch can 10-30 phut, cac phan t nho cua thuoc cothe xuyen thang vao mao mach, con cac phan t ln se chui qua cac machhach huyet i vao mau.

- Do tiem bap y au hn tiem di da (tr tiem penicilline, quinine)nen tranh tiem nhng chat lang ong (depot), cung nh nhng chat gayhoai t (nh dung dch mang tnh kiem) vao bap tht.

- Ni tiem bap , thng vung mong, 1/3 ngoai t gai chau trctren en au lan mong. Tranh chch trung than kinh toa (sciaiique)

- am bao vo trung va khong c tiem trung mach mau (keo pistonong tiem len coi co mau hay khong?)

Tiem tnh mach (Voie intraveineuse)Tiem thang vao tnh mach, thuoc trc tiep vao tuan hoan, nen van e

hap thu t at ra ayLi iem:

- Hieu ng tc th, dung trong trng hp khan cap.- Hieu ng co the kiem soat c, neu thay co phan ng xau, co the

ngng tiem ngay. Mat khac, bang cach tiem truyen nho giot tnh mach(perfusion) cham va lien tuc, e duy tr nong o hu hieu cua thuoc trongmau mot cach lau dai.

- Apo dung cho nhng chat thuoc gay kch ng, hoai t cac mo, gayau, neu tiem di da hay tiem bap (mot so thuoc khang sinh v..v)

Bat li :

- Nguy hiem, tiem tnh mach, thuoc en thang tim va cac trung khuthan kinh, nhanh chong kch ng hoac c che cac ni o. ieu o can heen toc o tiem va nong o cua thuoc.

- Phan ng phan ve xay ra nang ne hn neu tiem vao ng tnh mach- Co kha nang gay sot, do dung dch tiem co sinh nhiet to nguon goc vi

trung- Nhieu kha nang gay nhiem (AID, viem gan)Ni tiem : Tnh mach nep khuyu tay: tnh mach hien ngoai (tiem

truyen lau)Nhng qui nh tiem tnh mach :

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- at kim nam gia long tnh mach, du vay thuoc van co the kch ngmo mach mau, nh thiopental.

- Khong c tiem vao ong mach, thay v tiem tnh mach (nguy choai t)

- Tiem rat cham, nh rang thi gian tiem tren mot phut, la thi giancan cho mot chu ky cua tuan hoan mau. Cho du ngng tiem tnh machkhuyu tay, thuoc van tiep tuc en nao trong 10 15 giay tiep theo.

Nhng ng ngoai ruot khac- Tiem ong mach (Intra arterielle IA): Rat t x dung, neu can trong

cac trng hp sau.- Cac chat gian mach, tiem vao ong mach ui benh nhan viem

ong mach

- Chat can quang X vao ong mach chu, ong mach canh.- Hoa tr cho benh nhan ung th (K)- Tiem trong tim (Intra cardiaque) : Cho cac trng hp tuyet vong

(adrenaline)- Tiem vao cot song (Intra archidienne IR) : Tuan hoan nao tuy rat

yeu, cac dch c tiem vao o, khuech tan rat cham. Tiem thuoc gay tevao cot song, nham gii hai vung te chi di va vung ho chau

- Di mang nhen (sous arachnoidien, SA) con c goi la tiem trong

ong tuy (intra thecal).- Ngoai mang cng (epidural).- Ngoai thuoc te ra, co the tiem glucocorticoides vao dch nao tuy,

nhng phai tranh dung nhng dung dch kiem hoac acid v chung co thegay thng ton nao vnh vien.

- Nhng thuoc co oc tnh cho mo than kinh, ch c tiem trongnhng trng hp vo vong (penicilline, streptomycine).

Li va hai cua cac thuoc tiem chch

Li iem :- Cho phep ieu tr nhng thuoc khong hap thu hoac de b huy, de kchng, neu cho qua ng tieu hoa

- am bao tac ong nhanh, hau nh tc th (IV).Bat li :- Gay kch ng tai cho (apxe, viem tac tnh mach, tiem cham vao day

than kinh).- Nguy hiem do phan ng toan than ( nhat la khi tiem IV).

- Khong the rut thuoc ra khoi c the neu x dung qua lieu.- Chuan b dung cu vo trung tuyet oi.

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- Gia thuoc tiem at hn thuoc uong- Tiem IM va SC co the cho y ta thc hien, con cac cach tiem khac

phai do bac s lam.Nhng dang thuoc tiem:- Dung dch, trong o dung moi a so la nc cat cho nhng chat co

the hoa tan trong nc,- Dung moi la nhng chat hu c, cho cac chat khong trong nc

(alcoole, glycol).- Dung moi phai tng hp vi mau, khong kch ng mo di da hay

c, dung dch tiem the tch ln, cang ang trng vi huyet tng cang tot.- Ong tiem co the tch 1 5 ml- Chai thuy tinh hay chat deo (125 ml 1000 ml), kem theo day truyen

vo trung tuyet oi (IR, IV)3.5. HAP THU THUOC QUA TIEP XUC VI NIEM MAC.

Trc trang Li iem :- Khong bien oi thuoc bi cac enzyme tieu hoa.- Nong o cao ni tiep xuc, hap thu tot, tao hieu ng manh- Tre em b oi co the x dung c.- Ap dung cho nhng thuoc co mui v kho chu Bat li :- Khong ap dung c cho benh nhan b tieu chay.- Hap thu khong on nh oi vi thuoc khang sinh Dang thuoc : Thuoc an (Suppositoire). Nc thuc ra hau mon

(Lavement).Mieng, li

- Niem mac khong co lp sng, cac nhu li phan bo mach mau dayac, am bao s hap thu nhanh.

- Di li (voie perlinguale) : Thuoc trc tiep vao tuan hoan, khongqua gan nh thuoc uong, nen hieu ng nhanh.- Dang thuoc : Vien nen dung e ngam (glossettes, tablettes) tren li.

Dung dch nc hay alcool, nhu di li.Phe nang

Niem mac phe nang co dien tch rat ln (80 100 m ) , co he thongmach mau rat day, de hap thu cac chat:

2

- Hi (Vapeur) nh ether, chloroforme

- Kh (gaz) nh protoxyde dazote, halothane.

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- Kh dung (aerosol) : la nhng phu sng cua nhng hat co kch thcrat nho (0,3 3 m) nh cac kh dung cha chat adrenergiques.

- Khoi (thuoc la, can sa, thuoc phien, bui Nhng chat c hap thu trc tiep vao mau, co the tac ong tai cho,

hay toan than, khoi phai qua gan.3.6. HAP THU QUA TAC DUNG TAI CHO (VOIE LOCALE)

Nhng thuoc c x dung theo cach nay, nham ieu tr nhng benhtai cho.

Thuoc khong can vao mau, nhng oi khi van co the gay phan ngtoan than hoac phan ng khong mong muon, neu x dung tren dien kharong.

Da b- Nhng chat tan trong nc, khong hap thu c qua bieu b.- Nhng chat tan trong lipide, c hap thu qua nang long va tuyen ba,

nhn (v ch co mot lp te bao khong keratine hoa).- Moi chat hoa hoc tiep xuc vi da, eu co kha nang gay nhay cam

(Sensibilisant).- Nhng chat co the c da b hap thu nh alcaloides, base, steroique

(oestrogene, corticoides, vitamines tan trong dau)Dang thuoc : Pommades, cremes, dc lam bang hai loai ta dc:- Ta dc kem tham, nh m heo, lanoline, vaseline, danh cho ieu tr

tai cho.- Ta dc tham manh nh : stearate de glycol, polyoxyethylene glycol

(PEG) rat de tham va mau, can trong khi dung (cortisone).Niem mac

Mat- Thuoc te (dung e khao sat hoac e mo), thuoc chong nhiem trung,

chong viem, chong tang giam nhan ap (Glaucome), co the cho tiep xuc taimat, s hap thu thuoc qua lieu tai ay, cung co the gay tai bien (atropine,anti-cholinesterase khong thuan nghch).

- Dang thuoc : thuoc nc hoac crem, dung e nho , tra mat, pH va tadc phai nghien cu, kiem tra ky, sao cho khong kch ng mat.

Tiet nieu sinh duc : Thuoc thuc ra bong ai b chan thng(khang sinh, thuoc kh trung) cung co nguy c tham vao mau.

Thuoc at am ao (vien nen, noan dc nh polygynax )

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Mang phoi khp : Tiem thuoc vao mang phoi va khp (injectionintrapleurale & intra articulaire) can vo trung tuyet oi, nhat la tiemcorticoides vao khp.

IV. S PHAN PHOI THUOC VAO C THESau khi c hap thu vao mau, thuoc c phan phoi en cac mo. Qua

trnh phan phoi nay c chia ra lam hai giai oan : huyet tng va mo.4.1. Giai oan huyet tng :Pha nc chiem 58% the trong cua mot ngi ln bnh thng (tre em

77%, ngi gia < 58%). Pha nc gom nc cua huyet tng (40%), nccua dch ke (13%), nc cua te bao (41%). Nh pha nc ma thuoc nhanhchong hoa nhap vao mau va c a i khap ni (trong 1 phut thuoc atham c vao tuan hoan mau va pha loang ong eu trong toan bo the

tch mau).

Nc cua tebao

(41%)

Proteine cuahuyet tng(albumine)

Nc cuahuyet tng

4%

Nc cua dch ke(13%)

Protein cuamo

Te bao m(20%)

Trong mau thuoc di 2 dang : dang t do va dang gan ket viproteine trong huyet tng.

Nhng ac tnh cua noi gan ket- Thuoc co the gan ket vi mot hoac nhieu loai proteine trong huyet

tng nh albumine, 1 - globuline, - globuline va lipoproteine (phu).- Moi noi gia thuoc va proteine co tnh thuan nghch. Ngha la s noi

ket nay se phan ly, tra lai dang t do, khi nong o cua thuoc dang t dotrong mau giam.

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- Ty le gan ket tuy thuoc 2 thong so:Proteine/mau (nhat la albumine) : v du ty le gan ket se b giam trong

cac hoi chng than, x gan ( trong suy gan a en giam tong hpproteine).

ac tnh cua thuoc : t le gan ket se tang khi o hoa tan trong lipidecua thuoc tang (digitaline 90%, digoxine 25%) va khi ai tnh cua thuoctang th ty le gan ket cung tang.

Tom lc lai : Nhng phan t a lipide va nhng base yeu gan ket vi1 -globuline co tnh acide : thuoc giam au trung ng, thuoc chong co

giat, thuoc chong tram cam, thuoc phong toa (-bloquants),phenothiazine, digitalis, rifamycine co nh vi mot ai tnh yeu, tren nhieuv tr (sites) va khong bao hoa, se khong co s tng tac gia cac thuoc.

- Nhng thuoc la acide yeu thng gan ket vao albumine thuoc chongong mau loai uong, thuoc khang viem khong steroides, sulfamides,benzodiazepine, mot so penicilline, tetracycline, probenecide, acidenalidixique chung co ai tnh manh va co nh tren nhng v tr t hn, ieuo dan en bao hoa va co tng tac canh tranh gia cac thuoc.

- Noi ket thuan nghch nh nhng c che t nang lng, v du nh noitnh ien, noi ion, noi hydrogene, noi k nc (hydrophobie)(khong baogi co noi cong hoa tr).

Ket qua cua gan ket- Ch co dang thuoc t do la hoat ong, mot thuoc gan ket manh, tao

nen tac ong dc ly keo dai- Gan ket tao ra mot dang d tr, ung ra la mot dang thuoc co tac

dung cham (retard).- Khi au vec ieu tr, nhng lieu thuoc au tien b noi manh va vo

hoat, nhng lieu tiep theo (dose de charge) se cco li e bao hoa ni co

nh cua thuoc.

Thuoc trong mau

Dang gan ket Dang t do

R Hieu ng

Thuoc (dang t do) Enzymes Chuyen hoa

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Proteine tiep nhan Dang d tr

- Co hien tng canh tranh gia cac chat tren cung mot moi noi, ieu

o co the gay tai bien : thuoc chong ong mau loai uong (anti-vitamine K)dang gan ket 95%, dang t do 5%, neu b aspirine hoac phenylbutazonecanh tranh, du ch b thay the 5%, nhng se tang gap oi tac dung dc ly,gay nguy c xuat huyet. Sulfamide ha ng huyet cung b aspirine thaythe v tr gan ket, tao ra nguy c ha ng huyet, aspirine con thay the vtr gan ket cua methotrexate, lam tang oc tnh cua methotrexate.

- Cung tng t nh vay, cac chat noi sinh b Sulfamide khang sinhthay the v tr gan ket tren proteine huyet tng, phong thch bilirubine t

do, nen de gay vang da.- Dang gan ket vi proteine trong huyet tng rat a lipide lam tang

tnh hoa tan cua thuoc.Khi cac proteine trong huyet tng a bao hoa, th nong o cua thuoc

dang t do se tang len ot ngot.

4.2. GIAI OAN MO

La giai oan t mau thuoc c phan phoi vao cac mo khac, tr haimo ac biet : nao va nhau. S phan phoi nay tuy thuoc vao 3 yeu to :

Ti mau vao mo phan bo mach mau Mo c ti nhieu mau, thuoc se c phan phoi en nhieu hn.

Tuy mc o c ti mau, ngi ta chia cac mo c ti mau vao 3ngan.

- Ngan I : huyet tng- Ngan II : nhng c quan giau mach mau : tim, phoi, than, gan, nao,

tuyen noi tiet.- Ngan III : nhng c quan t mach mau : trung bnh nh da, c, t nhxng, rang, gan, day chang va rat t nh mo m (tnh a lipide quan tronghn o ti mau trong gan ket thuoc )

II I IIIC quan nhieu mau(tim, phoi, gan, than,

nao

Huyet tngC quan t mau

(te bao m, xng,

rang, gan, sun)HNH TRANG 42

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S tien trien theo thi gian cua nong o thuoc (C) trong cac ngan cua

c the : ay la he thong co 3 ngan I, II, III.

The tch phan phoi be mat vd(volume apparent de distribution)

The tch phan phoi be mat Vd, la mot the tch tng tng. Theo o,thuoc phan phoi e cung co mot nong o bang nong o thuoc co tronghuyet tng. The tich phan phoi be mat bang ty so gia tong lng thuocco trong c the va nong o thuoc trong huyet tng cung thi iem.

Vd = Q/C p

Q = Tong lng thuocC = Nong o thuoc trong huyet tng (L/Kg, mg/L)pSo lng Q trong c the ch c biet cung luc vi nong o C duy

nhat thi iem : cuoi luc ieu tr bang cach tiem tnh mach (IV) lieuln ( nhng thi iem khac nhau sau o, khong the tnh c, v khongthe tnh ra tong lng thuoc a c chuyen hoa va thai tr). The tch phanphoi cua mot so chat co the tng ng vi :

p

The tch cua huyet tng . Vd = 0,06 L/Kg (Heparine)Hoac the tch cua dch ngoai bao. Vd = 0,2 L/Kg (inuline,

mannitol).Hoac the tch nc tong cong cua c the . Vd = 0,6 L/Kg

(ethanol, phenazone, nc nang D O)2The tch phan phoi ln, co y ngha la thuoc co ai tnh manh oi vi mo

noi chung hoac co ai tnh manh oi vi mot so mo khac chuyen biet.

Ai tnh cua proteine mo oi vi thuoc moi mo, co s can bang ai tnh tng oi, gia proteine trong

huyet tng va proteine cua mo oi vi thuoc.V du : digitaline tuy co ty le gan ket cao vi proteine trong huyet

tng (90%), nhng van thch gan vi proteine mo c tim. Neu ai tnh cua thuoc oi vi proteine mo ai tnh cua thuoc oi vi

proteine huyet tng, th thuoc se c phan phoi nhanh cho mo. Trnghp ngc lai, s phan phoi thuoc se cham va thai tr ra ngoai.

Khi thuoc gan ket len proteine cua mo :

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Proteine ay co receptor cho hieu ng dc lyProteine ay ch la ni tiep nhan (acceptor) khong cho hieu ng

dc ly ma o co the la ni d tr.Proteine ay la enzymes cho d hoa thuoc

Mot so thuoc co tnh hng ti (Tropisme)ac biet oi vi mot so mo

Thuoc Hng ti cac moIode

Griseofulvine

Chloroquine

Curares

Tetracycline

Phenothiazine

Aminodarone

Arsenic

Tuyen giap

Mong tay, chan

Khp cua benh nhan Ni nghien cuve tacviem khp ong dclyTam ong than kinh c

Rang, sun, khp

Melamine cua mat da Ni nghien cuve tacDung phu

Than

Da, long

Hien tng tai phan phoi

Hien tng tai phan phoi thuoc rat bien oi : Thiopental phan phoi ratnhanh, con lu gi thuoc lai rat cham (Thesaurismose). Ty le gan ket vi

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proteine trong huyet tng cua thiopental (Nesdonal, Pentothal) la65%, dang ion hoa trong mau = 61%, nen thamvao mau, len nao, tac onggay me rat nhanh.. sau o thuoc c tai phan phoi vao c va mo m trongvong vai phut (trong 30 phut, nao mat 90% nong o Thiopental ban au)

hieu ng gay me se giam va mat han trong vong 30 phut. Luc nay, neutiep tuc tiem Thiopental, se dan en bao hoa nao va ngo oc, v khongthe tai hap thu c na.

4.3. THUOC KHUECH TAN QUA CAC HANG RAO NGAN CAN

ac biet, co mot so thuoc khong qua c cac hang rao can e dennao va nhau thai.

Hang rao mau nao bao gom :Cac mao quan, gom nhng te bao noi mac ghep kht ma thuoc

phai vt qua (tan trong lipide, khuech tan thu ong, hay chuyench chu ong).

Mang nenLp te bao hnh sao co nhieu khe h

Hang rao mau nao van co chuyen hoa thuoc : V du : te bao hnh saocha DOPA, men decarboxylase o chuyen DOPA thanh Dopamine.

am roi mang mach, cung co the thai tr thuoc (INH). Luc s sinh, hang rao mau nao cha hoan chnh, bilirubine t do xam

nhap vao nhan xam trung ng, gay vang da nhan (Icterenucleaire) Nhng yeu to quyet nh e cho thuoc qua hang rao mau nao :o hoa tan trong lipide +++ (v nao la mo giau lipide)Lng phan t nhoo ion hoa yeu trong huyet tngMoi noi long leo vi proteines

Hang rao mau nao khong tham cac thuocGan ket vi proteine IonsDang thuoc tan hoan toan trong nc

Hau qua thuoc tham vao nao :Nhng thuoc tham vao nao nhanh la thuoc de tan trong lipide :

Barbiturates, benzodiazepines, thiopental, methaqualone.Catecholamines b ion hoa pH huyet tng, khong qua c

hang rao mau nao. Nhng Dopamine, nor-adrenaline va GABA(Gamma-amino-butirique-acide) lai c tong hp ngay tai nao

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(tr acide amine : phenylalamine, acide glutamique do tham tmau vao).

Atropine (amine bac 3), qua c hang rao mau-nao, nen co thegay ao giac atropinique; trong luc o methyl-atropine co kha

nang ion hoa hn, th khong qua c hang rao mau-nao(Buscopan).

nhng tre sinh non hoac s sinh, do cau truc hang rao mau-nao cua cac chau cha hoan chnh, khi s dung nhng thuoc(ngay ca bilirubine na) co the qua hang rao mau-nao, gay vangda do tan huyet

Trong ieu tr viem mang nao, nen chon dung nhng loai khangsinh co the qua hang rao mau-nao (Sulfamides,

Chloramphenicol, Colimycine), ngay ca tiem vao tuy song (IR).Mot so tnh trang benh ly, lam cho hang rao mau-nao tr nen de

tham hn (viem mang nao, cao huyet ap nang, thieu mau naocuc bo, hon me kem theo nhiem toan acidose).

Penicilline G tiem bap (IM) qua hang rao mau- nao co the gayco giat ong kinh.

Aldomet qua c hang rao mau-nao, kch thch Receptor 2 trung ng gay lu lan (confusion)

Clonidine kch thch Receptor 2 trung ng gay ha huyet ap,nhng neu khong qua c hang rao mau nao, chonidine se lachat kch thch Receptor 2 ngoai bien, gay co mach tang huyetap

Nhng chat phong toa ( bloquants), qua c hang rao maunao, gay nen hien tng mong du (Onirisme)

Hang rao nhau thai

(barriere foeto-placentaire) Thuoc qua nhau thai, chu yeu bang khuech tan. Thc ra ay nh

mot tram trung chuyen (intermediaire de transfert), ca truc khoi soangmach mau, cho phep nhieu c che thong qua.

Khuech tan thu ong cho cac chat tan trong lipide nh kh gay me(N O, Halothane, Cyclopropane), thiopental2

Chuyen ch chu ong cho cac acide amine (histidine), ion Ca ,Mg .

++

++

Khuech tan gian d cho glucose.

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Am bao (huyet tng cua me) Thc bao : Khi mang thai, s tham cac chat t soang mau sang mao

mach (nhng mao mach nay nhung mao cua thai va tam mnh trongsoang mau), se tang len.

Nhng chat tan trong nc co trong lng phan t tren 1000(dextran), NH (nh Gleamine, Neostigmine) thc te khong qua c hangrao nhau thai.

4

Tat ca nhng thuoc qua c hang rao nhau thai, eu gay t nhieunguy hiem cho thai nhi. ang chu y la nhng thuoc Sulfamides,tetraciclines, morphine, phenobarbitales

Nhau con thieu kha nhieu men (Cholinesterase, MAO, Hydrolase )e phan huy thuoc, nh o co phan han che, ngan chan tac ong cua thuoc

len thai nhi.

V. CHUYEN HOA THUOC5.1. MUC CH CUA S CHUYEN HOA Bien nhng chat tan trong lipides, khong the thai tr trc tiep, thanh

nhng chat tan c trong nc, de dang cho thai tr qua nc tieu vi motlng nhieu nhat. (Cac thuoc kh trung nc tieu, aminosides).

e cho nhng chat chuyen hoa co the hoat ong manh hn : methyl dopa > methyl nor-adrenaline (Ha huyet ap)DOPA Dopamine (chong Parkinson) Imipramine Desmethyl imipramine (chong tram cam)Phenylbutazone Oxy phenylbutazone (khang

viem)Benzodiazepine Oxazepam (an than, gay ngu)Phenacetine Paracetamol (ha nhiet)

Lam cho a so cac thuoc tr nen vo hoat:Chlopromazine 30 chat chuyen hoaThalidomide 100 chat chuyen hoa

5.2.NI THC HIEN CHUYEN HOA SINH HOC : GAN : Bi cac Enzymes cua vi the (Cytochrome P450) hay enzyme

cua bao tng. NAO : L-DOPA Dopamine (do DOPA Decarboxylase) ONG TIEU HOA : Bi cac enzymes : Protease, lipase, va vi trung

ng ruot. HUYET THANH MAU : bi esterase

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(Proparacetamol Paracetamol; Aspirine a.salicylique)

NHAU : THAN : Vitamine D PHOI : Prostaglandines (PG)

5.3. S O CHUYEN HOA SINH HOC :

Chuyen hoa sinh hoc trai qua 2 pha : pha I va pha IIPHA I

Gom cac phan ngo Oxy hoao Kho Thuy phano Kh carbone (C)

PHA IIGom cac phan ng ket hp vi :

o Acide glycuroniqueo H 42 SOo Acide amineo Methyl hoa

Hap thu chuyen hoa sinh hoc Thaitr

Tan trong Lipide Tan trongnc

B : Hoat ong hay khong hoat ong

C, D : Vo hoat

5.4. C CHE CHUYEN HOA SINH HOC :PHA I : Oxy hoa :la phan ng chung nhat c x dung e bien oi cac chat

hu c nh

B

Pha I Pha II

Chat chuyen hoaC

ABCDA

Oxyd hoa : Alcool, aldehydes, nhom alkyl va SulfidrylHydroxy hoa cac vongKh alkyl-oxyde hoa

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Kh halogene a so phan ng oxy hoa c cac enzymes cua vi the gan, nhat la

Cytochrome P xuc tac, de sinh thanh nhng dan xuat co hydroxyde (OH)450V du : Phenobarbital p OH-phenobarbital. Mot cach tong quat phan ng oxy hoa do Cytochrome P 450 xay ra

nh sau :HNH TRANG 50

Nhng Enzymes khac khong phai cua vi the ganV du : - MAO trong cac ti the : Oxyde hoa cac Catecholamines,

ethanol aldehyde acide- Peroxidases, dehydrogenases, prostaglandine synthetase

Kh : nhom nitrogeneProtonsil SulfamideSous nitrate de bismuth dan xuat nitrite (oc oi

vi tre em)Cortisone hydrocortisoneSulindac dan xuat disulfure co hoat tnh chong

viem Thuy phan :Penicilline G b dch v (HCl) thuy phanAcetyl Choline b cholinesterase thuy phanInsuline, ACTH, b Protease thuy phan Kh nhom Carboxyl (-COOH) : L.DOPA, b kh carboxyl bi

Dopadecarboxylase DopaminePHA IINhng phan ng thuoc pha II, bieu lo ac tnh rieng cua loai (espece).

ngi la phan ng lien ket vi acide glycuronique, H , glycine. Duvi chat nao, thuoc sau khi lien ket se tr thanh dan xuat vo hoat ve sinhly va e tan trong nc hn, e thai tr qua than.

42 SO

- Ket hp vi acide glycuronique tao hp chat glycuro-hp (aspirine).- Ket hp vi acide sulfurique tao hp chat sulfo- hp (steroides)

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- Acide amines ma glycine la chu yeu, de ket hp vi acide thm vaacide mach thang (acide Salicylique acide Salicylurique).

- Ket hp vi acide acetique tao thanh dan xuat acetyl (acetyl hoa) vohoat (co xuc tac cua acetyl transferase va coenzyme A)

V du : Cac dan xuat cua aniline, Sulfamides, INH vaaminophenazone.

- Ket hp methyl hoa :Methyl hoa cac nhom -OH, -SH, -NH, -NH cua thuoc.2V du : Nor-adrenaline Metha-nor-adrenaline

COMT

(COMT = Catechol-O-methyl-transferase)Tom lai : Tat ca cac phan ng chuyen hoa thuoc, co u moi ac

tnh cua nhng phan ng enzymes :- Chuyen biet : Nhieu tieu loai cua cytochrome P , tng ng vi

cac c chat khac nhau.450

- De bao hoa : trong cac trng hp qua lieu, luon luon co s bao hoa,tuy nhien oi khi cung co tnh trang bao hoa trong ieu tr (Phenytoine,Verapamil), do s chuyen hoa le thuoc vao lieu thuoc. Trng hp nay chtang mot lieu thuoc nho cung se lam tang nong o rat ln cua thuoc ay.

5.5.NHNG YEU TO ANH HNG TOC O CHUYEN HOA

Loai ong vatCo s khac nhau ve toc o chuyen hoa gia con ngi va thu vat nen

thi gian tac ong cua thuoc cung khac nhau gia chung.V du : Cung mot lieu Pethidine, ngi hieu ng duy tr t 3- 4 gi,

nhng cho ngan hn. Pethidine, moi gi, khoang 20% c chuyen hoatrong c the con ngi, nhng cho co e 90%

Tuoi tre s sinh va sinh non : cha u enzymes e xuc tac phan ng ket

hp. Nen bilirubine t do khong ket hp u vi cac acide glycuronique nengay vang da, chloramphenicol cung vay, nong o chloramphenicol t dokhong ket hp u. Do chc nang nay cua cac chau cha hoan b, nen ratde gay ngo oc

ngi gia ca : thng do anh hng cua suy chc nang Gan-Than.

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Phai tnht b anh hng, nhng khi co mang thai, s ket hp vi acide

glycuronique b giam

Di truyen mot so ngi do di truyen gene, nen toc o chuyen hoa thuoc co

the nhanh hoac cham.V du : Mot so ngi, c cho cholinesteraes khong ien hnh vao

huyet tng, thay co hien tng thuy phan suxamethonium cham hncholinesterase bnh thng

Mot so ngi acetyl hoa INH cham, nguy c tch luy thuoc ln, segay nguy hiem. Trong luc o co mot so ngi acetyl hoa INH lai rat

nhanh, nen hieu ng mat nhanh. Can xem xet ieu chnh lieu thuoc cho 2loai ngi ke tren.

Co hai nhom ngi hydroxyl hoa nhanh va cham oi vi mot sothuoc t nh debrisoquine, mephenytoine, perhexilline.

Tnh trang bnh lyBenh ly cung lam bien oi hoat tnh enzymes cua gan, hoac huy te

bao gan, nen lam giam toc o chuyen hoa thuoc.

Cam ng enzymes Cam ng enzymes (Indution enzymatique) lien quan en loai

Isoenzyme cuacytochrome P . S cam ng nay can co thi gian tiep xucvi thuoc. e bao hoa hoac cho phan ng thuan nghch khi ngng thuoc.Co 2 loai cam ng :

450

- T cam ng (auto induction) : Thuoc kch thch chuyen hoa cua chnhno. Nen can tang dan lieu lng (chlor-promazine, meprobamte,

phenobarbital, tolbutamide, chlordiazepoxide, dyphenylhyd-antoine,warfarine)

- D cam ng (hetero-induction) : Thuoc kch thch s chuyen hoa cuathuoc khac. Can tang dan lieu lng cua thuoc khac o (rifamycine, thuocnga thai loai uong, phenobarbital, diphenylhyd-antoine, griseofulvine thng gay cam ng vi thuoc khac). Thuoc la va ru dung lau ngay,cung la chat gay cam ng enzymes

c che enzymes

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Ngc lai hien tng cam ng, c che enzymes lam tang ban huy tva tao nguy c tch luy thuoc.

2/1

V du : Nhng c che enzymes nh : T.A.O, IMAO, cimetidine,Allopurinol.

S canh tranh de vo hoat hoa cua hai thuoctren cung mot he enzymes

V du : Methanol Formol oc

Dehydrogenase

Ethanol AcetaldehydeNen co the cho ethanol e giai oc methanol.

5.6. TAM QUAN TRONG CUA CHUYEN HOA THUOC TRONGIEU TR

Quyet nh ng cho thuoc vao c the :V du : Nhng thuoc b dch v pha huy, hoac phai chu s chuyen hoa

khi qua gan (propranolol, isoprenaline, trinitrine ) co the chon ng athuoc khac, con neu uong co the tang lieu.

Quyet nh lieu lng:Toc o chuyen hoa thanh chat vo hoat nhanh hay cham, la can c

tham khao e quyet nh lieu lng, so lan cho thuoc moi ngay, hoac lulng tiem truyen tnh mach.

Thay oi chuyen hoa cua mot thuoc, bang cach cho mot thuockhac trc, hay ong thi vi thuoc ay, e gay ra s tang cng hay oi

khang thuoc.VI. THAI TR THUOCCh co thuoc trong huyet tng (ngan mach mau) c thanh thai khi

i qua mot c quan (gan than).6.1. THAI TR THAN :Than thai tr thuoc bang 3 c che sau : loc cau than, bai tiet chu

ong ong than va tai hap thu thu ong ong thanLoc cau than :

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- Phan t co kch thc 8 mm, nhng phan t gan ket vi proteinehuyet tng va nhng phan t thuoc qua ln khong the qua than bang cche loc,(co the qua bang khuech tan thu ong).

- Mot so chat khong c tai hap thu, cung khong c thai tr nh

inuline, mannitol (ngoai sinh) va Creatinine (noi sinh), c dung e nhlng he so thanh thai cua cau than (130 ml/phut).

Bai tiet chu ong ong than :- Nh cac he thong chuyen ch, ong than co the bai tiet mot so chat

nh penicilline G va mot so Cephalosporines. Nhng s bai tiet nayb cche bi probenecide, nen lam giam thai cac chat tren

Tai hap thu thu ong ong than :- Thng cac he thong chuyen ch theo hai chieu : thai ra long ong

than va tai hap thu chu ong tr vao (acide urique). Dang thuoc khong ionhoa c tai hap thu ong than gan va xa bi c che khuech tan thu ong ,t le vi o tan trong lipides cua dang khong ion hoa, co tuy thuoc vao pHcua nc tieu.

V du : No oc Barbiturates ieu tr bang NaHNO , kiem hoa nc

tieu, tang thai tr (aspirine cung vay v mang tnh acide)3

Ngo oc Amphetamine, co the acide hoa nc tieu bang NHe tang thai tr

Cl4

Hau qua tong quat :- Mot thuoc, noi chung co the chu nhieu tac ong thai tr. Thuoc co

the tng tac vi cac chat noi sinh than. V du : aspirine,phenylbutazone, thuoc li tieu thiazides lieu thap ngan chan ong thanbai tiet acide urique, gay cn goutte. Nhng lieu cao lai ngan chan ongthan tai hap thu acide urique, a en tnh trang tieu tien ra acide urique(effet uricosuriqua) kem theo cn au quan than do soi urate.

- Thuoc co the tng tac vi cac chat khac na. V du : Probenecidelam cham bai thai Pennicilline qua ng nieu va furosemide lam chambai thai lithium.

- suy than kem theo tch luy thuoc, oc tnh thuoc co nguy c tang cao.Vay viec chon lieu thuoc sao cho benh nhan thch nghi vi he so thanhthai creatinine.

- Co hai kha nang :Giam lieu, gi ung khoang cach gia cac lan cho thuoc.

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Khong giam lieu ma keo dai khoang cach gia cac lan chothuoc

6.2. THAI TR NGOAI THANMat:- Thuoc c thu hoi ve gan va bai tiet qua mat. S chuyen ong o

theo c che chuyen ch chu ong.- Nhng chat c bai thai qua mat chnh , gom : Digitaline, rifampine,

ampicilline, acide mat, cholesterol, d-tubocurarine.- Mot so thuoc phai qua cchu trnh ruot-gan, se keo dai them thi gian

nan lai trong c the nh : digitaline, morphine, chloramphenicol.He qua :- e ieu tr nhiem trung ng mat, ngi ta chon dung nhng loai

khang sinh bai thai qua mat : ampicilline, tetracycline, mot so sulfamidesva rifampicine.

- Novobiocine canh tranh vibilirubine e c chuyen ch chu ongt mau vao gan, bilirubine t do tang, gay vang da.

- Neu b tat ng dan mat, nhng thuoc bai thai qua mat se lai, cothe gay oc (rifampicine). Tuyen nc bot : Spirammycine, morphine, alcaloides khac, kim

loai nang (Hg, Bi) va amphetamine, la nhng thuoc c bai thai qua

tuyen nc bot, nen thng gay sng nu rang (hypertropie gingivale).- e li dung iem nay, ngi ta truy tm dau vet cua cac chat kch

thch (doping), (cung nh morphine strychnine) v doping tiet ra t tuyennc bot

- Nen dung spiramycine trong ieu tr viem hong Phan : Cac thuoc khang sinh va sulfamide cho qua ng ruot

(Neomycine, ganidan), cung nh nhng chat bai thai qua mat ma khongc tai hap thu qua ong tieu hoa, eu c bai thai qua phan.

Sa me : Hau het cac thuoc eu khuech tan trong sa me.Mo hoi : Iodura, bromure, ch, arsenic, thuy ngan, quinine, mot so

khang sinh, sulfamides, c thai tr theo mo hoi.Phoi : Chat kh, dung dch boc hi, nhat la cac chat gay me va ru,

bai thai qua phoi. V du : ru, eucalyptol, camphre (tinh dau) halothaneN v..v.O2

6.3. S CO NH LAU DAI CUA MOT SO THUOC TRONG CTHE (Pharmaco-thesaveis-mose)

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Cac muoi vang, polyvinylpyrolidone tren he vong mo. Arsenic tren da va long. Iode va cac dan xuat co Iode tren tuyen giap. Tetracyclines tren xng va rang ang hnh thanh Chat diet con trung (DDT) tren mo mMethotrexate tren gan.Muoi Ca tren than (hoi chng Burnet)+2

Phenytoine tren than kinh trung ngVII. NHNG THONG SO DC ONG HOC.Nhng thong so d ong hoc, c tnh toan t nhng nong o thuoc

co trong huyet tng va nc tieu. No giup ta ieu chnh c lng(Posologie) cho oi vi tng benh trang cua benh nhan.

7.1. CHO MOT LIEU THUOC TIEM NHANH QUA NG TNHMACH (IV) Thuoc phan phoi trong mot ngan trung ng : Mau

eCCtket

po

O

t

p

= )tketp

CC o ot

p= (loglog

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

- C = (thuoc)/ huyet tng thi iem (ngay sau khi tiem tnhmach).

tp

oo ot

- ke = Hang so thai tr- e = He so ly trch thuoc Log C

t p10050

101

AUC

t21

+ thi iem t =21t

+ ke =2

1

693,0

t

ket

693,021 = log2 =

21tke

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+21t la thi gian ban huy trong huyet tng : o la thi gian Cp t

giam i a eno

21C ng vi

21t

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

ttt

peBeAc

+=

+ A = (Thuoc)/huyet tng, ban dau cua pha phan phoi.

+ B = (thuoc)/ huyet tng, ban au cua pha thai tr.+ = o doc ng vi pha phan phoi+ = o doc ng vi pha thai tr.Moi pha ng vi : Thi gian ban huy ng vi pha phan phoi

Thi gian ban huy ng vi pha thai tr Ch co ban huy cua pha thai tr c bieu dien bang t

21 v thi gain

ban huy cua phan phoi a co thai tr.

7.2. CHO MOT LIEU DUY NHAT QUA NG MIENG:

Thuoc t ong tieu hoa c hap thu vao mau : van toc hap thu > vantoc thai tr c tang dan e at en nong o nh trong huyet tng

(Cmax). Luc nay van toc hap thu = van toc thai tr va sau o, van toc thaitr > van toc hap thu giam dan

t

p

ct

p

- SSC Surface sous la courbe = AUC. Tch phan nong o thuoc trong

huyet tng t 0 vo cc.

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7.3. THE TCH PHAN PHOI BE MAT (VD) :

Vd la the tch ly thuyet tng tng, trong o mot lng (Q) cua mot

thuoc phan tan ong nhat va co nong o bang nong o thuoc o tronghuyet tng cung mot thi iemVd =

Ct

Qt

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

- Co ng vi t = 0- C

21 ng vi t

21

- Co nong o nh toi a, ngay sau khi tiem vao tnh mach (IV) motlng Qo

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The tch phan phoi thi iem t = 0 Vd =Co

Qo

Ct

Qt=

Vd nho hn (~ 6L) th nong o thuoc ch quanh quan trong huyettng.

Vd ln hn (~ 6L) thuoc phan phoi en cac mo va c (thuoc)/mo >(thuoc)/ huyet tng.7.4. HE SO THANH THAI TONG CONG (CL).CL :Tong the tch huyet tng, c thai tr ra khoi c the trong mot

n v thi gian .Co 2 cong thc tnh Cl : T ng bieu hien Cp theo t : Cl = Vd ClKetKe

21

T dien tch di ng bieu dien AUC (SSC) theo thi gian (t)T lng thuoc Q cho vao c the e tm ClCL = QAUC

7.5. O KHA DUNG SINH HOC :

Dien ta ong thi ve toc o va cng o cua mot hoat cha i vaotrong mau.

o kha dung sinh hoc tuyet oi (F1) : La t so lng thuoc co mattrong mau, sau khi c cho va c the bang ng cho uong (per os), sovi lng thuoc tng ng c tiem qua ng tnh mach (IV)

AUC uong PO Lieu tiem IVAUC tiem IV Lieu cho uong

F 1 =

Cach tnh :- So sanh hai ng bieu dien (Thuoc)/huyet tng (Cp) theo thi gian

t - Tnh dien tch di ng bieu dien ( AUC) cua cung mot lngthuoc (Q) khi cho uong va tiem tnh mach Ket qua :- Thuoc trc tiep tiem vao tnh mach, o kha dung sinh hoc cua thuoc

o la 100% (F1 = 1)- Thuoc cho vao c the qua ng uong, do khong hap thu hoan toan,

nen o kha dung sinh hoc cua thuoc < 100% (F


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AUC thuoc thAUC thuoc chuanF =2

Thong so F giup so sanh nhng dang bao t cua cung mot loai thuoc2

F =2)(

)(

a

b

AUC

AUC

(a) va (b) : nhng dang bao che khac nhau cua cung mot loai thuoc7.6. KHI CHO THUOC NHIEU LAN :Nhng thong so dc ong hoc tren ngi sau khi cho mot lieu duy

nhat. Nhng tren thc te, benh nhan c ieu tr, can lap lai nhieu lan chothuoc

Bnh nguyen : Nong o thuoc on nh (CSS)(Steady State Concentration)

Khi van tochap thu (hay van toc tiem truyen ) = van toc thai tr.Luc o nong o thuoc se bnh on trong huyet tng va bnh nguyen xuathien.

Tong lieu a dungCL CSS =

Lu lng vao (Q/min) = Lu lng ra (Cl.Cp)Cp = Css = Q/min 1/Cl

Trng hp cho thuoc nhieu lan :

Css = * Tong lieu

n1Cl

n = khoang thi gian gia cac lieuCho thuoc qua ng ngoai mach mau. ng uong, khong lien tuc.

Css = (F lieu)/n 1/Cl)(F = kha dung sinh hoc ; n = khoang thi gian gia cac lieu; Css =

nong o trung bnh gia gia nhng nh o trong huyet tng sau moi lancho thuoc ).

Trc moi lan cho trc can xac nh nong o thap nhat cua lieu chotrc.

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anh gia thi gian e at c nong o bnh nguyen (Plateau):khoang 4 -5 t

21 V du : mot lieu A co thi gian ban huy (t1/2) = 12 gi

va c cach 12 gi cho lieu thuoc mot lan .Sau lieu I 12 gi : [A]p = 50% [A] ban auSau lieu II [A]p nh = 100 + 50 = 150%

12 gi sau : [A]p = 150/2 = 75%Sau lieu III [A]p nh = 100+75 = 175%

12 gi sau : [A]p = 175/2 = 87,5%Sau lieu IV [A]p nh = 100 + 87,5 = 187,5%

12 gi sau : [A]p = 187,5/2 = 93,75%Sau lieu V [A]p nh 100 + 93,75 = 193,75%

12 gi sau : [A]p = 193,75/2 = 96,87%

T Vt 21 tr i, nong o thuoc trong huyet tng dao ong gia 100%va 200% so vi nong o ban au.

Nong o on nh trong vung bnh nguyen phu thuoc vao nong o lieuau tien, nhng thi gian e at en o, eu nh nhau (Vt

21 ) bat ke lieu

thap hay cao.Ta co the at nhanh en nong o can bang Css bang cach cho mot lieu

nap ban au : Lieu nap = 2 lieu duy troi vi nhng thuoc co thi gain ban huy dai (t

2

1 ), cach dung mot lieunap abn au cho benh nhan se ton thi gian e at ti nong o canbang.

7.7. TNG QUAN GIA NONG O THUOC TRONG HUYETTNG VA HIEU QUA IEU TR :

oi vi nhng thuoc co pham vi ieu tr han hep, phai o nong othuoc huyet tng. Nhat la nhng trng hp thuoc a c x dung enlieu chuan roi ma van khong hieu qua.

V du : S dung (Barbital) nong o can bang cho benh nhan bbenh ong kinh ma van c tiep tuc len cn, khi xet en viec tang lieu themtrong pham vi ieu tr.

VIII. TNG TAC CUA THUOC8.1. NH NGHA :Tng tac cua thuoc la s bien oi hieu ng cua mot thuoc do co

mot thuoc khac hien dien trong c the.Hau qua cua tng tac thuoc co the lam tang hay giam hieu qua

cua nhng thuoc c dung.

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Tng tac thuoc xay ra trong qua trnh chuyen hoa, goi la tngtac dc ong hoc. Tng tac thuoc xay ra tai mat tac ong cuathuoc goi la tng tac dc lc hoc.

Hiep ong (Synergie) :

Hai chat A va B co cung mot hoat tnh dc ly, nhng khac nhau vecng o (EA>EB). Khi dung chung A va B, se cho mot hieu ng chung la

Co 3 trng hp xay ra :Hiep ong cong (S.additive) : khi = EA

+ EBHiep ong mot phan (S.partielle) : khi < EA

+ EBHiep ong boi tang (S. potentialisatrice) : khi > EA

+ EB oi khang (Antagonisme) :Hai chat A va B co cung mot hoat tnh dc ly, nhng khac nhau ve

cng o. Khi A va B phoi hp nhau se cho hieu ng .Co hai trng hp xay ra :oi khang hoan toan (A.totale) : = 0oi khang mot phan (A.partiel) : EB < EA

S tang cng (Potentiallisation)Khi hai chat A va B co hoat tnh dc ly khac nhau, hieu ng chung

() cua A va B ln hn mot trong hai hieu ng rieng le : > EA hoac >EB

8.2. C CHE TNG TAC THUOC :Tng tac dc lc

Tng tac dc lc la tng tac xay ra ngay tai ni tac ong cua thuoc:

Hiep ong : Co 4 c che giai thch ve hiep ong dc lc :Bao ve hoat chat cac receptor.Tang tnh nhay cam (hoac ai tnh) cua receptor oi vi thuoc.Tang gan thuoc vao receptorTang tac ong len cac receptor chuyen biet khac, e cho nhng

hieu ng dc lc tng ong.+ Thuoc tac ong tren cung 1 receptor:- Tng tac hiep ong hay oi khang, tuy theo nong o tng oi cua

thuoc c cho.

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Thuoc A lieu thap, A gan len mot phan cua receptor chuyen biet.Thuoc B (hiep ong vi A) co hoat tnh noi tai thap hn, cho cung luc viA lieu thap, se gan phan con lai cua receptor t do. Ket qua hieu ngchung () la hiep ong cong. Neu tang nong o [B], B se canh tranh chiem

phan cua A tren receptor, hieu ng cua A se giam en o triet tieu.Neu B co u so lng cang tranh lan het v tr cua A. Hiep ong cong

se tr thanh hiep ong tng phan va cuoi cung B tr neen oi khang vi A+ Thuoc tac ong hiep ong gian tiep tren cac receptor khac nhau :- Khi thuoc B huy mot phan hieu ng cua chat oi khang. V du :

Atropine phoi hp vi Adrenaline, se keo dai hieu ng tang nhp tim vatang huyet ap cua adrenaline, bang cach huy phan xa cua day X ( von lamcham nhp tim)

Hai thuoc A va B tac ong nhng v tr khac nhau tren ca receptorkhac, nhng eu cho cung mot hieu nh nh nhau :

V du 1 : Phoi hp hai thuoc khang sinh e diet vi trung- lactamines + aminosides se at en hieu ng hp ong boi tang (

tac ong len ca 30S ribosome cua vi trung).V du 2 : Furosemide (tac ong tai nganh len cua quai Henle)- Sprironolactone (tac ong tai ong ln xa), se at en hieu ng hiep

ong cong.

V du 3 : Theophylline + thuoc kch thch . Se cho hieu ng hiepong cong

2

ATP AMP vong AMP

Adenylare cyclase Phosphodiesterase

Chat kch thch 2 Theophyllineoi khang : hai chat oi khang co ai tnh va hoat tnh noi tai khac

nhau, canh tranh thuan nghch tren cung mot loai receptor.- Khi chat oi khang chiem het cac R va co hoat tanh noi tai = 0, oi

khang hoan toan xay ra- Khi chat oi khang co hoat tnh noi tai yeu, se xay ra oi khang mot

phan

- Khi hai chat co ai tnh khac biet va co nong o xap x nhau, se enoi khang mot phan.

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V du : Cac chat phong toa c che cac hieu ng cua Catecholamines:

Kch thch 1 AcebutolKch thch 2 Butoxamine

adrenaline

- Cac antihistamimmique type H 1 va H phong be hieu ng cuahistaminees tren receptor H 1 va H

2

2

Kch thch H 1 PromethazineKch thch H 2 Cimetidine

Histamine

- Naloxone thuoc giai oc morphine co ai tnh hn vi R cua morphinenhng co hoat tnh noi tai yeu. Khi Naloxone chiem lnh receptor cua

morphine, tuy co lam giam cng o hieu ng cua morphine nhng v thigian ban huy (1/2) cua naloxone ngan, nen khi nong o naloxone giam,morphine se tai hien va chiem lai receptor cua no.

Tng tac dc ong hocTng tac thuoc, dien ra cac giai oan chuyen hoa thuoc, nh nhng

c che sau :Trc va trong hap thu :

Tng tac thuoc xay ra rat nhieu ong tieu hoa, sau khi cho thuoc quang uong :Phc hp hoa (complexation) trong long ruot.+ Cac tetracyclines, va cac muoi nh :+ Cholestyramine hap thu nhieu thuoc va giam hoat tnh cua chung.

Nhat la digitale, khang vitamine K loai uong va vitamines tan trong dauIon hoa : tang ion hoa, se lam giam hap thu thuoc.+ Nhng chat kiem hoa, lam giam hap thu cac thuoc co tnh acide yeu

nh cac thuoc chong viem khong Steroides, khang vitamine K loai uong,cac Sulfamides.

Thay oi thi gian tiep xuc vi niem mac ng tieu hoa :+ Cac thuoc nhuan trang, lam tang van toc chuyen van qua ruot, giam

hap thu thuoc, nhat la cac thuoc dang tac dung cham, dang tac dung dai.+ Cac anticholinegiques (atropine, hyoscyamine) tr hoan lam chong

da day, nen tang hap thu cac thuoc o+ Cac thuoc che ch ng tieu hoa phu len be mat, ngan chan thuoc

tiep xuc vi niem mac, lam giam tai hap thu.S bien oi cua vi trung ng ruot :

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+ Cac thuoc khang sinh dung qua ng uong, co the giam hoac bienoi vi trung ng ruot, do o bien oi tac dung cua thuoc.

+ V du : Bnh nhan ieu tr bang khang vitamine K loai uong, co theb xuat huyet v nhng vi trung tong hp vitamine K ruot b giam.

S hien dien Lipide (dau ricin, olive) :+ Se lam tang hap thu qua ang oi vi mot so thuoc (griseofulvine)S canh tranh cac chat chuyen ch cua niem mac ng tieu hoa : lam

cho hang rao tiau hoa b khiem khuyet, gay tang hap thu qua ang.S thng ton nang ne niem mac tieu hoa : lam cho hang rao tieu hoa

b khiem khuyet, gay tang hap thu qua ang.Lien quan en cac ng cho thuoc khac, co the xay ra :

+ Tng k (incompatibilites) lam ket tua hay vo hoat cac chat ngay

trong vat ng tiem truyen ( Lactamine trong dung dch Glucose)+ Cac chat tan trong lipide se lam tang s khuech tan qua da cua cac

thuoc dung ngoai daKhi khuech tan : S khuech tan cua thuoc tiem bap (IM) se tang, neu

co cho them hyaluronidase, ngc lai, s khuech tan cua thuoc te se bgiam neu co mat thuoc co mach.

Chuyen van trong mau : co nguy c canh tranh tai ni gan ket trenproteine cua mau nhat la albumine. Albumine la ni gan ket cua cac thuoc

co tnh acide, thuoc khang vitamine K loai uong, thuoc chong viem khongSteroides, penicilline, thuoc ha ng huyet loai uong, tetracycline vaSulfamides

Nhng thuoc c phong thch dang t do, ma v tr cu cua no a bthuoc khac chiem c cung lai tang cng hieu ng cua chung.

Ngay trong chuyen hoa sinh hoc : Tng tac xay ra thng xuyen.Thuoc co the cam ng (induction) vi cac enzymes chuyen hoa thuocCytochrome P450), gia toc chuyen hoa thuoc thanh mot chat vo hoat, chat

co oc tnh hoac mot chat co hoat tnh cao hn.Thuoc cung co the c che cac enzymes chuyen hoa keo da hieu ngcua thuoc khac.

Thuoc A, gan chatvao proteine

Thuoc B, gan trungbnh vao proteine(b A chiem v tr)

Nguy c do tng tac

Phenyl-butazonePh enytoine

Salicylates

AcenocoumarolTolbutamide

Methotrexate

Xuat huyetHa ng huyet

Tang oc tnhMethotrexate

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Chat gay cam ng enzymes Thuoc dung chung b tng tac Phenobarbital Phenytoine Rifampicine Griseofulvine Carbamazepine Mot so hydrocarbure co Cl Hut thuoc la kinh nien Hydrocarbure a vong gay ung

th Ru

1. c vo hoat nhanh hn Thuoc chong dong khang vitamine

K [Estrogenest] thap, uong thuoc

nga thai Digoxine Theophylline Cyclosporine2. B bien the thanh dang : Hoat ong : Cyclophosphamide oc tnh : INH

Nhng thuoc c che enzymesThuoc c bao ve trc nguy c b

pha huy va tang hieu ng. Cimetidine Troleandomycine Miconazole Ketoconazole I.M.A.O Allopurinol

Thuoc chong ong khang vitamineK

Sulfamides ha ng huyet Benzodiazepine Estrogenes, bloquants Lidocaine, theophylline,

Phenytoine Mercaptopurine

Trong ton tr : Nhng chat co tnh acide, gan chat vao proteine cuamo, ton tr o va phong thch dan.

V du : Tolbutamide khi dung chung vi Sulfamides khang sinh,tolbutamide tuy b canh tranh thay the noi ket tren albumine huyet tng.Nhng tolbutamide van keo dai tac ong ha ng huyet mot cach khacthng, la v do tolbutamide lien tuc gan chac mo va t o phong thchlien tuc

Trong thai tr than :+ Loc va tai hap thu : Nhng chat lam thay oi pH cua nc tieu,

(thuoc li tieu NH OH. NaHCO ), se lam tang o ion hoa cua thuoc mang4 3

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tnh acide yeu hoac base. Tang ion hoa se tang bai thai chung ra ngoai cthe.

+ Tien trnh bai thai chu ong cua ong than : nhng thuoc co tnh acide(cac Salicylate, acetazolamide, probennecide, phenylbutazone,

indomethacine, chlorpromide, penicilline G) hoac cac chuyen hoa chat lienhp hay khong lien hp, eu c ong than bai thai chu ong nh enzymeschuyen ch. Co hien tng hai phan t khac nhau canh tranh tren cung motchat chuyen ch, ket qua mot chat c gi lai, con chat kia b thai ra.

V du : Probenecide giam van toc bai thai cua penicilline G,penicilline G c gi lai, nen tac dung c keo dai them, Indomethacinecung vay, nen co nguy c gay oc Indomethacine.

T TM GIAI APThuoc la nhng chat co anh hng en qua trnh song. Vay nhng thuoc

co lng phan t nho (


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o kha dung sinh hoc (bio-availability) phan anh ty suat cua lngthuoc c cho qua ng uong va lng thuoc thc te co mat trongtuan hoan mau, tnh bang AUC. Ve s o minh hoa.

5 c che xuyen mang te bao.Ap dung phng trnh Henderson Hasselbalch e chng minh s hap thu

cac chat acide yeu va base yeu.Trnh bay 5 ac tnh cua chuyen ch chu ong (transport actif).S hap thu cua acid yeu va base yeu moi trng pH da day.Do ac tnh cua ruot, nen s hap thu thuoc tai o co nhng thay oi

tng oan hay neu v du chng minh.Li hai trong tiem di da, tiem bap va tnh mach.Li hai khi a thuoc qua trc trangVe s o tong quat ve phan phoi thuoc trong giai oan huyet tngNeu v du minh hoa s canh tranh tren cung mot moi noi cua thuoc

giai oan huyet tngPhan biet bm va kenh mang te bao.Phan biet ai tnh va hoat tnh noi tai cua thuoc tren receptor ac hieu.Phan biet pH va pKNhng ac iem hap thu thuoc ng tieu hoa va ngoai ng tieu

hoa

Nhng ac iem cua noi gan ket thuan nghch va khong thuan nghchgia thuoc va proteine trong huyet tng va trong mo

Tnh hng ti (tropisme) ac tnh cua thuoc oi vi mot so mo.Phan phoi thuoc trong nc va trong m.S khuech tan cua thuoc qua hang rao mau nao va hang rao mau

nhau.Trnh bay 2 pha bien oi sinh hoc trong chuyen hoa thuoc va nhng yeu

to anh hng.

Hien tng cam ng men va c che men trong chuyen hoa thuoc.Trnh bay 3 c che thai tr thuoc qua than.Tham khao nhng thong so dc ong hoc va dc lc cua thuoc.Phan biet tng tac dc ong va dc lc cua thuoc.

Documents

1. Duoc Ly Dai Cuong