Pharmacology Notes - StudentVIP · Pharmacology Notes Pharmacology – drug action, how medicines...
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Pharmacology Notes Pharmacology – drug action, how medicines work, how body processes them • Pharmacodynamics à effects of drug on body • Pharmacokinetics and drug metabolism à effects of body on drug Glossary of Terms Terms Definition/Description Agonist Ligand/small molecule that binds to receptor (usually orthosteric binding site) and activates receptor e.g. acetylcholine Antagonist Binds to orthosteric site of receptor, but has intrinsic activity of 0 so does not activate it e.g. atropine Ligand A molecule that binds to another (usually larger) molecule Dose-response or concentration effect relationship Dose-response – refers to adding drug to a living system like a body Concentration-effect e.g. guinea-pig ileum Orthosteric binding Binding to the active site Allosteric binding Site that differs from the orthosteric binding site Competitive binding Will compete for the binding site Non-competitive binding Binding to a different site from the orthosteric site – doesn’t necessarily mean it has to bind a receptor – could bind downstream e.g. interact with G proteins or ion channel Efficacy Ability to initiate a maximum response after receptor binding Potency Measured by measuring functional physiological response and finding EC50, the lower the value, the more potent the drug EC 50 Effective concentration to cause a half maximal response pD 2 -logEC50 K D Dissociation constant - concentration of ligand that results in half occupancy of receptors form a ligand-receptor complex (applies a 1:1 ligand: receptor ratio) Indicator of affinity, measured by a radioactive ligand (K B for antagonist) Affinity Strength of binding of drug to its target, preferability with high specificity K B Dissociation constant of antagonist Found from schild plot or direct binding experiment Desensitization v. tachyphylaxis Desensitisation – biological response to drug diminishes when it is given continuously or repeatedly, down regulation of receptor – done through kinases à arrestin binding etc. Tachyphylaxis – acute rapid decrease in response to drug after its administration, like tolerance Terms mean the same thing Selectivity Ability of drug to bind preferentially to one site over another. As no drugs are entirely specific, you get that one drug is more selective to a receptor over another à has preference to one site over another, e.g. muscarine is more selective for muscarinic over nicotinic, beta blockers are antagonists that bind to B receptors, non-selective would be something that binds to either B1 or B2, or something else may be selective over B1 than B2 Specificity Ability of a given drug concentration to produce one effect over another. Chemical binding interaction between the ligand and the
Transcript of Pharmacology Notes - StudentVIP · Pharmacology Notes Pharmacology – drug action, how medicines...
Pharmacology Notes Pharmacology–drugaction,howmedicineswork,howbodyprocessesthem
• Pharmacodynamicsàeffectsofdrugonbody• Pharmacokineticsanddrugmetabolismàeffectsofbodyondrug
GlossaryofTermsTerms Definition/DescriptionAgonist Ligand/smallmoleculethatbindstoreceptor(usuallyorthosteric
bindingsite)andactivatesreceptore.g.acetylcholineAntagonist Bindstoorthostericsiteofreceptor,buthasintrinsicactivityof0so
doesnotactivateite.g.atropineLigand Amoleculethatbindstoanother(usuallylarger)molecule
Dose-responseorconcentrationeffectrelationship
Dose-response–referstoaddingdrugtoalivingsystemlikeabodyConcentration-effecte.g.guinea-pigileum
Orthostericbinding BindingtotheactivesiteAllostericbinding Sitethatdiffersfromtheorthostericbindingsite
Competitivebinding WillcompeteforthebindingsiteNon-competitivebinding Bindingtoadifferentsitefromtheorthostericsite–doesn’t
necessarilymeanithastobindareceptor–couldbinddownstreame.g.interactwithGproteinsorionchannel
Efficacy AbilitytoinitiateamaximumresponseafterreceptorbindingPotency Measuredbymeasuringfunctionalphysiologicalresponseandfinding
EC50,thelowerthevalue,themorepotentthedrugEC50 EffectiveconcentrationtocauseahalfmaximalresponsepD2 -logEC50KD Dissociationconstant-concentrationofligandthatresultsinhalf
occupancyofreceptorsformaligand-receptorcomplex(appliesa1:1ligand:receptorratio)Indicatorofaffinity,measuredbyaradioactiveligand(KBforantagonist)
Affinity Strengthofbindingofdrugtoitstarget,preferabilitywithhighspecificity
KB DissociationconstantofantagonistFoundfromschildplotordirectbindingexperiment
Desensitizationv.tachyphylaxis
Desensitisation–biologicalresponsetodrugdiminisheswhenitisgivencontinuouslyorrepeatedly,downregulationofreceptor–donethroughkinasesàarrestinbindingetc.Tachyphylaxis–acuterapiddecreaseinresponsetodrugafteritsadministration,liketoleranceTermsmeanthesamething
Selectivity Abilityofdrugtobindpreferentiallytoonesiteoveranother.Asnodrugsareentirelyspecific,yougetthatonedrugismoreselectivetoareceptoroveranotheràhaspreferencetoonesiteoveranother,e.g.muscarineismoreselectiveformuscarinicovernicotinic,betablockersareantagoniststhatbindtoBreceptors,non-selectivewouldbesomethingthatbindstoeitherB1orB2,orsomethingelsemaybeselectiveoverB1thanB2
Specificity Abilityofagivendrugconcentrationtoproduceoneeffectoveranother.Chemicalbindinginteractionbetweentheligandandthe
receptor,desiredoutcomeistohavehighspecificityorbindingbutoftenneverreallyachieved,canalsoworkinreverse,thereceptor
Principles of drug action
• Cellsurfacetargets–transporters,receptors,ionchannels• Intracellulartargets–enzymes,nuclearreceptors,proteinsynthesis• Drugscanincreaseordecreaseactivityoftheirtargets:
o Receptors–agonists,antagonists,modulatorso Ionchannels–blockers,modulatorso Enzymes–inhibitors,falsesubstrateso Transporters–blockers,falsesubstrates
• Drugs:o Smallhydrophilic–actatcellsurfaceo Lipidpermeable–crossmembranetoinhibitanenzymeorregulategeneexpression
Provideexamplesofdrugsandhowtheyworkateachofthefollowingtargets:
• Aneurotransmittertransportero Antidepressantse.g.fluoxetine,nortriptyline
§ Blockserotonin,dopamineandnoradrenalinetransporters§ Moreofthosehormonesstuckinextracellularspace§ Nortriptylinebindsatthebottomofanexternalcavity,preventingdopaminefrom
bindingandpreventingclosureoftheexternalvestibuleo Cocaine
§ Blocksdopamineandserotonintransporters§ Stimulant§ Appetitesuppressant§ Topicalanaesthetic,usedineye,noseandthroatsurgery§ Dopaminetransportinhibitor§ Na+channelblocker
o Amphetamine§ Substrateofdopamine,noradrenaline
transporters§ Moreincell–transportedmoreefficiently
thantheotherhormonessoistransportedinstead(kindofeffectivelyblockingtheuptakeoftheothers)
• Anintracellularenzyme
o Increaserateofchemicalreactionsinthebodyo Aspirin
§ Cyclooxygenase-enzymeassociatedwithendoplasmicreticulum§ Catalysesfirststepinconversionofarachnoidicacidtoprostaglandinsandarange
ofinflammatorycompounds§ Extractedfrombarkofwillowtreeàsalicylicacidàaspirin
§ LowdoseofaspirinusedtoirreversiblyinhibitCOXinplatelets–stopsplatelets
fromclottingblood§ Aspirinbindstoactivesite
o Indomethacin§ VerypotentCOXinhibitor
o Paracetamol• AG-proteincoupledreceptor
o ~50%ofdrugsworkonGPCRso Salbutamol-β2adrenergicreceptoragonist
§ NAdnormallyactivatesβandαadrenergicreceptors§ Insalbutamol,theN-trimethylgrouphasselectivityforβ2adrenergicreceptors
§ Stimulatesβ2–causesbronchodilationandisatreatmentforasthma§ Stimulationofβ2receptorsinduceschangeinreceptorassociationwiththeα
subunitoftheGprotein§ Activatedαsubunitandβsubunitsdissociate§ LeadstoactivationofenzymeadenylcyclasethatformscyclicAMPfromATP§ cAMPrelaxesbronchialsmoothmuscleanddecreasesairwayresistance
• Thereceptor-agonistcomplexinducesconformationalchangeinGprotein,causingαsubunittobindGTP.α-GTPcomplexdissociatesfromGproteinandactivates(orinhibits)membraneenzymeorchannel.Signalendsbecauseα-GTPhasinstrinsicDTPaseactivityandturnsitselfoffbyhydrolysingGTPtoGDP.α-GDPthenreassociateswithβγsubunits
• Anionchannelo Allowreadytransferofionsdowntheirelectrochemicalgradiento Controlionicgradientsacrosscellmembrane–Na+blockerwillblockinfluxofNa+ionsà
canreduceactivityofneurons§ Open-closedstateiscontrolledbymembranepotential(voltage-gatedchannels)or
bytransmittersubstances(ligand-gatedchannels)§ Mostlocalanaestheticsareweakbasesthatexistmainlyinprotonatedformatbody
pH–drugspenetratenerveinnon-ionised(lipophilic)formbutonceinsideaxon,becomeprotonatedandblockNa+channelspreventinggenerationofAPs
o E.g.lidocaineandcocaine§ Ionchannelscontroltheionicgradientsacrossthecellmembrane§ LettingNa+in,allowsthemtomovedownconcentrationgradientandchange
membranepotentialbymakingcellpositive§ Localanaestheticsareweakbases§ Theneutralformcancrossthemembraneandaccessthedrugbindingsite§ Byblockingionchannels,theyreducetheactivityofneuronsandsensory
informationisstopped
• Bacterialproteinsynthesiso Targetbacterialribosomes(bacterialribosomesaredifferenttoeukaryoticones)o Don’tactuallykillthecell–juststopbacteriafromgrowingo Tetracycline
§ InterferewithattachmentoftRNAtomRNA-ribosomecomplexo Chloramphenicol
§ Bindsto50Sportionofribosomeandinhibitsformationofpeptidebond
o Erythromycin§ Bindsto50Sportion,preventstranslocation-movementofribosomealongmRNA
o Streptomycin§ Changesshapeof30Sportion,causescodeonmRNAtobereadincorrectly
• Anuclearreceptor
o Tamoxifen§ Tamoxifenwasfirstmadein1962andwasdesignedtobeananti-fertilitydrug-but
itstimulatedovulationinsteadofsuppressingit§ 1973–foundusefultotreatEstrogenreceptorpositivebreastcancer§ Preventestrogendependentstimulationofbreastcancercellgrowth§ Estrogenreceptorantagonist§ Stimulatesovulationandusedfortreatingestrogenreceptorpositivebreastcancer
aspreventsestrogendependentstimulationofbreastcancercellgrowth§ Bindstoestrogenreceptorandhence,whenestrogenenterscell,itcan’tbindtothe
receptor§ Hydrophobicandnotmanychargedgroups§ Estrogenreceptormediatedgeneregulation
• Estrogenboundtoestrogenreceptordimer• TheligandboundreceptorbindstoreceptorresponseelementsinDNA
sequencetoregulategeneexpression• Tamoxifenboundtoreceptordoesnotrecognisethereceptorresponse
element–geneexpressioncan’toccur
Comparetheactionsofamphetamineandcocaineonthedopaminetransporter• Cocaineblocksdopamineandserotonintransporters,leavingthesehormonesstuckinthe
extracellularspace• Amphetaminesareasubstrateofthetransporter,andhence,competeforreuptakewithdopamine
HowdoeslidocaineaccessitsbindingsiteonNa+Channels?
• MostlocalanaestheticsareweakbasesthatexistintheprotonatedformatbodypH• Thedrugspenetratethenerveinthenon-ionisedform(asalipidsolublefree-base)butonceinside
theaxon,sometimere-joinwiththeproton• ThesethenenterandplugtheNa+channelsafterbindingtoareceptor
Howdoestamoxifeninhibitcancercellgrowth?
• Tamoxifenentersacancercellandbindstotheestrogenreceptors• Whenestrogenentersthecell,itcan’tbindtothereceptors• Cancercellproliferationispreventedasitneedsthisestrogenbindingtoregulategeneexpression
Whatmakessalbutamolselectiveforbadrenergicreceptorsoveraadrenergicreceptors?
• It’sN-trimethylgroupisselectiveforB2adrenergicreceptorsbutnotaComparethemechanismsofactionofaspirinandindomethacininhibitionofthecyclooxygenaseenzyme?
• IndomethacinisaverypotentCOXinhibitorbuthassignificantrisks–cardiovascularandGItoxicityo Itisareversibleinhibitoro Goodfortheshortterm
• Aspirinisanirreversibleinhibitor–can’tretrieveplateletactivityo ProlongedinhibitionofCOX(sitsinmembraneofendoplasmicreticulum)inplatelets–can
beusedtopreventclotting,cancauseexcessiveGIbleeding
Drug-receptor interactions 1: agonists Antagonist–combinewithreceptors,butdonotactivatethem–reduceprobabilityofagonist/transmittersubstancecombiningwithreceptor
Agonist–smallmoleculethatactivatesareceptorthathasaphysiologicalregulatoryfunction• Activationmeansreceptorisaffectedbyboundmoleculeinwayastoalterreceptor’sbehaviour
towardscellandelicitatissueresponse• E.g.acetylcholine(ACh)
o Endogenousandreleasedmainlyfromnerveso Activatesanorthostericbindingsiteonseveralreceptors
§ Muscarinic§ Nicotinic
o ChangesphysiologicalstateofcellthathasreceptorsthatbindtoAch
• Bindingforcesbetweenagonistandreceptor
o Electrostatic(charge)–longrangebinding,initialattraction• Thenifmoleculesuitablyshapedtofitbindingsiteofreceptor
§ Hbonding§ Vanderwaals
o HydrophobicLawofmassaction–at equilibrium, rate of chemical reaction is proportional to product of concentration of reactants (drug and free receptor)
• Assumesbindingisreversible• Ifyouwanttoincreasereactiongoingright,increaseamountofdrugORincreasenumberof
receptors
Affinity–indicatedbythedissociationconstant
• Indicatespotencyof‘drug’andgenerallyasaffinityincreasessotoodoesbindingspecificity• Wewantdrugswithhighaffinity–ifhighaffinity,willbindatlowconcentration• Dissociationconstantisinverseofanassociationconstant• Indicatesaffinityofamoleculethatbinds• KDdenotesthedissociationconstant,butsometimeswrittenasKA(M=mol/L)• KD–concentrationofligandthatresultsinhalfoccupancyofreceptorsformaligand-receptor
complex(appliesa1:1ligand:receptorratio)• Reflectpropertiesofligandandreceptor
Relationbetweenligandconcentrationandamountbound
• Bindingassay–proportionaloccupancyvsdrugconcentration• Functionalassay–shortening(%max)vsdrugconcentration
Scatchardplot–determiningKDandreceptornumber
• Relationshipbetweenamountbound(B)andligandconcentration(Xa)
• Bmax–largernumbermeansmorereceptors• KD–smallernumbermeansgreateraffinity
Concentration-responsecurves
• Ifoccupancyisproportionaltoresponse,thenhill-langmuirequationcanalsobeusedtodescriberelationshipbetweenconcentrationandresponse
• SimilarrelationshipbutKD=EC50
o Maxresponsecanoccurwithoutfullreceptoroccupancyo Transductionpathwayscanamplifytheeffecto KDisforagonistsandantagonistsbecauseitreflectsaffinityoftheligandandnotintrinsic
efficacy(transductionefficiency)o EC50istheeffectiveconcentrationtocauseahalfmaximalresponse
negative log!!
Shapeofresponsecurves
PA – proportion of ligand bound XA – [Ligand] KD – dissociation constant
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