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 1 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

L e a rning o b je c tive s 2  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

Pha rma c o kine tic s 3  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  3 rd pa ra me te r – ha lf life

Vo lume o f distrib utio n (Vd) 4  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

Vo lume o f distrib utio n (Vd) 5 F a c to rs De c re a sing Vd F a c to rs I nc re a sing Vd  Hydro philic drug s  L ipo philic drug s  De c re a se d pla sma pro te in  I nc re a se d pla sma pro te in b inding b inding  De c re a se d tissue b inding  I nc re a se d tissue b inding

Co mpa rtme nt Mo de ls 6 T wo c o mpa rtme nt One c o mpa rtme nt mo de ls mo de ls  Pe riphe ra l tissue s  Pla sma  Hig hly pe rfuse d o rg a ns  L ive r & kidne ys Ce ntra l E limina tio n Co mpa rtme nt Pe riphe ra l Co mpa rtme nt

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Cle a ra nc e 8  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

Cle a ra nc e – fa c to rs tha t e ffe c t 9  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

E limina tio n ra te s 10  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 o 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

E limina tio n ra te s 11  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

ADME – fina lly! 12  Ab so rptio n  Distrib utio n  Me ta b o lism  E xc re tio n

Ab so rptio n 13  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 o 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

Ab so rptio n - E nte ra l ro ute o f 14 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 All swa llo we d  Ora l me dic a tio ns  Sub ling ua l Sub ling ua l  Re c ta l He a rt GI T ra c t L ive r Re c ta l

Ab so rptio n - Pa re nte ra l ro ute o f 15 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 All  I A He a rt pa re nte ra l  SC me dic a tio ns  I ntra the c a l  I GI T ra c t ntra syno via l L ive r  I ntra o sse us  I ntra pe rito ne a l

Ab so rptio n - T o pic a l ro ute o f 16 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 All He a rt tra nsde rma l  I ntra ute rine me dic a tio ns  T ra nsmuc o sa l – na sa l (no t o ra lly) GI T ra c t L ive r

Ab so rptio n - Ma ke sure yo u kno w…. 17  I nha la tio n He a rt GI T ra c t L ive r

Ab so rptio n - Bio a va ila b ility 18 1 E nte ra l 2 Pa re nte ra l De pe nds o n: He a rt ROA • Drug • c ha ra c te ristic s GI T ra c t T he b o dy • L ive r 3 T o pic a l

Ab so rptio n - Bio a va ila b ility 19 Drug ROA T he Bo dy Cha ra c te ristic s  pH  F irst pa ss me ta b o lism  Hydro philic ity vs.  Hydro philic ity vs.  Blo o d flo w lipo philic ity lipo philic ity  E  Do sa g e fo rm nzyme s  Curre nt GI c o nditio ns  pKa  F o o d vs. e mpty sto ma c h  pH  E nzyme s a va ila b ility  GI mo tility

Ab so rptio n - F irst Pa ss E ffe c t 20  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

Distrib utio n 21  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 o 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 Pe riphe ra l Co mpa rtme nt

Distrib utio n 22  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

Distrib utio n – mo re o n pla sma pro te ins 23

Distrib utio n – hig hly pro te in b o und 24 drug s (>90%)  Drug s > tha n 90% pro te in b o und  Ma y b e displa c e d  T o 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 o xic e ffe c ts

Bre a k time 25