Antianginal Drugs.pdf

Antianginal Drugs
Introduction
Classification
MOA and synthesis

1. Lecture by
Dr. Jasmine Chaudhary
Associate Professor
MMCP
Antianginal Drugs

2. Introduction
Drugsusedforthetreatmentofanginapectoris.
Thewordanginameans“tochoke”
Itisanischemicheartdiseasecausedbyrestrictedbloodflowinarteriesthatsupply
theheart.
Astranglingfeelingisobservedinchest.
Usuallyoccursduetoimbalanceinoxygensupplyandoxygendemandofheart.
Oxygensupplydecreasesinsituationofcoronaryspasmwhichisprovokedby
variousphysicalfactorslikecoldandpharmacologicalfactorslikecatecholamines.
Otherfactorsincludenarrowingofaorticvalve,anemiaetc.
Oxygendemandusuallyincreasesinsituationofstress,exerciseetc.

3. Causes
CAD (Coronary artery disease) is one of major cause of
angina.
Other causes include
Anemia
Abnormal heart rhythm
Disease of heart muscle.

4. Symptoms
Usuallycharacterizedbysudden,severepain(discomfort)inchest(substernalpain)
whichoftenradiatestoleftshoulderdowntoleftarm.
Pressure,fullnessorsqueezingpaininthechestusuallylastformorethan5minutes
Othersymptomsinclude
Shortnessofbreath
Nausea
Fatigue
Anxiety
Sweating
Dizzinness

5. Types of Angina
ClassicalorTypicalStableAngina
Usuallyoccursduetophysicalexertionlikeexerciseormanicsituations.
Subsidesontakingrest.
UnstableAngina(duetocoronaryobstruction)
Atheroscleroticcoronaryarterydisease/Coronaryspasm/Formationof
thrombuscanbethecause
Canoccuratrest(HeartAttack)Emergency
Prinzmetalorvarientangina
Usuallyoccursatrestinmorning
Itisreversiblecoronaryspasm.Occurstoverysmallextent

6. Factors which increase the condition
Obesity
Tobaccouse
Diabetes
HighBloodpressure
Highcholesterol
Familyhistoryofheartdisease
Lackofexercise
Stress

7. Treatment Strategies
Tomaintainbalancebetweenoxygensupplyandoxygendemand
whichcanbedoneby
Lifestylechanges(avoidsmoking,stressandhighmealsand
followingproperdietandexerciseschedule.
AntianginalDrugs
Surgery

8. Classification of AntianginalDrugs
OrganicNitrates:Nitroglycerin,IsosorbideNitrate,Amylnitrate,
Pentaeryhritoltetranitrate
Vasodilators:Dipyridamole
Calciumchannelblockers:
Phenylalkylamines:Verapamil,Bepridil,
Benzothiazepines:Diltiazem,
Dihydropyridines:Nifedipine,Amlodipine,Felodipine,
Nicardipine,Nimodipine
Potassiumchannelopeners:Nicorandil
Beta-blockers:Metoprolol,Atenolol,Propranolol

9. Vasodilators
OrganicNitrates:Nitroglycerin(Glyceryltrinitrate),IsosorbideNitrate,
Amylnitrate,Pentaerythritoltetranitrate
Dipyridamole
Organic Nitrates
•Firstlinedrugeffectiveinalltypesofangina.
•Simplenitrousandnitricacidestersofalcohols.
•Usedinbothtreatmentandprophylaxisagainstanginaattacks.
•Classification
Shortacting–Nitroglycerin,Amylnitrate
Longacting-Isosorbidenitrate,Pentaerythritoltetranitrate

10. Nitrous oxide (NO)
Activates Guanyl cyclase
GTP cGMP
MLCK MLCK-P
Calcium channels
Ca
Organic nitrates
+ Calmodulin
Ca-Calmodulin
Mysosin
Contraction
+ Actin
Actinomyosin
Myosin-P

11. Amyl nitrite
3-(methylbutyloxy) nitrite
Nitroglycerin (Glyceryl trinitrate)
1,2,3-trinitroxypropane

12. Pentaerythritol tetranitrate
Isosorbide dinitrate

13. Dipyridamole
Antiplatelet drug
Inhibit bloot clot formation when given chronically
At high doses, Cause blood vessel dilation.
Given with blood thinners like warfarin to avoid formation of clots
cAMP Vasodilation
Inactive cAMP
Phosphodiesterase
Dipyridamole

14. Calcium channel blockers
Cause relaxation of heart muscles as well as smooth muscles.
Phenylalkylamines:Verapamil,Bepridil
Benzothiazepines:Diltiazem
Dihydropyridines:Nifedipine,Amlodipine,Felodipine,Nicardipine,
Nimodipine
Modeofaction
Influx of calcium through calcium channels lead to depolarisation
which further leads to contraction.
CCBs block this calcium influx by binding to L type Calcium
channels causing muscle relaxation.

15. Phenylalkylamines
Verapamil
First calcium channel antagonist to be introduced into therapy in the early 1960s
Possess antiarrhythmic, antianginal, and antihypertensive activity
Bepridil
N-benzyl-N-[3-(2-methylpropoxy)-2-(pyrrolidin-1-yl)propyl]aniline
Calciumchannelblockerwhichactsbyvasodilation.
Hasinhibitoryeffectonbothcalciumchannelsandsodiumchannels
Diltiazem (Benzothiazepine)

16. Dihydropyridines
Name of
drug
R1 R2 R3 R5
Nifedipine2-NO
2C
6H
4 CH
3 CH
3 CH
3
Nicardipine3-NO
2C
6H
4 (CH
2)
2NCH
2(CH
3)C
6H
5CH
3 CH
3
Nimodipine2-NO
2C
6H
4 -CH(CH
3)
2 CH
3 CH
2CH
2OCH
3
Amlodipine2-chlorophenylC
2H
5 CH
2OCH
2CH
2NH
2CH
3
Felodipine2,-dichlorophenylC
2H
5 CH
3 CH
3

17. Dimethyl-2,6-dimethyl-4-(2-nitrophenyl)-
1,4-dihydropyridine-3,5-dicarboxylate
(Nifedipine)
3-{2-[benzyl (methyl) amino] ethyl}-5-O-
methyl -2,6-dimethyl-4-(3-nitrophenyl)-
1,4-dihydropyridine-3,5-dicarboxylate
(Nicardipine)
3-O-ethyl-5-O-methyl-2-aminoethoxymethyl)-
4-(2-chlorophenyl)-6-methyl-1,4-
dihydropyridine-3,5-dicarboxylate
(Amlodipine)

19. SAR
Nifedipine is prototype of this class.
1,4-dihydropyridine skeleton is essential for activity.
A secondary nitrogen in dihydropyridine ring is also
required.
Substitution at C-4 should be either aromatic or
heteroaromatic.
Aromatic ring can be substiuted by electron withdrawing
groups.
Further ortho-substitution at aromatic ring is more
preferable than meta. Para substitution results in loss of
activity.
C2 and C6 should be substituted by alkyl groups.

20. Potassium channel opener: Nicorandil
AntianginaldrugactivatesATPsensitiveK+channelsleading
tohyperpolerizationofvascularsmoothmuscle.
ItalsoactsasaNOdonorandrelaxesbloodvesselsby
increasingcGMP.