Antianginal drugs

Pharmacology of antianginal drugs

1. AntianginalDrugs
Prepared By:
Dr. Ajay Kumar
M.Pharm., Ph.D.
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2. Coronary arterydisease
•Angina Pectoris (Ischemic HeartDisease)
•Acute CoronarySyndrome
•UnstableAngina
•Non-ST elevation myocardial infarction(NSTEMI)
•ST-segment elevation myocardial infarction
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3. Causes of chestpain
•Pericarditis(causedbyinfectiousagents,e.g.,bacteria,fungi,
andviruses,autoimmunedisorders,renalfailure,andtrauma)
•MitralValveProlapse
•PulmonaryEmbolism(infarctofthelung)
•Pleurisy(painassociated with inflammationof the pleural
lining of the lungs)
•Hyperventilation Syndrome (is caused by fear or panic induced
hyperventilation)
•Trauma/Rib Fracture
•Chest WallTwingeSyndrome (PrecordialCatch) is due to
intercostal muscle spasm.
•Costochondritis (an inflammation of the cartilage between the
rib end and the sternum)
•Esophagitis, Acute or Chronic (GERD)
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4. AntianginalDrugs
•Anginapectorisreferstoa
stranglingorpressure-like
paincausedbycardiac
ischemia.Thepainisusually
locatedsubsternallybutis
sometimesperceivedinthe
neck,shoulderandarm,or
epigastrium.
•Womendevelopanginaata
lateragethanmenandare
lesslikelytohaveclassic
substernalpain.
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5. AntianginalDrugs
•Antianginaldrugsarethosethatprevent,abortor
terminate attacks of angina pectoris.
•Types of angina
•Atheroscleroticangina(classicangina[commonform]):
Attacksarepredictablyprovoked(stableangina)byexercise,
emotion,eatingorcoitusandsubsidewhentheincreased
energydemandiswithdrawn.
•Vasospasticangina(restangina,variantangina,or
Prinzmetal’sangina[uncommonform]):Attacksoccurat
restorduringsleepandareunpredictable.Vasospastic
anginaisresponsibleforlessthan10%ofanginacases.
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6. AntianginalDrugs
Coronary artery caliber changes in classical and variant angina
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7. AntianginalDrugs
•Types of angina
–Unstableangina(crescendoangina,alsoknownas
acutecoronarysyndrome):Itischaracterizedby
increasedfrequencyandseverityofattacksthatresult
fromacombinationofatheroscleroticplaques,platelet
aggregationatfracturedplaques,andvasospasm.
Reference: Drugs Used in the Treatment of Angina Pectoris. In: Trevor AJ, Katzung BG, Kruidering-
Hall M.eds.Katzung & Trevor's Pharmacology: Examination & Board Review, 11e New York, NY:
McGraw-Hill;2015.
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8. Treatment of AnginaPectoris
•Drugs used in angina exploit two mainstrategies:
–reduction of oxygendemand
–increase of oxygen delivery to themyocardium
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9. Classification of antianginaldrugs
•Nitrates
–Shortacting:Glyceryltrinitrate(GTN,Nitroglycerine)
–Longacting:Isosorbidedinitrate(shortactingby
sublingualroute),Isosorbide,mononitrate,Erythrityl
tetranitrate,Pentaerythritoltetranitrate
•βBlockers:Propranolol,Metoprolol,Atenololandothers.
•Calciumchannelblockers
–Phenylalkylamine:Verapamil
–Benzothiazepine:Diltiazem
–Dihydropyridines:Nifedipine,Felodipine,Amlodipine,
Nitrendipine,Nimodipine,Lacidipine,Lercanidipine,
Benidipine
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10. Classification of antianginaldrugs
•Potassium channel opener: Nicorandil
•Others: Dipyridamole, Trimetazidine, Ranolazine,
Ivabradine, Oxyphedrine
Clinical classification
•Used to abort or terminate attack: GTN,
Isosorbide dinitrate (sublingually).
•Used for chronic prophylaxis: All other drugs.
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11. Nitrates/ OrganicNitrates
•Preloadreduction:Peripheralpoolingofblood→decreased
venousreturn(preloadreduction).
•Afterloadreduction:Nitratesalsoproducesomearteriolar
dilatation→slightlydecreasetotalperipheralresistanceor
afterloadonheart.
•Redistributionofcoronaryflow:Inthearterialtree,nitrates
preferentiallyrelaxbiggerconducting(angiographically
visible)coronaryarteriesthanarteriolesorresistancevessels.
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12. Nitrates/ OrganicNitrates
Mechanismofaction:
•TheorganicnitrateagentsareprodrugsthataresourcesofNO.
NOactivatesthesolubleisoformofguanylylcyclase,thereby
increasingintracellularlevelsofcGMP.Inturn,cGMP
promotesthedephosphorylationofthemyosinlightchainand
thereductionofcytosolicCa
2+
andleadstotherelaxationof
smoothmusclecellsinabroadrangeoftissues.
References: Eschenhagen T. Treatment of Ischemic Heart Disease. In: Brunton LL, Hilal-Dandan R,
Knollmann BC. eds. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e New
York, NY: McGraw-Hill
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13. Nitrates/ OrganicNitrates
Mechanism ofaction:
Mechanismofvascularsmoothmusclerelaxantactionofnitrodilatorslikeglyceryl
trinitrateandcalciumchannelblockers
References: Tripathi, K. (2013). Essentials of medical pharmacology (7th ed.). New Delhi: JaypeeBrothers.13

14. Nitrates/ OrganicNitrates
Pharmacokinetics:
•Organicnitratesarelipidsoluble,wellabsorbedfrom
buccalmucosa,intestinesandskin.
•Ingestedorally,allexceptisosorbidemononitrateundergo
extensiveandvariablefirstpassmetabolisminliver.They
arerapidlydenitratedbyaglutathionereductaseanda
mitochondrialaldehydedehydrogenase.
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15. Nitrates/OrganicNitrates
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16. Nitrates/ OrganicNitrates
Adverseeffects:
•Headacheisthemostcommonadverseeffectofnitrates.
Highdosesofnitratescanalsocauseposturalhypotension,
facialflushing,andtachycardia.
•Phosphodiesterasetype5inhibitorssuchassildenafil
potentiatetheactionofthenitrates.Toprecludethe
dangeroushypotensionthatmayoccur,thiscombinationis
contraindicated.
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17. Nitrates/ OrganicNitrates
Uses
•Anginapectoris
•Acutecoronarysyndromes
•Myocardialinfarction(MI)
•CHFandacuteLVF:Nitratesaffordreliefbyvenouspoolingof
blood→reducedvenousreturn(preload)→decreasedend
diastolicvolume→improvementinleftventricularfunction.
•Biliarycolic
•Esophagealspasm
•Cyanidepoisoning:Nitratesgeneratemethaemoglobin
whichhashighaffinityforcyanideradicalandforms
cyanomethaemoglobin.
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18. β-Blockers
•Theβ-adrenergicblockersdecreasetheoxygendemandsofthe
myocardiumbyblockingβ
1receptors,resultingindecreasedheart
rate,contractility,cardiacoutput,andbloodpressure.
•Allβblockersarenearlyequallyeffectiveindecreasingfrequency
andseverityofattacksandinincreasingexercisetolerancein
classicalangina,butcardioselectiveagents(atenolol,metoprolol)
arepreferredover nonselectiveβ
1+β
2blockers(e.g.
propranolol).
•Agentswithintrinsicsympathomimeticactivity(ISA)suchas
pindololshouldbeavoidedinpatientswithanginaandthosewho
havehadaMI.
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19. Calcium channelblockers
Pharmacologicalactions:
•Smoothmuscle:TheCCBscauserelaxationbydecreasing
intracellularavailabilityofCa
2+
.Thedihydropyridines(DHPs)
havethemostmarkedsmoothmusclerelaxantandvasodilator
action.
•Heart:CCBsprotectthetissuebyinhibitingtheentranceof
calciumintocardiacandsmoothmusclecellsofthecoronaryand
systemicarterialbedsanddecreasessmoothmuscletoneand
vascularresistance,afterload.
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20. Calcium channelblockers
Phenylalkylamine:Verapamil
•Itdilatesarteriolesanddecreasestotalperipheralresistance.
•Itslowsatrioventricular(AV)conductiondirectlyand
decreasesheartrate,contractility,bloodpressure,and
oxygendemand.
•Italsohassomeαadrenergicblockingactivity.
•Verapamilhasgreaternegativeinotropiceffectsthan
amlodipine,butitisaweakervasodilator.
•Verapamilshouldnotbegivenwithβblockers,digoxin,
cardiacdepressantslikequinidineanddisopyramide.
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21. Calcium channelblockers
Benzothiazepine:Diltiazem:
•DiltiazemalsoslowsAVconduction,decreasestherateof
firingofthesinusnodepacemaker,andisalsoacoronary
arteryvasodilator.
•Diltiazemcanrelievecoronaryarteryspasmandis
particularlyusefulinpatientswithvariantangina.
•Itissomewhatlesspotentvasodilatorthannifedipineand
verapamil,andhasmodestdirectnegativeinotropicaction,
butdirectdepressionofSAnodeandA-Vconductionare
equivalenttoverapamil.
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22. Calcium channelblockers
Dihydropyridine(DHP)calciumchannelblockers:Nifedipine
•NifedipineistheprototypeDHPwitharapidonsetandshort
durationofaction.Itcausesarteriolardilatationanddecreases
totalperipheralresistance.
•Nifedipineisusuallyadministeredasanextended-releaseoral
formulation.
•Itcausesdirectdepressantactiononheartinhigherdose.
•ADR:Frequentsideeffectsarepalpitation,flushing,ankle
edema,hypotension,headache,drowsinessandnausea.
Nifedipinehasparadoxicallyincreasedthefrequencyofanginain
somepatients.
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23. Calcium channelblockers
Otherdihydropyridine(DPH)calciumchannelblockers:
•Amlodipine,anoraldihydropyridine,functionsmainlyas
anarteriolarvasodilator.
•Nitrendipine,isacalciumchannelblockerwithaditional
actionofvasodilatationaction.Vasodilationactionisdue
toreleaseNOfromtheendotheliumandinhibitcAMP
phosphodiesterase.
•Lacidipine,isahighlyvasoselectivenewerDHP.
•Nimodipine,isshort-actingDHPwhichpenetratesblood-
brainbarrierveryefficientlyduetohighlipidsolubility.
•DPHwithlongdurationofaction:Lercanidipine,
Benidipine.
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24. Calcium channelblockers
Pharmacokineticcharacteristics of calcium Channel
blockers:
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25. Calcium channelblockers
Uses:
•Calciumchannelblockerscanbesafelygiventopatients
withobstructivelungdiseaseandperipheralvascular
diseaseinwhomβblockersarecontraindicated.
•CCBareusedforthetreatmentof
–angina pectoris
–hypertension
–cardiac arrhythmias
–hypertrophic cardiomyopathy
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26. Potassium ChannelOpeners
Nicorandil:
•AntianginalactionofnicorandilismediatedthroughATP
sensitiveK+channels(KATP)therebyhyperpolarizing
vascularsmoothmuscle.
•Nicorandiliswellabsorbedorally,nearlycompletely
metabolizedinliverandisexcretedinurine.
•Administeredi.v.duringangioplastyforacuteMI,itis
believedtoimproveoutcome.
•ADR:Flushing,palpitation,weakness,headache,dizziness,
nauseaandvomiting.
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27. Other antianginaldrugs
Dipyridamole •Dipyridamoleinhibits platelet aggregation
•It is a powerful coronary dilator
Trimetazidine •This antianginaldrug acts by nonhaemodynamic
mechanisms.
•The mechanism of action of trimetazidineis uncertain, but
it may improve cellular tolerance to ischaemiaby inhibiting
mitochondrial long chain 3-ketoacyl-CoAthiolase.
Ranolazine •This novel antianginal drug primarily acts by inhibiting a
late Na
+
current (late I
Na) in the myocardium.
Ivabradine •This ‘pure’ heart rate lowering antianginal drug has been
introduced recently as an alternative to β blockers.
•It blocks cardiac pacemaker (sino-atrial) cell ‘f’ channels.
Oxyphedrine •Improve myocardial metabolism.
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28. Distribution of CVD deaths in
males
Distribution of CVD deaths in
females
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29. Thankyou
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