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Pharmacology - I  (PV Publication).pdf
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Pharmacology - I (PV Publication).pdf

  • 1. Scanned by CamScanner A T e x t B o o k o î PHARMACOLOGY= ı " . S tr ic tly A s p e r S y ı la b u s P re s c r ib e d fo r B P h a r m a c y , S e m e s te r IV b y P h a r m a c y C o u n c il o f In d ia , N e w D e ı h i Dr M a da n Ka u s hi k P e e V e e (R e g d )
  • 2. Scanned by CamScanner C O N T E N T S 飞 u b n o hađ ion towoı ogy 3, 1 2 H is to r i ç a 1 ı a n d m a r k s o f p h m a g u Scope o £ Ptu m a c o Ao gy 6, 14 N a tu r e a n d s o u r c e o f d r u g s 9, U Ë ņ c on ce pt 11 1 6 R o u te s o t d r u g a d m in is tr a tio n 1 2 , 1 7 ı ? Ķ 15, 1 8 A d d ic tio n 1 8 , 1 9 T o le r a n c e 1 9 , 1 10 D r u g deı teA Tac cp hy 21, 1 12 Id io s yn c r a s y 2 2 , 1 13 A lle r ga y = 1 H m s 25, 1 15 E m rym e in d u c tio n , e n z w e in h ib itio n , O t d 33 G e = a ı T bt m a coı o gr n 4 5 9 9 U » m h n 2 2 īT i n ciple o f d r u g a c tio n 4 7 , 2 2 1 M e c h a n is m o f &agartim 2 3 D n ı g re c e pto r i n te r a c tio n 50 , 2 3 1 R e c e p to r th e o r ie s X Z L ı i m o t r e c e p to ts 53, 2 4 1 T r a n s d u c ń o n m e c h a n is m 5 3 , 25 D « e ı d ı ū o n s hip 59, 2 5 1 T h e r a p e u tic in d e x 6 1 , 2 6 C o m m d i d P 61 2 7 F a c to r s m o d ifyin g d r u g a c tio n 6 4 , 2 8 A d m & q 69, L 9 m ı g i n tm c ū o n s 7 5, 2 10 D n ı g d is c o v e r y a n d « ım o E n e w m 8p 78 , 2 11 p h a r m a c o v igila n c e 8 0 h h m a a o (D m » A c tin g o n p e ń ph e r a l N e r v o u s s y s te m 1 oo 2 0 5 3ı 0 ı E = n a io n a n d lrm c ı io n o f pe r iph e ra l n e r v o u s s ys te m 1 0 1 , 3 2 N e u U««mi=i=il0c 31 1 s te p s i m v o lv e d in n e u r o h u m o r a ıtr a n s n i n im 105, 32 2 C u i n m n nitte r 106 , 3 2 3 C 1a s s ifı c a tio n o f n e u r o tr a n s m , 33 pa ı h o r niı n e tĵc s s ys te m a n d d r u gs 1 09 , 3 3 1 c h o ı in Ħ 圳 , aAnūc h o d ru gs 1 1 8 , 3 4 p a r a s p n p a th o lytic C h a p te r 4 P h m a c o lo gy o f D r u ga A c tin g o n C e n tra l N e r v o u a S yı te m I 206 2 96 I 4 0 N e u ro h u m o r a l tr m m is s io n in e n tr a in e r v o s s ys te m 2 4 1 G a m m a a m in o b u ty r ic a c id (G A B A ) 208, 4 2 G iu ta m a te n e u r o tra n s m itte r (G L IJ) z g 2 11, 4 3 G lyc in e 213, 4 4 D o p a ı n in e rg ic p a th w a ys 2 15, 4 5 Se r o to n in 21 9, r 4 6 G e n e ra l a n e s the tic s W 4 6 1 】 n h a la tio n a l g e n e r a l a n a e s th e tic s 224, 4 7 ¥ [JT C H yp n o tic s , s e d a tiv e ś 24 1, 4 8 C e n tr a lly a c tin g m u s c le r e la x a n ts 25 5, 4 9 Y f aT A n ti e p ile p tic d r u g s 262, 4 10 A lco h o l270, 4 11 D i s u lf】 r a m 2 75, 4 12 M e th a n o i li i n o l277 C h a p te r 5 P h a tm a c n ln By o f D r u g i A c tin g o n C e n tr a l N e r v o u ı S y a te m U 29 7 38 0 e e 己 垂 5 1 A n tip s yc h o tic d r u g s 298, 5 2 A n tid e p r e s s a n t d r u gs 308, 5 3 A n ti a n x i ln m e ty d r u g s 320 , 5 4 A n ti m a n ie s o r m o o d s ta b liz e rs 32 5, 5 6 H a llu c in o g e n s a g iT a 3 2 8, 5 7 A n tip a r k in s o n s d r u g s 331, 5 7 A n tia Lzh e im e r s a ge n ts 3 38, 5 8 O p io id a n a lge sics a n d a n ta go n is ı s 343, 5 8 1 N a r c o tic a n a lg e s ic s 343, 5 8 2 q n n O p io id a n ta g o n is ts p h a rm a c o lo gy 3 56, 5 9 C N S S U l a n t s a n d n o o tr o p ic s b A ł 3 5 8 bmi In d e x Ĉ 0 S O rJ u H (i) (iii)
  • 4. Scanned by CamScanner 靆 佷 rä]l A T e x t B o o k o f P h a r m a c o l g y (V ° j l ĺ 2 H I S TO R IC A L LA N D M A R K S O F p H A R M A c o L B § I ıu sq b si n ce the begi n n in g o fthe s p e c ie s , p e o ple h a v e tr e a te d p a in a n d d is e a s e w ith s uBÉ áces deriv ed fro m pl a n ts , an i m a ls, a n d m in e r a ls H o w e v e r Th e s c ie n c e o f p h a rm a c o lo gy is le s s than 15o yea rs o l d u she red in b y th e a b ility to is o la h ? p ı ı r e c o m p o u n d s ijbthe e sı a bl i shm en t o f 1he sd m ti ß c m e th o d H is to r ic a lly th e s e le c tio n a n d U S e o f drı s ífere b X , ) d m g ı ls a g e n o x io . :4 9 呷 二职 賺 。 . . 石 。ぶ 蒯 p a ぷ 二 ニ ア 葛 歹 苁 二 碡钰。 Se co n d Irı e se c o n d p ha s e o f d r u g u s a g e E x p e r i e n c e e n a b le d Þ Ēō ĦĖ to u n ders m d w M d ı s u bstan c e s w ere a c tu a lly beneicial in r e lie v in g p a r tic ı ı la r d iģ e a s e sym p加m & 1heß rstedirredrugsw e r e p r o b a b ly s im p le external p r e p a r a tio n s s u c h a s c o o l m u d o r a s o o g W the e a d ie st 】 o n o w ı ıp r e s c r i p tio n s fr o m 2 1oo B C E includelves « m l a i n ing ? w O v e r m a n y o e n h ir i e s p e o p le learned th e th e r a p e u tic v a lu e o Ê n a ural pr o du d s thro u gh triala n d e n D r B y 1500 B C E E gyp ti a n p r e s a i p tio n s c a lle d fo r c a s to l o il o pi u m ļ a n d 0 chn g i lha t a re s tal u se d to d a y In c h in a a n c ie n t s c r o 丑s fr o m a Į l tim e l isted P fo r 】 ı a b a l medicines fo r m o r e th a n 5 o d is e a s e s D io s c o r id e s ' d r e e k aı m y su r ge o n w ħ o h ed in the lst c e n h n y d e sc r ib e d m o r e th a n 60 o m e d ic in a l p la t ħe co l J e d e d an d s ħ udi e d a s lre b a irele d w ith th e R o m a n a rm y S u s r u ta a H in d u p h y s iþ ja n Isl am i c P o s t la Jn o u sl y A v ic a u ia » a n d c h r is ti a n m o n k s c u ltiv a te d a n d ie d desa ibed ı ħ e pr w ķ o íA yı m e djc m e d c n e in th e 5 th c e n tu ı y D u r in g th e Midbrï Ą ges, Ĥ e u se o fhr r ba l G e n e ľ a ı P h a rm a c o lo w t d e p a r tm e n t a t th e u n iv e r s ity o f M ic h ig a n in 18 9 1 a n d is c o m id e r e d th e fa th e r o f A ı n e r ic a n )ıl i uiı ent p h a s e 7 ħe g o a l o f p h a r m a c o lo g y is to u n d e r s ta n d th e m e c h a n is m s b y w h ic h J d w in te r a c t w ith b io lo g ic s y s te m s to e n a b le th e r a tio n a l u s e o f e ffe c tiv e a g e n ts in th e )f lia gp°s is a n d tr e a tm e n t o f d is e a s e T he s u c c e s s o f p h a rm a c o lo g y in th is ta s k h a s le d to a n e x p lo s io n o f n e w d r u g d e v e lo p m e n t p a r tic u la r ly in th e p a s t 5 0 y e a r s T w e n tie th c e n tu r y riġ ęHqpp m e n ts in c lu d e th e is o la tio n a n d u s e o f in s u lin fo r d ia b e te s th e d is c o v e r y o f :ı Ř timic r o b ia l a n d a n tin e o p la s tic d r u g s a n d th e a d v e n t o f m o d e m p s y c h o p h a r m a c o lo g y t ad v a n c e s i n m o l ec u l ar b i ol og y , e n e t ics , ń d d r u g de s i gn s u g g e s t t ha t ne w d r u g ¥$lopment a n d p h a r m a c o lo g ie in n o v a tio n s w ill p r o v id e e v e n gr e a te r a d v a n c e s in th e tr e a tm e n t o f m e d ic a l d is o r d e rs in th is c e n tu r y j qosc ĥ 9İ b 03 eß ı i N o b e l p e ı so n a i T q ı iı ylMetchnikofi P a u l E iu lic h N O B E L P R IZ E P H A R M A C O L O G Y Y e a r A w a rd s ig n iĦc a ı ı t d is c o v u y in p h a m a c o lo gy 190 8 F iis t a n tiı n ic ro b ia l druce (m gi c bu llet) Z 9 J T lo a 感 靶 ト 剧 ? 坫 め to
  • 5. Scanned by CamScanner į ł Ł,l ť t ' . R Į,ţi y TjA Te x t B ' " o f p h . ' " ' " ì N O B E L P R IZ E P H A R M A C O L O G Y ' " h z N o be lP en o n s S ig n ific a n t d lı c o v e ry Si r )a q Es BlacJ G eı tr u de E l to n G e o ı g e ü H Hc ħ i n gs A ı f r ed G i h ı a n Adarti n R o dbe l J 1994 ı Jis c o v e zy o f G p r o te in s a n d th e J, a c e l ı s i ł £ Robeı tFunh80 【 o u is ı gn a rm F e rid l i 1998 R e c o g n iti o n ' ' " . ' ' " " . i g n Kän de l C arl sso n P a u l G i nee n ga r d E ric 2 000 R o le o i d o p a m in e in s c h iz o p h re n ia 'p iėh tra n s d u c lio n in th e n e r v o u s s y ' "mgrëi □ s c o P E o F PHARMACOĹo :ln The p hn m a co lo gy is a n e x pe r i m e n ta l s c i e n c e a n d o n e o f th e y o u n g e s t discipı ine¢ bHł æ h)o f the ba s i c m e d ic a l sciences Tħ e s c o p e o f p h a r m a c o lo g y js c o n s ta n tl y enĮ ġ jN Jts COntribution to m e d id ru l th e r a p y h a s m a d e its p o s iti o n in th e m e d íc a ] fiëR ln &Ĥ đ i8 medicines, o fgr e a te r im p o r ta n c e Its r e ı a tio n s h ip to th e o th e r m e d ic a l s c ie n c e s is in te r e s ti n g tha te n a bl e s m e đc a ı s h ı d e n ts to tı n d e rs ta n d th e b e tte r p o s iti o n o f th is s c ie n c e W ħ e n the r e is a n ĵm ba l a n æ in th e n o r m a l b o d il y p r o c e s s a p a th o lo g ic a l c o n d itio n (illn e s s )is p ese n t Th e n a dr u g o r p h a rm a c e u ti c a l a g e n t (c h e m ı c a ıp r o d u c t) is a d m in is te r e d to thė s u Ħ e re r b c u re the dis e a se d c o n d iti o n T ħe a c tio n o f th e d r u g in tr o d u c e d in th e b o d y to c u r e P a tho ge n i c s ta te is s h zd e d by th e p h a rm a c o Jo g y p ħ a r m a c o ı o g y u s e s c h e m ic a l s u b s ta n c e s to Pro du c e c ha n ge in fu n c ti o n a n d m o rp h o lo g y h th e Jiv ín g s y s te m (m e n & a n im a ls ) Jtis J a ı o v m by go in g thr o u g h the p a s t M s to ry o f r e s e a r c h a n d in v e n tió n s T1ì e tlt a lk a lo id m o tpM n e w a s iso l a te d fr o n ı p la n t o p itı m by th e G e r m a n A p o th e c a ry s e r h ı m e r in th e y e a r 1807 ı n 1828 w o he r sJm the s iz e d u r e a ı r o m a m m o n iu m c y a n a tE : e r h l N Į Ī4 0 C N N H 2 C O N H 2 A m m o n iu m c ya n a te U r e a m a de u re a w itho u ta kidn q y t he yea r 19oo A be la n d M s a s s o c i a te s is o la te d a d r e n a ı in (e p jn e p h r in e ) fr o m th e m e d u lı a o ra dren a lglan ds h the yea r 1901 R e i d H u n tis o la te d a c e ty Jc h o Jin e fr o m th e a d r e n a l g la n d s s in c e th e n a Ja r ge n u m be r o fn e w dru gs h a v e be e n s yn th e s iz e d a n d p r e p a r e d e v e r y y e a r ín th e s e ie n tiı ic ł ie Jd 艮 v o lm ı te e r s in th e la b o r a to r y T o d e te r m in e th e e ffic a c y a n d s a fe ty o f th e n e w p r o d u c ts (2 ) T h e o p tim a l c o n d itio n s o f u s e M e th o d ' (r o u te ) o f a d m in is tr a tio n o f d r u g i e To b e a d m in is te r e d o r a lly , b y p a r e n te r a l r o u te m a y h a r m th e concerned ndividual T ħ e n e w p r o d u c t s y n th e s iz e d o r in v e n te d r e q u ir e s r ig o r o u s p h a r m a c o lo g ie s h l d y a n d e y ąĮp a ł j o n to d e te r m in e its m e c h a n is m o f a c tio n th e r a p e u tic u s e s to x ic ity e tc T he s tu d y o f miĤ ųqfism a n d e x c r e tio n o f th e d r u g is m u s t to b e c o n d u c te d T h e c lin ic a l tr ia ı s a r e m a d e in tbę da ţ A t o r y o n a n im a ls a n d o n h u m a n v o lu n te e r s R e q p ira to ı ) P h i * Ðn lĺí) n C a rd ı o v a s c u ı a r P h a rm a c q ı o g y o J b T 9 in o J b o r r e z ıJ ı rn Ja d J P h . rm a c o ı o a r Vı ï ß lßJa į i U ĵ İlŔ i liJ Ħq 1 2 A d ı a o ra m re p re s e n tı n o th e a c o p e o f p h a rm a c o lo Ĥ v L - 囪 自 为 니 一 概 蚓 コ
  • 6. Scanned by CamScanner 妇 區 · 區 Ieral p h a rm a c o l m rđ T o x ic o d yn a m ic s d e s a rib e s th e h a r m fu l e ffe c ts th a t th e P T o x ic o k in e tic s e n c o m p a s s e s th e a b s o r p tio n d is tr ib u tio n b io tr a n s p h a rm a c o gn e tic s m s is a r e la tiv e ly n e w fie ld a n d d e a ls w ith th e s i n ı d y o f g e n e tic a lly C l c ľ p h a rm a c o lo g y C lin ic a l p h a r m a c o lo g y is th e d iv is io n w h ich d e a ls w ith th e pomjpand to x ic ity o f n e w d r u g s in h u ı n a n s It is o f g r e a t im p °r ta n c e fo r th e e ffe c tiv e a n d p h a r m a c o lo g ic a l e ffe c ts o f d r u g s in m a n It p r o v id e s in fo r m a tio n a b o u t th e u s e ħı ln e s s SafQiçbfd r u g s in m a n □ N A T U ? A N D S O U R C E O F D R T h àj àrg" " p r e s e n te d b y th r e e n a m e . . H ic h is c o n u n o n ly k n o w n a s s n e x i s o u r c e s o f d r u g s u u n i a g Ť Ţ Ţ ïï ' " R C E O F iiT eJiluq« ı t S y n th e tic y d tJb n ìĥ X ı S e m i s W th e tic M ic ro o rg a n ı s m In J ilJ n T q D N A R e c o m b ı n a n t T e c h n o ı o g y ïriJ i n i ł m u rll ı frĵr F ig 1 3 o r ig in n f th e d r u g ħo m d iffe r e n t s o lu c e s P la n t S o u r c e T h e d r u gs a r e o b ta in e d fr o m p la n t o r ig in p la n ts c a n b e u s e d a s th e r a p e u tic rę§ OjtĮ çęi in s e v e r a l w a y s It c a n b e u s e d a s h e r b a l te a s o r o th e r h o m e m a d e r e m e d ie s w h e n thoı q rg j c o n s id e r e d a s m e d ic in a l p la n ts T h e y c a n b e u s e d a s c r u d e e x tr a c ts o r s ta n d a r d e n r ic h e d fr a c tio n s in p h a r m a c e u tic a l p r e p a r a tio n s s u c h a s tin c tu r e s flu id e x tr a c ts p o w d e r P¥fsñn c a p s u le s w h e n th e y a r e c o n s id e r e d a s p h y to p h a r m a c e u tic a l p r e p a r a tio n s o r h e r b a l 哼 fles F in a lly p la n ts c a n b e s u bj e c te d to s u c c e s s iv e e x tr a c tio n a n d p u r ific a tio n P $gwi ĵ w e s to is o la te th e c o m p o u n d s o f in te r e s t w h ic h c a n th e m s e lv e s b e a c tiv e a n d u s e d a ŕifï' aļ ı kea d r u g e x a m p le s b e in g q u in in e d ig o x in a n d e r g o ta m in e 瞬 寧 礬 薛
  • 7. Scanned by CamScanner M i cro bio ı o gi◆ l S o ı trc e s M a n y life s a v in g d r u g s a r e o b ta in e d fr o m ń in g i m o u ld s a n d ba c te ria e g p e n iď l in h o m P e n ic illiu m n o ta h ı m c h lo r a m p h e n ic o l fr o m S tr e p to m y c es v e n e z u e ı a e gri s o ńrlv in f a n a n ti fu n g a l d r u g ) fr o m P e n ic iu iu m g ń s e o fu lv u m n e o m )l c in ħo m Str ep to m yc e s fra dia e a n d eptomycin fr o m S tr e p to m y c e s g r is e u s sH n & yn M t ti c So » n ce « So m e tim e s semiynthetic p r o c e s s e s a r e u s e d to p r e p a r e d r u Þ - w he n the sjm the si s o fd r u gs f c o m p le x m o le c u le s ) ı n a y b e d ifó c u lt e x p e n s iv e a n d u n e c o n cŕm ic a l o r w he n the n a tu ra lso u r c e s n ı a y yß e ld im p u r e c o 呷 o u n d s In th e s e s itu a ti o n th is m e th bd s p la y a n im po rta n t ro l e Fo r e x a m p le s a r e semiynthetic h u m a n in s u lin a n d 6 a m in o p e ilic ilĮa n ic a c i d d e ń v a tiv e s Th e se a r e p r e p a re d by c h e m ic a lly m o d ifyin g s u b s ta n c e s th a t a r e a v a ila b le f r o m īı a h tra lso u r c e im p r o v e to im p r o v e its p o te n c y e ific a c y a n d a ls o r e d u c e s id e e ffe c ts ßn i tßtlr l G e rı e ra l P h a rm a c o ı o g w 1 ı : ĥ r【 ı { i J S ĺ ĥ J í Z rrO " ? b io y Jł a o ntial D " t " W j F ig 1 4 B a s ic c o n c e p t o f e s s e n tia l d r u g s e s s e n tia l m e d ic in e lis t c o n ta in s lim ite d c o s t e ffe c tiv e a n d s a fe m e d ic in e s , w h ile th e o p e n p h a rm a c e u tic a l m a r k e t is flo o d e d w ith a la r g e n u m b e r o f m e d ic in e s m a n y o f w h ic h a r e o f ı
  • 8. Scanned by CamScanner L ■ . . ' ' " p t . ' " n t ial medicines ha s h p n l í □ T e x t B o o k o f P h ' " a c o lo ivfi ı z í I A T e x t B o o k o f P h a ' " ' " ı W V ° q d o u bdi d rr a lu e Th e c o n c e p t o f e s s e n tia l medicines h a s b e e n w o r ld w id e a m R O U T ES O F D R U G A D M IN IS T R A W 1 J YI o JI sJ In tJ ej R o u k o fa d m i n is tr a tio n a r e h v o m a in r o u tw o f a d m in is tr a tio n o f d r u g s (1) E n te r a l s n u li P a l R o u te H o u te ( 2) ıEn ien ı R o u te 3 n 0 U ı e e n te ra l ro u te includes o r a l r o u te (B y m o u th ) n a s a l r o u te s u b li n g u a l m u te a n d ıe c r o u ,îginal O n lR o u te ( B y M o n th) io v íi This is a ı u h 】 ra l r o u t o f a d m in is tr a tio n o f d r u g s Ti n e d r u g s in th e fo r m c a p su le s po w de rs m ù? u r e s e a l e a d m in is te r e d th r o u g h th is r o u te w w w a罗 」, A dr a n ta ge Ŕ iİ ĉ ūqq 1 M is ıo u is th e m o s t c o n v e n ie n t r o u te o f d r u g a d m in is tr a tio n J s ßn o ] iı J Z P a tie n tca n the pr e s c rib e d m e d ic i n e s M m s e lf S liT 3 T he n js n o p a in b the p a tie n t this r o u te is v e ry c o n v e n ie t n d e c o n o m ic a l 1 o ¡ ß3 o l D is a dマ至 此妇魯 區 o 7 닥 ·o h 厂 1 The e ffeđ o fdrugmby o r a l r o u te is d e la y e d 570qT0t ' Iti s n o ta n e m e rge n c y r o u te js T o Ja 9 Ī ĥ 3 T he in ila n t dr u gs c a n n o t be g iv e n th r o u g h th is r o u te o b n l 4 Thjs ro u te (z n n o tbe u se d in c a s e o f u n c o n s c io u s a n d n o n « o o p e r a tiv e p a tie n ţb ßu . V Ī )lİe o q q u e 5 C e rtain d r u gs c an n o t be giv e n th r o u gh th i s T o u te a s th e y a r e d e s tr o y e d b?gaótric en z ym es C ar e sho u ld be taJce n tha t s u fficie n t qu a n tity o f w a te r s h o u ld b e g iv e n to p a tie n t w i dru g to Pre v en t stic kin g o f dr u g i n o e s o p ha g ı ı s a n d to d e c r e a s e im ita n t e fe c t o f w e d ic in e s - Xx = X ° ty h ' " ' " h . s h ' ' " , giv e . ' ' " c in e s h h q u iį .. ' ' " N ı ı ı ı «o ı te T C ertai n dru p s c T 吕 - ps)" nth, XPOd ' " l o c" ' "ect . N d . " g iv e . In th , f. R m o f ' " a l gu tta e (n a s a l ' " '。 。, 忒 に 慧 鞣。 。 gs . ' " '" . ' " ' ' ' 一 d ' ''。 叩 诊 デ" ' P ı ie o ń n e a r e a d m in is te re d in th e fo r m o fn a s a l dris q ń ióJT j) 自由自 § ı U a l R o u te m l rKĝ ta b le ts a r e p la c e d u n d e r th e to n g u e s u c k e d T h i s r o u te is u s e d a s t】 hm n Aa?äiı ges (1) O n s e t a c tio n is q u ic k ŕ. X e H y . ' ' " m a M ' ' " m e . . ' " . ' " _ c tio n in th e liv e r is a v o id e d (p r e v e n tėd ) a r e n o t a llo w e d to s w a llo w o r c h e w th e ta b le t is k e p t b e lo w to n g u e T h is r o u te is a ls o u s e d to p r o d u c e lo c a l o r s y s te m ic e ffe c t C 1o tr im a z o le v a g in a l s u p p o s ito ń e s a r e u s e d h i c a s e o f rul vo v a g in a l C a n d id ia s is O th e r ı n e d ic in e s 1ĵk e M ic o n a z o le k e to c o n a z o le e tc a r e a ls o a d m in is te r e d b y th is r o u te R e c ta ı R o u te th e d r u g s th r o u g h th is r o u te in th e fo r m o f s u p p o s ito r y o r e n e m a a r e g iv e n to p r o d u c e lo c a l o r s y s te m ic e ffe c t G lu c o s e P a r a ld i h y d e c a n b e a d m in is te r e d th r o u gh th is r o u te C h lo rp r o m a z in e s u p p o s ito ń e s a r e g iv e n fa r v o m itin g c o n tr o l S u p p o s ito ń e s a r e m e d ic in e s in c o rp o r a te d in w a x y b a s e w h ic h m e lts a t b o d y te m p e r a tu r e T h e ı n e d ic a te d s u p p o s ito ń e s a r e s to r e d in r e fr ig e r a to r In d o m e th a c in s u p p o s ito ń e s a r e a d m in is te r e d fo r r h e u m a to id a r th r itis a m in o p h y u in s u p p o s ito r y fo r b r o n c h ia l a s th m a E n e m a is liq u id p r e p a r a tio n in tr o d u c e d in th e c o lo n EVacuatėn e n e m a is u s e d fo r p u r g a tio n e ffe c t R e te n tio n e n e m a is m e a n t fo r a d m in is tr a tio n fł mg ódo r sy s t em i c as we l l as for loc a l us e . x a m p l e co r ū s o n e is g i ve n thr o u g h thi s ro u t e in u lc e r a tiv e c o liū s tA i đ v án tdËe s o f r e c ta l ro u te Ł Ĵ rwÐ itaūon o f g a s tric m u c o s a is a v o id e d b y th is r o u te (2) T h e d r u g s w h ic h a re d e s tr o y e d b y g a s tr ic e n z y m e s g a s tric a c id ity c a n b e e b im o t it d m in is te r e d b y th is r o u te (3) th e m e d ic in e s w h ic h a r e d e s tr o ye d d u r in g th e fir s t p a s s th r o u gh liv e r c a n b e
  • 10. Scanned by CamScanner a bi 】 iv to pro du c e iı s b io lo g " a l e ff e c t D e Ħn itio n it is a p r o p e r ty o f th e d r u g n o t th e r e c ep ha p p e n s o n c e the d r u g is b o u n d b o u n d to th e r e c e p to r a n d e ffic a c y d e te r n ı in e s w h. D if¢ e r e n t dr u g s tha t b in d to th e s a m e r e c e p to r a n d p r o d u c e th e s a m e ty p e o f r e s p o n s e w jjj typ i ca lly d iff e r fr o m e a c h o th e r in te r m s o f th e ir a ffin ity fp o te n c y ) a n d / o r e tftc a c y Th e te rn ı p o tem y js u s e d a s a c o m p a r a tiv e te r m fo r d is tin g u is h in g w h ic h a g o n is t h a s a h ig h e r a ffi n iy fo r a g i v e n r e c e p to r T h e d r u g w h ic h c a n p r o d u c e a n e ffe c t a t lo w e r d r u g c o n c e n tr a tio n s įs m o r e Į x )te n t (in Figuri 5 D r u g A is th e m o s t p o te n t a n d D r u g D is the ı e a s t p o te n t) 0 1 1 0 10 1 0 0 0 1 1 0 1 0 1 0 0 ł o m gł ¢ M U LŁ ( s e m ū o g s ¢ d e ) ș D r u g ţ (n M Æ )(s e m iı o g s c a ı e ) Ħ& = S cb r m a lic ū lï ı s h a tio n o f th e doseresponse c u r v e s fo r a s e d e s o f a g o n is ts (A B C a n d D ) th a t h ar e & e s a m e e fó c « J b ı ı t d iH Er in t- · o f th e ir p o te n c y T h e m o s t p o te n t d r u g (D r u g A ) h a s th e lo w e s t F m T a ln q a n d is a p p m « im a te ly 2 0 30 fo ld m o r e p o tm t th a n D r u g D : ' Im F ig 1 6 C o m p e titiv e a n d n o n c o m p e ū ū v e A n ta g o n is m Jių iv ÐrIT zJeirı o
  • 11. Scanned by CamScanner ħ ? the r i m ı e a se jn the dr u g d o s e d o e s n o t p r o d u c e a n y a d d itio n a l r e s p o n s e w h e n o n re cepto rs to pro du ce the r e s p o n s e a ll th e r e c e p to r s a r e n o t o c c u p ie d to p r o d u c e thė m a x i m a l re spo n se by a 6 01 a go n is t i e e a c h c e ll o r tis s u e h a s s o m e r e c e p to r s u n occupi w hiđn øy be calle d spa r e re c e p to rs M ax i m u m respo n se is p m d u c e d b y a g o n is t a t a c o n c e n tr a tio n th a t d o e s n o t r e qu ir e ı x cu pa n cy o fthe re c e p to r T h e y a r e n o t M d d e n o r rm a v a ila b le W n e n th e y a r e o c c u p ie d the y can be co u ple d to re s po n se T he y d o n o t ? fe r fr o m th e n o n s p a r e r e c e p to r M a x R e s p o n s e S pın ĝ , ı tmnnlblı c o n c e n b a u o n ı s 1o o hı g h th e s p a re r= c ÐĦo rs a re o c c u p ı e d andma=bnaı msponselsdimı nihed'Reprentedfn D & E ) įj F i 1 7 E ffe c t o f S p a r e r e c e p to r s 1o 3 SPare recePto«s n u y be de m o n s tr a te d b y u s in g ir r e v e r s ib le a n ta g o n is t to p r e v e n t bindiģo f 4 L m n s? pro dt« e an u n dim in is h e d m a x im a l r e s p o n s e in p r e s e n c e o f A n irr e v e iėible m a 9o n jst b av ai 】 a bl e r e c ep to rs T h e sp a r e r e c e p to r c o n c e p t c a n b e sh o w n w h e n th e agiİiist W by addiof b x i n( cu r a r e ) T h is to x in o c c u p ie s a t le a s t 5 0 % o f r e c e p to r s B u t știJ1 1 1u tthiey w a e n o Erequ ir ed fo r a c o m p le te ly n o rm a l tw itc h o f A c h ddktio i s a chim ūc dise a se c ha r a c te riz e d b y d r u g s e e k in g a n d u s e th a t is W m p usi v e . D I X cV gEs tha to6cu b co n tro Ļde spite h m h c o n se qu e n c e s a n d i n i n tere o ccw o v er ti m e w ith dr u g u s e c h a lle n ge a n a d d ic te d p e rs o n s s e n c o n tr o l M o s t d ru g s affe c t th e b r a in . R e w a r d c i r c u it b y flo o d in g it w ith th e c h e m ic a l m e s s e n g e f d o p a m in e T h is o v e r s tim u la ū o n o f th e r e w a r d c ir c u it c a u s e s th e in te n s e ly p le a s u r a b le m g h o v e r tim e th e b r a in a d j u s ts to th e e x c e s s d o p a m in e w h ic h r e d u c e s th e M g h th a t th e p e r s o n « r s t ta k in g th e t b a n e ffe c t k n o w n a s th e h ig h th e y fe lt w h e n n ī b iiiilaiı fe e ls c o m p a r e d to t e n t to le r a n c e X S o c ı a !e n v ı :" T ra u m a & a b u s e 19 ļ ) G e n e tic s e th n ic ı ty @ £ 二 c 5 l? g e n d e r 争 A d d ヒ划ö れ キ p p o o r s o c ia l s k iı ls u n s ta b le fa m ily æ p e e r p re s s u re = " ? M e n ta ı iı ı nes Z ï > , F ig 1 8 A m a jo r fa c to r in v o iv e s in th e d r u g a d d ic tio n D r u g a d d ic tio n in fo r m a tio n in d ic a te s a n y ty p e o f d r u g c a n b e a b u s e d o r c a u s e ċ u n g a d d ic tio n D r u g a d d ic tio n in v o lv e s e a s ily a c c e s s i b le d r u g s lik e to b a c c o a n d a lc o h o l a s w e ll a s ille g a l d r u g s lik e c o c a in e a n d h e r o in S o m e d r u g a d d ic tio n s Ľ k e a lc o h o lis m a p p e a r to b e d e c lin in g w h ile o th e r s lik e m e th a m p h e ta m in e a d d ic tio n is o n th e r is e D r u g a d d ic tio n in fo in d ic a te s th e fo llo w in g d r u g s a n d d r u g ty p e s a r e c o m m o n ly a s s o c ia te d w ith 山n g a d d ic tio n A lc o ho ı m o s t w id e ly a b u s e d d r u g w ith 2 0 % o f u s e r s b e c o m in g d e p e n d e n t o n it a t s o m e P o ī · Ţ O p ia te s s u b s ta n c e s d e ń v e d fr o m th e o p iu m p o p p y th e m o s t c o īn m o n d r u g a d d ic tio n is th a t o f h e r o in C òŁ a in e c r a c k u p to 10 % o f u s e r s g o o n to h e a v y d r u g u s e A m phe ta m i n es Ilk e c r y s ta l m e th u s e o n th e r is e in r u r a l c o m m u n itie s H à11u c in o g e n s lik e P C P L SD a n d m a r ij u a n a o fte n c o m b in e d w ith o th e r d r u g s P res c r i p ti o n m e dic a ti o n s u c h a s o x y c o d o n e a n d m o r p h in e O tì īe r c he m ica l s lik e to b a c c o s te r o id s a n d o th e r s □ T O L E R A N T h e to le r a n c e m a y be đ e f iï te cl a s u n u s u a l r e s is ta n c e to th e o T d in a r y d o s e o f a d r itg ıh i c o n tin u o u s a n d r e g u la r u s e o f d r u g s m a y c a u s e to le r a n c e It m a y b e a c q u ir e d c o n s ta n t u s e o f d r u g o r it m a y b e c o n ge n ita l R e p e a te d a d m in is tr a tio n o f d r u g p r o d u l 曜 ぼ 薩 ボ 」
  • 12. Scanned by CamScanner r r r r r r r r r r ŕ ĺ ŕ ĺ ŕ ĺ ŕ ĺ ŕ ĺ ĺ ŕ ĺ ŕ ĺ ŕ ĺ ŕ ĺ ŕp i , T . ". e ffe c tiv e The c e llu la r a c c lim a tiz a tio n to th e p r e s e n c e o f a d r u g ís tr u e to leranc " in a r uy the dru g p £ b e c e a l d fa ile d to r e s p o n d '" rugconcentrationswhich . " - x '" T oļ«ı a n cıc a n bıdı l ı m d a s th a re d u e lle n ı n re s p o n s e to th e d ru g a fte r re p e a ı e d a d m ı n i s tr a u o n s M ect lha tw a s o n c e o M a ïn a d a t a ı o w e r d o s ı :, e l a m a ( A ) N o dtu l (日 ) Fı rstdl (c ) = " (D ) = ł- . . 参 熟 . . . S M ï llo n W th d r w I T l e ra e = = = = X o f5 = = i '" n " " · ' " q e pe a te d u s e r re q u ir d a e y e r l h D r D į i Ħg 1 9 F u n d a m e n ta l c o n c e p t o f T o le r a n c e W ti e iı the dr u g i s dis c o n tin u e d th e To le r a n c e d l e n ica1G lycn yl tri n itra te is u s e d in d y n a m ite fa c to r ie s T h e n e w w o r k e r s ín d y n a diite facto ń es w hen i n ha le v a p o u r s o f G iy c e ry l tr in itr a te c a u s e ħ e a d a c h e T ħ e w o r k e r s o f J i s l o s t an d ifthe y r g tu m to w o r k th e y a g a in e x p e r ie n c e h e a d a c h e : j 2 i ; ı lG e n e ra l Pha rm aco lo 38 4 r R E su LT n rı a lıb es s 驟鸾騾黨" ' 对 병阳園踊 贸 可 ˜ 蠶 £ 唱 寓 俨 饨 da n Be f q u ı c l dy D ru g D ep e n d e n c e sl a n a l l ħ o m lh e a ya s a n d n M e r Ĺ , ı 0 0 0 s a n ae s m a c h M a bra in d n w l y H e a n ratedropı TW ı ı s e ı r o v e rhe a ı in g ls a rı s k ywlessanergldnBe u ge n t W I" ' " trate s pe e d . u p B ı o o d F ig 1 1 o A d ia g r a m s h o w s th e e ffe c t o f d r u g d e p e n d e n c e W ith r e p e a te d u s e o f h e r o in d e p e n d e n c e a ls o o c c u r s It d e v e lo p s w h e n th e n e u r o n s a d a p t to th e r e p e a te d d r u g e x p o s u r e a n d o n ly fu n c ū o n n o r m a lly in th e p r e s e n c e o f th e d r u g W n e n th e d r u g is w ith d r a w n s e v e r a l p h y s io lo g ie r e a c tio n s o c c u r T h e s e c a n b e m ild (e g fo r c a ffe in e ) o r e v e n life th r e a te n in g (e g fo r a lc o h o ı ) T h is is lcn o w n a s th e w ith d r a w a l s yn d r o m e In th e c a s e o f h e r o in w ith ? a w a l c a n b e v e r y s e r io u s a n d th e a b u s e r w iM u s e th e d r u g a g a in to a v o id th e w ith d r a w a l s y n d r o m e T he s ig n s a n d s y m p to m s d is p la y e d M o s t a ge n ts c a u s e a c h a n g e in th e le v e ı o f c o n s c io u s n e s s u s u a lly a d e c r e a s e in r e s p o n s iv e n e s s S u p p r e s s io n o f b r a in a c tiv ity c a n b e s o s e v e r e th a t th e p e r s o n m a y s to p b r e a th in g w h ic h c a n c a u s e d e a th A 1be m a tiv e ly th e u s e r m a y b e a gita te d a n g r y a n x io u s a n d u n a b le to s le e p H a l l u t i o n s a r e p o s s iÞ 1e A b n o r m a l v ita l s ig n s (te m p e r a tu r e p u ls e r a te r e s p ir a to r y r a te b ı o o d p r e s s u r e ) ąr e p o s s ible a n d c a n b e life t y·a te n in g c h e s t p a in is p o s s i b le äri d c a n b e c a u s e d b y h e a r t o r 1g d a m a g e f r o ° , d . Ĥ i ju s e A b d o m in a ı p a in n a u s e a v o m itin g a n d d ia r r h e a a r e p o s s i b le V o ı n itin g b lo o d o r b lo o d in b o w e l m o v e m e n ts c a n b e ı ife th r e a te n in g W ith d r a w a l s y i nd r o m e s a r e v a r ia b le d e p e n d in g o n th e a ge n t b u t c a n b e life th r e a te n in g @ 1 T A C C P H s I T he r e p e a te d a d m in is tr a tio n o f d r u g s a t s h o r t in te r v a ls p r o d u c e s le s s e ffe c t is c a lle d ta c c p h yla x is to T h e E p h e d ń n e 50 ı n i]ligr a m s h o w s e r e d u c in g e a n d th e s a m e e « e c t c a n n o tb e a c h ie v e d b y a d m in is tr a tio n o f th e s a m e d o s e T he c u r v e fo r th e a c tio n o f 5o m g a n d 3 o m g o f e p h e d r in e a t e r e d to a p a tie n t
  • 14. Scanned by CamScanner l ı ° L r ? iA T e x t B o o k o f P h a r m a c o ı v ° Y J pro du ce the requ i r e d e ffe c t T h e r e g u la r in ta k e o f a lc o h o ls o p iu m m lp hilı e R E s u LT H H p!s B = s s the dru g pn se n c e a n d fa ile d to r e s p o n d to d r u g c o n c e n tr a tio n s w h ic h a r e o r d in a r i ly R Es u LT : Th e bo dy ca n t o c c u rs M a ūi i dy w o n t H e u tı a le dro ps le a v in g the = ' its e w Oerheaı ingl s a rls k «s io f[u i$ In i a c do n s ris e s A Ll e e M e s s age s to m u s c l e s ı h o b Lvnu a ' " ' l e gs ca n tm o w w e lt K w m h d « ū a ū ı o b a n « w F ig 1 1 o A d ia g r a m s h o w s th e e ffe c t o f d r u g d e p e n d e n c e w ith r e p e a te d u s e o f h e r o in d e p e n d e n c e a ls o o c c u r s It d e v e lo p s w h e n th e n e u r o n s a d a p t to th e r e p e a te d d r u g e x p o s u r e a n d o n ly ń in c tio n n o r m a lly in th e p r e s e n c e o f th e d r u g W n e n th e d r u g is w ith ? a w n s e v e r a l p h y s io lo g ie r e a c ū o n s o c c u r T h e s e c a n b e m ild (e g fo r c a ffe in e ) o r e v e n life th r e a te n in g (e g fo r a lc o h o l) T h is is ı m o w n a s th e w ith d r a w a l s )m d ro m e In th e c a s e o f h e r o in w ith d r a w a l c a n b e v e r y s e r io u s a n d th e a b u s e r w iu u s e th e 山u g a g a in to a v o id th e w ith d r a w a l d r o m e T he s ig n s a n d s y m p to m s d is p la y e d M o s t a g e n ts c a u s e a c h a n g e in th e le v e l o f c o n s c io u s n e s s u s u a lly a d e c r e a s e in r e s p o n s iv e n e s s S u p p r e s s io n o f b r a in a c tiv ity c a n b e s o s e v e r e th a t th e p e r s o n m a y s to p b r e a th in g w h ic h c a n c a u s e d e a th A 1te m a tiv e ı y th e u s e r m a y b e a g ita te d a n g r y a n x io u s a n d u n a b ı e to s le e p H a l l u t i o n s a r e poss1e A b n o rm a l v ita l s ig n s (te m p e r a h u e p u ls e r a te r e s p ir a to r y r a te b lo o d p r e s s u r e ) a r e p o s s ib le a n d c a n b e life thr e a te n in g c h e s t p a jn iß p o s s i b le d Ca' b e c a u s e d Heat' . IUg d a ń a g e f r o g iiuse A b d o m in a l p a in n a u s e a v o m itin g a n d d ia r r h e a a r e p o s s ib le v o ı n itin g b lo o d o r b lo o d in b o w e l m o v e m e n ts c a n b e life th r e a te n in g w ith d r a w a l s y i nd r o m e s a r e v a r ia b le d e p e n d in g o n th e a ge n t b u t c a n b e life thr e a te n in g m T A C C P H Y E B T he r e p e a te d a d m i n is tr a tio n o f d r u g s a t s h o r t in te r v a ls p r o d u c e s le s s e ffe c t is c a lle d ta c cp h yla x is to T h e E p h e d r in e 50 m illigr a m s h o w s c u r v e r e d u c in g c u r v e a n d th e s a ı n e e ffe c t c a n n o t b e a c h ie v e d b y a d m in is tr a tio n o f th e s a m e d o s e T h e c u r v e fo r th e a c tio n o f 5 o m g a n d 3o m g o f e p h e d r in e a d m in is te r e d to a p a tie n t s h o w s l ik e this Th e s a m e e ffe c t b y a d m i n is te r in g s a m e d o s e o f 5 o m g o r 3 o m g o f e p h e d r iï ı e ą £ Ê I A ) Ii o a = ( B ) n r s t d g ( c ) . . . (D ) S'"nddrug ı x p o s u Ħ B X p o s u c . 参 粼 磉 . , 移. . = 班◆ ◆ ' " U " " P ' " , d ' " " q u lre d . " " l h u n d . D o i lig L 9 Fu n d a m e n ta l c o n c e p t o f T o le r a n c e y W M n the dr u g i s dix o n ti n u e d th e to le r a n c e u s u a lly d is a p p e a r s a fte r a tim e T h e lađo ri e s w he n i n ha l e v a po u r s o f G iyc e ry l tr ir ı itr a te c a u s e ħ e a d a c h e T h e w o r k e r s o f he ada w tm ū e y ar e a w a y fr o m the fa c to ry fo r a lo n g p e r io d o f tim e th e a c q u ir e d bk ppi n g t he wof the d r u g c a n r e s l it n " peciı ic w ith d r a w l
  • 15. Scanned by CamScanner i 22 = P r m lA T e x t B . o k o f P h ' " . ' " W íy d qı d æ a im o t be o bb i n e d To o b ta in s a m e e ffe c t M g h e r d o s e o f e p h e d rin e is r e q u ir e d to h a dm i n is t e re d . The u s u a la du lt d o se o f e p h e d ń n e b y m o u th is 15 ' g to 60 K h ild r . . UP be giv e n thR e ti m e s da ily tst m d d o s e do s e M e o d s o fa dm i n is h a ti m ıd r u gs a n d fa c to r s w h ic h m o d w th e ir d o s e o u r a tte n tio n w o u ld be dim ted b n ı e c ha n is m o f d r u gs a c tio n b y k e e p in g in m in d th e c o n tr a in d ic a tiċm s an d si de e ft e cl s o fd □ Į D IO SY N C Dh ı g idi o syn a a sy i m t r n w a r d r e a c tio n s to d r u gs th a t o c c u r in a s m a ll fr a c tio n o fJ» ti e n b a n d ha T e n o o bv i o u s re l a ti o n s M p to d o s e o r d u r a tio n o f th e r a p y T h e liv e r is a qumtgetfmbńđ y Tħ e iä o s JT ı e re s y in d u c e ĵn m a n y w a y s u c h a s b Æ E S O F ı D ı O S Y N E R E S Y ł ı ı ł 罗 蒙 蕪 , 纏 。 · fL1linducliono f id io sJm m a s y tli '" " " " da n dm X = " " d a lle rg e n T F ig 1 1 2 A d ia gr a m s h o w s th e ty p e o f a lle r g y ı ı in e s (itr ti c a r ia )a r e s k in r e a c tio n s th a t a p p e a r a s itc h y s w e u in g s a n d c a n o c c u r o n a n y p a r t o f th e b o d y It c a n b e c a u s e d b y a n a lle r gic r e a c ū o n s u c h a s to a fo o d o r m e d ic a tio n b u t th e y a ls o m a y o c c u r in n o n a l le r gic p e o p le T y p ic a l M v e s y m p to m s a r e R a is e d r e d w e lts a n d In te n s e itc M n g A tta gic i ĝc z a n a It is a n a lle r g ic r a s h th a t is u s u a lly n o t c a u s e d b y s k ĵn c o n ta c t w ith a n a lle r ge n a n d fe a h ı r e s th e fo llo w in g s y m p to m s Itc h in g r e d n e s s a n d o r dryiess o f th e s k in r a sh o n th e fa c e e sp e c ia lly c h ild r e n r a s h a r o u n d th e e y e s in th e e lb o w c r e a s e s a n d b e h in d th e kn e e s e sp e cia lly in a d u lts A ı ı e lg ic s ho c k ( a n a p h yla x is o r a n a p h yla c ū c s h o c k) T h is is a life th r e a te n in g r e a c tio n th a t c a n a ffe c t a n u m b e r o f o r g a n s a t th e s a m e tim e It typ ic a lly o c c u r s w h e n th e a l le r g e n is e a te n (fo r e x a m ple fo o d s )o r i n j e c te d (fo r e x a m p le a b e e s tin g) A lle r g ic s h o c k is c a u s e d b i d ĵla te d a n d ı ea ky blo o d v e s s e ls w h ic h r e s u lt in a d r o p in b lo o d p r e s s u r e s o m e o r a ll o f th e fo llo w in g sym p to m s m a y o c c u r H iv e s o r r e d d is h d is c o lo r a ū o n o f th e s k in N a s a l c o n ge s tio n S w e 】 Ľ n g o f the th ro a t s to m a c h p a in n a u s e a v o m itin g s h o r tn e s s o f b r e a th , w h e e z in g a n d lo w b lo o d p r e s su r e o r s h o c k 羹 難 鑿 - 。 一 毫 秘 国 纛 园 罾 国 至 葛 践
  • 16. Scanned by CamScanner I M IA T e x t B o o k o f P h a r ņ a c o M A ı teı g ic ey es f ; Bı lerg ic c ı m jM c tip itis )is in fla n ru n a tio n o f th e ti s s u e la y e r s (m e rrı b r a r ı 二 二 c o v e r the s u rfa c e o fthe e ye b a ll a n d th e u n d e r s u r fa c e o f th e y lid T h e in fla m m a " / tha t a re su lt o f a n a lle r gic r e a c ti o n a n d fe a tu r e s R e d n e s s u n d e r th e lid s a n W a te ry itchy e ye s a n d s w e llin g o f th e m e m b r a n e s Y e D v e r l o d , n,ct'Ts M e cha n ism o f dru g a lle ı g F D r u g h yp e r s e n s itiv ity r e s u lts fr o m in te r a c tio n s b e tw e e n a pha rm a co l o gi e a ge n t a n d th e h u m a n im m u n e s y s te m T h e s e typ e s o f r e a c tio n s c o n s tih rte o n l y a sm a l lsu bse t o fa 】 1 a dv u s e d r u g r e a c ū o n s A U e r g ic r e a c tio n s to m e d ic a tio n s r e p r e s X a s pecific ? g hw w w itiv ity r e a c b o n s m e d ia te d b y lg e b r u n u n == = °ĥ , Th e n ı o s t i m p a r l a n t d r u g re la te d ris k fa c to r s fo r d r u g h yp e r s e n s itiv ity c o n c e r n th e c h e m jca l pro pe rti es an d m o le c u la r w e ig h t o f th e d r u g L a r g e r d r u g s w ith g r e a te r s tr u c h ir a l c o m ple x ity ( e g n o n h u m a n p r o te in s ) a r e m o r e Ľ k e ly to b e im m u n o g e n ic H e te r o lo g o u s a n ti s e ra s tre p to 】 dn a s e a n d a r e e x a m p le s o f c o m p le x a n tig e n s c a p a b le o f e lic itin g hyp erse n sitiv ity re a c tio n s M o s t d r u gs ħ a v e a s m a lle r m o le c tı la r w e ig h t (le s s th a n l0 00 da lton s ) bu t n a y sti ll be c o m e im m u n o g e n ic b y c o u p lin g w ith c a r r ie r p r o te in s s u c h a s a l bu m i n to fo rm sim ple c h e m i c a 1 e r c o m p le x e s (h a p te n ) Ė ) 国 Fig ' '" y s t, " « . ' " g r a m o f ' " r m = R e x " i p b ' ' " n A b ' ' " . " D iģtr ib u tio n ņ L i 4 1 A B S O R P T ı O N A b s o rp tio n is d e fin e d a s th e p r o c e s s o f m o v e m e n t o f m c h a n g e d 山u g fr o m th e s ite o f a d m in is tra tio n to th e s y s te m ic c ir c u la tio n T h e p a s s a g e o f d Ju g fr o m its s ite o f a d m in is tr a tio n to its e n tr y in to b lo o d s tr e a m is c a lle d d r u g a b s o r p tio n T h e a b s o r p ū o n o f a d r u g r ėfe rs to its e n tr y fr o m th e r o u te o f a d m in is tr a tio n s ite to a b s o r p tio n in b lo o d s tr e a m a n d p a s sa ge o f d r u g a c r o s s c e ll m e m b r a n e s T h is p a s s a g e is r e s tr ic te d b y th e lip id s b a r r ie r p r e s e n t a t th e p e r m e a b le m e m b r a n e T he p r o c e s s o f a b s o r p tio n m a y b e s im p le d iffu s io n T h e d r u g s lik e u r e a a lc o h o l e a s ily a bs o r be d b y s i m p le d iffu s io n th e c e l l m e m b r a n e is a lip id b ila y e r s o th e lip id s o lu b le d r u g s d iffu s e q u ic k ly th a n w a te r so lu ble dru g s T h e c e ll m e ı n b r a n e is m o r e p e r m e a b le to n o n io n is e d d ru g s in c o m p a r is o n to io n i s e d w a te r s o lu b le d Ju gs th e dr u g m a y b e a b s o r b e d b y a c tiv e tr a n s p o r t p r o c e s s th e io n s w h ic h a r e tr a n s p o r te d b y this a c tiv e tr a n s p o r t p r o c e s s a r e K + N a + r a m in o a c id s o r g a n ic a c id s a n d b a s e s w e a k e le c tr o ly te s in io n is e d fo r m T h e d r u gs lik e p )x im id in e s glu c o s e a r e tr a n s p o r te d b y th is P r o c e s s T his p r o c e s s is m o r e r a p id th a n s im p le d ifħ rs io n P in o c y to s is is th e p r o c e s s o f a b s o rp tio n in u n ic e l lu la r o r ga n is m s lik e a m o e b a T h e c e l l in th is Pr o c e s s ta ke s u p flu id fr o m its s u r r o u n d in gs T h e m a j o r r o u te s o f d r u g a d m in is tr a tio n in c lu d e a ) o r a l (e n te r a ı · o r v ia th e in te s ti n e ) b )P a re n te r a ı (o the r th a n th e in te s tin e ) s u c h a s in tr a m u s c u la r (i m ) o r s u b c u ta n e o u s (s c ) 回国团团声 攤 明 二 聲 = 醒盛翩 然弊鱸 韉 。 酢 i蠲 "
  • 17. Scanned by CamScanner 一 二 義 羹 弊 囊 覊 難 礬 鞯 囊 贓 - 佇 廿 一 轻 瓠 娟 霾 4 The a bso q ti o n o fthe dru g thr o u gh s u b l in gu a l r o u te w h ic h is H o o r o f m o u th c a v ity is sm a u i n testi Iı e ı ha n t sto n ı a ch n e b rge r the s u r fa c e a re a o f a b s o r b in g m o r e w ill b e 5 £A c i dic dr u gs a re ra pi dl ' " n " " t , i x - a l a d m in is tr a tio n w h e r e a s E p h e d rin e i n sm a llin te s tin e s th is c a u se s th e d e la y in F!' 囌 辦 驪 瓏 。 覇 项 戳 部 鲻 襯 飘 驢 M e m b r a n e T r a n s p o r t を 参 p a s s iv e A c tiv e v la m a in ly b y T P r i v e r n tra n s p o r t er s : > 4 7 = (P U m p s ) S im p l e F a c iı i ta te d Ī d i ffu s io n v ţ p rim a ry S e c o n d a ry v ia v a rio u s v ia ı o n ĺ tra n s p o rte rs c h n n e s / 11 F ig 1 16 M o d e o f tr a n s p o r te r P a s s iv e m e m b r a n e tr a n s p o r t In p a s s iv e tr a n s p o r t th e d r u g m o le c u le u s u a lly p e n e tr a te s b y d i ffu sio q a lo n g a c o n c e n tr a tio n gr a d ie n t b y v ir tu e o f its s o lu b ility in th e lip id b ila y e r Su c h tr a n s fe r is d ir e c tly p r o p o r tio n a l to th e m a gn itu d e o f th e c o n c e n tr a tio n gr a d ie n t a c r o s s th e m e m br a n e
  • 18. Scanned by CamScanner : '" " " · a n d in te m a liz e d b y th e c e ll E x o cy to s is is th e d u r a b le p r o c e s s b y w h ic h a c e l l d ir e c ts th e c o n te n ts o f s e c r e ta r y v e s ic le s o u t o f th e c e ll m e m b r a n e T h e s e m e m b r a n e y b o 1Jn d v e s ic le s co n ta in s o lu b le p r o te in s to b e s e c r e te d to th e e x tr a c e llu la r e n v ir o n ı n e n t a s w e l l a s m e ı nb r a n e pro te i n s a n d lip id s th a t a r e s e n t to b e c o m e c o m p o n e n ts o f th e c e 】 1 m e m b r a n e 1 14 3 B I O A V A ı LA B ı L ı T Y D e fi n itio n : T h e F r a c tio n o f a d o s e o f d r u g th a t is a b s o r b e d fr o m its s ite o f a d m in is tr a tio n a n d re a c he s i n a n u n c h a n ge d fo r m th e s y s te m ic c ir c u la tio n is c a l le d b io a v a ila b i lity Th e p e rc e n ta ge o f th e d r u g a b s o r b e d is a m e a s u r e m e n t o f th e d r u g fo r m u la tio n s a b ility to de liv e r the d r u g to th e ta r g e t s ite A m o u n t a b s o r b e d is c o n v e n tio n a lly m e a s u r e d b y o n e o f tw o c r ite r ia e iM e r 1l e a r e a u n d e r the ti m e p la s m a c o n c e n tr a tio n c u r v e (A u c ) o r th e to ta l (c u m u la tiv e t a m o u n t o f d r u g e x cr e te d i n th e u r in e fo llo w in g d r u g a d m in is tr a tio n a c c o r d in g to th e B o s to n U n iv e r s ity Sch o o l o f M e d ic in e A lin e a r r e la tio n s h ip e x is ts b e tw e e n a r e a u n d e r th e c u r v e a n d d o s e w he n th e fr a c tio n o f d r u g a b s o rb e d is in d e p e n d e n t o f d o s e a n d e lim in a tio n r a te (h a lf-M e ) a n d v o lu m e o f d is tr ib u tio n a r e in d e p e n d e n t o f d o s e a n d d o s a ge fo r m F i 1 17 T n n m t n f d m p m n lp m lp ç h r v = r in u # n " p R
  • 19. Scanned by CamScanner ı Ţ B o o k o f p h a r m a c o lo g y To cı *v ı ł 【 w a M T C Ż ı » * u ď a d ie n A U c 一 r S u b ħ ıı a p e u ū c ı e v e ı ! m ı a ı ln B ) r ' E u m ïn a tïo n p ha s e ģ rį O « T m T im e 1 18 B io m ū a b iliı r A l i n m Ĥ y a f ū e n la ti o n s hip b e tw ee n a r e a u n d e r th e c u r v e a n d d o s e m a y o c c u r il fa r e x am p h Ĥ e a bw li a ıS is a s a tu r a b le o n e o r & d r u g fa ils to r e a c h th e s y s te m ic 1aı iı mbecansea{ e g bi ndin g o f d r u g in th e in te s tin e o r b io tr a s fo r m a tio n in th e l iv er du ? g ū e fi ns t b a ı ßi t ı ]u o u gh the p o r ta l s y s te m U 4A D I STR IB U TI O N D i sb i bu ūo n i n r o ł v es a re v e n ible tra n s fe r o f a d r u g be tw e e n c o m p a r tm e n ts It is d e fin e d a s e te v m ibı e transfer o f dr u g be tw e m o n e c o m p a r tm e n t to a n o th e r T h e b lo o d to ta l bciy w a le e x b a c el lu 】 u lym pha ū c a n d c e r e bro sp in a l flu ids a r e in v o lv e d in th e m o v e m e n t òf a dru g ı hro u gh d ı e bo dy D e pe n ä n g u po n its ch m c a l a n d p hys ic a lp r o p e r tie s th e d r u g m a y he bo u n d to P pr o te i n s o r diss o l v e d in b o d y fa t d e la yin g its p r o g r e s s to its s ite o f act io n m e tabo l ism o r e x a e tio n 1ti s a P o cess w he n the dru g j s a bso rbe d in the b o d y it i s d 沁出b u te d to v a r io u s b o d y tis s u e s ar d ĺl u i ds The d w hich pa ss ea sil y thr o u gh c e ll m e m br a n e s a c h ie v e w id e d is tr ib u tio n an d dru gs w hid ıdo n o t pa ss e n o u gh c e l l m em b r a n e h a s lim ite d d is tr i b u tio n T h e d r u g f ree dru g EJ ed m j a aIc* cu h ti n u h a se o fprggn a n t w o m e n d r u g e n tr y in to fe ta lb lo o d c ir c u la tio n is f e ◆ ci rn ila ti o y bl o od pt a cen ta lba n ie r T hi s ba rrie r e x is ts b e tw e e n m a te r n a l a n d 簌 認隹 颀.。 ' " , 。 。 , , 囀 hp i,二 。。。 。 '" i' " - 。 。 drugı rp jàso lu bı e n te rs the e r al ne p o u g s ys Ł em thro u gh 1 1 1 d l ra in ba rrie r Geneø cihı a c o lo g w ■ dr u gs c a n b e m e ta b o liz e d b y o x id a tio n r e d u c tio n h y d r o ly s is h y ? a tio n c o n j u g a tio n c o n d e n s a tio n o r is o m e r iz a tio n w h a te v e r th e p r o c e s s th e g o a l is to m a k e th e d r u g e a s ie r to e x c re te p l m se J T M c ti o n M a n y d r u g s m e ta b o lis m o c c u r s in 2 p h a s e s 1t in v o lv e s c o n j u g a tio n w ith a n e n do ge n D u s s u b s ta n c e (e g 9 lu c u r o n ic a c id s u lfa te , 8ly c i n e ) th e s e r e a c tio m a r e th e tic M e ta bo l ite s fo r m e d in s yn th e tic r e a c tio n s a r e m o r e p o la r a n d th u s m o r e r e a d i ly e x c r e te d b y the kidn e ys ( in u rin e ) a n d th e liv e r (in b ile ) th a n th o s e fo r m e d in n o n s yn th e tic r e a c tio n s d u g ro u p r ro v ı o e O u t F u n c t io n g ro u p F IB 1 1 9 A s y s te m a tic d ia B r a m o f m e ta b o ı is ï n o f d r u g
  • 20. Scanned by CamScanner r e @ja t e x t b o o k o f p h ıÆ m w e tic de d ĵd e n cy " drug° H e i u T n " - n b e in h e ritn A the ge n e ti c de d ĵd e n cy in dr u g m e ta b o lis m d r u g m e ta b o lis in g e iu lm te s c a n D m g m e tabo 】 i sm is di fĺe ı e n t h species In ra b b it a tr o p in e is m e ta b o lis e d đ u e to o fenzmealropinase H u n u n s a re 】 a c k o f th is e rn m ı e s o a tr o p in e is to x ic to ŞŞ n o n ro × f c 协 labb让 Đtrı ľ £ 14 6 EXCR M O N O F D R UG S n o jjJ n w he e by dru gs o r m e l a b o 】 ite s a ie im v e rs ib le tr a n s fe r r e d fr o m D m g o r l hei r m e ı a bo 】 i*e is re m o v e d fro m th e b o d y b y e x c re tio n " = c a i ś e m ū o n m e n ŁW n e n a d ru g is b k e n i e in ge s te d it is a b s o r b e d a n d ti ssı ı e s E u ids a n d o rga n s a f the bo d y It is th e n e x c re te d a fte r Ex a e tio n o fa dru g de a e a s e s iı s d m a tio n o f a c ū o n Th e e x a e tio n o f ı o x i d q M e dr u g m a y be e «a e te d i n a n a c tiv e o r in a c tiv e fo r m T h e a ccreted fro m bo dy h the fo l lo w in g w a ys /m e th o d s EJa J e ti o m du o ı lgh 】 ddn e ys Jß iao r ! The diu gs a r e e m e ted du o u gh kidn e ys by s Jjro d c jn :ro J Jn g lo q rrys n 9 n ï lJ . ı i ttdu c tio n in c r e a s e s th e a p p a r e n t V m a x fo r a b io tr a n s fo r m a tio n r e a c tio n b e c a u s e o f th e to ta l e n z ym e in v o lv e d in th e r e a c tio n in c r e a s e s T h is c a n ı e a d to in c r e a s e s o r d e a e a s e s in th e biogical e ffe c ts o f c h e m ic a ls d e p e n d in g u p o n w h e th e r th e p a r e n t c h e m ic a l o r th e m e ta b o lite is th e a c tiv e e n tity Ał e c ha n is m o f e n z y m e in d u c tio n A d 】 u g s m e ta b o lic c le a r a n c e c a n in c r e a s e & e ffic a c y de c re a s e s if a 2 n d d r u g in d u c e s th e e m y m e r e s p o n s i b le fo r th e v ic tim s 山u g m e ta b o lis m Si n c e th is m a y c o m p r o m is e th e e ffe c tiv e n e s s o r s a fe ty o f th e d Ju g th e F D A & o th e r s re co gn iz e d r u g in te r a c tio n s T h e p h e n o m e n o n o f in c r e a s e d d r u g m e ta b o lis m a b ility o f th e e n z ym e s b y s e v e r a l d r u g s a n d c h e m ic a ı s is c a lle d a n e m y m e in d u c tio n A n u ï n b e r o f d r u g s c an c a u s e a n in c r e a s e in liv e r e n z y m e a c tiv ity o v e r tim e T h is in a n in « e a s e th e m e ta bo lic r a te o f th e s a m e o r o th e r 山u g s P h e n o b a r b ito n e in d u c e d th e m e ta b o lis m its e lf - G e n e tra n s c r ip tio n ) I n n En z ym e In h ib i« o n E n z ym e in h ib iū o n r e fe r s to a d e c r e a s e in e n z y m e r e la te d p r o c e s s e s en z ym e P ro d u c tio n o r e m ym e a c tiv ity A n u m b e r o f c lin ic a lly im p o r ta n t i n te r a c tio n s be tw e e n d r u gs r e s u lt fr o m c Y p 4 5o in h ib itio n c Y p 45o in h i b ito r s a r e ? fe r e n t in th e ir sel e c tiv ity to w a r d e n z y m e s a n d a r e c la s s ifie d b y th e ir m e c h a n is m s o f a c tio n s o m e d r u g s a r e PO te n t c o m p e titiv e in h ib ito r s a n d c o m p e te fo r th e a c tiv e s ite b u t th e y a r e n o t a s u b s tr a te fo r t he e n z ym e ( e g , qu in id in e a n d c Y p 2D 6) w h ile o th e r d r u gs a r e n o n c o m p e titiv e in h ib ito r s ' 靈 爨 鑾 騵 韶 籲 餘 Į 9 M e c h a n ı s m o f E n z y m e ı n d u c tio n F ig 1 2 0 B a s ic m e c h a n is m o f e n z y m e in d u c ti
  • 21. Scanned by CamScanner İ İ r P P pre se n Ł İrjjı 【 n i s r : r e s e n ta tio n o f u n c o m p e titiv e In h ib ito r C bH pe ti tiï e In M b itio n F ig 1 2 2 A r e p r e B e n thtß L ĵs 】 u ge r An d ;G 9 T o ł s c c e T ı Ħ h ı S tq V E R Y S H O R T A N S W E R q u p h a r m a c o lo g y is th e s c ie n c e w h ic h d e a ls w ith p h a r m a c o k in e tic s a n d p h a r m a c o d y n a Jm ic s o f d r u g s o n h u m a n b o d y o r o n a n im a ls Q 2 w n a t a r e th e a ı lie d fie ld s o f P h a rm a c o lo g y ? A n s p h a r m a c o lo gy s c ie n c e a ls o in c lu d e s fie ld s s u c h a s (1) P h a r m a c y ( 2 ) P h a r m a c o g n o s y (3 ) . »ıto x ic o lo gy (4 )p o s o lo g y E a c h o f th e s e s u b d iv is io n s h a s a M g h ly s p e c ia liz e d ū e ld a n d m a k e s its đ i R i b i l t i o n to a c o m p o s ite k n o w le d g e o f d r u g s to th e w o r ld e s p e c ia u y to th e p e r s o n s o f V M e d ic a l p a r a m e d ic a l a n d N u r s in g fie ld c a te g o r y T h e k n o w le d g e o f P h a r m a c o lo g ie p r in c ip le s is e s s e n tia l fo r th e m a in te n a n c e o f o p tim a l h e a lth o f th e h u m a n ity a n d a n im a ls b s ı iĺ o ĺ s rlT A n e T h e d r u g s m a y b e d e ń v e d fr o m P la n ts (v e g e ta b le ) k in g d o m a n im a ls m i n e r a ls s w th e s is a n d m a r l fr o m m ic r o o r g a n is m s T h e d r u g s m o s tly w e r e d e r iv e d fr o m r o o ts le a v e s a n d b a r k o f p la n ts N o n c o m p e titiv e In h ib itio n ß 9 ı IT T h e a lk a lo id s gly c o s id e s o ils ( F ix e d a n d v o la tile o ils ) r e s in s g u m s T a n n in s a n d a n tib io tic s m e 蔗一 荔む !立 发で 三 苡 立 よ 丁 九に 竺 一 。 : Í切 八 A n s A n tib io tic s a re th e s u b s ta n c e s p r o d u c e d b y o r d e r iv e d fr o m liv in g o r g a n is m s T h e y a r e e d J rtjj j e ith e r to kill b a c te ń a o r p r e v e n t m u ltip lic a tio n o f d is e a s e c a u s in g or gm s T h e e x m p le is in s ' T P e n ic iı lin w h ic h is a c o m p le x o r ga n ic a c id o b ta i n e d fr o m p e n ic i lliu m n o ta tu m o r p e n id Jlim
  • 22. Scanned by CamScanner P H A ı NTR O D UC ı N G T H E C H A p T E R 西 日 一 iiam ı a c · i l e s a n d m e c ha n is m s o fdr u g a c ū o rt D ru g re ce pto t rs in te r a c tio n s Re cepto r eories d as d ic a ūo n o fr ec e p to ı s Slgnaı uctionın e c h iegu 】 a ūo n o fr ec ëp tl o r s iproteiïcoupledre c e p to r s lon e l re c e p to r Tra tsm e m bra n e e m ym e li n k e d re c e p to rs m b r a n e JA K ST A T b in dw Rece pto r a n d re c e p to rs th a t r e gu la te tra n s a ip tio n fa c to r s D o se r espo n s e re la ti o n s hip the ra pe u tic in de x C o m bi s e d e ff e c ts o fd r u gs Fa c to rs in o d ifyin g dĦı g a c ti o n A dv e rse dr u g r e a c tio n s D r u g i n te ra c tio n s (ph m a co kin e tic a n d pha m ı a c o dyn a m ic ) Dugdiscovery Pı 1 ed i n ic a le v a lu a đ o n p h a s e CUn icale v a lm do n o fn e w dru gs D m g dls co v e ry p l ı a s e a i n l c a ltrla lpha se % P aï m a ç o v lglla n c e ? Į
  • 23. Scanned by CamScanner P o s s ibı e d r u g r e Ja te d ; h Av į ą · c ha n ge iı ı lebodyte m p e r a tu r e O ĺj e J w h a t th e b o d y d o e s G e n e r a ı P h a r m a c o lo g y 4 ı to d r u g W n a t th e d r u g d «»e s to b o d y k n l yeiı (ı )P h y s ı o ı o g ı c a lfa c to r s la g e a n d re n a ı fu n c tı o n ) (ı ı )P a th o ı o g ı c a ı fa c to rs « e g K ı d n e y ı ı v · a n d m e ta b o ı ı c d ı s o rd ·r* ) (lı ı ) G e n e tı c v a rı a n ts Jn þ m z z Ð a a (ı v )Drugrug In te r a c tı o n s rł s fdo ı q (v )D e v e ı o p m e n t o f re s ı ıta n c e o r to ı e ra n c e 吕 n ĥ ß I d / ) m ŕ i1 L u r , ł i Ħ ęs i g liz e d b o d y c e lls In j D o p a m in e w h e n a d m in is te r e d to a p a tie n t it b ń n g s !b ów !Ē te ra ble r is e in b lo o d p r e s s u r e 瞻 阿 攤 國 F ig 2 1 A s y s te m a tic c o rr e la tio n o f p h a m a c o k in e tic s a n d p h a r m a c o d y n a m ic s
  • 24. Scanned by CamScanner 严 B i 88Fr z o n e ) o f the a n d o f ga s tr ic m u c o s a X = t p ł * ct m e n Ł 1ħ e d r u gs n ı a y b e ı ı ç p d a s a ı e p la c e m e n t w h e n su bs taı ı o e is fo u n d d e ó c ie n t ū ıth e b o d y T h e ı ı s e o f s u bc u ta n e o u s is a n a i n s ı 】 in fo r ä a b e ? Ħ ti e n ls sm a rty w e a ls o g iv e h o rn ı o n e s to p a tim ts l o n o r ^ ' W į X ? 2 1 M EC H A N Is M O F D R U G A c n o N e qpı dn n g bo ū o f a d i a m a n d dresponse r e la tio n s h ip T ħ e m e c h a n is m f d t u p is d a s s ió e d o n th e ba s is o fp r o p e r ti e s (a ) a n d c he m ic a lp r o w r ti e s o f d r u g s (b)biological The o f d m g m a y be p r i n m y a c ti o n a n d s e c o n d a ı y a c ti? T h e p r im a ry a c tio n o f the d m gs is the p ff p r t o ftmdged d r u g in the b o d y a n d the s e c o n d a ı y a c tio n o f th e d r u g w he n ađ o n h ū e bo dy 讌囊 fn w ĥ ic h (z ı ı s es c e llde a th a n d 】 ys is 7 ħ e e x a m p Je js o fs ilv e r n itr a te , s h o n g a d ds , ¢ 3) m 回 声o dlrc e lo c a ljn o a m ı ï ı a ti o n a r e c a JJe d a s c o u n te r irr ita n ts Jb r e x a m p le E x am p ı e B o ric kiu m i tr o o r ga n is m s a c tio n a r e c a lle d a s d is in fe c ta n ts C u bido pa ı e v o d o p a $ M e t h a n o l Re v ersi bl e a n tic h o l in e s tra s e s e g , N e o s tig n N on Co m titi o e ı n hibiti o n m e n o n c o m p e titiv e re s p o n s e is ir re v e rs ib le u n til th e n e w e n z yı n e . . In n p e d F o ŕ e x a m p le bı genJimted M e e ffe c ts o f n o n c o m p e titiv e in h ib itio n a r e l i画 画 画 画 画 E 4 n in e , p h y s o s tigm in e
  • 25. Scanned by CamScanner k o f P h In e r m dbl e a n tic ho l in e sh a s e s e g , O iga n 叩 h o sp ha te c o m p o u n d s q c l o m q ge n a s e In hibito rs e g A s pirirĻ In d o m e tha d n M A O i b ıs e g , 】 pro n ja z i d P he n e lz in e Fto to n P In hi bito rs e g O m ep r a z o le E s o m ep r a z o le s ı= » Fa ' "COı y o c c u p a tio n T h e o ı y It i s a n id e a th a t a r e s p o n s e e m a n a te s fr o m a r e c e p to r o n ly w h e n it is In d u c e d F it T h e o ry a c tiv a te th e m re s u ltin g in a b io lo gic a l r e s p o n s e th a t is p r o p o r tio n a l to th e a m o tı n t o f d r u g X-caeff' ' " . D ir - tly p r . p o , ' " a l '" " n u m b , r o f ' ' " p m ' ' " p ie d D + R D R - E w h e n a ll th e re c e p to rs a r e o c c u p ie d th e y d o n o t r a tio n a liz e h o w tw o d r u g s c a n o c c u p y th e o pe r a tio n a lM o de ıA m o d ifie d , Semimpirical a p p r o a c h th a t is b a s e d o n o c c u p a n c y th e o r y m o dilie d to in c o rp o ra te a fa c to r r e la tin g a g o n is t r e c e p to r c o m p le x a n d r e s p o n s e The kusl«te (m u lti s ta te) re c ep to r m o de l It w a s d e v e lo p e d o n th e b a s is o f th e k i n e tic s o f c o m pe titiv e a n d a llo s te ń c in h ib iti o n a s w e ll a s th r o u g h in te r p r e ta tio n o f th e r e s u lts o f d ir e c t bin d in g e x p e ri n n e n ts It p o s tu la te s th a t a r e c e p to r r e g a r d le s s o f th e p r e s e n c e o r a b s e n c e o f a li吕 a n d , e x i s ts in tw o d is tin c t s ta te s th e R (r e la x e d a c tiv e o r o n ) a n d T (T e n s e i n a c tiv e o r o ff) s ta te s w hic h a re in e qu i lib r iu m w ith e a c h o th e r T h e r e is a m o le c u la r le v e l c o n c e p tu a l m o d e l o f R e c e p to r T he s e m o d e ls e m p h a s iz e th e fa c t th a t m a n y r e c e p to r s a r e n o t j u s t s im p le = so j r 8 1 b . R Bg ,
  • 26. Scanned by CamScanner 52 1 ı E GÏ IA Te " H o f P h O tħ er ı e « p to rs ha v e co m ple x m u Jtiu n it S c h ı r e s be in g c o m p o s e d o f m o r e p r o ı ditalory a n d i n h i bito ry in te ra c ti o n s e x is t be tw e e n th e s e s u b u n its a n d tħ e dtu 吕 apfur in te ra c ti o n F e w r e c e p to rs a r e n o t o n ly d yn a m ic in te r m s o f th bu talso m o biı e jn the m e m bra n e li ke a n ic e be r8 in th e o c e a n recep to r The Fu u a 9o n is ts bin d o n Jy to R · a n d P a r ti a ı a g o n is ts bjn d p r e ı ėr e r ı ti a ljy t o R a n d R · a re ïn e qu iı i btiu m (e gu ili briu m c o n s ta n t L ) , w h ic h defines th e ba s a l a c tiv il y of ńı u in v eı se bi n d o n ly to R a n d P a r ti a l in v e ı s e a g o n is ts bin d p r e fe r e n ti a lly to R an tı go n i sts l m v e e qu a Ja u in iti e s fo r bo th R a n d R · ( iı o e M ec t o n b a s a l a c tiv ity ) D L D ◆ ◆ : -_ -x Pı ru" a l c ha n ge r a r tia lr e sp o n s e m o n e o r t w herat o f m a cr o m o le a ı l a r p e r tu r ba tio n js p o s s jbJe a s p e d Jic F ig 1 2 T r a n s d u c e r m e c h a n is m G p r o te in c o ł tp ı t d re c ep to r s (G p c R ß ) G p C R s a r e th e la r g e s t fa m ily o f m e m b r a n e p r o te in s a n d m e d i a te m o s t c e llu la r r e s p o n s e s to h o r m o n e s a n d n e m o tr a n s m itte r s , a s w e ll a s b e in g r e sp °n s ible fo r v is io n , o lfa c tio n a n d ta s te A t th e m o s t b a s ic Ie v e l, a ll G P C R s a r e c ha ra c te riz e d b y the presence o f s e v e n membranpanning a h e lic a l s e gm e n ts s e p a r a te d b y alternatingntracellular a n d e x tr a c e llu la ŕ lo o p r e g io n s If a g o n is t o r a n ta g o n is t b in d s to th e G p r o te in c o u p le d r e c e p to r it c a u s e s th e r e c e p to r a n d G p r o te in to c h a n g e c o n fo r ı n a tio n ı n d ı n
  • 28. Scanned by CamScanner , ty fo s ln e In p r o te in s F i 2 7 F . . I k d T lin tn Tan sı n em bra ne ]_ S T A T b in d in g T h e tyT o s in e k in a s e a c tiv ity o f JA K is a c tiv a te d w h e n th e r e gu la to r y m o le c u le b in d s a n d b r in g s tw o r e c e p to r m o le c u le s to g e th e r to fo r m a d im e r R e c e p to r d im e r iz a tio n b r in g s th e tw o JA R s in to c lo s e p r o x im ity w h e r e th e y c a n P h o s p h o ry lq te e a c h o th e r P h o s p h o r y la tio n fu r th e r a c tiv a te s JA K a u o w in g it to p h o s p h o ry la te th e r e c e p to r Th e p h o s p h o ty r o s in e r e s id u e s o n th e r e c e p to r p r o te in s a r e b in d in g s ite s fo r s T A T ST A T s ta n d s fo r S ig n a l T r a n s d u c e r a n d A c tiv a to r o f T r a n s c ń p tio n T h e S T A T p r o te in s a r e c o n s id e r e d la te n t tr a n s c rip tio n fa c to r s L a te n t m e a n s th a t th e y a r e a lw a y ś p r e s e n t in th e cy to p la s m a n d w a itin g to b e a c tiv a te d b y JA K w h e n s T A T b in d s to th e r e c e p to r th a t b r in it in to a P o s itjo n w h e r e it c a n b e phosphoat d b y A K o n c e p h o s p h o r y la te d tw o £ n u c le u s w h e re it b in d s To s p e c ific s e q u e n c e s in th e D N A In a c tiv a tio n o c c u r s w h e n P h o s p h a ta s e s r e m o v e p h o s p h a te gr o u p s fr o m v a r io u s p r o te in s in th e s ign a lin g p a th w a y p o lm ı tia ı n e a r tħ e c ha n n e l Tħe m e m b r a n e p o te n tia l a Jte r s th e c o n f' " ' " " o f th e t H p o n s e Io c h a n g æ in the m e m ı m n e p o te n ti a 】b u t th e y c a n a ls o ń u tc H & z 6 A s n te r n a ū c d ia g r a m o f n ı o v e m m t o f io n s a n d th e ir e ffe c te 匡 歹
  • 29. Scanned by CamScanner r m lA T e x t B o o k o F P h a r m a c o lo g y Iv o l i c yto M n ı · " - ı 国 叫 国 S T A T d r fo tm i 5 S T A T D RM E R S TA T D IM E R / Ħņ U S J« e m a d c d ia p a m o f T m m m drm b ı a ı ł e ıe « e p to r ņ ı o a ln e k in a a e a c tiv lly o FJA K O th e r m e m b e r re c ep tı m h tęgritu is o b ı i g a te h e te r o d im e r s m e a n s th e y h a v e tw o s u b u n its a (a l p ha ) a n d P ( be la ) Ih te grin s Jn m a m m a ls h a v e tw e n ty to u r a a n d n in e P s u b u n its In tqgliru a r e b a n sm e m bï a n e re c ep to rs tha t Ta c iJlta te ceJlxtraceJIular m a tr ix (E C M ) U Po n li gan d bi n d in & in te griru a c tiv a te a fg rı a l tr a n s d u c tio n p a th w a y s th a t m e d ia te æ uu la r aĺ ab s u c l r a s ï eg u la tio n o f th e c e u c y c le , a n o qg a n iz a tio n o f th e in tr a c e Jlu la r c ypo aı e le to n , a n d m o v em e n t o f n e w r e c e p to rs to th e c e lt m e m b r a n e H ı e p r e s e n c e o f in te griru a lı o w a ra pid a n d fı e db ı e re s po n s e s to e v m ts a t th e c e ı ı s u r fa c e (e g s ign a l p ı a te le ts to in iti a te a n in te rac ti o n w i c o a gu 】 a tim fa c to rs ) N u d t a r r¢ c tp to r T he Iipid m ı u b ı e d r u gs d i f th r o u gh c e ı ı m e m b r a n e s a n d b in d e ith e r in the c elı u ı ar c yto s o J o r in the n u c J a ı s G m e e x p r e s s io n is a lte r e d a n d p r o te in s yn th e s is ĵs e ither im r e a ae d o r d e cr e a a e d , w H c h c a u s e s the c e u u Ja r r e s p o n s e T h is m e c h a n is m Js the a b w e s Ļ a n d e ffe cts c an u su a JJy be m e a s u r e d in te rm s o f h o u r e r a th e r th a n m in u te s o r s e c ■匡 G e n e ra ı Pharmacoı o f 5 9 F ig 2 9 N u c le a r r e c e p to r V a ń o u s d r u g a c ts th r o u g h n u c le a r r e c e p to r L ip o p h ilic s u b s ta n c e s s u c h a s s te r o id h o r m o n e s a n d th y r o id h o r m o n e s c a n d iffu s e th r o u g h th e c e ll m e m b r a n e a n d in te r a c t w ith r e c e p to r s in th e c y to p la s m o r n u c le u s T he h o r m o n e r e c e p to r c o m p le x th e n a lte r s g e n e tr a n s c r ip tio n ca u s in g the s y n th e s is o f e ffe c to rs p r o te in s m R N A T h e h o rm o n e r e c e p to r c o m p le x in te r a c ts w ith D N A in p a ir s th e s e m a y b e id e n tic a l (h o m o d im e r ic ) o r n o n id e n tic a l ( h e te r o d im e r ic ) p a irs @ o s E ? S P O N S E R E L A T IO N S 匢ı 7ħe R e la tio n s h ip be tw e e n d r u g r e sp o n s e a n d d r u g c o n c e n tr a tio n a re th e e ffe c t o f a d r u g is de p e n d e n t o n th e c o n c e n tra tio n o f th e d r u g a t th e ta r ge t s ite (r e c e p to r ) w h e r e d r u g r e c e p to r bin din g i s jn e q u ilib r iu m 7 e d r u g c o n c e n tr a tio n s in tu m d e p e n d o n p h a rm a c o kin e tic a n d d o sin g fa c to r s G e n e ra lly th e in te n s iv o f r e s p o n s e in c r e a s e s w ith d r u g c o n c e n tr a tio n s T he r e sp o n s e c a n b e p lo tte d a g a in s t d r u g c o n c e n tr a ti o n , y ie ld in g a h yp e r b o lic c u r v e th a t illu s tr a te s a s ha rp in c re m e n t in e ffe c t th a t d im in is h e s to w a r d a p la te a u (m a x im a l e ffe c t) w h ile d r u g c o n c e n tr a tio n in c r e a s e s T he ra n ge o f d o s e s o v e r a lin e a r re la tio n s h ip b e tw e e n d o s e a n d r e s p o n s e is g e n e r a te d W n e n d o se s (x a x is ) a re c o n v e r te d fr o m a rith m e tic to ]o g a r ith m ic s c a le , th e p lo tte d ı o g d o s e re sp o n s e c u r v e w ill c h a n g e to a ß ig m o id äl c u r v e T h e im p o r ta n t lin e a r s lo p e (2 5 75 % o f th e m a x im u m )b e c o m e s v is ib le fo r ń ı r th e r c h a r a c te r iz a tio n
  • 30. Scanned by CamScanner 貫鯊 夕髦 籲 轟 P» . ı i r ıa T e x t B o o k o f m . ' " 0 g y M ūņı ı i concentrations m e a lo n g th e n n e a r p o r tio m o f th e c u r v d o s e s lo w e r o c c u r ń th h ig h r d o s e s f n e a r th e m a x im a l e ff e c t) T h e d a la p lo tte d in a r itł m ie tic s c a le T he a p e u t" rearl d d o s e )c a n b e s u b 4 le r a p e u tic w h ile to x ic e ffe c ts a r e lik e ly to p m d u ce s ıħıi c c u r v e in s te a & £c ji o ec ti ve d o s e a t h a l f r e sp o n s e a s a n in d ic a to r o f p o te n c y e s p e c ia lly u s e ħ d w he n compatg d iH e r e n t a fo r th e s a m e r e c e p to r T h e s iı n ila r r e la tio n s h ip c a n be p lo tte d a s tħ e ń m c ti o n o f ? e d o s e o f d r u g a d m in is te r e d a n d r e fi n r e d to a s doserespom c u r v e a s s u m ū rg tħ a t ? e d o s e s a d m in is ūe re d a n d p la s m a d r u g c o n c e n tr a tio n s r e m a in in e q u iı i b riu n _ B t 三 贸 然 自 富 穿 Ħ& 2 1o A w texo a äc e lq g coaı cenbationitect c u r v e illu s tr a tin g its fo u r c h a r a c te ń s tic r a ı ia M æ M e ¢ f& d iım n u n n d a s a fm d io n o f i n c re a s in g d r u g concentration s ru r o u n d in g th e ta ı g e t n c ep to r i n fa r e d Ĥ P d ra g r n n r m h a tin m W p o lt m r a n d e ffi c a c p R e sp o n se s to d r u g s m a y be g r a d e d (r e s p o n s e m a g n itu d e is @ w p rp po «ti o n a ı to do se )o r qu a n ta l ( TW n se is a ll o r n o n e ) C o m p a r is o n s be tw e e n d r u g s a r e u su all y m a ? ba se d o n il le m e dia n e fk c tiv e d o s e th a t p r o d u c e s a r e s p o n s e in 5 0 % o f p a ti en ts ? e ED bn P o ten cy reı e rs to ? e a m o u n t o f dr u s re qu ir e d to p r o d u c e a n e ffe c t o f a g iv e n in te n s ity It is c o n Ve n i m t to ae t i n ten sity rra lu e a t the E C Įo w hic h i s the m e d ia n e ffe c tiv e c o n c e n tr a tio h Cilat onesponds to 50% o f the m a x i n ı a l r e sp o ı rs e T h e h igh e r the p o te n ¢ o f a d r u g th e To w e r tħ e concentration n ee de d to r ea c h E c į o o fte n p o te n cy a n d to x ic ity a r e li n ke d b e c a u s e the fo x ic n e w o ı u e js an ex teı u ïo n o f the the r a p e u tic e ffe c t th e r e fo r e a m o re p o te n t d r u g is n o tn e c e ss a rily a be tter dru & G e n e h a r m a c 0 lg æa 园 E D Ľ d o s e w h ı c h w ïı ı b e ĝ , M E D M T D (m o re th a n th ı s w ı p ro d u c e s ı g n s o f to x ı c lly ) A ls o c a ı e d h ig h e s t n o n to x lc d o s e (H N T D ) Fi吕 ユ11 m e gı a p h r e p r e s e n ts th e s a fe ty o f a d i u g a s d e te m n in e d b y q u a n ta l d o s e r e s p o n s e c u r v e s h e & » w hich is th e d o s e th a t p r o v id e s a th e r a p e u tic e ffe c t (e g v a s o d ila tin n ) in 50 % o f p a ū e n ts th e T D so w hic h 沁出e d o s e p r o d u c in g a to x ic e ffe t* in 5 0 % n f p a tie n ts (e g a r th y tlu ia ) a n d th e L D sn W h ic h is 1h e le th a ı do se in 5 0 % n f p a tie n ts 2 5 1 TH ER A P E UT ı C IN D E X It is t he r a tio o f L D 5 0 to E D 5 0 T h e r a tio o f L D 1 a n d E D 9 9 w ill g iv e b e tte r in d e x s a fe ty o f th e dr u g 1ħ e th e r a p e u tic in d e x is a m e a n s o f c o m p a r in g th e a m o u n t o f a d r u g r e q u ir e d to a tta in the the r a p e u tic le v e l in 5 0 % o f p a tie n ts to th e a m o u n t th a t is le th a l to 5 0 % o f p a ū e n ts It is e x p re s s e d a s th e r a tio L D 5o /E D 5o A h ig h th e r a p e u tic in d e x is p r e fe r a b le a s th e m a r gin o f sa fe ty b e tw e e n th e d o s e th a t w o u ld b e s u tftc ie n t to a c h ie v e th e r a p e u tic le v e ls a n d tł ı a t w h ic h w o u ld p r o d u c e to x ic e ffe c ts is h igh T h e ra p e u tı c ı n d e x M e d ı a n le th a l d o s e M e d ı a n e ffe c tı v e d o s e o r L D so E D so @ C O M B IN E D E F F E C T S O F D R U Syn u g le m It c o m e s fr o m th e G r e e k w o r d s y n e r g o s m e a n in g w o r k in g to ge th e r It r e fe r s to the in te r a c tio n b e tw e e n tw o o r m o r e d ru gs Sy n e r g is m r e fe r s to th e e ffe c t c a u s e d w h e n e x p o su r e to tw o o r m o r e d r u gs a t a s tim e r e s u lts in h e a lth e ffe c ts th a t a r e gr e a te r th a n th e su m o fthe e ffe c ts o f th e in d iv id u a l d r u g T he r e a re e x a m p le s in c lu d s
  • 31. Scanned by CamScanner r m lA T e x t l m a o T ľ h a r rń a ç o ı o W I) ) C m bo n te b a c N o r id e a n d e th a n o l (E th yl a lc o h o l) a l e in d iv id u a lly to x ic to th e liv g r b u t to N e r ? q p u c e m u c h m o r e liv e r in i w y th a n th e s u n ıo f th e ir in d iv id u a l e ffe c ts o n the anagesicfp a in r e lie v e r 】 a n d o th e r s e d a ı iv e h yp n o tic d r u g s m e g m e ı g i sm c a n be a d d itiv e a n d s u p ra a d itiv e M diM pc w ħ e n M o d r u gs w ith s im ila r m e c h a n is m s a r e g iv e n to g e th e r Th e y ty p ic a lly p ı o d u æ a d d itir e e ff e c ts o fd r u g A + đ o f d r u g A + e ffe c t o f d r u g B F o r e x a m p le J ı A spń ı+ p a m cE ta m o 】 A n a lg e s ic e M x t Z m o d jp- e + A te n o lo ı A n tih yp e r te n s iv e 3 M i l ic o x id ¢ + ï ł a ïo lh p n e v A n e s th e ti c { A dd i ti a M b c t (1◆1 2 ) Ąıp k i n ◆ p a « * ba m at A B A ◆ B n n 1 / , U , S tł l M r U ïo x a z o ı e ◆ M m e th o p r ïm != = i w ' 一 1 / L , L S u p ra « d d ı tM e e fFe c t (1◆l 4) Į 习 」 = 四国 e d p w m a c o lm s y n e r g is m It is th e s i t i o n w h e r e th e le s s to x ic th a n th e in d iv id u a l e ffe c ts fo r m a n y a n tid o te s fo r p o is o n in g s F o r e x a m p le c a n a n ta g o n iz e th e to x ic e ffe c ts o f m e th y l a lc o h o l (m e th a n o l) b y : , ; , fr o - ' " ? y m ' ' " ' ' " S th ' ' " h . o l : d ts P taı ronism It is b a s e d o n th e p h y s ic a l p r o p e r ty o f d r u g s F o r e x a m p le c h a r c o a l a d s o rbs a 】 ı a lo id s a n d c än p r e v e ń t th e ir a b s o r p tio n It is u s e d fo r c h a r c o a l p o is in g m o ı ¢ ic * l m t« go n is m It o c c u r s w h e n a d r u g r e d u c e s th e c o n c m tr a tio n o f a n a g o n is t b y f o M g a c h e m ic a l c o m p le x a n d b e c o m e in a c tiv e p r o d u c t Fo r e x a m p le 1 10 1N 0 + o x id ie e a lk a lo id s It is u s e d fo r g a s tr ic la v a g e in p o is o n in g 2 T aJm in s + A 1k a lo id s It is in s o ı u b le a lk a lo id is fo r m e d 3 c h e la th ı g a ge n ts + M e ta l C o m p le x acokinetic a n ta g o n ia m o c c u r s w h e n o n e d r u g a c c e le r a te s th e m e ta b o ı ite rh yaio lo gic a l a n ta 8 o n is m in v o lv e s d r u g a c tiv a tio n o f tw o ? fe r m t r e c e p to r s o r b y d iffe r e n t m e c ha n i s m s th a t e x is t to m a in ta in h o m e o s ta s is F o r e x a m p le (1) th e e ffe c t o f n o r e p in e p h r in e to in c re a se b lo o d p r e s s u r e ( v ia s ti m u la tio n o f a a d r e n e r g ic r e c e p to r s ) c a n b e a n ta g o n iz e d b y a dm in is tra tio n o f a c e ty lc h o lin e w h ic h c a u s e s v a s o d ila ū o n b y th e r e le a s e o f n itr ic o x id e fr o m the v a sc u la r (a r te r io la r ) e n d o th e liu m (2) G 1u c a g o n a n d in s u lin o n b lo o d s u g a r le v e l ( 3 ) H is ta m ĵn e a n d a d r e n a lin e o n b r o n c h ia l a s th m a R e c e p to r A n ta 8 o n is m A n ta go n is ts in te r fe r e th e ir e ffe c ts b y b in d in g to th e r e c e p to r s th e y ta rge t a t v a rio u s p o s s ib le lo c a tio n s S o m e a n ta go n is ts ta r g e t th e s a m e b in d in g s ite a s th e r e c e p to r a go n is t w h ile s o m e b in d to a llo s te r ic s ite s o n r e c e p to r s A n ta g o n is ts m a y a ls o i n te r a c t a t u n iqu e b in d in g s ite s n o t n o r m a lly in v o lv e d in th e r e g u la tio n o f a r e c e p to r s a c tiv ity Th e b in d in g o f a r e c e p to r a n ta g o n is t to th e r e c e p to r it ta r g e ts m a y b e p e r m a n e n t O r te m po ra ry d e p e n d i n g o n th e n a h ı r e o f th e b o n d fo r m e d T h e a n ta g o n is m is s p e c ific e g a n a n tich o l in e r gic is d e c r e a s e d th e s p a s m o f in te s tin e in d u c e d b y c h o lin e r g ic a g o n is ts b u t m a y n o t by M s ta m in e o r 5 H T w h ic h a c t thr o u gh th e ? fe r e n t s e ts o f r e c e p to r s S u c h a n ta g o n is t m a y b e c o m p e titiv e a n d n o n c o m p e titiv e
  • 32. Scanned by CamScanner P V G ď回 回P 쌘 田 。 o ı 咪珲皿 ヤ 6 S 四 国回国园ı 国 国 T h e ir b a r r ie r s a r e n o t ħrlly d e v e lo p e d (B B B b lo o d b r a in b a r r ie r ) th m a r e m o r e B ) s e n s itiv e to c N s s tim u la n ts A 】 1 p a r ts o f th e b o d y a r e a ffe c te d b y th e d r u g kid n e y s is in c r e a s e d H e p a tic m e ta b o liz in g c a p a c ity is a ls o u n d e r d e v e lo p e d c h lo r a m p h e n ic o l m a y c a u s e gï e y b a b y s y n ? o m e T h e d o s e m a y b e m o d ifie d u s in g e ith e r th e b o d y s u r fa c e a r e a :, w e ig h t D o s e to b e p r e s c r ib e d f a c e a r e a (m 2)x a d u lt d o s e 1 7 D o s e to b e p r e s c r ib e d W t in k g × A D TO B o d y s u r fa c e a r e a in m 2 o f c h ild C h ild d o s e x A D 1 7 (a v e r a g e b o d y s u r fa c e a r e a in A D ) tif m e It is reversbly b in d to r e c e p to r s a t th e s a m e b in d in g s ite a s the e n d o ge n o u s lig an d o r a g o n is t w ith o u t a c ti v a tin g th e r e c e p to r C o 呷 e titiv e a q ta g o n is ķ co m pe te w ith a go n is ts fo r the s a m e b in d in g s ite o n th e r e c e p to r W n ile b o ġ i to e ĮĻ, re c e pto r a o o m pe titiv e a n ta go n is t is b lo c k e d a g o n is t b in d in g iĮodß lstrf£ N o n o e a n İagon isk lt bħ ı ds to th e r e c e p to r it ta r ge ts a t a n a llo s te r ic s ite o r a iş ite İ g ţbe r th a n th e a c ti v e site a n a go n i s t bin ds to Th is typ e o f b in d in g is n o n c o m p e titi v e b e u ş ę h e r e c e pto r a n ta go n is t do e s ı ı o t ha v e to c o m p e te w ith a g o n is ts fo r b in d in g A n n c qp g? ę ,W e a n ta go n ist pr o du c e s irs by in d u c in g a c o n fo r m a tio n c h a n g e in th e receRtg£ 中 cha n ge s the sha pe o flĵhe a c ti v e bin d in g s i r e v e n ti n g a go n is ts fr o m b in d in g Ĵ o l 3ĵ 9 119 g n İ v ł o įĮo ì C T O R S M O D IF Y IN G D R U G A C T H u Įo s r[ T V a ria ti o n in re spo n se to the s a m e d o se o f a d r u g b e tw e e n d iffe r e n t p a tie n ts a n d e ý e n ù d ĵe sa m e pa ti e n t o n diM ere n t o c c as io n s w i ll o c c tı r T he r a n g e o f v a r ia b ility m a y b e llm k gd i o r li m ite d dep e n di n g o n the pha m a c o ki n e ti c & p ha r m a c o d yn a m ic c h a r a c te r is tic s o ńj E h e bd r u g n ı e fo ll o w in g a re the fa c to rs w H c h m o dify the d o s a g e o f d r u gs M e d e ta ils a r e a s u n d e r 1 A æ In f a n ķ a n d d ildr m r e qu ire le ss d o se i e D iffe re n t d o s e fr o m a d u lts In iņ fa đ a n d c hil d re n t he m e ta bo l i sin g W e s a n d the e x c r e to ry p r o c e s s is n o t ń d ly devlQpęd W o l d a ge p a ăe n ķ ) re qu ir e r e d u c e d d o s e b e c a u s e ö (n a ţ g a ħs h )i p o fu n c ti o n du e to o ld a ge e f[ e c t T he a d u lt d o se i s fo r p e o p le b e tw e e n 18 a n d 60W a rs o f a g e Tħ e ti s s u e s o f a n i n fa n t & c hild a r e M ghly s e n s iti v e to a la r ge n u m b e r o f d r u gs C hild re n lı n d e r 12 yı s r e qu ir e a fr a c tio n o fa d u ı t d o se be c a u s e p ÐT 'h】 (.ť í A ) D ru g m e ta bo hz in g Em n e tem is h e ffid m t in th e m ( G lu c u ro n id a tio n ) tä ke ș 3 m o n ths to de v elo p) リロ了 Įお」 ) り了 2 S e x M a le in d iv id u a ls r e q u ir e la r g e d o s e o r d r u g in c o m p a ń s o n to fe m a le s w h ic h r e q u ir e l e ss d o s e T e s to s te r o n e in c r e a s e s th e r a te o f b io tr a n s fo r m a tio n o f drug D e c r e a s e d m e ta b o lis m o f s o m e d r u g s in fe m a le (D ia z e p a m ) o c c u r s F e m a le s a r e m o r e s u s c e p tib le to a u to n o m ie d r u g s (e s tr o g e n in h ib its c h o lin e e s te r a s e ) D r u g s u s e d fo r u lc e r m a y c a u s e i n cr e a s e d p r o la c tin D u ri n g enstruation s a lic y la te s a n d s tr o n g p u r g a tiv e s s h o u ld b e a v o id e d a s th e y m a y in a e a s e b le e d in g S o m e d r u gs w h e n a d m in is te r e d to p r e a n t w o m e n m a y c a u s e h a r m ħJ1 e ffe c t to fo e h ı s a fte r c r o s s in g p la c e n ta l b a r r ie r m a y c a u s e fo e ta l a b n o r m a lity ln p r e g n a n c y fo l lo w in g a r e to b e c o n s id e r e d (a ) C a r d ia c o u tp u t (2 ) G F R a n d r e n a l e lim in a ū o n o f d r u g s (3 ) 71 e v o lu m e o f d is tr ib u tio n ( 4 )M e ta b o lic r a te o f s o m e d Ju gs L ip o p h ilic d r u g s c r o s s p la c e n ta ı b a rrie r & a r e s lo w ly e x c r e te d D u r in g p r e gn a n c y u te r in e s tim u la n ts s tr o n g p u r g a tiv e s a n d d ru gs li k e ly to h a v e te r a to ge n ic e ffe c ts s h o u ld b e a v o id e d e s p e c ia l ly d u r in g th e fir s t tr i m e s te r n o d r u g s h o u ld b e giv e n u n le s s a b s o lu te ly n e c e s s a r y 3 B o dy w e iBh t T h e d o s e o f th e d r u g is u s u a lly r e la te d to b o d y w e igh t A p e r s o n o f o v e r w e igh t (Obe s e in d iv id u a l) r e q u ir e s a la r ge d o s e th an th e n o r m a l in d iv id u a l If th e d r u g is fa t so l u bl e th e n s o m e p o r tio n o f a d o s e is a c c u m u la te d in b o d y fa t s o th e la r g e d o s e is r e q u ir e d b r fa tty i n d iv id u a ls T h e d o s e o f th e d r u g is u s u a lly e x p r e s s e d a s m g p e r k g o fb o d y w e ig h t A pe r s o n w ith u n d e r w e igh t r e qu ir e s a s m a lle r d o s e 4 R o u te o f a d m in is tra tio n T h e d r u gs w h e n a d m in is te r e d b y in tr a v e n o u s o r in tr a m u s c u la r ro u te r e qu ir e le s s d o s e in c o m p a r is o n to o r a l r o u te T h e d r u gs g iv e n b y IM /IV r o u te h a v e qu i c k o n s e t a c tio n T h e a c tio n b y m o u th (o r a lr o u te )is d e la y e d a n d s lo w T h e d r u gs g iv e n b y re c ta l r o u te a r e a b s o r b e d s lo w ly a n d o n ly a p a r t o f th e d ru g is a b s o rb e d S o a la r g e d o s e is 羹 一 霜 一 国 团 团 目 · r w - W ' ' " N f' " " ° ' " m
  • 33. Scanned by CamScanner W ' ' " ä ū . " Tħe p a tie n t w ith d is tr e s s in g s y m p to m s n e e d s ' '" " 0 . . n h n z A d d ic tio n D ru g d e p e n d e n c e o r a d d itio n is a s ta te o f p e r io d ic o r c h r o n ic intôiation w H c h is detrimental th e p e r s o n a n d s o c i e ty It b e c o m e s a lm o s t im p o s s ib le to c a r t y o u t X fu n c ū ' ' " . ' ' " ' ' " " . ' " ' ' " ' " henoniëniodif A ) E u pho r ia s e n se o fha ppi n ı e i s a n d fo rg e tń ı ln e s s r f 西 e 짐 과了 b Jle Y jqı n s B ) T o le ra n ce du e to i n crea se d p r o d u c tio n o f e n z y m e s rro ilq r o a dß 【 9 1 Ji as C ) PsycM c depen de n ce ( H abih ia ti o n ) p e n . " " . . s b " " b . . " " f d r u g . . h D ) Phys i a l dqpen de n æ It is a be ha v io u r a l pattern o f c o m p u ls iv e d r u g a b ë9 v ī1ł äř (Absti n eiu e q m ū o m e ) ı e itl e sm ess etc sym p to m s a p p e a r ı ik e p s y c h ic c r a v in g b o d y a c h e iH i o iř a1i ä) ì & spec i e s an d R a ce c a s to r o i 】A p tı r ga tiv e is in e ffe c tiv e in c h in e s e . . d il, tin įĮF is til Ĵ A ゴa ß!l 汀 (ĥ ) g o 7 b yı fÐb (gu lb o J u Ja (cl bs Jó lyjÐĵ ï l{þ 日 6 力召 团 团 团 团 国 国 ı 王 国 e ra ï P h a r m a c o lo U g n p a bid la i įy s ta tė A n p a th o lo g ic a l c o n d itio n o f liv e r a n d k id n e y is v e r y im p o i t a n t T h e Hiiã&nain s ite fo r d e to x ific a tio n o f d r u g s s o in c a s e o f a n y d is e a s e o f liv e r th e a c tio n o f Ĵ b a d e c r e a s e d w n e n th e r e is a n y d y s ń in c tio n o f k id n e y w h ic h is m a in o r g a n o f e x c r e tio n th e a c tio n o f th e d r u g is d e la y e d b e c a u s e o f s lo w e x cr e tio n o f 山 u g s In c a s e o f s o m e c a u s e th a t r e s u lt in d e cr e a s e d a b s o r p tio n o f d r u g s (A ]í lhwer d is e a s e s p r o lo n g d u r a tio n o f th e a c tio n o c c u r s b e c a u s e o f in c r e a s e d h a lf life jß r]așpa p r o te in b in d in g fo r w a r fa r in to lb u ta ı n id e is d e c r e a s e d le a d in g to a d v e r s e Jfflits If h e p a tic b lo o d H o w is r e d u c e d c le a r a n c e o f morphine p r o p a n o lo l m a y b e zobacted Im p a ir e d liv e r m ic r o s o m a l e n z p n e s m a y le a d to to x ic le v e ls o f D ia z e p a m 9 , P i c i n a n d th e o p h y u in e (B ) In r e n a l D is e a s e G F R ta b u la r ń rn c tio n a n d p la s m a a lb u ï n in m a y b e a ffe c te d le a d in g to a b n o r m a l e ffe c ts o f d ig o x in lith iu m g e n ta m y c in a n d p e n ic illin (ĉ Ĺ u ptritio n p la s m a p r o te in b in d in g of d r u g s is r e d u c e d a lo n g w ith th e n u m b e r o f m ic r o s o m a l e m y m e s le a d in g to a n in c r e a s e d p o r tio n o f fr e e u n b o u n d d Jn g e g rı o İJß jfarin 10rroEı wnı nental a n d tim e o f a d m in is tr a tio n M e ta b o lis m is lo w in h o t a n d h u m id c lim a tm H u r g a tiv e s a c t b e tte r in s u n u n e r w h ile d iu r e tic s a c t b e tte r in w in te r s O x id a tio n o f d r u g s is lo w a t h ig h e r a ltitu d e s T h e tim e o f a d m in is tr a tio n is a ls o h ig h ly im p o r ta n t 】 n a n e m p ty s to m a c h 山u g s a r e m o r e q u ic k ly a b s o r b e d F o o d in th e s to m a c h m a y a ffe c t a b s o rp tio n o f th e d r u g T h e d iu r e tic s a r e a d m in is te r e d in th e m o i n g a n d n o t in th e e v e n in g a s it r e q u ir e s th e u s e o f th e to ile t s e v e r a l tim e s fo r m ic h u itio n S o d u r in g n ig h t th e s le e p o f a n in d iv id u a l m a y b e d is tu r b e d H y p n o tic s (p r o d u c in g s le e p ) a c t b e tte r w h e n a d m in is te r e d a t m i n d s m a lle r d o s e s a r e r e q u ir e d A m in o gly c o s id e 1ĵk e s tr e p to m y c in w h e n g iv e n J S L ' '" a ' ' " e w ' ' " c u 1. . B l. c k . G e . ' " s n o t o b s e r v e d a fte r in tr a m u s c u la r 1ļ ..iqıt F a c to r s P h a r m a c o g e n e tic s is th e s tu d y o f th e r e la tio n s h ip b e tw e e n ge n e tic fąg ţq ţ fo ëm d d r u g r e s p o n s e T h e g e n e tic a b n o r m a litie s in flu e n c e th e d o s e o f a d r u g a n d r e s p o n s e to d r u g s It a ffe c ts th e d r u g r e s p o n s e in in d iv id u a ls a t 2 le v e ls (P A t ţĮl- le v e l o f r e c e p to r s ( ' l l i le v e l o f d r u gs m e ta b o liz in g e n z w e a ) It h a s b e e n r e p o r te d th a t d u e to g e n e tic v a ń a tio n s th e d e fic ie n c y o f glu c o s e 6 p h o s p h a te d r u g ) d e h y d r o g e n a s e in c e r ta in r a c e s r e s u lts in in c r e a s e d to x ic ity o f p r im a q u in e (a n tim a la r ia l b ) D u e to ge n e tic v a r ia tio n s in fe w in d iv id u a ls is o n ia z id (a n a n ti tu b e r c u la r d r u g ) is fa s tly a c e ty la te d a n d in s o m e p e r s o n s it is s lo w ly a c e ty la te d le a d i n g to m o r e c h a n c e s o f d e fic ie n c y 層 眉 目 ■ 一 .
  • 34. Scanned by CamScanner r m alA Te x t B o ò k o f P h a rm a c o ı g g y w ) 1 , J e n z ym e T h u s ? e fa c to rs in te rji e rin g tv ith th e fu n c ti o n s s u c h a s r a te o f p la 3u r s m a d r u g Æ m a i n tie n ı n s o m e s t ge a n y d r u g w ill c u m u la te in th e b o d y if th e ÐFa te o f a b a is M g he r tha n r a te o f e lim in a tio n īħe s lo w e x e ? a tio n o f d r u g s is Prtiņaar ı ia b Je fu c a u se c u m u da tiv e M Jdd q F o f e x a m poe p ro lo n ge d u s e o f c h lo r o q u in e c a u wetinal d F u ı lı o a d in g d o se o f d ig o x in s h o u ld n o t b e g iv e n if th e p a tie n t h a s r e c e iv e d ,įt Wthin p a st n T æ ' b n ıc ı 3 t o je r u ı c e h m e n a d ru g js a d m in is te r e d r e g u la r ly to a p a tie n t to r a lo n g p eiio d it b e c o m e s n « e s a ry to in c r ea s e th e d o s e P a ti e n t d e v e lo p s to le r a n c e ( a c o n d itio n o f ta ld n g th e e x c e ss d o ó e w itħ o u tp m d u c i n g s }m p tu m s o f to x ic ity o f d r u g ) T o p r o d u c e th e s a m ë e ł ie ċ t In tħ e bo dy a ı a rg e d o se is r e q u ir e d īħ e to ı e r a n c e o f d r u g u s u a lly d is a p p e a r s o n w ith dĮ ąJ?(a l o f : the W R e sis tan ◆ to tħ e n o r m a J th a a p e u tic d o s e o f th e d r u g p r o d u c in g a le s s e r r e s p o n s e p n o m thm pe u tk d m e js fi n o w n a s to le r a n c e T h is is a c q u ir e d c h a r a c te r E x ' 呷 ł 中相 ç l 】 ?d e m o tp ħ in e the p e rs o n is i n iti a u y r e sp o n s iv e if c o n ti n u e d c h a n g e s o c c u r a t th e c e liu ia r a n d Pı rarmacoJcineticlevr e d u c in g th e a c tio n T h u s o n e h a s to jn c r e a s e th e d o s e o f Bm ş tu o v er c o m e n iı a Ð # ņ A lc o h o 】 ic s do n o t r e spo n d to h yp n o tic s a n d analgesic th e d o s e o f w h ic h h a s to b e in c r e d m a n y f o lds 】 n fa ¢ ı h e y n ı a y e v e n to le r a te to x ic le v e ls C rū ss T o ıĦa A p e s o n to l a a n t to d r u gs re s e m blin g ĵn c h e m ic a l s tr u c tu r e is k n o w n a s c ro ss to le ra n c e M o se dru gs ı e se m b lin g in c h e m ic a l s tr u c tu r e s s h o w c r o s s to le r a n c e If a pa lo n js t o m w hi n e ħ e a l s o s h o w s to le r a n c e to p a th e d in e (s yn th e tic 茹 ·ı iv e ) a n d c o d l ◆ Ľ d u K e a ı a z e p a m a n d İ lu r e z e p a m H ţç ņ m p le te a Dss E o ccu Is w ith the dr u g s s h a īin g th e s a m e p h a rm a c o lo g ic a l p r o p e r tie s X Į Jo m pks include ba rbiM ra le s a n d ge n e r a l a i ı e s th e ti c s s ite o f a c tio n is C N S w iįķtė samephaı macogitalproperties c o s s lennce m a y be o bse r v e d a ltho u gh th ey a r e 隸 ï peated adminintitmĻ ū e se s to re s a r e e x ha u s te d a n d p h a rm a c o lo gic a l a c tio n is n d t 3r' X ' " " ijßh m Jn M M ġ Ffa ll, D o s e r e la te d C o m m o n R e s p h a to r y B le e d in g w ith S e r o to n ĵn R e la i e ri to th e p h a r m a c o lo gie a c tio n o f d e p r e s s io n w ith w a r ff i n s p ? o m e w ith th e d r u g e x a gg e r a te d p h a r m a c o lo g ie o pio id s S S R Js rb ? e P ı e d ic ta b le L o w m o r ta lity D r y OUt!OWith P ic w lic a n tid e p r e s s a n ts Wfdiciabte N o n o s e r e ı a te d m. r +. n c o m m o n N o t I mm u n o l og i e W i thh o l d a n d l ' " a m l r e 】 a te d to th e r e a c tio iı s a v o id in fı ı h u e p h a r m a c o lo gie a n a p h y ı a x is to Ibíq s T 6 a c tio n o f th e d r u 8 p e n ic iĽ ĵn £ o U ó Tja īn U n p r e d ic ta b le 1d io s w c r a tic ! q mó x a H i gh m o r t al ity r e a c t ion s j Jł A. 9T m a ] i8n a n t :Þ ń e j n ? h y p e r th e r ı n ia w ith c D a s e r e l a te d a n d ti m e r e la te d p ih ı ita r y g e n e r a l a n e s th e tic s (C hr o n ic ) U i c o n u n o n R e la te d to th e a d r e n a 1 a x is D o & r e la te d c u m u ı a ti v e d a s e H yp o th a la 】 n ic - B y a n d Tiin e o s te o n e c r o sis o f; (O u n n ic j th e j a w w ith U n c o ı n m o n
  • 35. Scanned by CamScanner s ◆ 玎 n a s e A s g w d a u o p u a u ı o ïB p e 汹脳 曾 卜 ! ヨ 【 【 邬 p a J u ? u a dx a u o 怀)e a ı 阿 四 四 lo o a ı w m u n u e 可 信(M 璃 羽W お 髫 呷 a s 》邸 e 吖 (s q eEpo se a W W e tu a pao a Äd e ı a qł jo u o q e n u g u o j w a w a j u ? a ? ao u xe w pu e a lw w w ď Ħptu e q s s ? ï s l ł e w ł J A JJ? u e s ? n d w Ãn e n m J a tm o J a ql q£ n o ı p le a a v ÃR e a Sı re qw q p ? m tīa » o s Į ł J?uaapĮ s u u a ła w p e q ı o iu ł ı = u iepgauaq»qpı ł «a Jgn a de ı a q papwł şĮ rđ ql u e q ł ı a q ł o ß ru p e Âq p a sn e ? p ?w a Äı æ Ę » W a Ħs V rp ū » i a p s m ĺ ĄĘdæ w ヨ 呷 尹 日 a a s īa A p e a qła q o sa p o q p a m Ätu o ı n m m sta E # lu a a a s a n a ı a q L s u o Įł J e a H ı {ł pWsuaaMH J° a M ı 0 1 a a u s Į s a = Ĺł oå a łeJ sw ł ol uĮ B u m e J sa ŊsJa n e s u ó ıg !sa m ] n p ų a u u a u a J J a d o t o 1 s ıo J ł u n o J ? e s u o g J e a l p a ļ e w a u i« u n u ı u q ı a A a M o H P a ł e Įp a u ï a u n w re q pa w & Ħ H 二二。。 Ã。。 · 二 沪 a 。二 严 d 一 Ãq p æ - " ' 二 。 . ' ご · 裘 。 ぶ し 二 三 了コ ニ 茗 1一 図 他 叫 。 . x j a a e u o p a e a J 9 w p u e i Ĥ 9 ! q a ru p ı E ı a w B n ı p s ı ı u a q . J a w e a u q » ı a o s . ı a Ja ı s P a JJa s lĮc c p ı ı a u p m ı n o l ł ı s am d d= a e J a io ł ? q o 1 p ie s s ! ł u a g = d e Ála sJ a A u o J c o u Ą c ı [ ųŁ w e t ı o J n n = m c x q & m J )o ł ı atlła ru p e Jo s IJ a u a a s ı a A p e s a q p J s a p 6 1 n s ł a a JJa J !x o 】£ lı ł a (Z) a 9 J o Ãn e u o g u a au ţu T ı Æ q 1!a a s o p a q l a m e a a q o l o Ð g t u ı e q d ı e j a u a u ı i =o Ą )A ó o lo a e u u e q d Jo w o g ł x a ıv r w ı T t Į O 01 ' " 罐 、 ご ? く , ,
  • 36. Scanned by CamScanner 靉 骥類 多 多 数鳥芦 荟 衾雩券" ".: , 寡, 戛乙 く ぢ こ 帛 llı a T e i lt B o o k o f P ı a rm a c o lo g y (v o w ı ■ 昌 :X . kin re a c tio n e ith e r to s u n lig h t o r to a r tu ic ia l h gh t D r u gs m a y b e ą c a u s e o f tha t c a n b e im p lic a ı e d in th e s e typ e s o f r e a c tio n s R e c e n tl y n o n s te r o id a l a n ti 삐 岭ry d r u gs ha v e b e e n s h o w n to b e a c o m m o n c a u s e o f p h o to s e n s itiv ity A s b o th sys!WėNd c o n s id e r a tio n ı ħ e p o te n tia 】 ris k o fo c c u Jr e n c e s u c h r e a c tio n s e s p e c ia lly in p e 叩 le c h r o n ic a lly e x p o s e d ı u u lt r a v io l e t r a d ia tio n M e d ï a ı io n t t x i P G u p d d ru g 园四国园 c a d i a s c u ır a d 1 e n 上 1 加 国国目日目回国回国 Fu m s m id e l ı ı m Thb zid ı I a n tib io tic @ e w ę l ı m a ı s u t io n a m *ı e t + I ţ c þro ño = c i n e ı + 1 3 Į] A Æ ? g a l G ri s e o ! ı Į ノ D M A RD ı I J + = = = a T b p td e n @ m ı L + I ' I Ke to p rd e 1 1 T a bJe Sh o w s the P ho to to x ic a n d p h to a lle lgic re a c tio n Rn s J u b n i D ı u g D e p e n de n c e a n d D r u g w iM dra w a l r e a c tio n D r u g d e p e n de n c e is a bo u t u sin g ill ega l i dru gs ï o r e x a m pı e a dia be t ic ca n be co m e d e p e n d e n t o n N ęJ w g ı n s u ı i n W i tho u t tħ i s dug tM s p e rso n w o u Jd die D r u g de pe n d e n c e is differņt A n a b o n o r a bu s e a ltho u g h p e o ple co m m o n l y u se a ll th re e te rm s in te r c h qn ge a þ jr ĽG c n e r a l p h a r m a c o m . & · a lw a y s r e fe r s to a p h p ic a l s ta te o f c h e m ic a l r e lia n c e o n · d r u g to fe e l n o r m a l A h i m A p e r s o n c a n b e d e p e n d e n t o n a d r u g w ith o u t b e in g p h y s ic a lly a d d ic te d to it In o th e r m e n tálid is tre s s a s e n s e o f lo s s o r e v e n d e p re s s io n w h e n h is d r u g is n o t a v a 山山le b u t th is is T e iàtd ËĖn lc ity It is th e c a p a b ility o f d r u g s c a u s in g m a lfo r m a tio n s a b n o r ı n a litie s o r o th e r a gėhť ihät c a n d is tu r b th e d e v e lo p m e n t o f th e e m b r y ° o r fe tu s T ë r a to g e n s h a lt th e p r e g n a n c y raaiť i? maternal in fe c tio n s c h e m ic a ls a n d d r u g s T h e fo llo w in g d r u g c a u s e th e abńtirł ilityin fe tu s T h e s e a r e g iv e n in ta b le íi i n o r rl A b n o m a lity D ru g Thado mide I p h o c o m e lia m u ltip le d e te c ts : la s tic d r u g s 蔭三 上 卜 . 一 ? 。。 。 紐 " ì c åhæt% th e le a d in g c a u s e o f h u m a n m o r ta lity a ll o v e r th e w o r ld M o s t c a n c e r tis s u e s s h o w i ñuìh k o f c o m p le x c h r o m o s o m a l a b e r r a tio n s T h e in d u c tio n a n d a c c u m u la tio n o f g e n e ū c ¢ d &Ëà(ċ a n c a u s e g e n o m ic in s ta b ility a n d it is k n o w n a s a c r u c ia l s te p in th e g e n e r a tio n o f : ċaiJeeŕncogenicitys tu d ie s o f c a r c in o ge n ic p o te n tia l u s in g g e n o to x ic ity a s s a ys a r e o n th e ïł iįĺ Àlær e d g e n e e x p r e s s io n a b n o r m a l c e l l g ro w th , a n d d is r u p tio n o f n o r m a l c e l l c t i o n l ä y b ël fel at ed w i th t he gen o t ox i c ef fec t o f d r u g s.
  • 37. Scanned by CamScanner 磬 四日团团■■際四国国 r = D I D I D I D I D I D I D I D I D I D I D I D I D I : - H : : : : : : : : : : : : : . ' ' ' ' ' ' , ' ' ' ' ' ' " EiO l ı aT e x t B P h a r m a . M a ı G e E " l Pharmacoı g C o ' - 0 n ı ― ― IG a s b ith u pP e ; . . į ° - p i n , H ypo l e ı s io n c N s A n x ie y efupnyumer'"ľ 1 2 0 a + Ł a rbid op a p s yc h o sis ¢ Meaylpı emOIOne ¢ Ħ,mobaı bine p re dn is o lo n e C o gn itiv e d ys fu n c tio n 白 手 C ys titi s M ya lgia e JJ S lls e ffe c ts 雞 。 襄 薤 蓑 蓑 A ' " m j a 識 國 i iìt r e a § Ë in p h a r m a c o d y n a m ic e ffe c t (w h e r e a s m a ll in c r e a s e in d o s e r e s u lts in a la r g e s a 6 s n n í i n c r e a s e in p la s m a le v e l) B o n e m a n o w s u p p r e s s io n ;n o ìz a g T qq u e iı igh İirs t pa ss m e ta bo ı i s m It is d u e to th e d r u gs a r e e x te n s iv e ly m e ta b o lis e d in th e liv e r o r H ie m o brii I g a s tr o in te s tin a l tr a c t a n d a r e th e r e fo r e s e n s itiv e to th e e ffe c ts o f m e ta b o lic in h ib iū o n o r o i lĵ u b n İ in d u c tio n S i }ı gı e m e cJı a n i s m o fe li m in a ti o n It is il n te r a c tin g o f d r u g c a n c a u s e a s ign ific a n t in c r e a s e in ) ßm a ó lq p la s m a c o n c e n tr a ū o n (e g R e n a l c le a r a n c e c y to c h r o m e m e ta b o lis m ) a b b a e @ d r u g in t e r a c t io d n ı g a n d a ffe c ts its a c tiv ity b y in c r e a s in g o r d e c r e a s in g its e ffe c t c a u s in g a s id e ļ n = t J ' " ' " ' " d r u g fo o d in'"actions d r u g m e d ic a l c o n d ' " " m e c h a n is m s In v iv o in te r a c tio n s m a y b e ħ Jr th e r s u b d iv id e d in to p h a r m a c o d p a m ic o r ay o c c u r b e tw e e n tw o d r u g s a p p lie d to p ic a lly o r b e tw e e n a to p ic a l a n d a s y s te m ic d r u g : d is e a s e in te r a c tio n s (fo r e x a m p le to p ic a l c o r tic o s te r o id a n d a lo e v e r a ) m a y a ls o o c c u r T h e d r u g in te ra c tio n c a n o c c u r s a t a n y le v e l Ĥ i F ig 2 1 3 A d i u g in te r a c tio n a t v u io u s le v e l 囊