290607531-Pharmacology PDF

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! 1!PHARMOCOLOGY+–+week+0:+Introduction+to+Pharmacology+and+Principles+of+Pharmacokinetics+!What%is%a%drug?% #! it!is!a!chemical!substance!with!a!known!structure!when!used!on!a!living!organism!produces!a!biological! effect! #! it!is!NOT!a!nutrient!or!an!essential!dietary!ingredient!! General%Concept...

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PHARMOCOLOGY+–+week+0:+Introduction+to+Pharmacology+and+Principles+of+Pharmacokinetics+ ! What%is%a%drug?% #!it!is!a!chemical!substance!with!a!known!structure!when!used!on!a!living!organism!produces!a!biological! effect! #!it!is!NOT!a!nutrient!or!an!essential!dietary!ingredient! ! General%Concepts%of%Pharmacology! #!clinical!pharmacology!is:! % *!the!study!of!drugs!in!healthy!volunteers!and!patients! ! *evaluation!of:! #!ability!of!the!drug!to!produce!a!desired!result! #!safety!of!the!drugs! #!comparative!trials!between!different!forms!of!treatment! ! *surveillance!of!patterns!of!drug!use!and!any!adverse!effects!that!can!occur% % 9%the!‘flow’!of!pharmacology!is!as!follows:! ! *Drug%dose%administration! ! *disintegration%of%the%drug%(also!known!as!pharmaceutical)! *adsorption,%distribution,%metabolism%and%excretion%of%the%drug%within!the!body! (pharmacokinetics)!!!VERY!IMPORTANT! ! #!this!is!what!the!BODY!does!to!the!DRUG! ! *drug9receptor%interaction!at!the!cellular!level!(pharmacodynamics)!!!VERY!IMPORTANT! #!this!is!what!the!DRUG!does!to!the!BODY ! #!it!demonstrates!the!physiological!and!biochemical!effects!of!drugs!and!their!mechanism! of!action!at!either!the!macromolecular,!subcellular!or!organ!system!levels! ! *drug%effect%or%response%(pharmacotherapeutics)! #!this!is!the!application!of!pharmacological!information!together!with!knowledge!of!the! disease!!!which!allows!the!prevention!or!cure!of!the!a!disease! ! Drug%Nomenclature% #!a!type!of!drug!can!be!named!differently.!It!can!be!called!by!its:! ! *chemical!name! ! *generic!name!(non#proprietary/not!registered)! ! *brand!name! ! Example:! Chemical!name!#!N#acetyl#p#aminophenol! Generic!name!–!paracetamol! Brand!name!–!Panadol,!Febridol!etc! ! Routes%of%Drug%Delivery%and%Administration% #!the!different!ways!that!a!drug!can!be!administered!include:! *Oral!#!can!be!done!sublingually! #!this!is!the!most!COMMON!route!of!delivery!as!it!is!!!convenient,!relatively!safe!and!economical! #!the!disadvantages!of!administering!orally!are!that!it!cannot!be!used!for:! ! ! *drugs!that!can!be!inactivated!by!gastric!acids! *drugs!with!large!first3pass4effects!(when!a!large!amount!of!drug!is!metabolised!before!it! reaches!the!systemic!circulation)! *drugs!that!can!irritate!the!gut!! ! *Inhalation% *Topical%–!this!is!applied!directly!to!the!target!area!(i.e.!can!be!in!the!form!of!a!cream!etc)! #!this!can!also!be!known!as!transdermal!(which!is!when!the!drug!is!applied!on!the!skin!(such!as! in!the!form!of!a!cream!or!patch)! *Rectal% %

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*Injection%–!this!can!include:!subcutaneous,!intramuscular,!intravenous! % Advantages% Disadvantages% #!can!be!given!in!a!slow!and!sustained! #!can!be!painful! Intramuscular% way! #!can!lead!to!muscular!distrophy! % !

Subcutaneous%

Intravenous% %

#!can!be!given!in!a!slow!and!sustained! way!

#!cannot!be!used!for!drugs!that:! *irritates!cutaneous!tissues! *have!to!be!given!in!high! volumes!

#!bypasses!absorption!to!give!an! immediate!effect! #!can!achieve!100%!bioavailability!

#!higher!risk!of!causing!toxicity! #!more!expensive!to!administer! compared!to!the!other!ways!

! Pharmcokinetics% #!pharmacokinetics!is!what!the!BODY!does!to!the!DRUG,!and!it!as!follows:! ! ABSORPTION!!!DISTRIBUTION!!!METABOLISM!!!ELIMINATION! ! !

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! ! #!essentially,!the!main!goal!of!the!drug!(after!administration)!is!to!reach!the!blood!circulation/plasma! ! *this!is!done!via!absorption!of!the!drug!from!the!gut,!skin,!muscle!etc! #!after!absorption!it!is!distributed!via!the!blood!and!hepatic!circulation/system!to!target!organs!and! eventually!excreted/eliminated/

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#!pharmacokinetics!is!the!study!of!the!!! ! *DURATION!(time!course)!of!drug!in!the!BODY!(such!as!in!the!plasma,!in!the!tissues!or!urine)! ! *!as!well!as!the!relationship!between!the!DURATION!and!the!DOSE!of!the!drug!given! % MEC:%minimum!effective!concentration! MTC:!minimum!toxic!concentration! ! Therapeutic%Window:!the! dose/concentration!!of!the!drug!between! MEC!and!MTC! *this!is!the!range!of!drug!dosages!which!can! treat!disease!effectively!without!causing! toxicity! % 9%Absorption%of%Drugs% *the!different!mechanisms!of!absorption!of!drugs!from!the!GI!tract!include:! #!passive!diffusion!!!the!drugs!that!uses!these!mechanism!can!be!categorised!into!those!that!are:! *water#soluble!(these!drugs!move!through!aqueous!channel!or!pores)! *lipid#soluble!(these!drugs!dissolve!straight!through!the!membrane)! #!facilitated!diffusion!!!these!require!protein!transporters! #!active!transport!!!requires!protein!transporters!and!ATP! #!endocytosis!or!exocytosis! ! *the!different!factors!that!affect!absorption!of!drugs!include:! ! #!pH%level%at%the%site%of%absorption!! *a!drug!passes!through!a!membrane!more! readily!in!it!uncharged/unionised!state! *whether!a!drug!is!charged!or!uncharged,! depends!on!the!pH!level!at!the!absorption!site! and!strength!of!the!weak!acids!and!bases! *!weak%acids!absorbs!better!when!the!pH!(of! the!environment)!is!LESS%THAN!pKa!! *weak%bases%absorbs!better!when!the!pH%is! MORE%THAN%pKa! ! ! ! ! weak!acids:!!pH!!pKa! ! *note:!pKa!denotes!the!strength!of!the!weak!acid!/base! !the!larger!the!value!of!the!pKa!the!more!basic!the!drug!is! the!smaller%the!value!of!the!pKa!the!more!acidic%the!drug!is! ! ! *note!2:!highly!acidic!or!basic!drugs!do!not!absorb!well! ! ! #!blood%flow!to%the%absorption%site! #!total%surface%area!that!is!available!for!absorption!!!i.e.!microvilli!in!the!intestinal!surface! greatly!increases!the!ability!for!absorption!in!comparison!to!that!of!the!stomach! ! #!contact%time!at!site!of!the!absorption!!!i.e.!the!greater!the!contact!time!the!more!absorption! #exposure%of%drug%to%P9glycoprotein!!!P#glycoproteins!are!multidrug!transembrane! transported!protein.!! *this!protein!metabolises!drugs,!THEREFORE!the!higher!the!frequency!and!the!longer!the! drug!is!exposed!to!this!protein!the!more!drug!is!going!to!be!transported!out!of!the!cell! ! ! Bioavailability! #!bioavailability!is!!!the!fraction!(F)!of!the!administered!drug!that!can!reach!the!systemic!circulation! !

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#!it!is!always!in!comparison!to!that!of!drugs!that!is!intravenously!administered!!!as!this!method!is! considered!to!be!100%!of!the!drug!entering!the!systemic!circulation! !"#$!!"#$%!!"#$%!!"!!"#$ !×!100! !"#$%$"&$'"&"() = ! !"#!!"!!" ! #!factors!that!affect!bioavailability!include:! *first%pass%hepatic%metabolism! #!this!is!a!phenomenon!of!drug!absorption!and!metabolism!which!causes!the! concentration!of!a!drug!to!decrease!before!it!reaches!the!systemic!circulation! #!this!is!usually!when!the!drug!enters!the!hepatic!portal!circulation!of!the!liver!before!it! enters!the!systemic!circulation! #!drugs!that!have!HIGH!first!pass!metabolism!are!metabolised!extensively!!and!have!a! lower!concentration!when!it!reaches!the!systemic!circulation!and!its!target! #!examples:!aspirin,!morphine,!propranolol,!lidocaine! ! ! *solubility%of%the%drug! ! ! #!depending!on!whether!the!drug!is!hydrophilic!of!lipophilic! ! ! #!lipophilic!describes!the!ability!of!the!drug!to!readily!cross!cell!membranes! #!THEREFORE,!the!drug!should!be!LARGELY!lipophilic,!and!yet!be!SLIGHTLY!hydrophilic!is! ideal! ! *chemical%instability! ! ! #!this!refers!to!the!stability!of!drugs!in!certain!environments!(i.e.!acidic)! ! *drug%formulation% 9this!refers!to!how!the!drugs!are!made,!which!then!in!turn!affects!the!dissolution!of!the! drug!and!HENCE!alter!the!rate!of!absorption.!Such!as!its:! ! ! ! *particle!size! ! ! ! *crystal!polymorphism! *enteric!coating:!a!polymer!barrier!which!is!applied!on!oral!medication!which! protects!the!drug!against!acidic!environments!etc! ! #[bioequivalence]!!!this!is!a!term!used!in!p’kinetics!when!two!drugs!are!pharmaceutically!equivalent! such!that!the!drug’s!bioavailability,!effects,!efficacy!and!safety!are!the!same! ! *example:!different!brands!have!the!same!concentration!etc!of!the!same!drug! #![therapeutic%equivalence]!!!refers!to!a!drug!that!has!the!same!effect/treatment!of!a! disease/condition!as!one!or!more!different!drugs! ! *example:!when!different!drugs!produces!the!same!effect! ! Half9life! #![half%life]!!!(t1/2)!this!refers!to!the!time4taken!for!the!concentration!of!the!drug!to!fall!to!one!half!of!its! original!blood!levels! *short!half!life:!when!the!drug!has!a!shorter4duration4of4action,!as!the!drug!is!quickly!removed! from!the!body! *long!half!life:!when!the!drug!has!longer4duration4of4action,!removed!slower!from!the!body! ! ! Drug%Distribution% ! #[drug%distribution]!!this!refers!to!the!process!by!which!a!drug! reversibly!leaves!the!blood!stream,!to!the!extracellular!fluid!then!into!the! cells!of!the!tissues! ! *this!occurs!after!drug4absorption! #!In!intravenous!injections,!there!are!NO!absorption!phase! #!right!after!injection!of!the!drug,!there!is!a!rapid!fall!in!its!concentration!!! this!is!the!distribution%phase% #!when!the!elimination%phase%is!reached!when!there!is!an!equilibrium! between!the!plasma!and!the!tissues%

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#factors!that!affects!drug!distribution!include:! *blood%flow!!!brain!vs!fat.!Adipose!tissues/fat!has!low!blood!flow!and!hence!receives!less!drugs! in!comparison!with!the!brain!which!has!high!blood!flow! *capillary%permeability!!!the!differences!in!capillary!structure!(e.g.!continuous!capillaries,! fenestrated!capillaries)!can!affect!the!ability!of!a!drug!to!cross!from!one!fluid!compartment!to!the! next!(i.e.!from!the!blood!into!the!extracellular!fluid)! *molecular%size%! ! %larger!molecules!have!more!trouble!crossing!barriers! *lipid%solubility%! ! %especially!through!the!BBB! *drugs!that!are!lipophilic!can!cross!the!barrier,!polar!and!ionized!molecules!have!trouble! crossing!(they!have!restricted!entry)! *propofol!and!thiopental!can!both!cross!the!BBB!really!quickly! ! *binding%proteins%(plasma%protein%binding)% % % *the!majority!of!drugs!are!reversibility!bound!to!plasma!proteins!called!albumin4 ! ! *they!can!also!bind!to:!lipoproteins,!glycoproteins!and!beta#globulins! *these!proteins!acts!as!a!drug4reservoir!such!that!!!‘free!drug’!is!released!from!the!protein! as!the!concentration!in!the!plasma!drops!to!keep!the!total!drug!concentration!constant! *depending!on!whether!the!drug!is!acidic!or!basic!they!bind!to!different!proteins:! ! #![acidic!drugs]!!!binds!to!albumin!(examples:!warfarin,!NSAIDs,!sulfonamides)! ! #![basic]!!!binds!to!glycoproteins!and!beta9globulin!(example:!quinine)! *the!binding!sites!on!these!proteins!can!be!saturated! *different!drugs!can!also!COMPETE!for!the!same!binding!site,!SUCH!THAT!drugs!with!a! higher!affinity!for!the!binding!site!will!displace!those!with!a!lower!affinity! ! ! Volume%of%distribution! *[volume%of%distribution]!!!(Vd)!refers!to!the!fluid!volume!required!to!contain!the!entire!drug!in!the! body!at!the!same!concentration!measured!in!the!plasma! !"#!$#%&'%("#!!"!!"#$!!"!!!!!!"#$ ! ! #!it!can!be!represented!by!the!equation:!!!! = ! !

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! *Co!refers!to!the!concentration!of!drug!in!the!plasma!at!‘time!zero’!(beginning!of!injection)! #!this!equation!can!be!used!to!determine!the!loading4dose!of!a!drug!!!it!can!be!used!to!determine! the!dose!of!the!drug!and!toxic!effect!!

! *most!drugs!can!distribute!into!several!compartments!at!once! #!these!compartments!include:!plasma,!intracellular!fluid!(cytoplasm),!interstitial!fluid!(a! component!of!the!ECF)! *some!drugs!can!distribute!into!one!or!two!compartments:! ! #!example:!heparin!!!very!high!molecular!weight,!can!only!be!found!in!the!plasma!fluid! ! ! *note!–!drugs!that!are!highly!bound!to!protein!only!stays!in!the!plasma!too!! ! Reactions%of%drug%metabolism! 9%drug%metabolism!involves!two!kinds!of!biochemical!reaction!!!phase/I%and!phase/II!

% 9%phase%I! ! *these!involve!reactions!that!are!catabolic!(i.e.!oxidation,!reduction!and/or!hydrolysis)! ! *from!the!different!reactions!the!drugs!can!become!activated,!unchanged!or!inactivated! *this!phase!often!involves!the!introduction!of!a!hydyoxyl!group!(OH)!into!the!molecule!!!this! hydroxyl!group!can!then!be!used!as!the!‘point!of!attack’!in!the!conjugating!system!(which!occurs! in!the!second!phase)! #!in!other!words,!lipophilic!molecules!are!converted!into!a!more!polar!molecule!by! introducing!a!functional!group!

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#!phase%II% % *this!phase!is!the!conjugation4phase! *the!reactions!that!occur!in!this!phase!are!usually!anabolic/synthetic!!!inactive!products!are! usually!made! *!in!this!phase!a!substituent!(such!as!glucoronide)!is!added!to!the!hydroxyl!group! ! *the!resulting!products!from!this!phase!are!then!excreted! ! ! #!products!that!are!polar,!water%soluble%or!%inactive%metabolite:!excreted!by!kidney! ! ! #!products!that!are!lipophilic:!retained!by!kidney! ! *the!products!can!also!be!excreted!via!bile! ! #!some!drugs!can!bypass!phase!II!altogether,!they!can!directly!enter!phase!II!metabolism.! ! *these!drugs!can!only!be!found!in!faecal!matter! ! #!the!majority!of!reactions!in!phase!I!and!II!occurs!in!the!liver! ! #!the!reactions!in!phase!I!involves!cytochrome%P450%(CYP450)!enzymes! ! *these!are!hepatic!drug#metabolising!enzymes!(microsomal!mixed#function!oxidases! *these!enzymes!main!function!is!to!metabolise!drugs!in!the!human!liver!(and!ultimately!facilitate! elimination)!by!the!means!of!biotransformation! ! *CYP450!has!many!variations,!including:! 9%CYP3A4/5!–!which!is!the!main!enzyme! 9%CYP2D6%!#!!when!codeine!binds!to!it,!its!capacity!to!metabolise!substrates!decrease! % *CYP%inducers4(substances!that!enhances!these!proteins’!functions)!include:! ! ! *cigarette! ! ! *alcohol!(chronic!drinking)! ! ! *St!John’s!wort! ! *CYP%inhibitors!include:! ! ! *grapefruit!juice! ! ! *cimetidine! ! ! *omeprazole! ! Mode%of%administration! #!intravenous!injection!(not!very!relavent)! #!oral%dose! ! *this!is!when!a!single!dose!will!give!a!single!peak!in!plasma! ! concentration! *after!the!dose,!the!drug!concentration!will!decline!continuously,! until!another!dose!is!given! ! *repeated!doses!result!in!oscillations!in!plasma!concentration! ! !

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PHARMACOLOGY+–+week+0:+Pharmacodynamics+ ! Pharmacodynamics! "!the!philosophy!behind!pharmacodynamics!is:!a!drug!will!not!work!unless!it!is!bound! *i.e.!the!drug!needs!to!be!able!to!bind!to!its!target!to!be!able!to!produce!an!effect!and!hence!cause! a!physiological3response!!![a!drug!+!drug!target!!!physiological!response]! ! "!most!drug!targets!are!protein!molecules,!these!can!include:! ! *receptors,!enzymes,!carrier!molecules!and!ion!channels! Binding3site3specificity! "!specificity!between!the!binding!site!and!the!drug!is!reciprocal!! *such!that!the!drug!can!be!specific!to!the!target,!but!the!target!can!also!be!specific!to!that! particular!drug!! *in!other!words,!individual!classes!of!drugs!bind!only!to!certain!targets,!and!individual!targets! recognise!only!certain!classes!of!drugs! ! "!however!!NO!drugs!are!completely!specific!in!to!their!targets! *the!majority!of!the!time,!increase!in!doses!of!a!drug!will!affect!targets!other!than!the!principal! one,!which!leads!to!side!effects!

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! Receptors! "![receptors]!can!be!defined!as:! a!target3molecule/protein!which!recognises!endogenous!chemical!signals!(such!as!hormones,! NT,!inflammatory!mediators!etc)!OR!drug!molecules,!in!order!to!produce3physiological3and3 biochemical3effects! ! "!in!simpler!terms,!when!a!drug!binds!to!a!receptor!a!pharmacological0effect!is!produced! ! *(e.g.!adrenaline!binds!to!β"receptor!!!causing!increase!in!force!and!rate!of!heartbeat)! ! ! Affinity3vs3Efficacy3 [ligand]!–!a!complex!formed!of!a!molecule!that!has!bound!to!a!receptor! ! [Affinity]!–!the!ability!of!the!drug!to3bind3to!a!receptor! ! *affinity0governs0the0tendency0of00a0drug0to0bind0to0its0receptor0 ! *HIGH!affinity!=!strong!binding!ability!(has!the!ability!to!produce!effects!at!low!conc.)! ! *LOW!affinity!=!weak!binding!ability!(requires!a!higher!conc.!to!produce!an!effect)! ! *note:!without!affinity!(when!the!drug!does!not!bind)!there!is!no!efficacy!! ! ! [Efficacy]!–!the!ability!of!a!drug,!once!bound!to!a!receptor,!to!activate!the!receptor!and!hence!produce3a3 pharmacological3response3 3 *also!known!as!the!intrinsic!activity! *efficacy!is!pretty!much!the!“product”!that!is!produced!once!the!drug!binds!to!receptor! *efficacy0denotes0the0tendency0of0a0bound0drug0to0activate0its0receptor!(it!is!the!ability!for!the!drug! and!receptor!complex!to!produce!a!response! *different!drugs!can!have!the!SAME!AFFINITY!to!the!receptor!but!DIFFERENT!EFFICACY! ! Agonist3vs3Antagonists3 Agonist3 "!a!drug!which!binds!to!the! receptor!and!produces!a! pharmacological!effect! 100%!affinity!! 100%!efficacy!

Partial3Agonist3 "!has!affinity!for!receptor! "!but!lower0efficacy!compared!to! another!agonist!acting!at!the!same! receptor! 100%!affinity! 50%!efficacy!

Antagonist3 "!a!drug!which!competes!and! binds!to!the!same!receptor! "!but!does!NOT!activate!the! receptor! 100%!affinity! 0%!efficacy!

! "!there!are!different!types!of!agonists,!these!include:! ! *agonist! ! *partial3agonist:3it!produces!a!submaximum!response! *inverse3agonist:!molecule!binds!to!a0receptor!in!its!inactive0 state!and!produces!a!negative0response/a!response!that!is! opposite!to!that!of!its!corresponding!agonist! ! "!an!antagonist!can!be:!!

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competitive!!! "noncompetitive! *competitive3! "!a!drug!will!selectively!bind!to!a!particular!receptor!WITHOUT!activating!it,!NO! pharmacological!response!will!be!produced! "!it!prevents!the!agonist!from!binding! "!at!a!given!concentration,!the!agonist!occupancy!will!reduce!in!the!presence!of!an! antagonist!!!HOWEVER!by!increasing!the!concentration!of!the!agonist!(in!relation!to!the! antagonist)!the!agonist!occupancy!can!be!restored!!!THEREFORE!making!it!reversible0 *noncompetitive!! "!this!is!when!the!drug!binds!to!a!receptor!which!is!not!the!receptor!in!which!the!agonist! binds,!NO!pharmacological!effect!will!be!produced!even!if!the!agonist!binds! "!the!effect!is!irreversible,!until!the!antagonist!molecule!is!released! "!increasing!the!conc.!of!the!agonist!still!wont’!be!able!to!produce!a!maximal!effect!when! the!noncompetitive!antagonist!is!present! *!this!therefore!means!that!in!the!presence!of!a!non"competitive!antagonist!!!the! Emax3of3the3agonists3becomes3‘depressed’3(decreases)! ! !

Dose3response3curve3 "![dose3response3curve]!(DRC)! ! *also!known!as!a!concentration!response!curve,!concentration!response!relationship! ! *the!graph/curve!is!used!to!measure!or!quantify!a!drug"receptor!reaction! ! "!under!normal!circumstances!!!when!a!drug!is!administered,!the3 response3will3increase3in3proportion3to3the3dose3until3all3the3 receptors3are3occupied3(when!all!binding!sites!are!saturated/when! saturation!is!reached)! *when!this!occurs,!increasing!the!dose!farther!will!NOT!produce!any! further!increases!in!the!response! ! ! "!from!a!DRC!different!pieces!of!information!can!be!gathered,!including:! *Emax3–3this!refers!to/denotes!the!maximal&effect!that!can!be!produced!by!a!drug! ! *it!is!a!measure!of!the!efficacy3of!a!drug! *EC50!–!refers!to!the!dose!or!concentration3of3a3drug3at350%!of!its!maximal!effect!(Emax)! ! *it!is!a!measure!of!the3potency!of!a!drug!! ! *note:!potency!refers!to!how!strong!the!effect!of!the!drug!is! *KA3–3refers!to!the!concentration3of3a3drug!that!has!occupied!50%!of!the!total!number!of! receptors!at!equilibrium.!This!is!the!dissocitation0constant.!The3LOWER3the3value,3the3HIGHER3 the3affinity3the3drug3has3to3the3receptor3 ! ! ! !

"!Hypobolic3(arithmetic)3vs3Sigmoid3(log3scale)3 Hypobolic3 3 T3this!type!of!graph!is! difficult!to!analyse! mathematically!

%!maximal!response!

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LogTscale!

3 T3allows!the!illustration! of!proportionate!doses! at!equal!intervals! "!straighter!lines! "!easier!to!analyse! mathematically! 3

3 T3Drug3efficacy3vs3drug3potency3 "!the!Emax!value!determines!the!drug0effectiveness! ! ! *the!Emax!value!refers!to!the!drug’s!maximal0efficacy0 ! *the!drug’s!effectiveness!has!nothing!to!do!with!the!drug’s!potency! "!note:!drug!potency!refers!to!the!strength0of!the!effect!(illustrated!by!the!E50)! ! *from!the!graph!it!can!be!seen!that!the:! "Efficacy!for!all!3!drugs!are!the!same!! #!Drug!A!=!Drug!B!=!Drug!C! "!Potency!are!#!Drug!A!>!Drug!B!>!Drug!C! "!t...