I ntro duc tio n to Pha rma c o kine tic s 1 Unive rsity o f Ha - - PowerPoint PPT Presentation

I ntro duc tio n to Pha rma c o kine tic s

Unive rsity o f Ha wa i‘ i Hilo Pre -Nursing Pro g ra m NURS 203 – Ge ne ra l Pha rma c o lo g y Da nita Na rc iso Pha rm D

1

L e a rning o b je c tive s

 Unde rsta nd c o mpa rtme nt mo de ls a nd ho w the y e ffe c ts drug

c o nc e ntra tio ns

 Unde rsta nd the two ma in pa ra me te rs o f pha rma c o kine tic s (Vd a nd Cl)  Unde rsta nd ADME

a nd the c ha ra c te ristic s o f e a c h

 K

no w ho w to e stima te ho w muc h drug re ma ins a fte r X ho urs a fte r a dministra tio ns

2

Pha rma c o kine tic s

 Wha t is pha rma c o kine tic s

 T

he study o f the a b so rptio n, distrib utio n, me ta b o lism, a nd e limina tio ns o f drug s with re spe c t to time (ADME )

 T

wo ma in pa ra me te rs

 Vo lume o f distrib utio n  Cle a ra nc e

 3rd pa ra me te r – ha lf life

3

Vo lume o f distrib utio n (Vd)

 Vd is a the o re tic a l spa c e – me a sure d in lite rs

 Ave ra g e b lo o d vo lume = 3 lite rs  Vd c o uld b e g re a te r tha n 3 lite rs, ho w?

 50 mg o f drug in yo ur b o dy  5 mg in the b lo o d  Vd = 10 L

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Vo lume o f distrib utio n (Vd)

F a c to rs I nc re a sing Vd

 L

ipo philic drug s

 De c re a se d pla sma pro te in

b inding

 I

nc re a se d tissue b inding

F a c to rs De c re a sing Vd

 Hydro philic drug s  I

nc re a se d pla sma pro te in b inding

 De c re a se d tissue b inding

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Co mpa rtme nt Mo de ls

One c o mpa rtme nt mo de ls

 Pla sma  Hig hly pe rfuse d o rg a ns

 L

ive r & kidne ys

T wo c o mpa rtme nt mo de ls

 Pe riphe ra l tissue s

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Ce ntra l Co mpa rtme nt E limina tio n Pe riphe ra l Co mpa rtme nt

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Cle a ra nc e

 Cle a ra nc e : Po rtio n o f the drug re mo ve d fro m the vo lume o f distrib utio n

pe r unit time (L / hr)

 Me c ha nisms fo r c le a ra nc e (c a n b e a c o mb ina tio n)

 Re na l e limina tio n  He pa tic me ta b o lism  Bilia ry e xc re tio n

8

Cle a ra nc e – fa c to rs tha t e ffe c t

 Ra te s

 Ab so rptio n ra te s

 I

V – fa st

 Ora l – slo w  Re c ta l - spo ra dic

 Distrib utio n ra te s

 Co mpa rtme nt mo de ls – 1 vs. 2

 Me ta b o lism ra te s

 Bio tra nsfo rma tio n, o r me ta b o lite s

 E

limina tio n ra te s

 I

nvo lve s 2 va ria b le s drug c o nc e ntra tio n a nd time

 E

limina tio n ra te = -dC/ dt

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E limina tio n ra te s

 Ra te s o f e limina tio n

 F

irst o rd e r

 T

he a mo unt o f drug re mo ve d o ve r time c ha ng e s

 T

he fra c tio n o f drug re mo ve d re ma ins c o nsta nt.

 Co nc e ntra tio n de pe nde nt

 Hig he r c o nc e ntra tio n = hig he r ra te o f re mo va l  L

• we r c o nc e ntra tio n = lo we r ra te o f re mo va l

 Ha lf-life

 Amo unt o f time fo r the drug c o nc e ntra tio n to de c re a se b y ½ in the vo lume o f distrib utio n  100 mg o f drug x wa s g ive n. Drug x ha s a ha lf life o f 2 ho urs. In 6 ho urs ho w ma ny mg s o f drug x wo uld b e

re ma ining ?

 Ze ro o rd e r

 Amo unt o f drug re mo ve d pe r unit time re ma ins the sa me  F

ra c tio n o f drug re mo ve d de c re a se s

 Co nc e ntra tio n inde pe nde nt  Co nc e pt o f ha lf-life do e s no t a pply

 Mixe d o rd e r

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E limina tio n ra te s

 Ze ro o rde r

 Amo unt o f drug re mo ve d pe r unit time re ma ins the sa me  F

ra c tio n o f drug re mo ve d de c re a se s

 Co nc e ntra tio n inde pe nde nt  Co nc e pt o f ha lf-life do e s no t a pply

 Mixe d o rde r

 Whe n e nzyme s pla y a ro le in e limina tio n  Mixture o f first o rde r e limina tio n a nd ze ro o rde r  F

irst o rde r, e nzyme sa tura tio n, Ze ro o rde r

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ADME – fina lly!

 Ab so rptio n  Distrib utio n  Me ta b o lism  E

xc re tio n

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Ab so rptio n

 Ab so rptio n: T

ra nsfe r o f drug fro m the site o f a dministra tio n to syste mic c irc ula tio n

 Administra tio n

 E

nte ra l: T hro ug h dig e stive syste m

 Pa re nte ra l: Stra ig ht into the va sc ula ture  T

• pic a l: T

hro ug h the skin, tissue s, o r me mb ra ne s

 Ac c o mplishe d o nly AF

T E R drug ma ke s it to syste mic c irc ula tio n

13

Ab so rptio n - E nte ra l ro ute o f a dministra tio n

 T

hro ug h the GI tra c t – ta b le ts, c a psule s, suspe nsio ns, so lutio ns & suppo sito rie s

 Ora l  Sub ling ua l  Re c ta l

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L ive r GI T ra c t He a rt All swa llo we d me dic a tio ns Sub ling ua l Re c ta l

Ab so rptio n - Pa re nte ra l ro ute o f a dministra tio n

 Dire c tly into syste mic c irc ula tio n – a ny a dministra tio n “o the r tha n e nte ra l”

 I

V

 I

M

 I

A

 SC  I

ntra the c a l

 I

ntra syno via l

 I

ntra o sse us

 I

ntra pe rito ne a l

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L ive r GI T ra c t He a rt All pa re nte ra l me dic a tio ns

Ab so rptio n - T

• pic a l ro ute o f

a dministra tio n

 Dire c tly o nto the skin o r tissue tha t is e xpo se d to a n a re a o utside the b o dy –

liq uids, po wde rs, c re a ms, o intme nts, g e ls, spra ys pa tc he s

 T

ra nsde rma l

 Ophtha lmic  Va g ina l  I

ntra ute rine

 T

ra nsmuc o sa l – na sa l (no t o ra lly)

16

L ive r GI T ra c t He a rt All tra nsde rma l me dic a tio ns

Ab so rptio n - Ma ke sure yo u kno w….

 I

nha la tio n

17

L ive r GI T ra c t He a rt

Ab so rptio n - Bio a va ila b ility

18

L ive r GI T ra c t He a rt E nte ra l Pa re nte ra l T

• pic a l

De pe nds o n:

• ROA
• Drug

c ha ra c te ristic s

• T

he b o dy 1 3 2

Ab so rptio n - Bio a va ila b ility

ROA

 F

irst pa ss me ta b o lism

 Hydro philic ity vs.

lipo philic ity

 Curre nt GI

c o nditio ns

 F

• o d vs. e mpty

sto ma c h

 pH  E

nzyme s a va ila b ility

 GI

mo tility

 pH  Blo o d flo w  E

nzyme s

19

Drug Cha ra c te ristic s T he Bo dy

 Hydro philic ity vs.

lipo philic ity

 Do sa g e fo rm  pKa

Ab so rptio n - F irst Pa ss E ffe c t

 Ca n e ffe c t o ra lly a dministe re d drug s b y up to 90% a nd mo re

 Po te nc y?

 Using a no n-o ra l ro ute a nd do sa g e fo rm c a n he lp

 Co stly  Wro ng drug c ha ra c te ristic s

 Drug de sig n c a n he lp – pro drug s

 A drug tha t must unde rg o first pa ss me ta b o lism b e fo re the a c tive drug

c o mpo und/ mo le c ule is re le a se d

20

Distrib utio n

 Distrib utio n – Re lo c a tio n o f the drug fro m the syste mic c irc ula tio n to its site

• f a c tio n

 Mo ve me nt b e twe e n c o mpa rtme nts  E

xit the va sc ula ture

21

Pe riphe ra l Co mpa rtme nt

Distrib utio n

 Distrib utio n de pe nds o n:

 Size o f the drug mo le c ule  L

ipid so lub ility

 Drug pK

a a nd the tissue / b lo o d pH

 Pe rfusio n to site o f a c tio n  Binding o f pla sma pro te ins

22

Distrib utio n – mo re o n pla sma pro te ins

23

Distrib utio n – hig hly pro te in b o und drug s (>90%)

 Drug s > tha n 90% pro te in b o und  Ma y b e displa c e d

 T

• xic e ffe c ts

 Displa c ing drug ma y inte rfe re with c le a ra nc e

 Re duc e d numb e r o f pla sma pro te ins

 T

• xic e ffe c ts

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Bre a k time

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