• Angina pectoris is a characteristic sudden severe pressing chest
pain or heaviness radiating to the neck, jaw, back and arms.
• Angina is caused by coronary flow that is insufficient to meet
oxygen demands of the myocardium. Angina can be precipitated
by any activity/process that creates an imbalance in O2 supply and
demand.
• Typically angina lasts for seconds to minutes, up to 15 minutes.
Classically angina is not associated with ischemic cell death,
anginal symptoms lasting longer than 60 minutes indicates
myocardial death.
Angina occurs in three overlapping patterns:
Stable angina
Unstable angina
Prinzmetal (variant) angina
• The experience of angina is quite variable, often described as chest
pain it is frequently associated with adjectives indicating a
compressive tightness that is often quite debilitating.
• Angina indicates that myocardial oxygen demand is exceeding
supply.
“Stable” indicates the reproducible nature of the
angina; the same activity at the same intensity faithfully
produces symptoms. Typically this type of angina is relieved by
rest or acute use of nitroglycerin.
Unstable Angina
• Unstable angina occurs when anginal symptoms occur with less
cardiac demand; previously tolerated activities elicit symptoms, of
great concern is angina at rest. These episodes are less or un-
responsive to nitroglycerine or rest.
•
It occurs due to ruptured or dislodged lipid plaque, thrombus
formation or release of vasoconstructor substances.
• This is a relatively uncommon pattern of myocardial ischemia
usually occurring at rest and often in young individuals
(particularly women) lacking classic risk factors or significant
demonstrable coronary disease.
• It is caused by spasms of coronary artery that decreases blood
flow to the myocardium.
• The anginal attacks generally occur in the early morning hours.
• These attacks can be triggered by alcohol, drinking iced drinks,
rapid eye movement sleep, ergonovine, cocaine, nicotine,
acetylcholine, and hyperventilation.
Classification of Antianginal drugs
1) Nitrates and nitrites
a) Nitrates: e.g. Nitroglycerin (1), Erythritol tetranitrate (2), Trolnitrate phosphate
(3), Isosorbide dinitrate (4), Pentaerythritol tetranitrate (5), Mannitol hexanitrate
(6).
b) Nitrites: e.g. Amyl nitrite (7), Sodium nitrite (8), Nitroprusside sodium (9).
2) Calcium Channel Blockers
a) Aryl alkyl amine derivative: e.g. Verapamil (10)
b) Benzothiazepine: e.g. Diltiazem (11)
c) Dihydropyridine derivative: e.g. Nifedipine (12), Nimodipine (13), Nitrendipine
(14), Nicardipine (15), Amlodipine (16), Felodipine (17), Isradipine (18).
d) Newer second generation alkyl amine derivative: e.g. Bepridil (19)
3) β-Adrenergic Antagonist: e.g. Propranolol (see antihypertensives)
4) Miscellaneous Coronary Vasodilators: e.g. Dipyridamol (20), Cyclandelate (21),
Chemistry:
• Nitrovasodilators are small nitrate or nitrite esters of simple organic
alcohols, whereas normal organic esters, e.g. RCOOR’, are a
combination of an organic acid (RCOOH) with an organic alcohol
(R’OH), The nitrovasodilators are esters of nitrous (HNO2) or nitric
(HNO3) acid with an organic alcohol. It is important to note that all
nitrate (nitrite) esters consist of an O-N bond, and not a C-N bond.
The common name nitroglycerine,
• The nitrovasodilators are small uncharged organic molecules. A
specific advantage results from this characteristic.
• Because of their non-polar nature these agents exhibit very high
lipid permeability. Thus rapid treatment of acute anginal episodes
is possible through fast absorption relieving the patient of severe
pain.
• Preparations of these agents should be protected from moisture.
• In addition, these nitrate esters also exhibit potential for
explosion. Thus many are available in diluted forms in the
presence of excipients that minimize the potential for hazardous
explosion.
Mechanism of action of Nitrates and nitrites
• These act by the formation free radical nitric oxide (NO), which interact with
and activate guanylate cyclase.
• Nitric oxide forms a reductive nitrothiol intermediate activate a soluble
cytosolic form of the enzyme guanylate cyclase and cGMP formation is
thereby increased.
• The guanylate cyclase increases the synthesis of guanosine 3’, 5’monophosphate, which activates a protein kinase which mediates
dephosphorylation of myosin responsible for the maintenance of the
contractile state in smooth muscle.
mechanism of muscle contraction and relaxation. Action of cAMP or cGMP (cyclic
adenine or guanosine monophosphate) results in phosphorylation of MLCK (myosin
light chain kinase) that prevents myosin from being phosphorylated, thus retaining
muscles in the relaxed state. See text for details.
• The biochemical events that regulate the contraction and relaxation function of
all muscle (smooth, cardiac, skeletal). The state of muscle (contraction or
relaxation) is controlled by the action of myosin-actin pair of proteins. Depending
on whether myosin is phosphorylated or not, the action of actin results in either
contraction or relaxation of the muscle.
•
The nitric oxide released by nitrovasodilators activates guanylate cyclase an
enzyme that produces cGMP. Increase in the concentration of cGMP, in turn,
activates protein kinases that phosphorylate MLCK, thus preventing the
phosphorylation of myosin and resulting in muscle relaxation,
• Figure 2. Muscle relaxation, or vasodilation, results in reduced workload for the
heart, thus easing anginal pain.
Simplified biochemical mechanism of muscle contraction and relaxation. Action of cAMP
or cGMP (cyclic adenine or guanosine monophosphate) results in phosphorylation of
MLCK (myosin light chain kinase) that prevents myosin from being phosphorylated, thus
retaining muscles in the relaxed state. See text for details.
Mechanism of action of Calcium Channel Blockers
These drugs acts by selectively inhibit calcium ion influx into heart
muscle and inhibit calcium ion influx into vascular smooth muscle. It
dilates the main coronary arterioles, and by inhibiting coronary
artery spasm, they increase myocardial oxygen delivery in patients
with Prinzmetal’s angina.
Dihydropyridine
SAR
•
The 1,4 dihydropyridine ring is essential for activity . Substitution at N1 position
or use Of piperidine and pyridine ring system greatly decreases or abolishes the
activity.
• Optimum activity is obtained with 1,4 dihydropyridine, substituted with two
alkyl groups at C2 And C6 , two ester groups at C3 and C5 and a para substituted
phenyl group at C4.
• Substituted phenyl ring at C4 optimizes activity(heteroaromatic ring produces similar
effects but are not used due to animal toxicity.
• Phenyl ring substitution is imp for size and position. Compounds with ortho and meta
substitution possess optimal activity, while those of para substituted or unsubstituted
shows decrease in activity. Electron withdrawing ortho or meta substitution or
electron donating groups demonstrates good activity.
• Esters groups at C3 and C5positions optimise the activity. Other electron withdrawing
groups decreased antagonist activity.
• With the exception of amlodipine all 1,4 DHP have C2 and C6 methylgroups.
Amlodipine is more potent than nifedipine.
benzothiazepines
Aralkylamines
Diarylaminopropylamine ether
Mechanism of action of β-Adrenergic Antagonist
• The β-Adrenergic Antagonist decreases sympathetic stimulation
of the heart and thus reduces the heart rate and decreases
myocardial contractibility. These effects in turn decrease the
oxygen requirements of the myocardium, both during exercise
and at rest.
• Propranolol is nonselective B1 and B2 blocker.
• Propranolol, is a common nonselective β-blocker of both cardiac and bronchial
adrenergic receptors. It is typically used for exertion-induced angina which
originates from coronary atherosclerosis.
• Drugs with β-blocking activity slow the heart rate and decrease the force of
contraction of muscles, thus these drugs are useful in treating hypertension and
cardiac arrythmias, in addition to angina. Propanolol is also typically used in
combination with organic nitrates or calcium channel blockers to enhance its
anti-anginal efficacy.
Miscellaneous agents