Antianginal Drugs PDF

Antianginal Drugs Yam Mun Fei School of Pharmaceutical Sciences Universiti Sains Malaysia Introduction The coronary arteries branch off the aorta immediately after leaving the heart and deliver blood to the myocardium. Coronary vessels of the heart sho...

Antianginal Drugs Yam Mun Fei School of Pharmaceutical Sciences Universiti Sains Malaysia Introduction The coronary arteries branch off the aorta immediately after leaving the heart and deliver blood to the myocardium. Coronary vessels of the heart showing both the arterial and venous circulation  The coronary arteries are very susceptible to the development of fatty deposits, commonly referred to as plaque. The fatty substance in plaque is mainly cholesterol. Individuals with high blood cholesterol levels are subject to the formation of these cholesterol-laden plaques that reduce coronary blood flow. Atherosclerosis is the term used to describe the fatty degeneration of the coronary arteries. The reduction in coronary blood flow caused by atherosclerosis is referred to as ischemia. Individuals who develop atherosclerosis and experience cardiac ischemia are classified as having coronary artery disease (CAD). Angina pectoris, described as pain in the chest, is caused by CAD. The pain is due to insufficient blood flow and oxygen supply to the myocardium. Complete blockage of one or more of the coronary arteries results in a myocardial infarction (MI) or heart attack. The treatment of CAD is aimed at reducing the number and severity of anginal attacks, limiting progression of atherosclerosis, and preventing the occurrence of myocardial infarction and possible death. Important nondrug components to the treatment of CAD include diets that limit fat and cholesterol, exercise, elimination of smoking, and weight control. The three classes of drugs used in the treatment of angina pectoris and CAD are the nitrates, beta-adrenergic blockers, and calcium channel blockers. Classification of angina pectoris There are several different types of angina pectoris. The most common type is caused by exercise, overexertion, or stress. This type is classified as exertional angina and its occurrence is usually predictable. It is caused by insufficient coronary blood flow due to atherosclerotic plaques. Individuals with this type of angina usually know the activities that will bring on the anginal attack. Stopping the activity and resting often provides some relief. The second type of angina is referred to as variant or Prinzmetal angina. The cause is vasospasm of one or more of the coronary arteries. This type of angina is variable because it is unpredictable and can occur at any time, even during sleep. Drugs that relax arterial smooth muscle and produce arteriolar dilation are effective in relieving the vasospasm. Some individuals have both the exertional and variant type of angina. Unstable angina is a more serious condition that usually occurs with advanced coronary artery disease. It usually occurs in coronary arteries that are almost completely blocked. In this situation there is the risk that blood platelets will become activated and initiate formation of a blood clot that can completely block the artery and cause a myocardial infarction. Instable angina requires aggressive therapy with antianginal, anticoagulant, and antiplatelet drugs in order to prevent blood clot formation. This is also the point in treatment when various procedures such as angioplasty and coronary artery bypass are considered. Nitrates The nitrates were once known as coronary dilators, but research has shown that during angina these drugs do not produce significant effects on coronary arteries that are atherosclerotic and hardened by arteriosclerosis. Ischemia itself is a potent vasodilator so that during attacks of angina the coronary arteries are already maximally dilated. The main effect of the nitrates is to produce a general vasodilation of systemic veins and arteries. This reduces venous return, cardiac work, and oxygen consumption. Reduction of cardiac work and oxygen consumption provides relief of ischemia and pain. The nitrates are used in two ways. First, they are administered during attacks of angina to relieve the intense pain. The most common route of administration is sublingual. The drugs in this group have an almost immediate onset of action, although their duration is short. Second, they are administered prophylactically on a daily basis to prevent attacks of angina. Mechanism of Action The mechanism of action of these drugs is to relax vascular smooth muscle. This effect is caused by nitrate ions, which are enzymatically released from nitrate drugs. These nitrate ions are converted by enzymes in blood vessels to nitric oxide (NO). Nitric oxide is a potent vasodilator that relaxes vascular smooth muscle. Venodilation (dilation of veins) is greater than arteriolar dilation at the lower dosage ranges of these drugs. The main effects produced by vasodilation are a decrease in venous return to the heart (decrease in preload) and a decrease in blood pressure (decrease in afterload). Consequently, cardiac work is reduced. With a reduction in cardiac work, less oxygen is required by the heart, and relief of pain is accomplished. In the vasospastic form of angina, the vasodilating effect of the nitrates is effective in relieving vasospasm of the coronary arteries. Clinical use of nitrate drugs Nitroglycerin, isosorbide dinitrate, and isosorbide mononitrate are the three available nitrate drugs used to treat angina and CAD. They can be administered in several different forms. Sublingual Nitroglycerin Nitroglycerin is available as a sublingual tablet and as a sublingual spray for relief of acute anginal attacks. Patients place the nitroglycerin tablet under the tongue and allow the tablet to dissolve without swallowing. Use of the sublingual pump involves one or two sprays under the tongue. The effects of sublingual administration usually occur within 1 to 3 minutes, with the peak effect occurring at about 5 minutes. The duration of action is approximately 30 minutes. Sublingual administration avoids first-pass metabolism by the liver. This method of administration provides the fastest relief for acute angina. Nitroglycerin Ointment 2% The ointment is applied topically to an area of the chest or abdomen and is covered with a plastic dressing. Absorption occurs through the skin, with an onset of action of 30 minutes and a duration of 4 to 8 hours, depending on the amount applied. Each inch of ointment squeezed from the tube contains approximately 15 mg of nitroglycerin. Nitroglycerin ointment is used prophylactically to prevent the occurrence of angina. Nitroglycerin Extended-Release Capsules Nitroglycerin is available in capsules of 2.5, 6.5, and 9.0 mg that release the drug gradually over a prolonged period. Duration of action is 8 to 12 hours. The extended release capsules are used daily to prevent the occurrence of anginal attacks (prophylaxis). Transdermal Nitroglycerin (Transderm-Nitro) This nitroglycerin is contained within an adhesive patch that is applied on the torso. The nitroglycerin is slowly and uniformly released into the bloodstream over a 24-hour period. Transdermal use is indicated for the prevention of angina. Continuous daily exposure to nitrates, especially throughout the 24-hour period, can lead to rapid development of drug tolerance. It is recommended that there should be a 10- to 12-hour drug-free period each day. Consequently, patients who use the transdermal patch are advised to remove the patch at night during sleep. Nitroglycerin for Intravenous Infusion Nitroglycerin can be administered intravenously in emergency and surgical situations in the hospital. The onset of action is rapid, but the duration of action of IV nitroglycerin is short and drug effects quickly wear off once the infusion is stopped. Adverse Effects The main adverse effects of the nitrates are related to the vasodilating action. Cutaneous flushing, dizziness, headache, weakness, and fainting may be experienced. Sudden or excessive drops in blood pressure can cause reflex tachycardia. Patient Education Since anginal attacks are unpredictable, it is important for patients to carry the prescribed medication at all times. Nitroglycerin is volatile, and tablets lose potency if exposed to air or light. Therefore, it is important that tablets be carried in light-resistant, airtight containers. Also, standard practice is not to use nitroglycerin tablets that are more than 6 months old since there may be significant loss of potency. When patients experience angina, they should be instructed to sit down, place a nitroglycerin tablet under the tongue, and allow it to dissolve without swallowing. Relief should occur within 5 minutes. If it does not, they should repeat the process with another tablet. If there is no relief after three tablets, patients should notify the physician or seek medical assistance. Patients should be aware of the common side effects, such as cutaneous flushing, headache, and dizziness. They should be advised to lie down if they feel faint. These effects are expected and only last for a few minutes. In addition, patients should become aware of the activities that cause angina (overexertion, emotional upset, or overeating) and try to avoid these situations if possible. Drug Interaction An important drug interaction may occur with nitrate drugs and drugs used to treat erectile dysfunction (ED). Sildenafil (Viagra), tadalafil (Cialis), and vardenafil (Levitra), used to treat ED, work by inhibiting a phosphodiesterase enzyme. Inhibiting this enzyme increases the formation of nitric oxide (NO), which causes relaxation of smooth muscle. In the penis, the relaxation of smooth muscle and the subsequent increased blood flow is required to establish and maintain an erection. Since the nitrates also increase NO, the ED drugs can potentiate the effects of the nitrates and cause excessive vasodilation, hypotension, reflex tachycardia, and potentially myocardial infarction. Consequently, these two drug classes should not be administered at the same time. Beta-adrenergic blocking drugs The beta-blockers antagonize or reverse the effects of sympathetic activation caused by exercise and other physical or mental exertions. In the heart, sympathetic stimulation (beta-1 receptors) increases heart rate, force of myocardial contractions, and oxygen consumption. The therapeutic action of beta-blockers in the treatment of angina lies in the ability of these drugs to decrease heart rate and force of contractions. These changes decrease cardiac work and therefore oxygen consumption. Decreasing oxygen consumption often prevents development of myocardial ischemia and pain. Beta-blockers are indicated for the long-term (chronic) management of angina pectoris. Patients taking beta- blockers usually have less frequent anginal attacks or a delayed onset of pain during physical exertion. This is another way of saying that they have increased work capacity or exercise tolerance. While all beta-blockers decrease cardiac work and oxygen consumption, propranolol and the other (in next slide) are usually the preferred beta-blockers for the treatment of angina and CAD. Beta-blockers can be used in combination with nitrates in patients who require more than one drug to control angina. When used in combination with nitrates, blockade of beta-1 receptors will usually prevent the reflex tachycardia that may occur with the nitrates. Adverse Effects Adverse effects of beta-blockers include drowsiness, tiredness, and GI disturbances such as nausea and diarrhea. Excessive drug dosage can cause bradycardia, hypotension, and possible development of heart failure. Nonselective beta-blockers, like propranolol, should not be given to individuals with asthma or COPD. Blockade of beta-2 receptors in the respiratory tract can cause bronchoconstriction.  Calcium channel blockers Mechanism of Action The most important action of calcium channel blockers in the treatment of angina and CAD is to block the influx of calcium ions into vascular smooth muscle. Contraction of vascular smooth muscle is very dependent on calcium influx (movement from extracellular to intracellular sites), which normally occurs during membrane depolarization (action potential) of smooth muscle. At the doses used in angina, the calcium channel blockers relax arterial smooth muscle and have little effect on veins. The primary effect is arteriolar vasodilation and reduction of blood pressure. This reduces cardiac work (afterload) and oxygen consumption. The calcium channel blockers are primarily taken on a daily basis to prevent angina and are also the preferred drugs for treatment of variant or Prinzmetal angina. They are the most effective drugs to relieve vasospasm. In addition to arteriolar dilation, two of the calcium channel blockers, verapamil and diltiazem, also block the influx of calcium ions in cardiac muscle and in the SA and AV nodes. As previously discussed in lectures with the antiarrhythmic drugs, these actions decrease heart rate, AV conduction, and the force of myocardial contraction. The cardiac actions of verapamil and diltiazem also reduce cardiac work and can contribute to the antianginal effect. The remaining calcium channel blockers (chemically classified as dihydropyridines) are arterial dilators with very little direct actions on the heart. Calcium channel blockers with direct cardiac effects Verapamil ( Calan, Isoptin ) Verapamil is used to treat supraventricular arrhythmias (previous lecture). In addition, its vasodilating properties allow it to be considered for the treatment of angina. Because of its prominent effects on the heart, verapamil also can decrease heart rate, AV conduction, and the force of myocardial contraction. These actions decrease cardiac work and oxygen consumption. However, excessive depression of cardiac function can precipitate heart failure. Diltiazem ( Cardizem ) The vasodilating and cardiac effects of diltiazem are similar to those of verapamil. However, diltiazem is considered to have slightly less cardiac depressant effects but greater vasodilating actions than verapamil. Calcium channel blockers without direct cardiac effects Nifedipine ( Procardia ) Nifedipine has very little effect on heart rate and myocardial contraction, but it is a very potent arterial vasodilator that lowers blood pressure (decreases afterload) and causes relaxation of coronary artery spasm. Nicardipine ( Cardene ) Nicardipine is similar to nifedipine in that the main pharmacological effects are vasodilation and relaxation of coronary artery spasm. Other Calcium Antagonists Amlodipine ( Norvasc ), felodipine ( Plendil ), and isradipine ( DynaCirc ) are additional calcium antagonists. These drugs have little or no direct actions on the heart and are primarily arterial vasodilators with actions and adverse effects similar to nifedipine. Adverse Effects Common adverse effects of the calcium antagonists include headache, facial flushing, dizziness, hypotension, and minor gastrointestinal (GI) disturbances. Constipation is one of the more common side effects of verapamil. The calcium channel blockers that do not have direct cardiac effects, like nifedipine, are potent vasodilators that can cause reflex tachycardia if blood pressure drops below normal. With overdosage, verapamil and diltiazem can cause bradycardia, AV block, and decreased myocardial contraction that can lead to heart failure. The use of either verapamil or diltiazem with beta-blockers is generally contraindicated; the combination can cause excessive cardiac depression and heart failure. Preferred therapy for treatment of angina pectoris All patients with CAD should carry with them one of the sublingual nitrate drugs for immediate treatment of a sudden attack of angina. Exertional, Fixed, or Stable Angina The nitrates, beta-blockers, and calcium channel blockers are all very effective in controlling the exertional type of angina. The choice often depends on other cardiovascular conditions that the patient may have. For example, patients with hypertension are best treated with calcium channel blockers or beta-blockers since both drug classes are effective in the treatment of hypertension. If there is increased sympathetic activation, then beta-blockers would be the better choice. If combination therapy is required, it should be guided by patient response. Variant or Prinzmetal Angina Vasospasm is the major feature of this type of angina. The calcium channel blockers, which relax arterial smooth muscle, are the preferred drugs. The nitrates are also effective. However, chronic use of nitrates requires a drug-free interval, usually at night, in order to avoid drug tolerance. Consequently, the patient would not be protected from vasospasm during this period. The combination of a calcium blocker and nitrate is often the preferred choice when additional treatment is required. Unstable Angina Patients with unstable angina are at serious risk of developing a myocardial infarction. Antiplatelet and anticoagulant therapy is essential to prevent formation of a blood clot at the site of arterial blockage. This also is the point when coronary artery bypass grafting or percutaneous coronary interventions, such as stent implantations, are considered. While antianginal drugs are useful for prevention of anginal attacks, the patient needs to reevaluate lifestyle, diet, lipid profile, exercise, and smoking habit in order to prevent progression of disease.