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