The document discusses various drugs used for the treatment of angina pectoris, including nitrates, beta blockers, calcium channel blockers, and others. Nitrates work by reducing preload and afterload on the heart, thereby decreasing oxygen demand. They act by converting to nitric oxide which increases cGMP levels to cause vasodilation. Beta blockers decrease heart rate and contractility to lower myocardial oxygen consumption. Calcium channel blockers inhibit calcium influx into cardiac and vascular smooth muscle to produce vasodilation and reduce workload on the heart. The document provides details on the mechanisms, uses and adverse effects of these major classes of antianginal medications.

1. ANTIANGINAL
DRUGS
Dr. MONIKA SINGH
BP501T Medchem-II 1

2. SyllabusUnit-II 10 Hours
Anti-Anginal: Vasodilators: Amyl Nitrite, Nitroglycerin*,
Pentaerythritol tetranitrate, Isosorbide Dinitrite*,
Dipyridamole. Calcium channel blockers: Verapamil,
Bepridil hydrochloride, Diltiazem hydrochloride,
Nifedipine, Amlodipine, Felodipine, Nicardipine,
Nimodipine.
Diuretics: Carbonic Anhydrase Inhibitors: Acetazolamide*, Methazolamide,
Dichlorphenamide. Thiazides: Chlorthiazide*, Hydrochlorothiazide, Hydroflumethiazide,
Cyclothiazide, Loop Diuretics: Furosemide*, Bumetanide, Ethacrynic acid. Potassium sparing
Diuretics: Spironolactone, Triamterene, Amiloride. Osmotic Diuretics: Mannitol.
Anti-hypertensive Agents: Timolol, Captopril, Lisinopril, Enalapril, Benazepril hydrochloride,
Quinapril Hydrochloride, Methyldopate Hydrochloride* Clonidine hydrochloride,
Guanethidine Monosulphate, Guanabenz Acetate, Sodium Nitroprusside, Diazoxide,
Minoxidil, Reserpine, Hydralazine hydrochloride.
BP501T Medchem-II 2

3. Coronary artery disease
• Angina Pectoris (Ischemic Heart Disease)
• Acute Coronary Syndrome
• Unstable Angina
• non-ST elevation myocardial infarction
(NSTEMI)
• ST-segment elevation myocardial infarction
(STEMI)
BP501T Medchem-II Unit-II 3

4. Causes of chest pain
• Pericarditis (caused by a variety of infectious agents e.g
bacteria, fungi, and viruses, autoimmune disorders,
renal failure, and trauma)
• Mitral Valve Prolapse
• Pulmonary Embolism (is an infarct of the lung)
• Pleurisy (is chest pain associatedwith inflammation of
the pleural lining of the lungs)
• Hyperventilation Syndrome (is caused by fear or panic
induced hyperventilation)
• Trauma/Rib Fracture
• Chest Wall Twinge Syndrome (Precordial Catch) (is due to
intercostal muscle spasm)
• Costochondritis (an inflammation of the cartilage between
the rib end and the sternum)
• Esophagitis, Acute or Chronic (GERD)
BP501T Medchem-II Unit-II 4

5. Antianginal Drugs
• Angina pectoris refers to a
strangling or pressure-like
pain caused by cardiac
ischemia. The pain is
usually located substernally
but is sometimes perceived
in the neck, shoulder and
arm, or epigastrium.
• Women develop angina at a
later age than men and are
less likely to have classic
substernal pain.
• Antianginal drugs are those that
prevent, abort or terminate attacks of
angina pectoris.
BP501T Medchem-II Unit-II 5

6. Types of angina
– Atherosclerotic angina (classic angina
[common form]): Attacks are predictably
provoked (stable angina) by exercise, emotion,
eating or coitus and subside when the
increased energy demand is withdrawn. Rest,
by reducing cardiac work, usually leads to
complete relief of the pain within 15 min.
Atherosclerotic angina constitutes about 90%
of angina cases.
– Vasospastic angina (rest angina,
variant angina, or Prinzmetal’s angina
[uncommon form]): Attacks occur at rest or
during sleep and are unpredictable.
Vasospastic angina is responsible for less than
10% of angina cases.
Unstable angina (crescendo angina, also
known as acute coronary syndrome):It
is characterized by increased frequency and
severity of attacks that result from combination
of atherosclerotic aggregation plaques (fatty
deposits) , at fractured plaques, and platelet
vasospasm.
Coronary artery calibre changesin
classical and variant angina
BP501T Medchem-II Unit-II 6

7. Treatment of Angina Pectoris
• Drugs used in angina exploit two main strategies:
– reduction of oxygen demand
– increase of oxygen delivery to the myocardium
BP501T Medchem-II Unit-II 7

8. Classification of antianginal drugs
• Nitrates
– Short acting: Glyceryl trinitrate (GTN, Nitroglycerine*)
– Long acting: Isosorbide dinitrate (short acting by
sublingual route), Amyl Nitrite, Pentaerythritol
tetranitrate, Isosorbide Dinitrite*, Dipyridamole.
• βBlockers: Propranolol, Metoprolol, Atenolol and others.
• PotassiumChannelOpeners: Minoxidil and Diazoxide
• Calcium channel blockers
– Phenyl alkylamine: Verapamil
– Benzothiazepine: Diltiazem
– Dihydropyridines: Nifedipine, Felodipine, Amlodipine,
Nicardipine, Nimodipine
– Diaminopropanol ether : Bepridil 8

9. Classification of antianginal drugs
• 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.
BP501T Medchem-II Unit-II 9

10. Nitrates/ Organic Nitrates
• Preload reduction: Peripheral pooling of blood →
decreased venous return (preload reduction).
• Afterload reduction: Nitrates also produce some
arteriolar dilatation → slightly decrease total peripheral
resistance or afterload on heart.
• Redistribution of coronary flow: In the arterial tree,
nitrates preferentially relax bigger conducting
(angiographically visible) coronary arteries than arterioles
or resistance vessels.
BP501T Medchem-II Unit-II 10

11. Nitrates/ Organic Nitrates
Mechanism of action:
• The organic nitrate agents are prodrugs that are
sources of Nitric Oxide (NO).
• NO activates the soluble isoform of guanylyl
cyclase,
• thereby increasing intracellular levels of cGMP. In
turn, cGMP promotes the dephosphorylation of the
myosin light chain and
• the reduction of cytosolic Ca2+ and leads to the
relaxation of smooth muscle cells in a broad range
of tissues.
BP501T Medchem-II Unit-II 11

12. Mechanism of Vascular
smooth muscle relaxant action
of nitrodilators like glyceryl
trinitrate and calcium channel
blockers
• (- - -→) Inhibition
• CAM—Calmodulin;
• NO—Nitric oxide
• MLCK—Myosin
• light chain kinase
• MLCK-P—Phosphorylated
MLCK
• GTP—Guanosine triphosphate;
• cGMP—Cyclic
guanosine
monophosphate
References: Tripathi, K. (2013). Essentials of medical pharmacology (7th ed.). New Delhi: JaypeeBrothers.
Nitrates/ Organic Nitrates
Mechanism of action:
12

13. Nitrates/ Organic Nitrates
Pharmacokinetics:
• Organic nitrates are lipid soluble, well absorbed from
buccal mucosa, intestines and skin.
• Ingested orally, all except isosorbide mononitrate
undergo extensive and variable first pass metabolism
in liver. They are rapidly denitrated by a glutathione
reductase and a mitochondrial aldehyde
dehydrogenase.
BP501T Medchem-II Unit-II 13

14. Nitrates/ Organic Nitrates
Pharmacokinetics:
BP501T Medchem-II 14

15. Amyl nitrate
Iso -Amyl nitrite or Amyl Nitrite
Isosorbide dinitrate
Pentaerythritol tetranitrateBP501T Medchem-II Unit-II 15

16. dipyridamole
BP501T Medchem-II Unit-II 16

17. Nitrates/ Organic Nitrates
Adverse Effects:
• Headache is the most common adverse effect of nitrates
• High doses of nitrates can also cause postural
hypotension
• Facial flushing
• Tachycardia
• Nitrates + Sildenafil : Hypotension as Nitrates increases
cGMP levels while Sildenafil PDE inhibitor (Phosphodiesterase type 5
inhibitors ) it decreases cGMP metabolism, potentiate the action of the
nitrates. To preclude the dangerous hypotension that may occur, this
combination is contraindicated.
BP501T Medchem-II Unit-II
17

18. Adverse effects of Nitrates
Tolerance:
• Tolerance to the actions of nitrates develops rapidly as
the blood vessels become desensitized to vasodilation.
Tolerance can be overcome by providing a daily “nitrate-
free interval” to restore sensitivity to the drug.
Dependence:
• Sudden withdrawal after prolonged exposure has
resulted in spasm of coronary and peripheral blood
vessels. Withdrawal of nitrates should be gradual.
BP501T Medchem-II Unit-II 18

19. BP501T Medchem-II Unit-II 19
• Cross tolerance
"Monday morning headache" :
• This phenomenon for those who experience regular
nitroglycerin exposure in the workplace
• Workers may experience headache on starting few days
due to vasodilatory action of nitrates.
• Then tolerance develops to this vasodilatory action and
headache subsides.
• But No exposure of chemicals over the weekend
tolerance disappears
• When the symptoms reappear when they start work on
Monday

20. BP501T Medchem-II Unit-II 20
ROLE OF NITRATES IN ANGINA:
O2 supply
2O Demand
decrease in afterload
decrease in
preload
redistribution of
coronary blood flow
O2 supply 2O Demand

21. Nitrates/ Organic Nitrates
Uses:
• Angina pectoris: GTN produces relief within 3 min in
75% patients, the rest may require another dose or
take longer (upto 9 min).
• Acute coronary syndromes: Nitrates are useful by
decreasing preload as well as by increasing coronary
flow.
• Myocardial infarction (MI): GTN is frequently used
during evolving MI with the aim of relieving chest
pain, pulmonary congestion and limiting the area of
necrosis by favourably altering O2 balance in the
marginal partially ischaemic zone.
BP501T Medchem-II Unit-II 21

22. Uses:
• CHF and acute LVF: Nitrates afford relief by venous pooling of
blood → reduced venous return (preload) → decreased end
diastolic volume →improvement in left ventricular function.
• Biliary colic (a dull pain in the middle to upper right area of the abdomen.)
• Esophageal spasm (contractions of the esophagus are irregular, uncoordinated,
and sometimes powerful)
• Cyanide poisoning:
 (10ml 3%) Nitrates generate methaemoglobin which has
high affinity for cyanide radical (CN-) and forms
cyanomethaemoglobin.
 Cyanomethaemoglobin futher dissociate to give CN- and
cause poisoning.
 Therefore Sodium thiosulphate is given (50 ml 25%) so
as to form methaemoglobin+ Sodium thiocyanate which
is excreted in URINE.
BP501T Medchem-II Unit-II
22

23. 23
Cyanides
Chelation of Iron
in the
Cytochrome Oxidase
Tissue anoxia,
Seizures,
Coma, death
Haemoglobin
Methaemoglobin
1. Sodium nitrite
10ml
Cyanomethaemoglobin
2. Sodium thiosulphate 25m
Sodium thiocyanate
Excreted through urine

24. BP501T Medchem-II Unit-II 24
Acute attack:
Dose: 0.5mg Sublingual
nitroglycerin
Sublingual Isosorbidedinitrate
( Rationale behind giving sublingual route To
avoid first pass metabolism )
•If pain is not relieved repeat the dose after 5 min
•3 tablets in 15min
•Always in sitting position to avoid the syncope
• Nitrates increase exercise tolerance and postpone ECG
changes of ischemia.
For prophylaxis:
Oral route with long acting nitrates

25. BP501T Medchem-II Unit-II 25
Dose Onset Duration• Drug
Nitro glycerine
Tablet SL
Sustained release
Sublingual spay
Ointment
Trans dermal
0.5mg
2.5-5mg
0.4mg
½ -2 inch
5-15mg
1-2min
60min
1-2min
20-60min
30-60min
15-40min
8-12hrs
15-40min
4-6hrs
12hrs
Isosorbidedinitrate
Sublingual
Tablet
Sustained release
2 .5-10mg
10-40mg
40-80mg
10-30min
30-60min
60min
1-2hrs
4hrs
6-12hrs

26. Synthesis of Nitro Glycerin
BP501T Medchem-II Unit-II 26

27. Synthesis of Isosorbide dinitrate
p-Toluenesulfonic acid
BP501T Medchem-II Unit-II 27

28. βBlockers
• The β-adrenergic blockers decrease the oxygen
demands of the myocardium by blocking β1
receptors, resulting in decreased heart rate,
contractility, cardiac output, and blood pressure.
• All β blockers are nearly equally effective in
decreasing frequency and severity of attacks and in
increasing exercise tolerance in classical angina, but
cardioselective agents (atenolol, metoprolol) are
preferred over nonselective β1 + β2 blockers
(e.g.propranolol).
• Agents with intrinsic sympathomimetic activity (ISA)
such as pindolol should be avoided in patients with
angina and those who have had a MI.
BP501T Medchem-II Unit-II 28

29. BP501T Medchem-II Unit-II 29
I) They blocks the Beta1 receptors in the Heart.
negative inotropic
negative chronotropic action
decreases blood pressure
Reduces the workload on the heart
So reduces the oxygen demand
II)total coronary flow is rather reduced due to blockade of
dilator β2receptors.
•However, flow to the ischaemic subendocardial area is not
reduced because of favourable redistribution.
Only for Stable & unstable angina

30. BP501T Medchem-II Unit-II
30
PROPANOLOL ATENOLOL
LABETOLOL
β-adrenergic Blockers
TIMOLOL

31. Calcium channel blockers
BP501T Medchem-II 31

32. Calcium channel blockers
– Phenyl alkylamine: Verapamil
– Benzothiazepine: Diltiazem
– Dihydropyridines: Nifedipine, Felodipine,
Amlodipine, Nitrendipine, Nimodipine,
Lacidipine, Lercanidipine, Benidipine
– Diaminopropanol ether : Bepridil
BP501T Medchem-II Unit-II 32
Pharmacological actions:
• Smooth muscle: The CCBs cause relaxation by
decreasing intracellular availability of Ca2+. The
dihydropyridines (DHPs) have the most marked smooth
muscle relaxant and vasodilator action; verapamil is
somewhat weaker followed by diltiazem.

33. Calcium channel blockers
Pharmacological actions:
• Heart: Calcium influx is increased in ischemia because of
the membrane depolarization that hypoxia produces. The
calcium channel blockers protect the tissue by inhibiting
the entrance of calcium into cardiac and smooth muscle
cells of the coronary and systemic arterial beds and
decreases smooth muscle tone and vascular
resistance, afterload.
BP501T Medchem-II Unit-II 33

34. Calcium channel blockers
Phenyl alkylamine: Verapamil:
• It dilates arterioles and decreases total peripheral
resistance.
• It slows atrioventricular (AV) conduction directly and
decreases heart rate, contractility, blood pressure, and
oxygen demand.
• It also has some α adrenergic blockingactivity.
• Verapamil has greater negative inotropic effects than
amlodipine, but it is a weaker vasodilator.
• Verapamil should not be given with β blockers,
digoxin, cardiac depressants like quinidine and
disopyramide.
BP501T Medchem-II Unit-II 34

35. Calcium channel blockers
Benzothiazepine: Diltiazem:
• Diltiazem also slows AV conduction, decreases the
rate of firing of the sinus node pacemaker, and is also
a coronary artery vasodilator.
• Diltiazem can relieve coronary artery spasm and is
particularly useful in patients with variant angina.
• It is somewhat less potent vasodilator than nifedipine
and verapamil, and has modest direct negative
inotropic action, but direct depression of SA node
and A-V conduction are equivalent to verapamil.
BP501T Medchem-II Unit-II 35

36. Calcium channel blockers
Dihydropyridine (DHP) calcium channel blockers:
Nifedipine:
• Nifedipine is the prototype DHP with a rapid onset and
short duration of action. It causes arteriolar dilatation and
decreases total peripheral resistance.
• Nifedipine is usually administered as an extended-release
oral formulation.
• It causes direct depressant action on heart in higher dose.
• ADR: Frequent side effects are palpitation, flushing, ankle
edema, hypotension, headache, drowsiness and nausea.
Nifedipine has paradoxically increased the frequency of
angina in some patients.
BP501T Medchem-II Unit-II 36

37. Other dihydropyridine (DPH) calcium channel
blockers:
• Amlodipine, an oral dihydropyridine, functions mainly
as an arteriolar vasodilator.
• Nitrendipine, is a calcium channel blocker with
aditional action of vasodilatation action.
Vasodilation action is due to release NO from the
endothelium and inhibit cAMP
phosphodiesterase.
BP501T Medchem-II Unit-II 37

38. Verapamil Diltiazem
Nifedipine
ulina
38
5-[N-(3,4-dimethoxy phen ethyl) methylamino]-2-
(3,4-dimethoxy phenyl)-2-Isopropyl voleronitrile
(Dose: 40-160mg TID)

39. N
H
CH3
R
COOR''
'
R OOC
N1 substitution
reduses the activity
Ester group for
optimum
activity,-NO2
may decreases
the activity
Methyl group is
present except in
amlodipine
SAR of 1,4-
dihydropyridines
Potency is high
when compared to
others
Electron with
drawing groups
decreases the
activity
Presence of non
polar alkyl or
cyclo alkyl
reduces the
activity
BP501T Medchem-II
Unit-II
39

40. BP501T Medchem-II
Unit-II
40
Nimodepine

41. Calcium channel
blockersUses:
• Calcium channel blockers can be safely given to
patients with obstructive lung disease and
peripheral vascular disease in whom β blockers
are contraindicated.
• CCB are used for the treatment of
– angina pectoris
– hypertension
– cardiac arrhythmias
– hypertrophic cardiomyopathy
BP501T Medchem-II Unit-II 41

42. Potassium Channel Openers
Minoxidil:
• Antianginal action of minoxidil is mediated through
ATP sensitive K+ channels (KATP) thereby
hyperpolarizing vascular smooth muscle.
• Nicorandil is well absorbed orally, nearly completely
metabolized in liver and is excreted in urine.
Administered
i.v. during angioplasty for acute MI, it is believed to
improve outcome.
• ADR: Flushing, palpitation, weakness, headache,
dizziness, nausea and vomiting.
BP501T Medchem-II Unit-II 42

43. BP501T Medchem-II Unit-II
43
MINOXIDIL Diazoxide
DOSE: 20mg BD
Adverse effects:
flushing, palpitation, weakness, headache, mouth ulcers, nausea and vomiting
POTASSIUM CHANNEL OPENERS USES: Angina pectoris, Hypertension,
Congestive heart failure, Insulinoma, Alopecia, Bronchial asthma, Peripheral vascular
disease, Premature labour, Erectile dysfunction

44. Other antianginal
drugs
Dipyridamole • Dipyridamole inhibits platelet aggregation
• It is a powerful coronary dilator
Trimetazidine • This antianginal drug acts by
nonhaemodynamic mechanisms.
• The mechanism of action of trimetazidine is uncertain,
but it may improve cellular tolerance to ischaemia by
inhibiting mitochondrial long chain 3-ketoacyl-
CoAthiolase.
Ranolazine • This novel antianginal drug primarily acts by
inhibiting a late Na+ current (late INa) 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.
BP501T Medchem-II Unit-II 44

45. Beta1
Decreases HR
Force of contraction
Beta blocker
Nitrates
Veno dilators
Decreases Preload
Calcium channel
blockers
Arterio dilators
Decreases After load
Nitrates+ Beta blockers +Calcium channel blockers

46. Myocardial infarction
BP501T Medchem-II Unit-II 46
Myocardial infarction, commonly
known as a heart attack,
It is the irreversible necrosis of
heart muscle secondary to
prolonged ischemia.
which is most often caused by
plaque rupture with thrombus
formation in a coronary vessel.
resulting in an acute reduction of
blood supply to a portion of the
myocardium.

47. BP501T Medchem-II Unit-II 47

48. BP501T Medchem-II Unit-II
48
Myocardial Ischemia
Pain & Anxiety
Increased cardiac work
Cell death
Arrhythmias
Coronary thrombus
Beta blockers
Thrombolytics
Aspirin
Sympathetic stimulation
Beta blockers
Morphine, Nitrates
Tachy Brady
Lignocaine Atropine
ACE inhibitors
Heart failure
Worsen myocardial ischemia

49. BP501T Medchem-II Unit-II 49
1) Sublingual nitroglycerin 0.5mg ( max 3 doses in 15 min)
2) Oxygen
3) IV morphine 10mg may be repeated every 5-15 minutes until
the pain is relieved. Morphine relieves pain and reduces anxiety,
blocks sympathetic discharge also dilates blood vessels,
reduces preload & after load
Life-threatening irregular heartbeats (arrhythmias)
are the leading cause of death in the
first few hours of a heart attack

50. BP501T Medchem-II Unit-II 50
4) IV fluids: To treat hypotension
5) Aspirin 75-150mg: to prevent platelet aggregation
6) Thrombolytics: Streptokinase 1.5 million units IV infusion
over 1 hour. They should be started as early as possible ( with in 6
hours )
7) Beta blockers: IV Atenolol 5-10mg ,Limit the infract size,
reduce the arrhythmias
8) ACE inhibitors: should be started with in 24 hours To prevent
ventricular remodelling To prevent Heart failure
9) Ionotropic drugs: Dopamine, Dobutamine To support cardiac
function
10) Tachyarrhythmias : IV Lignocaine 1-2mg
11) Bradyarrhythmias : IV Atropine 0.5-1mg

51. BP501T Medchem-II Unit-II 51
Thank you