ANTIANGINAL DRUGS

Antianginal Drugs – Heart supplies blood to all parts of the body. However, it gets its own supply of blood through the coronary arteries (4% of cardiac output; oxygen extraction 75% in comparison to 25% in the systemic circulation). The coronary flow of blood occurs during the diastole only.

Angina pectoris is a clinical condition which occurs due to the imbalance between the oxygen supply and oxygen demand. It is manifested as a severe, pressing retrosternal (substernal) pain which radiates to the chest, left shoulder, upper arm and neck. There occurs accumulation of acidic metabolites due to ischaemic changes during obstruction in coronary flow. These metabolites stimulate myocardial pain mediating nerve endings.

In angina of effort (or exertional or classical angina), the pain appears on exercise, exertion, emotion or meals. It lasts for several seconds and subsides on rest. It occurs due to an increase in oxygen demand which cannot be met due to atherosclerosis of larger coronary arteries.

In variant (Prinzmetal ‘5) angina, on the other hand, the pain appears even during rest. It is usually unrelated to exercise. It occurs either due to coronary spasm or to platelet emboli causing reduction in coronary flow.

The unstable (crescendo or preinfarction) angina is characterized by recurrent attacks of angina. It occurs with minimal exertion. It is precipitated due to combination of athero scleroti-plaque, platelet aggregation at ruptured plaque and vasospasm.

Antianginal Drugs

1. Organic Nitrites and Nitrates

Traditionally, Antianginal Drugs like both nitrites and nitrates are referred as nitrates. Based on their onset and duration of action, Antianginal Drugs are classified into two groups:

i. Rapid onset and short duration of action of Antianginal Drugs: Glyceryl trinitrate (nitroglycerine), Amylnitrite

ii. Slow onset and long duration of action of Antianginal Drugs: Pentaerythritol tetranitrate, Isosorbide dinitrate, Isosorbide mononitrate

Mechanism of action of Antianginal Drugs

Antianginal Drugs like Organic nitrates enter smooth muscle cells and relax all types of vessels but the post-capillary vessels (venules and veins) are particularly sensitive. Inside the smooth muscle cells, they are rapidly denitrated to release reactive free radical nitric oxide (NO). In turn, nitric oxide is converted into a reactive nitrosothiol intermediate (R-S NO) which activates guanylyl cyclase and stimulates formation of cGMP. cGMP activates protein kinase and leads to relaxation. Further, raised intracellular cGMP may also reduce Ca entry which also contributes to relaxation.

Pharmacological Actions of Antianginal Drugs

Antianginal Drugs like Nitrates cause relaxation of smooth muscles directly (bronchi, ureter, sphincter of Oddi and blood vessels).

Cardiovascular system: Nitrates cause dilatation of both arterioles and venules but in low doses venodilatation is more marked than the arteriolar dilatation. Due to generalized venodilatation, blood tends to pool in the vein leading to fall in the venous return and fall in left ventricular end diastolic pressure (preload). The oxygen demand is also reduced due to diminished wail tension. There also occurs reduction in external cardiac work and oxygen demand due to lowering of arterial pressure by antianginal drugs like nitrites.

Nitrates cause selective vasodilatation of large epicardial vessels and help in redistribution of coronary blood flow to ischaemic subendocardial vessels by opening up of collaterals, without increasing the total flow. So the beneficial effect on heart is secondary to the vascular action of nitrate. However, in very large doses of antianginal drugs like nitrates depress myocardium.

Side effects of Antianginal Drugs: Throbbing headache (due to dilatation of meningeal vessels), flushing (due to dilatation of cutaneous vessels), rise in intraocular tension (due to dilatation of retinal vessels), dizziness, postural hypotension and tachycardia are commonly seen. Tolerance to headache and antianginal effect may develop on prolonged use.

Pharmacokinetics of Antianginal Drugs: Organic nitrates are absorbed well from gastrointestinal tract being lipid soluble. Glyceryl trinitrate, however, undergoes first pass metabolism and is ineffective orally. It is administered sublingually or as skin patch. Its metabolites (di- and mononitrates) are active. Other Antianginal Drugs like nitrates are given orally. The nitrates are metabolized by glutathione-organic nitrate reductase enzyme in liver. The metabolites are eliminated.

Therapeutic Uses of Antianginal Drugs

1. Angina pectoris; Nitrites and organic nitrates are used as prophylaxis and for treatment of classical as well as variant angina pectoris.

2. Nitroglycerine may be tried in biliary colic due to its spasmolytic effect.

3. Antianginal Drugs like Isosorbide dinitrate is being increasingly used to reduce the preload in intractable congestive cardiac failure and left ventricular failure patients, not responding to diuretic therapy.

4. Amyl nitrite inhalation or sodium nitrite (0.3—0.5 gm in 10 ml) i.v. may be used to treat cyanide poisoning, followed by administration of sodium thiosulphate (25%—SO ml i.v.).

5. Glyceryl trilnitrate is used as an adjunct to dilate coronaries during percutaneous coronary angioplasty and thrombolytic therapy of myocardial infarction.

6. Sublingual administration of nitroglycerine quickly relieves pain of oesophageal spasm. If given before a meal, it facilitates feeding in oesophageal achalasia by reducing oesophageal tone.

Contraindications of Antianginal Drugs

• Acute myocardial infarction because nitrates aggravate stroke by further reducing blood pressure.

• Severe anaemia because nitrates increase oxygen debt and hypoxia by forming methaemoglobinemia.

2. Beta-adrenoceptor Blocker antianginal drugs

Propranolol, atenolol and metoprolol are commonly used drugs in angina pectoris (stable angina). They increase exercise tolerance by diminishing the cardiac response to sympathoadrenal activity, decreasing the emotion or exercise-induced increase in heart rate and force of contraction. They also decrease work load on the heart by causing bradycardia and reduction in cardiac contractility. Thus they significantly reduce myocardial oxygen demand, the frequency and severity of anginal attacks and prevent ECG changes. Nearly 85% of the patients do not get attacks of angina if propranolol with nitroglycerine is used judiciously. If this combination is used for several years, there occurs significant decrease in the incidence of myocardial infarction and d9ath.

3. Calcium Channel Blocker antianginal drugs

Verapamil and diltiazem decrease myocardial contractile force, cardiac rate and oxygen demand. Nifedipine inhibits coronary arterial spasm, dilates arterioles and increases oxygen supply to myocardium in patients of variant angina. Nifedipine also diminishes workload of myocardium by reducing after-load because it causes peripheral vasodilatation. These drugs also have antiplatelet aggregatory effect which contributes to their beneficial effects in variant angina. These drugs are useful in the treatment of both angina of effort and variant angina.

Nifedipine can be used in AV conduction defects because it acts mainly on arterioles and does not decrease AV conduction. On the other hand, verapamil and diltiazem cannot be used due to their negative inotropic effect on heart. Nicardipine, felodipine, amlodipine, nitrendipine are other dihydropyridines. Their pharmacodynamic profile is similar to nifedipine. There occurs less reflex sympathetic stimulation with slower and longer acting dihydropyridines. At present, these drugs are preferred over nifedipine which has been reported to have increased mortality among post-myocardial infarction patients.

4. Potassium Channel Opener antianginal drugs

Nicorandil is a new antianginal drugs with nitrate like moiety. Its arterial vasodilator effect is due to its ability to activate ATP sensitive K channels leading to hyperpolarization of vascular smooth muscle. On the other hand, its venodilator effect is due to nitrate like activity, i.e. donating nitric oxide (NO) which leads to relaxation of blood vessels by increasing cGMP.

However, unlike nitrates tolerance does not develop to its effects. It increases coronary blood flow without causing coronary steal phenomenon and without producing significant cardiac effects. It is as effective antianginal drugs as nitrates, beta blockers, Ca channel blockers. Its side effects are flushing, palpitation, headache, dizziness, stomatitis, nausea and vomiting. It is contraindicated in presence of cardiogenic shock, left ventricular failure with low filling pressure and hypotension.

5. Antiplatelet antianginal drugs

i. Aspirin is used in low doses to reduce the incidence of ischaemia in patients of coronary artery disease. Recently, it is shown that aspirin blunts the vasodilator effect of ACE inhibitors, probably due to reduction in bradykinin mediated vasodilatory prostaglandin synthesis by aspirin.

ii. Ticlopidine and clopidogrel are anti- platelet antianginal drugs. They do not appear to interfere with prostaglandin synthesis. They reduce platelet aggregation by inhibiting binding of adenosine diphosphate (ADP) to its receptors irreversibly. Clopidogrel is safer antianginal drugs than ticlopidine (lesser thrombocytopenia and leucopenia). Like aspirin, it is used:

• In the secondary prevention of stroke.
• For unstable angina.
• To prevent thrombosis in patients undergoing coronary bypass surgery.

iii. Dipyridamol is a potent coronary dilator and also inhibits platelet aggregation. This antianginal drugs has minimal effect on blood pressure and cardiac output because it does not reduce venous return. It inhibits adenosine deaminase and phosphodiesterase enzymes. So there occurs accumulation of adenosine and cAMP respectively that then inhibit platelet aggregation and may also stimulate release of prostaglandin I2 It is not useful as an antianginal drugs because by dilating resistance vessels in the non-ischaemic zones, it diverts the already reduced blood flow away from ischaemic zone where it is most needed (coronary steal “phenomenon”). However, it is used:

• For prophylaxis of coronary and cerebral thrombosis in post-myocardial infarction and post-stroke patients.
• To prevent thrombosis in patients with prosthetic heart valves along with warfarin.
• To prevent platelet activation by extra- corporeal bypass pump, two days prior to open heart surgery.
• Important side effects are exacerbation of angina, headache, tachycardia and gastrointestinal distress.

6. Cytoprotective antianginal drugs

i. Trimetazidine is a calcium channel blocker antianginal drugs. It has cytoprotective effect on myocardium metabolism in the presence of ischemia. However, it has no effect in the presence of normal oxygen supply to myocardium. It has been found useful in angina of effort and in patients with stable angina in doses of 20 mg orally three times a day.

ii. Dilazep is a new but weaker calcium channel blocker. It also has cytoprotective effect on myocardium metabolism in the presence of ischaemia. This antianginal drugs is used for stable angina and for symptomatic relief in coronary artery spasm. Its side effects are gastrointestinal distress, headache, stomatitis and allergy.

Antianginal drugs of lesser importance are lidoflazine, oxyfedrine and pentoxiphylline. Their brief description is as under:

• Lidoflazine is another Ca channel blocker. It reduces AV conduction. It is not a popular antianginal drugs to decrease frequency of anginal attacks. Altered taste sensation occurs as side effect.
• Oxyfedrine improves myocardial metabolism to sustain stress due to hypoxia. It has beta-agonist action in low doses but f3- blocking properties in high doses. Its therapeutic potential is questionable in angina and myocardial infarction.
• Pentxiphylline (oxypentifylline) is a theobromine analogue. It reduces blood viscosity and improves blood flow in ischaemic area through microcirculation by inhibiting phosphodiesterase enzyme. It is used to treat transient ischaemic attacks.

Other used of antianginal drugs are: Non-haemorrhagic stroke, Chronic cerebrovascular insufficiency, To improve symptoms like vertigo and memory defects, Trophic leg ulcers, Obstructive circulatory disturbances of retina, To improve sperm motility, Diabetic neuropathy. In AIDS patients with increased TNF to inhibit production of tumor necrosis factor Many other drugs such as pap averine, cyclandelate, nicotinyl xanthinate, nicotinic acid, theophylline, prenylamine, kheline, MAO inhibitors and alcohol are practically of no value in angina pectoris.

Doses and Mode of Administration of commonly used antianginal drugs

1. For acute attack of angina:

• Nitroglycerine 0.5mg sublingually; if not relieved repeat every 5 minutes; maximum 3 doses; spit out tablet after relief.

• Isosorbide dinitrate 5—10 mg sublingual; as an alternative of nitroglycerine.

2. For prophylaxis:

i. Beta blockers: Propranolol 20—80 mg oral, three times a day; gradually increase doses if required. Atenolol 50—1 00 mg oral, once daily. Metoprolol 50—100 mg oral, twice a day.

ii. Organic nitrates: Isosorbide dinitrate 5—10 mg oral, four times a day; Isosorbide mononitrate 10—20 mg oral, thrice a day; Pentaerythritol tetranitrate 10—20mg oral, three times a day and Nitroglycerine transdermal ointment (2%) or patch (5—10 mg)/24 hr.

iii. Calcium channel blockers: Verapamil 40—80mg oral, three times a day; Diltiazem 30—60mg oral, three times a day; Nifedipine 5—10mg oral, three times a day; Nicardipine 20—40 mg oral, three times a day; Felodipine 5—10 mg oral, once daily; Amlodipine 5—10 mg oral, once daily and Nitrendipine 5—20 mg oral, once daily.

iv. Potassium channel openers: Nicorandil 5—20mg oral, twice a day.

3. For prophylaxis against myocardial infarction: Dipyridamole (75 mg) + aspirin (60—1 00 mg) one tablet three times a day.

Useful Antianginal Drugs Combinations

• The combined use of antianginal drugs that is beta blocker and organic nitrate is very effective in the treatment of classical exertional angina. Their additive effect is due to the fact that one drug blocks the adverse effects of the other on net myocardial oxygen consumption.

• The combination of antianginal drugs like nitrates with calcium channel blockers may be valuable in variant angina because nitrates decrease preload while calcium channel blockers decrease after load. Hence their combined use may decrease cardiac work to an extent not possible by either drug alone.

• A combination of antianginal drugs like amlodipine (causes tachycardia) and atenolol (causes bradycardia) may be useful to patients of exertional angina.

• In severe and resistant cases of classical angina, all the three group of antianginal drugs, viz. organic nitrates (decrease preload) + beta blocker (decreases cardiac work) + calcium channel blocker (decreases after load) can be used. However, combination of verapamil or diltiazem with a beta blocker increases the risk of conduction defects and left ventricular dysfunction. Hence antianginal drugs should be used with great care.