Anti-angina drugs: Definition, classification, pharmacological actions, dose, indications, contraindications

Anti-anginal drugs

Decreased blood flow through an artery into the body part that is unable to fulfill oxygen demand is termed ischemia. Ischaemia in the brain is called brain Ischaemia. Ischaemia in cardiac muscle is called cardiac Ischaemia or myocardial Ischaemia. Angina pectoris is the primary symptom of myocardial Ischaemia (Ischaemic pain). Angina pectoris is characterized by sudden severe squeezing, pressing, heaviness, tightness, or substernal pain usually radiating to the left shoulders and along the left arm flexor surface.

Pathogenesis:

Usually, in normal conditions, a decrease in blood supply does not precipitate angina pectoris. Angina pectoris appears if there is an increase in cardiac muscle oxygen demand due to any reason and decreased blood supply by the coronary artery. Blood supply to cardiac muscles through the coronary artery in atherosclerosis develops resistance in blood flow. There are three types of angina pectoris. These are Stable angina pectoris, variant angina pectoris, and unstable angina pectoris.

• 1. Stable angina pectoris (classical angina pectoris or typical angina pectoris): Physical exertion precipitates angina pectoris. During these conditions, there will be an increase in oxygen demand in cardiac tissues. However, cardiac tissues do not receive sufficient blood to supply the required oxygen.

• 2. Variant angina (Prinzmetal’s angina): It occurs due to a sudden coronary spasm in a localized part of the coronary artery. It may not be linked with severe atherosclerosis or an increase in cardiac muscle oxygen demand.

• 3. Unstable angina: Unstable angina is due to plaque rupture or vasospasm. This decreases blood supply and oxygen supply to cardiac muscles. After certain critical level chest pain develops. Chest pain in unstable angina is not associated with cardiac muscle.

Classification

• A. Organic nitrates: Nitroglycerine, isosorbide dinitrate, isosorbide mononitrate, Amyl nitrate

• B. β adrenergic receptor blockers: Propranolol

• C. Calcium channel blockers: Verapamil, diltiazem, nifedipine, amlodipine, nimodipine and nitrandipine

• D. Potassium channel blockers: nicorandil

A. ORGANIC NITRATES:

They act as vasodilators by relaxing the smooth muscles of blood vessels. The vasodilation effect also reduces coronary artery spasms. The vasodilation effect of organic nitrates and organic nitrites is much more prominent in veins than in arteries. This pools blood into veins and decreases blood return into the heart chamber. That leads to a decrease in heart diastolic size and the cardiac force required to pump blood. This leads to reduced cardiac oxygen demand.

Organic nitrates and organic nitrates are effective in all types of angina. Organic nitrates to increase exercise tolerance in angina pectoris patients.

• Mechanism of action of Organic Nitrates: Organic nitrates and organic nitrites are readily metabolized in smooth muscle cells to form highly reactive free radical nitric oxide (NO). Nitric oxides reduce the entry of calcium into smooth muscle cells of blood vessels and stimulate the efflux of calcium from smooth muscle cells of the blood vessel. That causes vasodilation.

• Pharmacokinetics: Organic nitrates are lipid soluble and are rapidly absorbed from the mucous membrane of the oral cavity, intestine, and skin. They undergo rapid first-pass metabolism in the liver.

• Side effects: Most of the side effects are mainly due to the vasodilation effect of organic nitrates. These side effects are the following

  • 1. Throbbing headache, lightheadedness, dizziness, low blood pressure, palpitation, faints, flushing in the neck and face, sweating, weakness, slight nausea, and burning sensation under the tongue. The body develops tolerance to these effects after using organic nitrates for a week.

  • 2. Anaemia

• Tolerance: Continuous use of organic nitrates may rapidly develop tolerance. Nitrate-free period inside the body reduces this tolerance. Administration of dosage form that supplies organic nitrates to the body continuously for 24 hours or large dose develops tolerance. A sublingual dose of the drug administered three times daily does not develop tolerance. Organic nitrates also develop cross-tolerance.

• Drug dependence: Attack of angina pectoris may increase during the nitrate-free period. Nitrate-free period may lead to coronary blood vessel and peripheral blood vessel constriction. That precipitates angina and may cause death. If drug dependence develops, then other classes of antianginal drugs should be supplemented and organic nitrates may be withdrawn gradually.

• Interaction: It should be avoided with some peripheral vasodilators like sildenafil. This combination may cause severe hypotension and myocardial infarction that may lead to death. Antihypertensive drugs with organic nitrates should be avoided.

GLYCERYL TRINITRATE (Nitroglycerine): It is a volatile liquid and prototype vasodilator to treat angina pectoris. It is the most widely used drug to produce quick relief from angina pain due to exercise or stress. Its duration of action depends upon dosage form and route of administration. Nitroglycerine sublingual tablets and nitroglycerine oral spray are the most commonly used dosage forms to control angina pectoris.

• Mechanism of action: Glyceryl trinitrate is metabolized in smooth muscles to nitrite to nitrous oxide. Nitrous oxide increases the smooth muscle relaxation.

• Pharmacological effects: Nitroglycerine causes vasodilation in peripheral blood vessels and coronary blood vessels. Peripheral blood vessel pools blood in vain and artery. This decreases the workforce of the heart and decreases cardiac muscle oxygen demand. Coronary blood vessel dilation increases blood supply and oxygen supply to cardiac muscles.

• Pharmacokinetics: Nitroglycerine is a lipid-soluble drug that is readily absorbed from the mucous membrane, and moderately absorbed from the intestine and skin. It undergoes first-pass metabolism in the liver and is also readily metabolized in body cells.

• Side effects: headache, postural hypotension, flushing, and tachycardia.

• Tolerance: Tolerance develops rapidly. Tolerance subsides during the nitrate-free period. Nitrate free period should be in the afternoon. Usually angina pectoris precipitate more commonly during the morning hour.

• Nitroglycerine sublingual tablets: Nitroglycerine sublingual tablet is used to avoid first-pass metabolism and quick absorption of the drug into the systemic circulation from the oral cavity mucus membrane. It produces its effect within minutes. Half-life is about 2 minutes. Thus the duration of action of the drug depends upon the duration of nitroglycerine present in the oral cavity. If the effect of the drug is not required, it can be spit out or swallowed into GIT. These will immediately terminate the effect of nitroglycerine.

• Nitroglycerine sublingual spray: It acts more promptly than a nitroglycerine sublingual tablet.

• Nitroglycerine patches: Nitroglycerine is also absorbed from the skin. The transdermal patch is applied to the skin. It can provide nitroglycerine continuously for 2 to 24 hours. The onset of action starts within an hour with a bioavailability of 70 to 90%. A nitroglycerine transdermal patch to apply on gum in between the gum and upper lips is also available. Its onset of action starts within a few minutes

• Nitroglycerine intravenous infusion: It is used in unstable angina, coronary vasospasm, hypertension, and heart surgery. The advantage of this dose is prompt action, the steady plasma concentration of the drug, and dose adjustment as per requirements; plasma concentration can be maintained as long as required.

ISOSORBIDE DINITRATE: Isosorbide dinitrate is solidly absorbed from mucous membranes in the oral cavity and GIT. It does not undergo extensive first-pass metabolism. Isosorbide dinitrate is metabolised in liver to form active metabolite isosorbide mono nitrate. Isosorbide mononitrate is further metabolized to an inactive metabolite. Both active metabolite isosorbide mononitrate and inactive metabolite are excreted in the urine. Thus, Isosorbide dinitrate onset of action is slow with a prolonged duration of action

The sublingual tablet shows the half-life of Isosorbide dinitrate about 30 minutes. However, Single-dose effects last for 4 hours to 6 hours. Thus it can be used as a prophylactic agent. This drug is not administered in the evening or in night. This helps to provide a nitrate-free period.

ISOSORBIDE MONONITRATE: It has a 4 to 6 hours half-life and 6 to 10 hours duration of action, with high bioavailability. It is administered orally. Partial metabolism in the liver forms inactive metabolites. Both unchanged Isosorbide mononitrate and its inactive metabolite are excreted in the urine. It should be administered once in the morning only. This helps to provide a “nitrate-free period”.

• Therapeutic uses: Nitrates are used to prevent and treat all types of angina pectoris.

B. β ADRENERGIC BLOCKERS:

β Adrenergic blockers are used to reduce the frequency of angina pectoris attacks, reduce the severity of angina attacks, increase exercise duration, increase exercise tolerance to stable angina, and increase the threshold of an angina attack. β Adrenergic blockers are administered alone or in combination with other β Adrenergic blockers to produce the above-said effects.

• Mechanism of action: β Adrenergic blockers inhibit the adrenergic effect (sympathetic nervous system effect) in the heart. This decreases heart rate (negative inotropic effect or bradycardia), cardiac contraction, and cardiac muscle oxygen demand. β Adrenergic blockers antagonize only stimulated sympathetic nervous system by blocking β Adrenergic receptors. Thus, β Adrenergic blockers are not effective in the resting stage.

• Therapeutic uses: All β Adrenergic receptor blockers are equally effective on stable angina. Examples are acebutolol and pindolol. During β Adrenergic receptor blocker therapy, heart rate and blood pressure should be regularly monitored.

• Sudden withdrawal of these drugs causes a severe attack of angina pectoris and cardiac death.

• Contraindications: β Adrenergic receptor blockers are contraindicated in patients suffering from diabetes, peripheral vascular disease, cardiovascular disease, congestive heart failure, bradycardia, bronchial asthma, and chronic obstructive pulmonary disease. It masks hypoglycemia symptoms in diabetic patients.

• Side effects: Bradycardia, heart failure, fatigue, depression, sleep disturbance, etc.

C. CALCIUM CHANNEL BLOCKERS:

Calcium channel blockers produce vasodilation by blocking the entry of calcium ions into smooth muscles of blood vessels. This decreases arterial and venous blood pressure. Mainly following three calcium channel blockers are used in angina pectoris: nifedipine, verapamil, and diltiazem.

• Nifedipine: Nifedipine mainly dilates arteries. This effect is useful in the treatment of variant angina. It acts by dilation of coronary arteries and reduction in coronary artery spasms. It is administered orally. It has 4 hours of duration of action and requires frequent dosing. Side effects: Hypotension, edema, flushing, headache, and reflex tachycardia.

• Verapamil: It affects SA and AV nodes to decrease impulse conduction. This decreases heart rate (negative inotropic effect) and decreases cardiac muscles' oxygen demand. These effects reduce chronic stable angina attacks. But verapamil is weak vasodilator. Verapamil has very low side effects than nifedipine due to its weak vasodilator effect. Verapamil is a better choice to control angina in patients suffering from fatigue, bronchospasm, impotence, and depression. Verapamil in combination with β Adrenergic receptor blocker gives better results.

• Diltiazem: Similar to verapamil but with a low degree of effect.

Alok Bains