Angina pectoris

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

Pathogenesis: Decreased blood flow through the coronary artery to cardiac muscles will supply insufficient oxygen to fulfil cardiac muscle oxygen demand. This causes angina pectoris attack. Usually, in normal conditions decreased 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 decreases due to spasms in the coronary artery or due to fatty deposits inside a coronary artery. These fatty deposits are called plaque. The narrowing of an artery by plaque is called atherosclerosis (atherosclerotic lesions) and develops resistance in blood flow.

Types of Angina pectoris

There are three types of angina pectoris. These are Stable angina pectoris, variant angina pectoris and unstable angina pectoris.

Stable angina pectoris: It is called classical angina pectoris or typical angina pectoris. Physical exertion precipitates angina pectoris. Examples of physical exertions are severe exercise, excessive walking, and stair climbing. Even coitus, emotion and eating can also precipitate stable 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 required oxygen. It is mainly due to resistance in blood flow inside a coronary artery.

Variant angina (Prinzmetal’s angina): It is not common form of angina. Pain due to variant angina may appear at rest during sleep or at work. It occurs due to a sudden coronary spasm in the localised part of the coronary artery. It may not be linked with severe atherosclerosis, arteriosclerotic coronary artery disease, or an increase in cardiac muscle oxygen demand. There will be the elevation of the ST segment in ECG while unstable angina is associated with depression in the ST segment of ECG.

Unstable angina: Unstable angina is due to plaque rapture. This causes thrombocyte deposition and thrombus formation in coronary blood vessels. It may be due to platelets activation, adhesion and aggregation, aggregation of coagulation pathway and thrombin formation, conversion of fibrinogen to fibrin and vasospasm. This decreases blood supply and oxygen supply to cardiac muscles that develop chest pain. Unstable angina is referred to as acute coronary syndrome. It includes ST-segment depression and non-ST segment elevation. Chest pain in unstable angina is not associated with cardiac muscle necrosis. However, decreased blood supply to cardiac muscles develops myocardial necrosis.

Classification of antianginal drugs

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

• B. β adrenergic receptor blockers: Propranolol

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

• D. Potassium channel blockers: nicorandil

Organic Nitrates:

Organic nitrates and organic nitrites are esters of nitrous acid or nitric acid and alcohol. They act as vasodilators by relaxing the smooth muscles of blood vessels. This vasodilator effect makes organic nitrates and organic nitrites suitable to treat angina pectoris, myocardial infarction and left ventricular failure. The vasodilation effect of organic nitrates redistributes blood from the endocardial region and exocardial region to the periphery blood vessels.

The vasodilation effect also reduces coronary artery spasms in the exocardial region. These effects reduce preload and afterload in the heart.

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 preload in the heart which is a decrease in blood return into the heart chamber. They decrease the cardiac force requirement to pump blood due to decreased venous return, reduced cardiac output, artery vasodilation and reduced resistance in blood flow. This leads to reduced cardiac oxygen demand.

They are effective in all types of anginas. Organic nitrates are used to treat variant angina pectoris due to these effects. Reduction in cardiac work and cardiac oxygen demand effect of organic nitrates and organic nitrites help to treat stable angina. Organic nitrates and organic nitrites help to increase exercise tolerance in angina pectoris patients.

• Mechanism of action: Organic nitrates and organic nitrites are readily metabolised in smooth muscle cells of blood vessels to form highly reactive free radical nitric oxide (NO). Nitric oxides stimulate the guanyl cyclase enzyme to produce cGMP (cyclic GMP). cGMP reduces the entry of calcium into smooth muscle cells of blood vessels and stimulates efflux of calcium from smooth muscle cells of blood vessels. That causes vasodilation.

  Actin and myosin play important roles in blood vessels' smooth muscle contraction. cGMP dephosphorylates myosin light chain kinase. This causes a decrease in the availability of phosphorylated myoscine light chain kinase (phosphorylated myoscine light chain kinase is an active state of myoscine). That reduces the interaction of myosin and kinase to result inhibition of blood vessel contraction. This leads to vasodilation.

• Pharmacokinetics: Organic nitrates differ in their physical properties. Amyl nitrate is highly volatile at room temperature; nitroglycerine is moderately volatile at room temperature while isosorbide nitrate is solid at room temperature.

  They 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 by the action of glutathione reductase. The duration of action of organic nitrates depends upon their rate of absorption and rate of metabolism. The sublingual route is preferred due to rapid absorption from the sublingual route and direct entry into blood circulation without first-pass metabolism.

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

  •  1. Side effects due to vasodilation are throbbing headache, light-headedness, syncope, 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. In a lying position these side effects subside while in a standing position, these side effects precipitate out. Alcohol also precipitates these side effects

  • 2. Anaemia

  • 3. Allergic condition but it is rare.

• Tolerance: Continuous use of organic nitrates may rapidly develop tolerance. Organic nitrates develop cross-tolerance. Organic nitrates utilise blood vessel endothelium thio compounds to produce nitrous oxide. Continuous administration of organic nitrates into the body depletes these compounds. Thus, after some period endothelium of blood vessels will not have thio compounds. There will be a loss of antianginal, anti-ischaemic and hemodynamic effects. Discontinuation of organic nitrates administration allows the body to regenerate these compounds in blood vessel endothelium. Thus after discontinuation for a few hours of organic nitrate, there will be no tolerance to the effect of organic nitrates.

  Nitrate “nitrate-free period” inside the body reduces this tolerance. Thus, administration of a dosage form that supplies organic nitrates to the body continuously for 24 hours develops tolerance. Example: Transdermal patch of organic nitrates, intravenous infusion for continuous 24 hours. Thus, if the drug is administered through a patch, then the patch should be taken off for 8 hours daily. Sublingual doses of drug administered three times daily do not develop tolerance. Higher doses also develop tolerance.

• Drug dependence: Attack of angina pectoris may increase during the nitrate-free period in chronic use of organic nitrates. This may lead to coronary blood vessel constriction and peripheral blood vessel constriction. That precipitates angina, and myocardial infarction, 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. (an active constituent to treat erectile impotency in males). This combination may cause severe hypotension, and myocardial infarction that may lead to death. Administration of 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. It can be used as both a short-acting vasodilator or antianginal drug and a long-acting vasodilator and antianginal drug. 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 metabolised in smooth muscles to form nitrite to nitrous oxide. Nitrous oxide increases the concentration of cGMP which causes dephosphorylation of myoscine. Dephosphorylated myoscine (inactive myoscine) leads to 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 force 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 metabolised in body cells. Thus, the sublingual route is preferred to avoid first-pass metabolism in the liver. The second choice is a transdermal patch.

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

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

• Dosage form: Nitroglycerine is a lipid-soluble volatile liquid that is administered as a sublingual tablet, oral spray, transdermal patch and oral tablet.

• Nitroglycerine sublingual tablets: Matrix of tablets is used to absorb volatile nitroglycerine. These tablets should be stored in tightly closed containers in a cool place to prevent drug volatilisation. 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 nitroglycerine sublingual tablet.

• Nitroglycerin tablet: The absorption rate of nitroglycerine from GIT is slower than the sublingual route. Nitroglycerin absorbed from GIT also undergoes first-pass metabolism in the liver. However, these disadvantages can be overcome by administering a large dose of nitroglycerine through the oral route.

  Sustained release tablet or capsule dosage form contains a large dose of nitroglycerine. These dosage forms are administered through the oral route to produce a prophylactic effect.

• Nitroglycerine patches: Nitroglycerine is also absorbed from the skin. A transdermal patch of nitroglycerine in the matrix (polymer/reservoir) fixed to an adhesive patch is applied on 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. It can provide drugs for 4 to 6 hours to control angina. (ischaemia pain).

• Nitroglycerine ointment: It contains 2% nitroglycerine. It has a slow onset of action. Its effect lasts for 4 to 7 hours.

• Nitroglycerine intravenous infusion: It is used in unstable angina, left ventricle fibrillation, coronary vasospasm, hypertension, during heart surgery. Advantages of this dose are prompt action, steady plasma concentration of drug, dose adjustment as per requirements; plasma concentration can be maintained as long as possible.

• Isosorbide dinitrate: Isosorbide dinitrate is a solid compound absorbed from mucous membranes in the oral cavity and GIT, does not undergo extensive first-pass metabolism and shows a variable rate of metabolism. Isosorbide dinitrate is metabolised in liver to form active metabolite isosorbide mononitrate. Isosorbide mononitrate is further metabolised to inactive glucuronide metabolites by glucuronidation. Both active metabolites are excreted in urine. Thus, Isosorbide mononitrate helps to prolong the duration of action of isosorbide dinitrate. Isosorbide dinitrate onset of action is slow with prolonged duration of action.

It is available in dosage forms sublingual tablets and oral tablets. Sublingual tablets show a half-life of Isosorbide dinitrate of about 30 minutes. 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 night. This helps to provide nitrate “nitrate-free period”. This will stop nitrate tolerance development.

Isosorbide mononitrate: It has 4 to 6 hours half-life and 6 to 10 hours duration of action, with high bioavailability. It is administered orally. Partially metabolises in the liver to form glucuronide metabolite. Both unchanged Isosorbide mononitrate and its glucuronide metabolite are excreted in urine. It is available as a sustained-release tablet. It should be administered once in the morning only. This helps to provide a “nitrate-free period” to avoid the development of tolerance in the body to nitrates.

Therapeutic uses: Nitrates are used to prevent and treat all types of angina pectoris, congestive heart failure, left ventricle fibrillation, and myocardial infarction. It is also used to control these abnormal conditions during heart surgery. Cyanide poisoning, biliary colic and oesophageal spasm can also be controlled by nitrates.

β Adrenergic blockers

 β Adrenergic blockers are used to reduce the frequency of angina pectoris attacks, reduce the severity of angina attacks, increase the threshold of angina attacks, increase exercise duration, and increase exercise tolerance to stable angina.

• 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. These drugs increase coronary blood vessel dilation in the ischaemic subendocardial area to decrease blood vessel pressure and increase blood supply to these areas. All these produce above said effects. These effects of β Adrenergic blockers are very mild in the resting stage of cardiac muscle cells. Because at the resting stage sympathetic system is not very active and β Adrenergic blockers antagonise only the stimulated sympathetic nervous system.

• Coronary blood vessel dilation in the ischaemic sub-endocardial area decreases blood vessel pressure and increases blood supply to these areas. This helps to increase exercise duration, tolerance to angina pectoris during exercise and to increase diastolic time.

• Therapeutic uses: All β Adrenergic receptor blockers are equally effective on stable angina. However, They are effective as prophylactic agents to prevent the risk of heart attack in patients suffering from ischaemic heart disease. During β Adrenergic receptor blocker therapy, heart rate and blood pressure should be regularly monitored. They are the drug of choice to treat myocardial infarction, angina pectoris with myocardial infarction or angina pectoris after myocardial infarction.

• β Adrenergic receptor blockers are used along with nitrates to treat variant angina or unstable angina. β Adrenergic receptor blockers with nifedipine a calcium-channel blocker are also effective. In both conditions, β Adrenergic receptor blockers show additional benefits in controlling angina pectoris.

• Abrupt reduction in the dose of β Adrenergic receptor blockers or sudden withdrawal of these drugs causes severe attacks of angina pectoris, myocardial infarction 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 hypoglycemic symptoms in diabetic patients.

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

Calcium channel blockers

Calcium channel blockers produce vasodilation by blocking the entrance of calcium ions in smooth muscles of blood vessels both systemic arteries and coronary arteries.

This decreases resistance in blood flow inside blood vessels. That decreases arterial and venous blood pressure.

Mainly following three calcium channel blockers are mainly used in angina pectoris. These are nifedipine, verapamil and deltiazem.

• Nifedipine: Nifedipine mainly dilates arteries. This effect is useful in the treatment of variant angina due to dilation of coronary arteries and reduction in coronary artery spasm. It is administered orally. It has 4 hours of duration of action and requires frequent dosing.

Side effects: Hypotension, oedema, flushing, headache and reflex tachycardia.

• Verapamil: It affects SA and AV nodes to decrease impulse conduction. Reduction in AV node impulse conduction controls supraventricular response during atrial fibrillation or atrial flutter. This decreases heart rate (negative inotropic effect) and decreases cardiac muscles' oxygen demand. But verapamil is weak vasodilator. Verapamil has a very low reflex tachycardia side effect than nifedipine due to its weak vasodilator effect. β Adrenergic receptor blockers are recommended for patients suffering from fatigue, bronchospasm, impotency, and depression. Verapamil is a better choice to control angina in these patients.

Verapamil decreases heart rate, and cardiac afterload decreases cardiac oxygen demand and a mild increase in blood supply to cardiac muscles. These effects reduce chronic stable angina attacks. Verapamil in combination with β Adrenergic receptor blockers gives better results. Stable angina patients also suffer from asthma or chronic pulmonary obstructive disease.

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

Alok Bains