2.1 Antianginal Agents (PCI).pdf

Reference slides of Unit 2.1 Antianginal Agents (Vasodilators and calcium channel blockers) for TY B Pharm (Sem V) as per PCI curriculum.

1. Antianginal Drugs
(Vasodilators and Calcium Channel Blockers)
for
B Pharm Sem V (PCI)
by
Prof. Jayshree Patil
Department of Pharmaceutical Chemistry,
AIKTC School of Pharmacy, New Panvel

2. Vasodilators
✓Amyl nitrite,
✓Nitroglycerin*,
✓Pentaerythritol tetranitrate,
✓Isosorbide dinitrite*,
✓Dipyridamole.

3. Angina Pectoris
Angina
Typical anginais the result of an
advanced state of atherosclerosis and
is provoked by food, exercise, and
emotional factors.
Itischaracterizedbyanincreasein
theSTsegmentofthe
electrocardiogram.
Variantoracuteanginaresultsfrom
suddenspasminthecoronaryartery
unrelatedtoatheroscleroticnarrowing
ofthecoronarycirculationandcan
occuratrest.
It is characterized by low ST segment
of the electrocardiogram.

4. Antianginal Drugs
Therapyofanginaisdirectedmainlytowardalleviatingand
preventinganginalattacksbyalteringtheoxygen
supply/oxygendemandratiotothecardiacmuscleordilating
thecoronaryvessels.
Threeclassesofdrugsarefoundtobeveryefficientin
thisregard,althoughviadifferentmechanisms.
Theseinclude
✓organicnitrates,
✓calcium channel blockers, and
✓b-adrenergic blockers.

5. NITROVASODILATORS

6. Smooth Muscle Relaxation
The contractile activity of all types of muscle (smooth, skeletal) is regulated primarily by the
reversible phosphorylation of myosin.
Myosin of smooth muscle consists of two heavy chains (molecular weight [MW] 200,000
each) that are coiled to produce a filamentous tail.
Eachheavychainisassociatedwithtwopairs
oflightchains(MW20,000and16,000)that
serveassubstratesforcalcium-and
calmodulindependentproteinkinasesinthe
contractionprocess.
Togetherwithactin(MW43,000),they
participateinacascadeofbiochemicalevents
thatarepartoftheprocessesofmuscle
contraction and relaxation.

7. Cyclic nucleotides, cyclic adenosine monophosphate (cAMP),and,especially,cyclic
guanosinemonophosphate(cGMP)playimportantrolesintheregulationofsmooth
muscletension.
cAMPisthemediatorassociatedwiththesmoothmusclerelaxantpropertiesofdrugssuchas-
adrenergicagonists.Itactivatestheproteinkinasesthatphosphorylate myosin light-chain kinase
(MLCK). PhosphorylationofMLCKinactivatesthiskinaseandpreventsitsactionwithCa2
andcalmodulintophosphorylatemyosin,whichinteractswithactintocausecontractionof
smooth muscle.
TheactivityofcGMPinsmoothmusclerelaxationisaffectedbyexogenousandendogenousagents.
Itissuggestedthatnitrovasodilatorsundergometabolictransformationinvascularsmooth
musclecellstoformnitricoxide(NO).NOmediatessmoothmusclerelaxationbyactivating
guanylatecyclasetoincreaseintracellularconcentrationsofcGMP.cGMPactivatesprotein
kinasesthatcanregulatefreeCa2levelsinthemusclecellandcauserelaxationofsmooth
muscleby phosphorylating MLCK.

8. Regulation of smooth muscle contraction
✓Contractionistriggeredbyaninfluxof
Ca2.TheincreaseoffreeCa2causes
bindingtocalmodulin(CM).
✓TheCa2MCMcomplexbindstomyosin
light-chainkinase(MLCK)andcauses
itsactivation(MLCK*).
✓MLCK* phosphorylates myosin, which
combineswithactintoproduce
contraction of smooth muscle.
✓Myosinisdephosphorylatedinthe
presence of myosin phosphatase tocause
musclerelaxation.
✓The-agonists activate adenylate cyclase
(AC)toraiselevelsofcAMP,whichin
turnactivateskinasesthatphosphorylate
MLCK, inactivating ittopreventmuscle
contraction.
Myosin phosphatase

9. ✓Nitric oxide(NO)formedinsmooth
musclefromnitrovasodilatorsmorfrom
endothelialcells(EDRF)activates
guanylatecyclase (GC*).
✓GC* activates cGMP-dependent protein
kinases thatphosphorylatemyosinlight-
chainkinase(MLCK),causingits
inactivationandsubsequentmuscle
relaxation.
Mechanism of nitro vasodilators
Ashort-livedfreeradicalgas,NOiswidelydistributedinthebodyandplaysanimportantrolebyits
effectthroughcGMPonthesmoothmusclevasculature.Itissynthesizedinthevascularendothelial
cellfromthesemiessentialaminoacidL-argininebyNOsynthase.
Afterproductioninthecell,itdiffusestothesmoothmusclecell,whereitactivatestheenzyme
guanylatecyclase,whichleadstoanincreaseincGMPandthenmusclerelaxation.Endothelium
derivedrelaxingfactor(EDRF),releasedfromtheendothelialcelltomediateitssmoothmuscle–
relaxingpropertiesthroughcGMP,isidenticalwithNO.

10. Amyl nitrite
Pentaerythritol tetranitrate
Isosorbide dinitrate
Nitroglycerin

11. AdverseEffects
➢Headacheandposturalhypotensionarethemostcommonsideeffectsoforganicnitrates.
➢Dizziness,nausea,vomiting,rapidpulse,andrestlessnessareamongtheadditionalside
effectsreported.
➢Anotherconcernassociatedwithprophylacticnitrateuseisthedevelopmentoftolerance.
Tolerance,usuallyintheformofashorteneddurationofaction,iscommonlyobserved
withchronicnitrateuse.
DrugInteractions
➢Themostsignificantinteractionsoforganicnitratesarewithvasodilators,alcohol,and
tricyclic
Antidepressantscausehypotension.
➢Ontheotherhand,concurrentadministrationwithsympathomimeticamines,suchas
ephedrineandnorepinephrine,canleadtoadecreaseintheantianginalefficacyofthe
organicnitrates.

12. Dipyridamole
Itmaybeusedforcoronaryandmyocardialinsufficiency.
Itsbiggestusetoday,however,isasanantithromboticinpatientswithprostheticheartvalves.
Dipyridamoleisalong-actingvasodilator.Itsvasodilatingactionisselectiveforthecoronarysystem;it
isindicatedforlong-termtherapyofchronicanginapectoris.
Thedrugalsoinhibitsadenosinedeaminaseinerythrocytesandinterfereswiththeuptakeofthe
vasodilatoradenosinebyerythrocytes.Theseactionspotentiatetheeffectofprostacyclin(PGI2),which
actsasaninhibitortoplateletaggregation.

13. Calcium Channel Blockers
✓Verapamil,
✓Bepridil hydrochloride,
✓Diltiazem hydrochloride,
✓Nifedipine,
✓Amlodipine,
✓Felodipine,
✓Nicardipine,
✓Nimodipine.

14. Thesecondmajortherapeuticapproachtothetreatmentofanginaistheuseofcalcium
channelblockers.
Inthe1906s,itwasrecognizedthatinhibitionofcalciumion(Ca2+)influxintomyocardial
cellscanbeadvantageousinpreventingangina.
Currently,theclassesofcalciumchannelblockersapprovedforuseintheprophylactic
treatmentofanginaincludethedihydropyridinesnifedipine,nicardipine,andamlodipine;the
benzothiazepine derivative diltiazem; the aralkyl amine derivativeverapamil;the
benzazepinonezatebradine,andthediaminopropanoletherbepridil.
Theseclassesofdrugsarereservedfortreatmentfailuresbecauseseriousarrhythmiascan
occur.

15. Calciumchannelblockerscanbedividedconvenientlyintothethreedifferentchemicalclassesofthe
prototypedrugsthathavebeenused:1,4-dihydropyridines (nifedipine), phenylalkylamines
(verapamil), benzothiazepines (diltiazem) and diaminopropanolether(bepridil).
The specific Ca2 channel antagonists verapamil, nifedipine,anddiltiazeminteractatspecificsitesonthe
calciumchannelprotein.Theseblockersdonotoccludethechannelphysicallybutbindtositesinthe
channel,becausetheycanpromotebothchannelactivationandantagonism.
Affinityforbindingsitesonthechannelvaries,dependingonthestatusofthechannel.Thechannelcan
existineitheranopen(O),resting(R),orinactivated(I)state,andtheequilibriumbetweenthemis
determinedbystimulusfrequencyandmembranepotential.
https://www.researchgate.net/publication/300084862_ICEPO_The_ion_channel_electrophysiology_ontology/figures?lo=1

16. Verapamilanddiltiazemdonotbindtoachannelintherestingstate,onlyafterthechannelhasbeen
opened.Theyareionized,water-solubleCa2-entryblockersthatreachtheirbindingsitesbythe
hydrophilicpathwaywhenthechannelisopen.
NifedipineisaneutralmoleculeatphysiologicalpHandcancauseinterferencewiththeCa2inthe
openorclosedstate.Intheclosedstate,nifedipinecantraversethephospholipidbilayertoreachits
bindingsitebecauseofitslipid solubility.
http://pittmedneuro.com/actionpotentials.html

17. Mechanism of Action
https://www.researchgate.net/publication/300084862_ICEPO_The_ion_channel_electrophysiology_ontology/figures?lo=1

18. ✓Thedepolarizationandcontractionofthemyocardialcellsaremediated,inpart,bycalciuminflux.
✓Theoverallprocessconsistsoftwodistinct,inwardioncurrents:First,sodiumionsflowrapidlyinto
thecellthroughthe“fastchannels,”andsubsequently,calciumentersmoreslowlythroughthe“slow
channels.”
✓Thecalciumionstriggercontractionindirectlybybindingandinhibitingtroponin,anatural
suppressorofthecontractileprocess.Oncetheinhibitoryeffectoftroponinisremoved,actinand
myosincaninteracttoproducethecontractileresponse.
✓Thecalciumchannelblockersproduceanegativeinotropiceffectbyinterruptingthecontractile
response.
✓Invascularsmoothmuscles,calciumcausesconstrictionbybindingtoaspecificintracellular
proteincalmodulintoformacomplexthatinitiatestheprocessofvascularconstriction.
✓Thecalciumchannelblockersinhibitvascularsmoothmusclecontractionby
deprivingthecellfromthecalciumions.

19. Theeffectsofthedifferentclassesofcalciumchannelblockersonthemyocardiumandthearteriesvary
fromclasstoclass.Althoughverapamilanddiltiazemaffectboththeheartandthearteriolarbed,the
dihydropyridineshavemuchlesseffectonthecardiactissuesandhigherspecificityforthearteriolar
vascularbed.
Therefore,bothverapamilanddiltiazemareusedclinicallyinthemanagementofangina,
hypertension,andcardiacarrhythmia,whereasthedihydropyridinesareusedmorefrequentlyas
antianginalandantihypertensiveagents.

20. 1,4 Dihydropyridines

21. Nifedipine
1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylate dimethyl ester, is a
dihydropyridine derivative that bearsnostructuralresemblancetotheothercalciumantagonists.
2,6positiondurationofaction
Mechanism:
➢Theprototypeofthisclass,nifedipine,haspotentperipheralvasodilatoryproperties.
➢Itinhibitsthevoltage-dependentcalciumchannelinthevascularsmoothmusclebuthaslittleor
nodirectdepressanteffectontheSAorAVnodes,eventhoughitinhibitscalciumcurrentin
normalandisolatedcardiactissues.
✓positions3and5arecarboxylic
groupsthatmustbeprotectedwith
anesterfunctionalgroup.
✓Distributionofdrug
position4requiresanaromatic
substitution possessing an electron-
withdrawing group(i.e.,Clor
NO2)intheorthoand/ormeta
position
Its nitro group is
essential for its
antianginal effect
SAR
1
3
2
4
5
6

22. Metabolism:
•Nifedipine is absorbed efficiently on oral or buccal administration.
•A substantial amount (90%) is protein bound.
•Systemic availability of an oral dose of the drug may be approximately 65%.
•Two inactive metabolites are the major products of nifedipine metabolism and are found in
equilibrium with each other. Only a trace of unchanged nifedipine is found in the urine
Uses:
▪Nifedipine is more effective in patients whose anginal episodes are caused by coronary
vasospasm and is used in the treatment of vasospastic angina as well as classic angina pectoris.
▪Because of its strong vasodilatory properties, it is used in selected patients to treat hypertension.

23. Amlodipine
Amlodipine, 2-[(2-aminoethoxy)methyl]4- (2-chlorophenyl)-
1,4-dihydro-6-methyl-3,5-pyridinedicarboxylic acid 3-ethyl
5-methyl ester (Norvasc), is a second generation 1,4-
dihyropyridinederivativeoftheprototypicalmolecule
nifedipine.
Likemostofthesecond-generationdihydropyridine
derivatives,ithasgreaterselectivityforthevascularsmooth
musclethanmyocardialtissue,alongerhalf-life(34hours),
andlessnegativeinotropythantheprototypicalnifedipine.
Amlodipineisusedinthetreatmentofchronicstableangina
andinthemanagementofmild-to-moderateessential
hypertension.
AmlodipinewasapprovedinSeptember2007asacombinationproductwitholmesartan
(Azor), an angiotensin II receptor antagonistforthetreatmentofhypertension.
Amlodipineisalsomarketedasacombinationtherapywithatorvastatinunderthetradename
Norvascforthemanagementofhighcholesterolandhighbloodpressure.

24. Felodipine
4-(2,3-dichlorophenyl)-1,4-dihydro- 2,6-dimethyl-
3,5-pyridinedicarboxylic acid ethyl methyl ester, is
a second-generation dihydropyridine channel
blockerofthenifedipinetype.Itismoreselective
forvascularsmoothmusclethanformyocardial
tissueandservesasaneffectivevasodilator.
Thedrugisusedinthetreatmentofanginaand
mild-to-moderateessentialhypertension.
Felodipine,likemostofthedihydropyridines,
exhibitsahighdegreeofproteinbindingandhasa
half-liferangingfrom10to18hours.
Nicardipine
1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)
3,5-pyridinedicarboxylic acid methyl 2-
[methyl(phenylmethyl)amino]ethyl ester
hydrochloride,isamorepotentvasodilatorof
thesystemic,coronary,cerebral,andrenal
vasculatureandhasbeenusedinthe
treatmentofmild,moderate,andsevere
hypertension.Thedrugisalsousedinthe
managementofstableangina.

25. Nimodipine
1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)- 3,5-
pyridinedicarboxylic acid 2-methoxyethyl 1-
methylethylester,isanotherdihydropyridine
calciumchannelblockerbutdiffersinthatitdilates
thecerebralbloodvesselsmoreeffectivelythando
theotherdihydropyridinederivatives.
Thisdrugisindicatedfortreatmentof subarachnoid
hemorrhage-associated neurological deficits.

26. PHENYLALKYLAMINES

27. Verapamil
5-[(3,4-dimethoxyphenethyl) methylamino]-2-(3,4-dimethoxyphenyl)-2-isopropylvaleronitrile,
wasintroducedin1962asacoronaryvasodilatorandistheprototypeoftheCa2antagonists
usedincardiovasculardiseases.
Mechanism:
➢Verapamil’smajoreffectisontheslowCa2
channel.TheresultisaslowingofAV
conductionandthesinusrate.
➢ItiscategorizedasaclassIV
antiarrhythmic
➢Thedrugreducessystemicvascular
resistanceandmeanbloodpressure,with
minoreffectson cardiac output.
Verapamilisasyntheticcompoundpossessingslightstructuralsimilaritytopapaverine.
Itcanbeseparatedintoitsopticallyactiveisomers,ofwhichthelevorotatoryenantiomeristhe
mostpotent.
https://www.youtube.com/watch?v=9DFrOlyRaEw

28. Metabolism:
➢Itisabsorbedrapidlyafteroral
administration.Thedrugis
metabolizedquicklyand,asaresult,
haslowbioavailability.
➢Theliveristhemainsiteoffirst-pass
metabolism,formingseveralproducts.
➢Thepreferentialmetabolicstep
involvesN-dealkylation,followedby
O-demethylation,andsubsequent
conjugationoftheproductbefore
elimination.
➢Themetaboliteshavenosignificant
biologicalactivity.Verapamilhasan
eliminationhalf-lifeofapproximately
5hours.
Uses:
Itisusedinthetreatmentof
✓anginapectoris,
✓arrhythmiasfromischemicmyocardial
syndromes
✓supraventricular arrhythmias.

29. BENZOTHIAZEPINES

30. Diltiazem
3-(acetoxy)-5-[2(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)1,5-benzothiazepin-4-one,
wasdevelopedandintroducedinJapanasacardiovascularagenttotreatanginapectoris.
Itwasobservedtodilateperipheralarteriesandarterioles.Thedrugincreasesmyocardialoxygen
supplybyrelievingcoronaryarteryspasmandreducesmyocardialoxygendemandbydecreasingheart
rateandreducingoverload.
Diltiazemhydrochlorideisusedinpatientswithvariantangina.Thedrughaselectrophysiological
propertiessimilartothoseofverapamilandisusedinclinicallysimilartreatmentconditionsasan
antiarrhythmicagent,butitislesspotent.

31. Metabolism:
Diltiazemhydrochlorideismetabolizedextensivelyafteroraldosing,byfirst-passmetabolism.Asa
result,thebioavailabilityisabout40%oftheadministereddose.Thedrugundergoesseveral
biotransformations,includingdeacetylation,oxidativeO-andN-demethylations,andconjugationof
thephenolicmetabolites.Ofthevariousmetabolitesonlytheprimarymetabolite,deacetyldiltiazem,
ispharmacologicallyactive.Deacetyldiltiazemhasabout40%to50%ofthepotencyoftheparent
compound.

32. DIAMINOPROPANOL
ETHER

33. Bepridil β-[(2- methylpropoxy)methyl]-N-phenyl-N-(phenylmethyl)-1-pyrrolidineethylamine,isa
secondgenerationalkylamine-type channel blocker, structurally unrelatedtothedihydropyridines.
Itsactionsarelessspecificthanthoseofthethreeprototypicalchannelblockers,verapamil,
diltiazem,andnifedipine.
InadditiontobeingaCa2channelblocker,itinhibitssodiumflowintothehearttissueandlengthens
cardiacrepolarization,causingbradycardia.
Cautionshouldbeusedifitisgiventoapatientwithhypokalemia.
Bepridilhydrochlorideisusedforstableangina.Thedrughasahalf-lifeof33hoursandishighly
bound to protein (99%).

34. REFERENCE BOOKS:
1.Foye’s Principles of Medicinal Chemistry, Thomas L. Lemke, David A Williams, Lippincott
Williams & Wilkins.
2.Wilson and Gisvold’sTextbook of Organic Medicinal and Pharmaceutical Chemistry, John M.
Beale, John H. Block, Lippincott Williams & Wilkins.