Types of receptors Receptor classification · 2018-08-31 · 4 Pharmacology: How Drugs Work...
Transcript of Types of receptors Receptor classification · 2018-08-31 · 4 Pharmacology: How Drugs Work...
Pharmacology:HowDrugsWorkPHRM200014
Typesofreceptors• Receptorclassification
§ Receptorsoftennamedforearliestknownactivator
§ Muscarinicreceptorsareactivatedbymuscarine§ Nicotinicreceptorsareactivatedbynicotine
o Receptorsarealsonamedforcognatehormoneorneurotransmitter
§ Muscarinicandnicotinicreceptorsareacetylcholine(ACh)receptors
§ Adrenoceptorsareactivatedbyadrenalineandnoradrenaline
§ Angiotensinreceptorsareactivatedbyangiotensin
o MuscarinicandnicotinicreceptorsareseparateclassesofAChreceptors
o Alpha-adrenoceptorsandbeta-adrenoceptorsareseparateclassesofadrenoceptors
o Receptorsubclasses
§ Alpha
• Alpha1onbloodvessels
• Alpha2onnerveterminals
§ Beta
• Beta1inheart
• Beta2inairways,somebloodvessels
§ Selectiveagonist/antagonistand/ormolecularcloningcanidentify
subtypes
• Receptorfamilieso Ionotropic
§ Agonistbindsdirectlytoanddirectlyregulatestheopeningofanion
channel
§ Receptorsthathaveaquickresponse,channelinfluences,changesin
ionchannelandiondirectionoftravelquickly
§ Ligand-gatedionchannels• E.gnicotinicreceptor(5subunits⍺2βγẟ)
o Locatedonskeletalmuscle
o Agonist=acetylcholine(ACh)
o 2AChbindto⍺subunitso Na+channelopensandsodiumionscanenterand
causechangeinbiochemicalstate
o Stimulatemusclecontraction o Metabotropic
§ Agonistbindingtriggersaseriesofintracellulareventsthat
produce“secondmessengers”toindirectlyproducecellularresponses
§ Takesabitlongertoelicitaresponse
§ G-proteincoupledreceptors,kinase-linkedreceptors
§ Kinase-linkedreceptors• Agonistbindstoextracellulardomainofatransmembraneprotein
• Thisactivatesenzymaticactivityoftheprotein’scytoplasmicdomain
o e.g.growthfactorreceptors
§ Agonistbindingcausesreceptordimerization
§ Activationoftyrosinekinase(cytoplasmicdomain)
§ Phosphorylatessubstratesthatregulatecellgrowth
Pharmacology:HowDrugsWorkPHRM2000124
DifferenceinroleofAdrenoceptorActivation
⍺-adrenoceptorsBloodvessel Constrict(⍺1)GIT Constrictsphincters
Pupil(dilation) Constrictradialmuscle
β-adrenoceptors
Heart Increaserate+force(β1)Bronchi(relaxationofsmoothm) Dilate(β2)GIT Slow
SkeletalMuscleBloodvessels Dilate
Kidney Reninsecretion
Liver,skeletalmuscle Glycogenolysis
SUBTYPESOFβ-ADRENOCEPTORS
β-adrenoceptors Selectiveagonist:isoprenalineSelectiveantagonist:propranolol
β1-adrenoceptors–HEART,KIDNEYSelectiveagonist:dobutamine–causesincreasein
heartrateandforce
Selectiveantagonist:atenolol-HYPERTENSION
β2-adrenoceptors–BRONCHI,BLOODVESSELSSelectiveagonist:salbutamol–ASTHMA–causes
dilationofbronchibyrelaxationofsmoothmuscle
SUBTYPESOF⍺-ADRENOCEPTORS
⍺-adrenoceptorsSelectiveantagonist:phentolamine
⍺1-adrenoceptors–POSTJUNCTIONALSITESSelectiveagonist:phenylephrine–causesconstrictionofbloodvessels
Selectiveantagonist:prazosin-HYPERTENSION
⍺2-adrenoceptors–‘PREJUNCTIONAL’INHIBITORYACTION
Selectiveagonist:clonidine–HYPERTENSION(rare,CNSEFFECT)
⍺2-adrenergicreceptorslocatedonthevascularpre-junctionalterminalswhereitinhibitsthe
releaseofnoradrenalineinaformofnegative
feedback.
Itisnotthesameasre-uptakeasitworksto
reducednoradrenalinelevelsinthesynapticcleft.
Also,receptorclassificationhaspolymorphiccharacteristics,meaningitcanchangedependingonreactivitytodifferentdrugsandmolecules.
PHRM20001Pharmacology:HowDrugsWork 39
PHASE2Metabolism• Conjugationofwatersolublemoleculetofunctiongroupondrug
o Bonding2groupstogethero Intheglucuronidationofmorphine,theprecursormoleculeofglucuronicacid:morphine
isn’tverywatersolublesowhenmetabolised,theend-productisasugarandwatersoublethereforeitgetsexcretedfaster
• Glucuronidation• Sulphation• Acetylation• Glutathioneconjugation
o Majordetoxificationprocess
Theendeffectofdrugmetabolismistoyieldwatersolublemetabolitesthatcannotbereadily
reabsorbed,andthereforegetexcreted
Drugelimination
• Drugsmaysimultaneouslygothroughdifferentpathways• Watersolubleenoughnottogetreabsorbed
Pharmacokinetics
• Manydrugsdistributerapidlyo Behaveasifinasinglecompartmento Onecompartmentmodel
• Absorption/eliminationofmanydrugso Proportionaltotheamountofdrugpresent(somoredrug=fasterelimination)o First-orderkinetics
• AdministrationofDrugs-IVcDrugsgivenbyrapid
intravenousadministrationdon’thavetoworryaboutreabsorption
• Rapidriseinconcentrationinblood• Drughashalf-life
o Timetakenforconcentrationtofallby½o Usuallymultipledosesaregiveninhalflives
• PeakconcentrationcanbedeterminedfromVd
Pharmacology:HowDrugsWorkPHRM2000116
• Type2:Non-competitivefunctionalantagonismo Twodrugswithopposingactionsinthesamecello Forexample,noradrenalineandacetylcholineintheheart
§ Noradrenalineandacetylcholinearethemajortransmittersintheperipheralautonomicnerves
§ Balanceofthesetwoallowconstantandregularmonitoringoftheheartrate,abletorespondtoeventsquickly
• Type3:Non-competitiveallostericmodulationo Allostericbindingsitecaneitherworkforor
againsttheagonisto Forexample,theCl-channelandGABAbinding,
whenaparticularcompoundbindstoanallostericsite,itincreasestheaffinityofthereceptorforGABA,leadingtoanincreaserateofCl-iontransfer
SummaryofPharmacodynamics(whatdrugsdo)
• AgonistsandantagonistsàBINDo Haveaffinityforspecificmoleculartargets
• AgonistsàMAKETHINGSHAPPENo Efficacyisthefunctionofreceptornumberandefficiencyofstimulus-responsecouplingo Potencymeasuredbyhowmuchdrugrequiredtoelicitresponse
• AntagonistsàSTOPOTHERDRUGSACTINGo Havenoefficacyinvitro(organbath)o Potencydefinedbyabilitytoinhibitagonistresponseso Criticalroleinclassifyingreceptors
• Concentration-responserelationshipsareimportantClassifyingreceptorswithantagonists
• Selectiveinhibitionisabletobedeterminedexperimentally• Bothneurotransmitterscausecontractions,basedonthe
numbersitappearsthatacetylcholineismorepotent(wouldn'tknowhowtheyinteractwiththereceptors(sameornot),helpeddeterminedbyantagonistaction)
Potencyandefficacyofdrugs
• Potentdrugsrequirelesstobegiventoachieveatherapeuticbenefito Lowerdosestomaximisebenefitandminimiserisk
• Therapeuticbenefitdoesnotalwaysrequirehighefficacyo Themaximumsafelyachievableeffectmostrelevant
§ Agonistsmimicactionofendogenousmoleculesattheirreceptor§ Antagonistsinhibittheactionofendogenousmoleculesattheirreceptor
Lecture31Summary–DrugsinSports
Whyusedrugsinsport?
• INJURYTREATMENT
o Legitimategenerally,includelocalanaestheticdrugs(reducesensation,numbnerves),analgesicdrugs
(reducepain),anti-inflammatorydrugs(reduceinflammation–NSAIDsorglucocorticoids)
• PERFORMANCEENHANCEMENT
o ProhibitedatalltimesbyWADA,includeanabolicagents(testosterone),growthfactors(EPO),non-
approvedsubstances(noexperimentationofanypharmacologicalsubstance)
o Prohibitedin-competitiononlyarestimulants(amphetamine,methamphetamineetc.)
• RECREATIONALLY
o Mixedfeelings
Anti-inflammatorydrugs
• Mechanism:membranephospholipidsconvertedtoarachidonicacidbyphospholipaseA2(glucocorticoidsstop
thisenzymeproduction,affectingproductionofearlierproteins),thentoprostaglandinsbyCOX1/2(NSAIDs
inhibitthisenzymegenerallybybindingtoactivesitecompetitivelyinhibitingit)
• GLUCOCORTICOIDS–anti-inflammatory,immunosuppression,skinthinning,musclewasting,centraladiposity,
somosteffectsdon’thelpathlete
o Systemicsideeffects=extensive,soonlyusedLOCALLY–reducesideeffects
• NSAIDs–anti-inflammatory,analgesic,antipyretic,gastriculceration,onlyfirst2aidathlete
o Sideeffect:gastriculceration–PGsinvolvedintheproductionofmucus,allowsstomachtocarryHCl
withoutdamagingstomach–sonomucusproduction=bad,soitisessentialtoprotectstomachwall.
SinceNSIADsblockPGproductionsoacidcanattackgastriccellsandmaycauseulcers.Mucous
productionlargelyundercontrolofCOX-1.
Anabolic-androgenicsteroids–unfairadvantage
• Differenttoglucocorticosteroids–stillhave4ringedstructure,butisrelatedtotestosterone,canbe
endogenous(producedbybody)orexogenous(notproducedbybody)
• Mechanism:lipophilicsocrossescellmembrane,bindstoreceptorinsidecell,steroid-receptorcomplex
translocatestonucleusàinteractswithtranscriptionfactorstomodulate(activate/repress)proteinexpression
• Effects:similartotestosterone,↑skeletalmusclemass/strength,virilisation,testicularatrophy,CVSeffects(left
ventriclethickening)
EPO
• Proteingrowthfactorproducedbykidneys
• Mechanism:bindsonEPOreceptorsinbonemarrowcellsstimulatingRBCgrowthà↑oxygencarrying
capacityofblood–increasedaerobiccapacity=moreoxygentomuscleand↓anaerobicrespiration
• Protein–socan'torallyadministerasmetabolisedingut,onlybyIV
• Causesbloodthickeningandclottingrisk(blockedcardiacvessel)
Stimulants
• Prohibitedin-competitiononly,includesamphetamine,methamphetamine,oraladministration,
manyareindirectlyactingsympathomimetics(displaceNAfromvesiclesinpre-synapticneurons,
activatingpostsynapticneuron)
• Effects:↑endurance,↓fatigue,appetite,↑alertness,aggressivenessàrealadvantage–BUTshortlived,also
causelotsofsideeffects:nervousness,irritability,insomnia,dehydration,addition/tolerance,CVSproblems
Drugtesting–urinesamples(assayingfordrugormetaboliteviachromatographicmethods)butchallengesexist
becauseofmaskingagents(diuretics),renaltubularsecretioninhibitors(probenecid),proteins(EPO)
Diuretics–increaseurinevolume=[drug]inurineless=hardertodetect
RTSI–blocksecretionbykidneyofdrugintourine
Proteins–shortlivedinblood,metabolisedintosmallregularaminoacids,shortpeptidesbeforeenteringurineàneed
totestbloodsample,butEPOunstableinrawbloodsample,andhardtodetectbychromatography,soneed
ANTIBODY-BASEDIMMUNOASSAYS=EXPENSIVE
PHRM20001Pharmacology:HowDrugsWork 1
DRUGS+MOLECULESLISTANDINFORMATIONDRUGS+MOLECULES Description
NifedipineIonchannelblocker,L-typeCa2+antagonist,reducesbloodvessel/smoothmusclecontraction,reducingBP,moreselectiveinheart,treatshypertension
FluoxetineCarriermoleculeblocker,selectiveserotoninreuptakeinhibitor,resultsinincreasedeffectofserotonin,antidepressant(2nd-gen)
AspirinInhibitsCOX(non-selective),reducedsynthesisofpainmediators(PGs),reducescatalyticactivityofenzyme,favoursPGI2ratherthanTXA3,reducespain
L-dopaUsesenzyme(dopadecarboxylase)toincreasedopaminesynthesistoputdopamineacrossblood-brainbarrier
MorphineActivatesμopioidreceptors,usedforpaininCNS,PNS:↓ACh=↓motility,also↓Ca2+inCVS=↓SNS=orthostatichypertension,giveni.v/i.m
NaloxoneBlocksopioidreceptors,usedforheroinoverdose,rapidhepaticmetabolism,reversessedationandrespiratorydepression
AcetylcholineAgonistfornicotinic(skeletalmuscle,ganglionictransmission)andmuscarinicreceptors(parasympatheticNS,sweat)
NoradrenalineCatecholamineagonistfor⍺andβadrenoceptorslocatedinthesympatheticNS(heart,bloodvessels,glands)
AdrenalineCatecholamineagonistfor⍺andβadrenoceptorslocatedinthesympatheticNS(mainlyreleasedfromtheadrenalgland)
CocaineBlocksreuptakeofNAvianeuronalhighaffinitymechanism,increaseslevelsofNAanddopamine
MAO-inhibitorPreventdigestionandenzymaticactivityofmonoamineoxidase(locatedinsidethesynapse)blockingrecycling
AmphetamineIndirectactingsympathomimetic,mimicsNA,hashigheraffinitytovesiclesandreleasetoincreasestimulationtoadrenoceptors
Isoprenaline β(1or2)Syntheticcatecholaminesympathomimetic,agonistPropranolol β(1or2)adrenoceptorselectiveantagonistàtreatinghypertensionPhentolamine ⍺(1or2)adrenoceptorselectiveantagonistPhenylephrine
⍺1adrenoceptorselectiveagonistactingonpost-junctionalreceptorsviaGq,causesconstrictionofbloodvesselsbyCa2+influx
Prazosin⍺1adrenoceptorselectiveantagonist,usefulfortreatinghypertension(highBP)–usedincombinationwithotherdrugs(inhibitsNA-mediatedvasocon.To↓SNSvasculartoneàSIDEEFFECTS:orthostaticeffects=venouspooling
Clonidine⍺2adrenoceptorselectiveagonistactingonpre-junctionalreceptorsviaGi,inhibitingreuptakeofNA(neg.feedback),hypertension
Dobutamineβ1adrenoceptorselectiveagonist,worksinheartandkidneyviaGs,causesincreaseinheartrateandforce
Atenololβ1adrenoceptorselectiveantagonistinheartandkidney;hypertension,hydrophilic(antagonisingβ1à↓HRviaSAnode,↓SV=↓COand↓BP
SalbutamolShortactingβ2adrenoceptorselectiveagonist,worksinbronchiandbloodvesselsviaGs,relaxationofsmoothmuscle,dilationofbronchi,treatingasthma
BotulinumToxinToxinthatinhibitsAChbypreventingfusionandreleaseofAChvesicleswithmembrane,endocytosedandcleavesSNAREproteins,potent
Atropine Muscariniccholinoceptorantagonist(blocksACh)Hyoscine Muscariniccholinoceptorantagonist(blocksACh)Ipratropiumetal Muscariniccholinoceptorantagonist(blocksACh)
d-TubocurarineNicotiniccholinoceptorantagonist,skeletalmusclerelaxantatNMJ,competitivelypreventsnicotinicAChreceptoractivation,reversible