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Trace: basic_principles_of_pharm

BASIC PRINCIPLES OF PHARMACOLOGY (a JiTT Session Resource)

Craig C!ar"son# P$%

Learning O&'ec(i)es
By the end of the self study you should be able to: 1. escribe !he !wo primar" proper!ies of a #r$% recep!or& an# how a recep!or #iffers from an iner! bin#in% si!e. '. efine !he followin% #r$% proper!ies: a%onis!& an!a%onis!& affini!"& efficac"& ( po!enc". ). escribe a !"pical #ose*response c$r+e for a #r$%& an# label !he posi!ions on !he c$r+e !ha! are $se# !o #efine #r$% po!enc" an# efficac".

,. -.plain !he #ifference be!ween selec!i+i!" an# specifici!" of #r$% effec!& an# which is more commonl" obser+e#. /. 1. escribe wha! is mean! b" !he !erm Therape$!ic 0in#ow. escribe an# e.plain !he effec!2s3 of compe!i!i+e an# non*compe!i!i+e an!a%onis!s on !he #ose*response c$r+e for an a%onis!.

4. -.plain how a 5$an!al #ose*response c$r+e is cons!r$c!e#. 6. -.plain wha! is mean! b" a##i!i+e an# s"ner%is!ic #r$% effec!s. 7. efine wha! #esensi!i8a!ion means ( e.plain how i! ma" occ$r.

19. efine !he !erms - /9& : /9& T /9 an# Therape$!ic ;n#e.. You are e*+ec(e, (o $a)e rea, ($is $an,ou( an, co-+!e(e, ($e on!ine B!ac"&oar, (M.Tu!ane) Me, P$ar- /ui0 &. 1 AM &e2ore ($e ,a. o2 ($is c!ass session3 Bring .our 4c!ic"ers5 6i($ .ou (o c!ass3

%EFINITIONS

P$ar-aco!og. * is !he science of !he in!erac!ion of chemical a%en!s 2#r$%s3 wi!h li+in% s"s!ems. ;! encompasses !he s!$#" of !he biochemical an# ph"siolo%ic aspec!s of #r$% effec!s& incl$#in% absorp!ion& #is!rib$!ion& me!abolism& elimina!ion& !o.ici!"& an# specific mechanisms of #r$% ac!ion. %rug * a s$bs!ance 2chemical a%en!3 !ha! affec!s a biolo%ical s"s!em in a po!en!iall" $sef$l wa". r$%s are $se# in !he pre+en!ion& #ia%nosis& !rea!men! or c$re of #isease in man or o!her animals. Poison * <n" chemical a%en! !ha! pro#$ces a harmf$l effec! 2e.%. arsenic=lea#3. >o!e: #r$%s in hi%h concen!ra!ions become poisons. To*in * a poison of biolo%ical ori%in 2e.%. !e!ro#o!o.in3

T6o Pri-ar. Branc$es o2 P$ar-aco!og.

The !wo ma?or branches of pharmacolo%" are: +$ar-aco,.na-ics an# +$ar-aco"ine(ics. P$ar-aco,.na-ics * The s!$#" of !he rela!ionship be!ween concen!ra!ions of #r$% an# !he biolo%ic effec!s 2ph"siolo%ical or biochemical3 wi!h !ime. ;n opera!ional !erms @wha! #r$%s #o !o !he bo#"A. Bor mos! #r$%s i! is necessar" !o know !he si!e of ac!ion an# mechanism of ac!ion a! !he le+el of !he or%an& f$nc!ional s"s!em& or !iss$e. Bor e.ample& !he effec! ma" be locali8e# !o !he brain& !he ne$rom$sc$lar ?$nc!ion& !he hear!& !he ki#ne"& e!c. The mechanism of ac!ion can !"picall" be #escribe# in biochemical or molec$lar !erms. Mos! #r$%s e.er! effec!s on se+eral or%ans or !iss$es& an# ha+e $nwan!e# 2si#e3 effec!s as well as !herape$!ic effec!s. There is a #ose*response rela!ionship for bo!h !herape$!ic an# si#e effec!s. Bac!ors in !he pa!ien! !ha! affec! responses incl$#e a%e& wei%h!& se.& #ie!& race& #isease& !ra$ma& an# conc$rren! !rea!men! wi!h o!her #r$%s. P$ar-aco"ine(ics * The s!$#" of !he absorp!ion& #is!rib$!ion& me!abolism an# e.cre!ion of #r$%s from !he bo#". ;n opera!ional !erms @wha! !he bo#" #oes !o #r$%sA. To pro#$ce i!s charac!eris!ic effec!s& a #r$% m$s! be presen! in an appropria!e concen!ra!ion a! i!s si!es of ac!ion. Th$s& i! is impor!an! !o know !he in!errela!ionship of !he absorp!ion& #is!rib$!ion& bin#in%& bio!ransforma!ion& an# e.cre!ion of a #r$% an# i!s concen!ra!ion a! i!s loc$s of ac!ion. < knowle#%e of !he pharmacokine!ics of a #r$% is necessar" !o answer s$ch !herape$!icall" impor!an! 5$es!ions as: @C" which ro$!e sho$l# ; %i+e !his #r$%DA& @0ha! #ose sho$l# ; %i+e !o pro#$ce !he #esire# effec!DA& @<! wha! !ime in!er+als sho$l# !he #r$% be %i+enDA& @0ha! #oses will ca$se !o.ici!"DA& @ oes !he pa!ien!s a%e& #isease s!a!e& or concomi!an! !herap" wi!h o!her #r$%s al!er !he effec! of !his #r$%DA Ma?or iss$es in+ol+e# in #efinin% !he pharmacokine!ic proper!ies of a #r$% incl$#e knowle#%e of i!s:

A&sor+(ion * 2oral or paren!eral3 * < #r$% m$s! be absorbe# an# achie+e a#e5$a!e concen!ra!ion a! i!s si!e of ac!ion in or#er !o pro#$ce i!s biolo%ical effec!s. The ma?or ro$!es of #r$% a#minis!ra!ion incl$#e: a3 oral 2enteral * or +ia !he in!es!ine3E b3 parenteral

2o!her !han !he in!es!ine3 s$ch as in!ram$sc$lar 2i.m.3 or s$bc$!aneo$s 2s.c.3: an# c3 #irec! in?ec!ions in!o !he car#io+asc$lar s"s!em 2intravenously or i.+.3. 0hen a #r$% is applie# !o a bo#" s$rface 2e.%.& F.;. !rac!& skin& l$n%s& e!c.3& i!s ra!e of absorp!ion will #e!ermine !he !ime for i!s ma.imal concen!ra!ion in plasma an# a! !he recep!or !o pro#$ce i!s peak effec!.

%is(ri&u(ion * The bloo#& !o!al bo#" wa!er& e.!racell$lar& l"mpha!ic an# cerebrospinal fl$i#s are in+ol+e# in mo+emen! of #r$% !hro$%h !he bo#". epen#in% $pon i!s chemical an# ph"sical proper!ies& !he #r$% ma" be bo$n# !o plasma pro!eins or #issol+e# in bo#" fa!& #ela"in% i!s pro%ress !o i!s si!e of ac!ion& me!abolism or e.cre!ion. Me(a&o!is- * Gow #r$%s are han#le# biochemicall" b" !he bo#" an# incl$#es h"#rol"sis& con?$%a!ion& an# o.i#a!ion*re#$c!ion. E*cre(ion * The ki#ne" is !he mos! impor!an! or%an for e.cre!ion of #r$%s. r$%s !ha! are e.cre!e# in !he feces are mos!l" #eri+e# from $nabsorbe#& orall"*in%es!e# #r$%s or from me!aboli!es e.cre!e# in !he bile. The l$n%s an# swea! $s$all" pla" a minor role.

O($er Branc$es o2 P$ar-aco!og.

A3 C!inica! P$ar-aco!og. an, T$era+eu(ics

This #iscipline is in!eres!e# in charac!eri8in% !he ;n#ica!ions an# !herape$!ic $ses of #r$%s* -mphasis is place# on !he !herape$!ic $se of #r$%s for !he !rea!men! of #isease in !he clinical "ears wi!h clinical pharmacolo%"& in!ernal me#icine an# !herape$!ics. The ph"sician m$s! wei%h !he po!en!ial benefi! a%ains! !he risks of a#+erse effec!s in a %i+en #isease. ;! is impor!an! !o know !ha! !he presence of #isease or or%an pa!holo%" ma" infl$ence !he ac!ions of a #r$%. Hon#i!ions s$ch as a%e& pre%nanc"& concomi!an! a#minis!ra!ion of o!her #r$%s& an# #isease ma" al!er !he pa!ien!Is response !o a %i+en #r$%. <n impor!an! concern in !herape$!ics is #r$% Bioa)ai!a&i!i(. * The frac!ion of #r$% a#minis!ere# which is ac!$all" absorbe# in!o !he s"s!emic circ$la!ion 2oral #osin%3. Prepara!ions of !he same #r$% b" #ifferen! man$fac!$rers ma" ha+e a #ifferen! bioa+ailabili!".
B3 To*ico!og.

The aspec! of pharmacolo%" !ha! #eals wi!h !he a#+erse effec!s of #r$%s. ;! is concerne# no! onl" wi!h #r$%s $se# in !herap" b$! also wi!h o!her chemicals !ha! ma" be responsible for ho$sehol#& en+ironmen!al or in#$s!rial e.pos$re.

Basic Princi+!es o2 P$ar-aco,.na-ics

Ho6 ,o %rugs E*er( ($eir E22ec(s7

That combining group of the protoplasmic molecule to which the introduced group is anchored will hereafter be termed receptor. P<U: -GJ:;HG& 1797 Corpora non agunt nisi fixata [substances do not act unless bound]. P<U: -GJ:;HG& 171) The #efini!ion of a #r$% as an" chemical !ha! per!$rbs a biolo%ical s"s!em s$%%es!s !ha! !he" can pro#$ce !heir effec!s b" m$l!iple mechanisms. -.amples of m$l!iple mechanisms for #r$% ac!ion incl$#e: chemical in!erac!ions wi!h o!her molec$les #$e !o a #r$%s aci#ic or basic proper!ies 2e.%. an!aci#s& or Pro!amine s$lfa!e * a heparin an!a%onis!3& !heir abili!" !o ac! as a membrane s$rfac!an! 2ampho!ericin C3& or !heir abili!" !o #ena!$re pro!eins 2as!rin%en!s3. Gowe+er& mos! #r$%s e.er! !heir !herape$!ic effec!s b" bin#in% !o specific rece+(or si(es. Receptors have two important properties * !he" &in, #r$%s 2li%an#s3 wi!h rela!i+el" hi%h affini!"& an# af!er !he" bin# a #r$%& !he" (rans,uce a signa! !o pro#$ce a biolo%ical effec!. This la!er proper!" #is!in%$ishes recep!ors from iner! bin#in% si!es& s$ch as <lb$min or K1*aci# %l"copro!ein& which are bloo# pro!eins !ha! a+i#l" bin# man" #r$%s& b$! do not !rans#$ce a si%nal. Man" #r$% recep!ors can !rans#$ce biolo%ical si%nals a! +er" low concen!ra!ions 2i.e. !he" are hi%hl" efficien!3. Bor e.ample& calc$la!ions from s!$#ies of a!ropine bin#in% !o !he in!es!inal ile$m s$%%es! !ha! onl" 9.9'L of !he cell s$rface is compose# of ace!"lcholine recep!ors 2an area comparable !o !he s$rface area of ;celan# rela!i+e !o !he s$rface area of !he -ar!h3 2Menakin& 17743.

Rece+(or Su&(.+es
r$% recep!ors can be classifie# in!o se+eral ma?or s$b!"pes incl$#in%:

En0.-es 2e.%. allop$rinol inhibi!ion of .an!hine o.i#ase3. Ion c$anne!s 2e.%. #*!$boc$rarine blocka#e of !he nico!inic recep!or=channelE +erapamil blocka#e of Ha channels3. Me-&rane rece+(ors 2e.%. a!ropine blocka#e of m$scarinic recep!ors& epinephrine s!im$la!ion of K* or N* a#rener%ic recep!ors3. S!im$la!ion of membrane recep!ors !"picall" res$l!s in !he al!ere# ac!i+i!" of membrane*associa!e# en8"mes or channels +ia ac!i+a!ion of specific G8+ro(eins loca!e# on !he in!racell$lar membrane s$rface. <n e.cep!ion !o !his r$le are recep!ors wi!h !"rosine kinase ac!i+i!" 2see below3. O ;n!racell$lar recep!ors 2e.%. es!ro%en in!erac!ion wi!h n$clear recep!ors3.

T$e C$e-ica! Basis 2or %rug8Rece+(or In(erac(ions

r$%s can in!erac! wi!h recep!ors !hro$%h a +arie!" of chemical in!erac!ions incl$#in%:

E!ec(ros(a(ic in(erac(ions 2h"#ro%en bon#s& Pan #er 0aals forces3 * !he mos! common mechanism. H.,ro+$o&ic in(erac(ions 2impor!an! for lipi# sol$ble #r$%s3.

Co)a!en( &on,s 2e.%. pheno."ben8amine bin#in% !o K*a#rener%ic recep!ors3 * leas! common S(ereos+eci2ic in(erac(ions 2Q/9L of #r$%s e.is! as s!ereoisomers an# in!erac! s!ereospecificall" wi!h recep!ors. e.%. S 2*3 Har+e#ilol bin#s !o bo!h K*a#rencep!ors an# N* a#rener%ic recep!ors& whereas J2R3 Har+e#ilol bin#s selec!i+el" !o K*a#rener%ic recep!ors3.

T$e %ose Res+onse Re!a(ions$i+

The frac!ion of recep!ors occ$pie# b" a #r$% is a f$nc!ion of !he #r$% concen!ra!ion. <s !he #r$% concen!ra!ion is increase#& a pro%ressi+el" hi%her frac!ion of a+ailable recep!ors will become occ$pie# b" #r$% $n!il all a+ailable recep!ors become bo$n#. <n ill$s!ra!ion of !he rela!ionship be!ween #r$% concen!ra!ion an# recep!or occ$panc" b" #r$% is shown in Bi%$re 1.

Figure 93 The dose-response relationship. hen plotted on a linear scale !left panel"# a doseresponse relationship is h$perbolic# and can t$picall$ be well described b$ a %angmuir binding isotherm. &t high concentrations the response reaches a maximum due to saturation of available receptors b$ drug. hen plotted on a semi-log scale !logarithm of drug concentration vs. effect"# the relationship becomes sigmoidal !'-shaped". The semi-log plot is the preferred method for plotting dose-response relationships because it becomes easier to accuratel$ determine the (C)* value !the concentration which produces )*+ of the maximum response" b$ placing it on a linear portion of the curve.

Agonis(s an, An(agonis(s

r$%s are commonl" #i+i#e# in!o !wo basic ca!e%ories: a%onis!s an# an!a%onis!s. Agonis(s are #r$%s !ha! bind an# activate recep!ors. C!assica! an(agonis(s are #r$%s !ha! bin# !o recep!ors without activating them& an# conse5$en!l" pre+en! !he bin#in% of o!her a%onis!s. ;f "o$ concep!$ali8e #r$%*recep!or in!erac!ions as a @lock an# ke"A mo#el& a%onis!s are ke"s !ha! fi! in!o

a lock 2recep!or3 an# open 2ac!i+a!e3 !hem& whereas an!a%onis!s fi! in!o !he lock an# ?am !he mechanism. Two f$n#amen!al proper!ies of a%onis!s are affini!" an# efficac". A22ini(. can be #efine# as !he !enaci!" wi!h which a #r$% bin#s !o i!s recep!or. ;n s!a!is!ical !erms& i! can be #efine# as !he probabili!" !ha! a #r$% molec$le will bin# !o an a+ailable recep!or a! an" %i+en ins!an! in !ime. E22icac. is an inheren! proper!" of an a%onis! !ha! #e!ermines i!s abili!" !o pro#$ce i!s biolo%ical effec!. C" #efini!ion& i! is a proper!" of !he #r$%& no! !he recep!or or !iss$e. &ffinit$ gets the drug bound to the receptor# and efficac$ determines what happens once the drug is bound. ifferen! #r$%s !ha! bin# !o !he same recep!or an# pro#$ce !he same !"pe of response will !"picall" #iffer from each o!her in !erms of !heir affini!" 2po!enc"3 an#=or efficac". The !erm potency is $se# as a compara!i+e !erm for #is!in%$ishin% which a%onis! has a hi%her affini!" for a %i+en recep!or 2Bi%$re '3.

Figure :3 'chematic illustration of the dose-response curves for a series of agonists !&# ,# C and -" that have the same efficac$# but differ in terms of their potency. The most potent drug !-rug &" has the lowest (C)* value# and is approximatel$ .*-/* fold more potent than -rug -. <%onis!s can also #iffer in !erms of !heir efficac"& or ma.im$m response. Bi%$re ) shows a plo! of fo$r a%onis!s !ha! #iffer in !erms of !heir rela!i+e efficac". r$% < is !he mos! efficacio$s& an# r$% !he leas!. r$%s !ha! pro#$ce less !han ma.imal ac!i+a!ion of a recep!or are of!en referre# !o as +ar(ia! agonis(s. r$% & which pro#$ces +er" li!!le ac!i+a!ion& wo$l# mos! likel" f$nc!ion as a %oo# an(agonis( for r$%s <& C or H since i! bin#s !o !he recep!or 2no!e: same affini!"3& b$! pro#$ces onl" a minimal le+el of ac!i+a!ion.

Figure 13 -ose-response relationships for four agonists that var$ in efficac$. (ach drug has essentiall$ the same (C)* value !e0ui-potent"# but differ in terms of the maximum response the$ can produce at high concentrations that saturate all available receptor sites. -rug & has a relative efficac$ that is . times than -rug C# and 12** times more than -rug -.

Signa! Trans,uc(ion Mec$anis-s 2or Agonis(s

Once an a%onis! has bo$n# !o i!s recep!or& i!s effec!s are !rans#$ce# in!o a cell$lar response b" one of se+eral #ifferen! mechanisms. < few of !he mos! common mechanisms incl$#e: a3 #irec! ac!i+a!ion of an ion channel& b3 F*pro!ein ac!i+a!ion of an ion channel& c3 F*pro!ein ac!i+a!ion of a secon# messen%er s"s!em& or #3 recep!or ac!i+a!ion of an in!racell$lar en8"me 2e.%. !"rosine kinase3. -.amples of !hese mechanisms are shown below. %irec( ac(i)a(ion o2 an ion c$anne! The #r$% recep!or is s!r$c!$rall" a!!ache# !o an ion channel. Cin#in% of !he #r$% !o !he recep!or si!e2s3 res$l!s in a conforma!ional chan%e in !he recep!or=channel comple. !ha! !"picall" ca$ses !he ion channel !o open. This res$l!s in a flow of channel permean! ions 2e.%. >a an# M for nico!inic recep!ors3 #own !heir elec!rochemical %ra#ien! wi!h a res$l!an! chan%e in membrane po!en!ial 2Bi%$re ,3. -.amples:

nico!inic choliner%ic recep!ors 2ne$rom$sc$lar ?$nc!ion& %an%lia3 F<C< recep!ors an# recep!ors for e.ci!a!or" amino aci#s 2%l"cine& %l$!ama!e& aspar!a!e

Figure ;3 %igand-gated ion channel. ,inding of . molecules of acet$lcholine to the nicotinic receptor3channel complex causes the channel to open. 4n s5eletal muscle# this results in a depolari6ation of the membrane potential# the production of an action potential# and contraction !the biological response". G8+ro(ein ac(i)a(ion o2 an ion c$anne! The #r$% recep!or s!im$la!es an ion channel +ia ac!i+a!ion of a F pro!ein 2Bi%$re /3. -i!her !he alpha or be!a=%amma s$b$ni!s s!im$la!e !he channel !o open. <s an e.ample& !his is !he mechanism b" which ace!"lcholine ac!s !o slow !he hear! ra!e. -.ample:

m' * choliner%ic recep!ors

Figure <3 7-protein activated ion channel. ,inding of an agonist to the m. receptor activates a 7-protein !7i" which in turn stimulates a 8-selective channel to open. The increase in 8 permeabilit$ will h$perpolari6e the membrane potential. G8+ro(ein ac(i)a(ion o2 a secon, -essenger casca,e There are !wo well charac!eri8e# secon# messen%er casca#e mechanisms. One in+ol+es !he F* pro!ein 2Fs3 me#ia!e# ac!i+a!ion of a#en"l"l c"clase& wi!h s$bse5$en! forma!ion of camp an# ac!i+a!ion of pro!ein kinase < 2PM*<3 2Bi%$re 13. The secon# in+ol+es !he F*pro!ein ac!i+a!ion of phospholipase H 2P:H3& which breaks #own phosphoinosi!i#e !o ;P) an# #iac"l%l"cerol 2Bi%$re 43. <F ac!s as a secon# messen%er !o s!im$la!e pro!ein kinase H& an# ;P) s!im$la!es !he release of Ha ions from in!racell$lar s!ores. -.amples:

<#en"l"l c"clase= c<MP= PM*<: N*a#renorecep!ors& K'*a#renorecep!ors Phospholipase H = iac"l%l"cerol= ;P):K1*a#renorecep!ors& an%io!ensin& m1*choliner%ic

Figure =3 -rug induced activation of the c&9:3:8-& pathwa$. ;orepinephrine binding to beta2-adrenergic receptors stimulates aden$late c$clase !&C"# which converts &T: to c&9:. c&9: acts as a second messenger to stimulate protein 5inase & !:8-&"# which in turn phosphor$lates a variet$ of proteins# generating a biological response. !e.g. this mechanism is responsible for norepinephrine<s abilit$ to increase the force of contraction of heart muscle# which results from the phosphor$lation of the %-t$pe Ca channel b$ :8-&".

Figure >3 -rug induced activation of the phosphoinositide3 :8-C pathwa$. &ngiotensin 44 binding to &T2 receptors activates phospholipase C !:%C". :%C brea5s down phosphoinositol into diac$lgl$cerol !-&7" and 4:/. -&7 acts as a second messenger to activate protein 5inase

C !:8-C"# which phosphor$lates a variet$ of intracellular proteins. 4:/ stimulates the release of Ca from intracellular stores. These mechanisms are believed to mediate the vasoconstrictive effects of &ng 44 on vascular smooth muscle. Rece+(ors !in"e, (o C.(o+!as-ic En0.-es (e3g3 T.rosine ?inases) This class of recep!ors me#ia!es !he firs! s!eps in !he !rans#$c!ion of si%nals carrie# b" ins$lin an# a wi#e +arie!" of %row!h fac!ors s$ch as epi#ermal %row!h fac!or 2-FB3& a!rial na!ri$re!ic fac!or 2<>B3 an# !ransformin% %row!h fac!or be!a 2TFB*N3. These recep!ors con!ain an e.!racell$lar #omain !ha! bin#s !o a specific li%an#& an# a c"!oplasmic #omain !ha! !"picall" con!ains a pro!ein !"rosine kinase 2Bi%$re 63. Gowe+er& o!her en8"mes s$ch as serine kinases& or a %$an"l"l c"clase ma" also be co$ple# !o a recep!or an# work b" !he same mechanism. -.amples: -FB& ;ns$lin& +ario$s %row!h fac!ors

Figure @3 The binding of a ligand to receptors produces a change in receptor conformation that allows receptors to interact. The interaction between receptors causes the t$ronsine 5inases to become active# resulting in auto-phosphor$lation of the en6$me domains# and phosphor$lation of t$rosine residues on different downstream signaling proteins !'='-:". The autophosphor$lation t$picall$ results in a prolonged response to the agonist !e.g. insulin" that persists after the removal of the ligand from the receptor site.

An(agonis(sA Co-+e(i(i)e )s3 Nonco-+e(i(i)e

<n!a%onis!s are #r$%s !ha! bin# !o recep!ors 2ha+e affini!"3& b$! #o no! pro#$ce a s$bs!an!ial #e%ree of recep!or s!im$la!ion 2!he" ha+e +er" low efficac"3. <n!a%onis!s are !"picall" classifie# as compe!i!i+e or noncompe!i!i+e. Co-+e(i(i)e an(agonis(s bin# re+ersibl" !o !he same recep!or si!e as !he a%onis!. Ceca$se !he" bin# re+ersibl" an# compe!e for !he same bin#in% si!e& !heir inhibi!or" effec!s can be @s$rmo$n!e#A b" a##i!ion of a hi%her concen!ra!ion of a%onis! 2Bi%$re

7<3. This effec! pro#$ces a ri%h!war# parallel shif! of !he #ose*response for !he a%onis! 2!owar#s hi%her concen!ra!ions3. ;n !he presence of a compe!i!i+e an!a%onis!& a%onis!s can s!ill pro#$ce !he same 2e.%. 199L3 ma.imal effec! as in !he absence of an an!a%onis!& !he onl" #ifference bein% !ha! hi%her a%onis! concen!ra!ions are nee#e# !o pro#$ce !he same le+el of effec!. The +as! ma?ori!" of clinicall" $se# #r$%s !ha! ac! as recep!or an!a%onis!s are competitive an!a%onis!s. Nonco-+e(i(i)e an(agonis(s ei!her bin# irreversibl$ 2e.%. b" co+alen! bon#s3 !o !he same si!e as !he a%onis!& or bin# !o a #ifferen! si!e which re#$ces !he bin#in% of !he a%onis! b" an allosteric mechanism. The primar" effec! of a noncompe!i!i+e an!a%onis! is a reduction in the maximal effect pro#$ce# b" !he a%onis! 2see Bi%$re 7 C3. 2;n some cases !he slope ma" also be re#$ce#.3 ;n con!ras! !o a compe!i!i+e an!a%onis!& !he effec! of a noncompe!i!i+e an!a%onis! cannot be re+erse# b" simpl" increasin% !he concen!ra!ion of !he a%onis!& since !he law of mass ac!ion #oes no! appl".

Figure B3 (xamples of Competitive and ;oncompetitive &ntagonism. &. Competitive &ntagonism# where both the agonist !4soproterenol" and the antagonist !:ropranolol" bind reversibl$ to the same receptor subt$pe !>-adrenoceptor". 4n the presence of the competitive antagonist# the dose-response curve is shifted to the right in a parallel manner. ,. ;oncompetitive antagonism. :henox$ben6amine binds irreversibl$ !with covalent bonds" to ?adrenergic receptors. This reduces the fraction of available receptors# and reduces the maximal effect that can be produced b$ the agonist.

Re)erse Agonis(s
Some #r$%s& in some biolo%ical s"s!ems& ha+e been shown !o ac! as @re)erse agonis(sA in !ha! !he" +ro,uce a res+onse ($a( is o++osi(e o2 ($a( (.+ica!!. +ro,uce, &. a rece+(or when i! is s!im$la!e# b" a con+en!ional a%onis!. One mechanism !ha! has been propose# !o e.plain s$ch an effec! is b" a #r$%*in#$ce# #ecrease in !he basal ac!i+i!" of !he recep!or. Bor e.ample& some 7-

protein coupled receptors appear to have a basal or tonic level of intrinsic activit$ in the absence of a hormone or neurotransmitter. This res$l!s in a !onic le+el of s!im$la!ion of #owns!ream e+en!s& s$ch as s!im$la!ion of a#en"la!e c"clase. 0hen a @re+erse a%onis!A bin#s !o !his recep!or& i! ac!s similar !o a con+en!ional an!a%onis! b" bin#in% !o !he recep!or wi!ho$! @s!im$la!in% i!A. Gowe+er& in a##i!ion& the binding of the reverse agonist to the receptor alters the receptor confirmation in such a wa$ as to decrease its interaction with 7-proteins& res$l!in% in a #ecrease in basal s!im$la!ion of F*pro!eins an# a re#$c!ion in !he ac!i+i!" of a#en"la!e c"clase.

O($er Mec$anis-s o2 %rug An(agonisThere are o!her !"pes of @an!a%onismA in+ol+in% #r$% effec!s. P$.sio!ogica! an(agonisin+ol+es #r$% ac!i+a!ion of !wo #ifferen! compensa!or" biolo%ical mechanisms !ha! e.is! !o main!ain homeos!asis. Bor e.ample& !he effec! of norepinephrine !o increase bloo# press$re 2+ia s!im$la!ion of K*a#rener%ic recep!ors3 can be an!a%oni8e# b" a#minis!ra!ion of ace!"lcholine& which ca$ses +aso#ila!ion b" release of ni!ric o.i#e from !he +asc$lar 2ar!eriolar3 en#o!heli$m. C$e-ica! an(agonis- occ$rs when a #r$% re#$ces !he concen!ra!ion of an a%onis! b" formin% a chemical comple. 2e.%. chela!in% a%en!s3. P$ar-aco"ine(ic an(agonis- occ$rs when one #r$% acclera!es !he me!abolism or elimina!ion of ano!her 2e.%. phenobarbi!al*in#$ce# en8"me in#$c!ion increases !he me!abolism of !he an!icoa%$lan! co$ma#in3.

%rugs o2(en 6or" on -u!(i+!e rece+(ors

r$%s of!en work on more !han one recep!or& an# as a res$l! pro#$ce more !han one kin# of biolo%ical response 2Bi%$re 193. One %oo# e.ample is norepinephrine 2>-3& !he s"mpa!he!ic ne$ro!ransmi!!er which can re!a* bronchial smoo!h m$scle& b$! cons(ric( ar!erial smoo!h m$scle. This res$l!s from >- bin#in% !o #ifferen! a#rener%ic recep!or s$b!"pes 2K an# N3. Cronchial smoo!h m$scle is rich in N a#rener%ic recep!ors& whereas ar!erial smoo!h m$scle is rich in K a#rener%ic recep!ors. 0hen s!im$la!e#& !he K recep!or s$b!"pe !rans#$ces a #ifferen! !"pe of biolo%ical si%nal compare# !o N a#rener%ic recep!ors. -ach recep!or s$b!"pe selec!i+el" in!erac!s wi!h #ifferen! F pro!eins ( !h$s ac!i+a!e #ifferen! in!racell$lar messen%er pa!hwa"s& res$l!in% in #ifferen! biolo%ical responses.

Figure 9C3 & single drug can interact with multiple receptors. ;orepinephrine can deliver two t$pes of messages b$ interacting with different adrenergic receptor subt$pes !? and >". These receptors are coupled to different intracellular messenger s$stems# and produce different responses when stimulated. These receptor subt$pes are not t$picall$ expressed in e0ual amounts in the same tissue !e.g. vascular smooth muscle contains more ? receptors !? @ > "# whereas bronchial tissue contains more > receptors !> @ ?".

S+eci2ici(. )s3 Se!ec(i)i(.# an, ($e T$era+eu(ic

in,o6

;f a #r$% has one effec!& an# onl" one effec! on all biolo%ical s"s!ems i! possesses !he proper!" of s+eci2ici(.. ;n e.perience& !he +as! ma?ori!" of #r$%s are se!ec(i)e ra!her !han specific. This is !he case beca$se mos! #r$%s will ac! on more !han one recep!or si!e once !he" reach an appropria!el" hi%h concen!ra!ion. Two e.amples incl$#e: a3 +erapamil& a blocker of :*!"pe Ha channels& b$! which blocks >a channels a! hi%h concen!ra!ionsE b3 "ohimbine a #r$% $se# !herape$!icall" as an K'*a#renocep!or blocker b$! which also blocks /*GT recep!ors& K1*a#renocep!ors& >a channels& monoamine o.i#ase& an# cholines!erase a! hi%her concen!ra!ions. The concen!ra!ion ran%e o+er which a #r$% pro#$ces i!s !herape$!ic effec! is known as i!s ($era+eu(ic 6in,o6. <n ill$s!ra!ion of !he !herape$!ic win#ow for selec!i+e blocka#e of K'*a#renocep!ors b" "ohimbine is shown in Bi%$re 11.

Figure 993 The therapeutic window for selective bloc5ade of ?. - adrenoceptors b$ $ohimbine. 'imilar to most drugs# $ohimbine lac5s true specificit$ in its biological actions.

EC<C )s E%<C D

$a(Es ($e ,i22erenceFF7

EC50 used for in vitro studies only 0hen in+es!i%a!in% #r$% effec!s in a !iss$e ba!h se!!in%& #r$% concen!ra!ions are !"picall" precisel" known& $nless one is $sin% an imp$re so$rce of !he #r$% 2e.%. S!. SohnTs wor! U a herbal me#ica!ion con!ainin% a mi.!$re of ac!i+e in%re#ien!s& wi!h +ar"in% p$ri!" be!ween prepara!ions3. Gence when s!$#"in% #r$% effec!s in +i!ro& one can mos! commonl" compare #r$% effec!s !o #r$% concen!ra!ions an# a concen!ra!ion pro#$cin% /9L of a ma.imal effec! 2!he -H/93 can be #efine#. There Are Two Definitions of ED50 one for whole animal vs population studies ;n con!ras! !o a !iss$e ba!h e.perimen!& when a,-inis(ering a ,rug (o an in(ac( ani-a! or +a(ien(& one !"picall" %i+es a specific @#oseA 2e.%. /99 m% orall" or i.+.3. The concen!ra!ion of #r$% achie+e# in !he bloo#s!ream 2e.%. 1 or 19 $%=ml3 in response !o %i+in% !his fi.e# #ose will #epen# on which bo#" compar!men!s !he #r$% #is!rib$!es in!o 2e.%. e.!racell$lar +s. e.!racell$lar pl$s in!racell$lar space3& an# will +ar" as a f$nc!ion of !ime #epen#in% $pon !he ra!e of #r$% #is!rib$!ion in!o bo#" compar!men!s& an# !he ra!e of #r$% me!abolism an#=or elimina!ion from !he bo#" b" !he ki#ne"s. So as a res$l!& in whole animal e.perimen!s& we !alk of #oses !ha! pro#$ce a %i+en ma%ni!$#e of !herape$!ic effec!& e.%. /9L of !he ma.imal effec! - /9& an# no! -H/9. One can also #efine $o6 ,rug e22ec(s )ar. in a +o+u!a(ion o2 ani-a!s or +a(ien(s. These s!$#ies !"picall" in+ol+e %i+in% a ran%e of #oses !o a lar%e pop$la!ion of animals=pa!ien!s an# meas$rin% an all*or*none !"pe of @5$an!alA response 2s$ch as U #oes !his #ose pro#$ce +omi!in%&

or c$re a hea#ache wi!hin 1 ho$rs !imeD3. ;n !his si!$a!ion& one can #efine !he minim$m #ose nee#e# !o pro#$ce !he #esire# effec! in each animal or pa!ien!. The res$l!s of !his !"pe of s!$#" can be plo!!e# in !he form of a 5$an!al #ose response c$r+e 2Bi%$re 1'3. ;n a pop$la!ion s!$#"& !he #ose !ha! pro#$ces !he #esire# effec! in /9L of !he pop$la!ion is referre# !o as !he @me#ian effec!i+e #oseA an# is 2$nfor!$na!el"3 also abbre+ia!e# as !he - /9 or - /9. To su--ari0e# E%<C is a )a!ue ,e2ine, in 6$o!e ani-a! or +o+u!a(ion s(u,ies3

T$e Guan(a! %ose8Res+onse

The #ose response rela!ionships shown in Bi%$res ' ( ) are e.amples of %ra#e# responses& in which !he response occ$rs in %ra#a!ions propor!ional !o !he n$mber of recep!ors occ$pie# b" an a%onis!. r$% responses can also be #efine# as uantal. ;n !his case& !he obser+e# response is #escribe# 2#efine#3 on an @all*or*noneA basis. <n ill$s!ra!ion of a 5$an!al #ose*response rela!ionship is shown in Bi%$re 1'& which #epic!s !he rela!ionship be!ween !he #ose of a #r$% +s. !he fre5$enc" !ha! !his #ose pro#$ces a minim$m effec! 2e.%. lowerin% of bloo# press$re b" 19 mm G%3. 0i!h a s$fficien!l" lar%e pa!ien! pop$la!ion& !his !"pe of rela!ionship is of!en well*fi! b" a Fa$ssian #is!rib$!ion& in which s!a!is!ical parame!ers can be $se# !o pre#ic! !he +ariabili!" of #r$% response in !he pa!ien! pop$la!ion. T$e ,ose a( 6$ic$ <CH o2 ($e su&'ec(s res+on, is ($e E%<C. This !"pe of #ose*response rela!ionship is mos! $sef$l for #efinin% 5$an!al e+en!s s$ch as !he pre+en!ion of con+$lsions& arrh"!hmia or #ea!h b" a #r$%.

Figure 9:3 Auantal effects. & set of data obtained after administration of increasing doses of a drug to a group of patients# and observation of the minimum dose at which each patient responded with the desired outcome. The results have been plotted as a histogram# and fit with a gaussian curve. B C mean responseD E C standard deviation.

%rug Sa2e(. I ($e T$era+eu(ic In,e*

r$%s ha+e !herape$!ic effec!s& !o.ic si#e effec!s& an# in some cases le!hal effec!s. Si#e effec!s an# le!hal effec!s are !"picall" #ose*#epen#en!& an# can be 5$an!i!a!e# b" #efinin% !he #ose !ha! pro#$ces a !o.ic effec! in /9L of !he pop$la!ion 2T /93 an# 2a! leas! in animals3 le!hal effec!s in /9L of !he pop$la!ion 2: /93. The #ose*rela!ionships for !o.ic an# le!hal effec!s ma" ha+e #ifferen! slopes compare# !o !herape$!ic #ose*response rela!ionship beca$se !he" pro#$ce effec!s b" #ifferen! recep!ors or mechanisms 2e.%. Bi%$re 73. ;! is of +al$e !o know !he rela!i+e #ifference be!ween !he a+era%e !o.ic #ose an# !he a+era%e !herape$!ic #ose. The mos! common wa" !o #efine !his rela!ionship is $sin% !he T$era+eu(ic In,e* 2T;3& which is #efine# as !he ra!io be!ween !he T /9 an# - /9 or TIJT%<CKE%<C. 2The T; is also some!imes referre# !o as !he !herape$!ic ra!io3. < #r$% ha+in% a T; of ' wo$l# be rela!i+el" $nsafe& beca$se #o$blin% !he #ose 2e.%. !akin% ' !able!s +s. one3 wo$l# pro#$ce $n#esirable si#e effec!s in half !he pa!ien!s. T$e $ig$er ($e TI# ($e sa2er ($e ,rug3 ;n animals& !he Therape$!ic ;n#e. is of!en #efine# in !erms of a comparison of !he a+era%e le!hal #ose +s. a+era%e effec!i+e #ose& i.e. T; V : /9=- /9. <no!her less commonl$ used in#e. is !he Certain 'afet$ Factor V : 1=- 77& which #efines !he ra!io be!ween !he concen!ra!ion of #r$% !ha! is le!hal !o 1L of !he pop$la!ion +s. !he #ose which is !herape$!icall" effec!i+e in 77L of !he pop$la!ion. ;f !his n$mber is m$ch %rea!er !han one& i! is a rela!i+el" safe #r$%. The reason !his in#e. is less commonl" $se# is beca$se the %-2 value# at least for human populations# is t$picall$ un5nown or poorl$ defined# for ethical reasonsG

Figure 913 The relationship between the dose-response relationships for producing therapeutic and toxic side effects. The Therapeutic 4ndex !T4" is defined as the ratio of the T-)*3(-)*.

Su--a(ion an, Po(en(ia(ion

The a+era%e hospi!ali8e# pa!ien! is !"picall" %i+en m$l!iple #r$%s concomi!an!l"& wi!h !he na!ional a+era%e bein% W6 #r$%s. ;! is impor!an! !o reco%ni8e !ha! #r$%s ma" in!erac! wi!h each o!her in @a%onis!icA or an!a%onis!ic wa"s. This !opic will be co+ere# in more #ep!h la!er #$rin% !he co$rse. -.amples of ph"siolo%ical& chemical an# pharmacokine!ic an!a%onism were #isc$sse# abo+e 2pa%e 63. Two common !"pes of @a%onis!icA #r$% in!erac!ions are a##i!i+e or

s"ner%is!ic in!erac!ions. 0hen !wo #r$%s wi!h similar mechanisms are %i+en !o%e!her& !he" !"picall" pro#$ce a,,i(i)e effec!s. This is also referre# !o as su--a(ion. Gowe+er& if !he effec! of !wo #r$%s e.cee#s !he s$m of !heir in#i+i#$al effec!s& !his is referre# !o as +o(en(ia(ion or s.nergis-. Po!en!ia!ion re5$ires !ha! !he #r$%s ac! a! #ifferen! recep!ors or effec!or s"s!ems. <n e.ample of po!en!ia!ion wo$l# be !he increase in beneficial effec!s no!e# in !he !rea!men! of <; S b" combina!ion !herap" wi!h <XT 2a n$cleosi#e analo% !ha! inhibi!s G;P re+erse !ranscrip!ase3 an# a pro!ease inhibi!or 2pro!ease ac!i+i!" is impor!an! for +iral replica!ion3& or !he combine# effec!s of norepinephrine an# cocaine on ar!erial bloo# press$re. <n a##i!ional 2%raphical ill$s!ra!ion3 of a##i!i+e an# s"ner%is!ic effec!s is shown in Bi%$re 1,.

Figure 9;3 4llustration of drug combinations producing 'ummation vs. '$nergistic effects. TopH -rugs & and , produce e0ual effects# and their effects are additive when combined. ,ottomH The combination of half the dose of -rug & and , produces a response greater than & or , alone.

%esensi(i0a(ion
Jecep!or*me#ia!e# responses !o #r$%s& hormones an# ne$ro!ransmi!!ers commonl" #esensi!i8e wi!h !ime. Bollowin% an ini!ial response 2s$ch as cell$lar acc$m$la!ion of c<MP& >a infl$.& M effl$.3 !he response pro#$ce# b" !he a%onis! will %ra#$all" #iminish o+er secon#s !o min$!es #espi!e !he con!in$al presence of !he a%onis! 2Bi%$re 1/3. This @,esensi(i0a(ionA is !"picall" rapi#l" re+ersible af!er remo+al of !he a%onis! 2or increase# le+el of a ne$ro!ransmi!!er3 for a few min$!es. The mechanism $n#erl"in% #esensi!i8a!ion +aries from s"s!em !o s"s!em& an# is some!imes obsc$re. Two mechanisms !ha! ha+e been #oc$men!e# incl$#e: 13 Change in the receptor: where !he a%onis!*in#$ce# chan%es in recep!or conforma!ion res$l! in recep!or phosphor"la!ion& which #iminishes !he abili!" of !he recep!or !o in!erac! wi!h F pro!eins& an# '3 %oss of receptors: #$e !o in!ernali8a!ion in!o en#oc"!ic +esicles 2which can also promo!e #ephosphor"la!ion& increasin% !he ra!e a! which f$ll" f$nc!ionin% recep!ors can be replenishe# in !he plasma membrane3 Japi# c"clin% in!o ( o$! of en#oc"!ic +esicles can occ$r o+er a !ime co$rse of se+eral min$!es. <##i!ional mechanisms or al!era!ions in @#own s!reamA por!ions of si%nal !rans#$c!ion mechanisms are also possible.

Figure 9<3 -esensiti6ation. -espite the constant presence of acet$lcholine# the response evo5ed b$ stimulation of muscarinic receptors !see Figure )" cannot be maintained. This ma$ contribute !along with s$mpathetic reflexes" to the phenomena 5nown as vagal escape.

Re2erencesA
1. Gollin%er M<: ;n!ro#$c!ion !o Pharmacolo%". Ta"lor ( Brancis& 1774. '. Menakin T: Pharmacolo%ic <nal"sis of r$%*Jecep!or ;n!erac!ion. )r# -#i!ion& :ippinco!!*Ja+en& 1774. ). Sweene" F: Hlinical Pharmacolo%"& < concep!$al approach. Hh$rchill :i+in%s!on& 1779.

Ho6 a&ou( a /ui07 ?e.6or,s

a%onis!& an!a%onis!& po!enc"& affini!"& efficac"& selec!i+i!"& specifici!"& !herape$!ic*win#ow& 5$an!al& #ose*response*c$r+e& #esensi!i8a!ion& - /9& : /9& T /9& !herape$!ic*in#e.

Conce+( Ma+ on C!assica! %rugs

Ma"e .our o6n )ersionF Cons(ruc(ing conce+( -a+s is a 2un 6a. (o !earnF

basic_principles_of_pharm.!.! Y :as! mo#ifie#: '91)=94=16 19:') b" cclarks

| Me#ical Pharmacolo%" | TMe#0eb