Angina pectoris is the most common type of ischemic heart disease. Decreased blood flow to the heart muscle, usually at times of increased cardiac demand, elicits pain that is relieved upon rest or with the use of nitrates. The blood supply to the heart is compromised, most often due to coronary artery disease. Increase in the demand for oxygen is usually the cause for ischemia in stable (exertional) angina. The ischemia in some forms of angina (like Prinzmetal’s angina) results from reduction in oxygen supply. In some patients it may be due to a mixed effect of reduced supply and increased demand. The diagnosis of angina is primarily clinical. The supporting evidence with diagnostic tests is significant only at later stages.
Organic nitrates and nitrites are the most important anti-anginal group of drugs. They are the only group of drugs that are used to treat an acute attack of angina. Nitrates are also useful in long term prophylaxis of angina.
Actions of Nitrates
The beneficial actions of nitrates arise from the smooth muscle relaxing action of the nitrates. Nitrates release nitrous oxide leading to relaxation of the smooth muscles. The vascular smooth muscles of veins respond maximum to the effects of nitrates. The relaxation of vascular smooth muscles of veins result in reduced venous return to the heart. Nitrates also cause reduction of peripheral resistance by dilation of arteries. Both these effects reduce the work load on the heart and reduce the oxygen requirement of the heart. This is critical in reducing the pain of angina resulting from the ischemia of the heart muscles. The nitrates also cause dilation of the coronary blood vessels which results in redistribution of coronary blood supply to the ischemic area. This also contributes to the utility of nitrates in angina. In addition to its use in stable angina, nitrates are also useful in other forms of angina namely vasospastic (Prinzemetal’s) angina and unstable angina.
Types of Nitrates
Various nitrates are available for clinical use in angina. Nitrates for treatment of acute angina includes the short-acting nitrates like nitroglycerine and isosorbide dinitrate, both of which are given sublingually (placed below the tongue). Amyl nitrate is another short-acting which may be used in acute angina attacks. Amyl nitrate, however, is less popular as it has to be given by inhalation.
The long-acting nitrates are useful in long-term prevention of angina attacks. The long-acting nitrate preparations include nitroglycerin (ointment, slow-release tablets, transdermal patches), isosorbide dinitrate (oral tablets), pentaerythritol tetranitrate (oral tablets) and isosorbide mononitrate (oral tablets).
Intravenous nitrates are used in hypertensive emergencies, myocardial infarction and acute severe heart failure.
The major adverse effects of nitrates result from its vasodilating effects. It can cause throbbing head ache, postural hypotension and reflex tachycardia. The tachycardia can sometimes be dangerous in patients with high risk angina, that it may precipitate an ischemic event. Sodium and water retention and edema of the legs are also seen with nitrate use. Development of tolerance is another problem with nitrates. Continuous use of nitrates can result in considerable reduction in its effects due to development of tolerance.
Calcium channel blockers (CCBs)
Calcium channel blockers are useful in long term prevention of angina. It is best suited for angina patients with concomitant hypertension. The cardio-selective CCBs and some of the selected vaso-selective CCBs (like amlodipine, nicardipine and felodipine) are used in treatment of angina. Calcium channel blockers are also useful in other cardiac conditions like vasospastic angina, hypertension, cardiac arrhythmias, and hypertrophic cardiomyopathy.
Actions of the Calcium chanel blockets
Both the groups of CCBs reduce work load of heart by different mechanisms and thereby reduce the oxygen requirement of the heart muslces. Cardio-selective CCBs exert its anti-anginal actions primarily by the depression of the cardiac functions (heart rate and force of contraction). Vaso-selective CCBs prevent angina primarily by its vasodilating effects. The vaso-selective CCBs can increase the heart rate and may precipitate ischemic events in some patients. This is more common with short-acting preparations.
Beta adrenergic blockers
Beta adrenergic blockers (like propranolol, atenolol etc) are effective in preventing recurrent attacks of angina and it is used for prophylaxis against angina. Beta blockers suppress the cardiac functions (heart rate and force of contraction). This reduces the oxygen demand of the heart and produces the beneficial effects in angina. Beta blockers are of maximum benefit in angina patients with concomitant hypertension.
Potassium channel openers
Potassium channel openers (like nicorandil) are useful in treatment of angina. Nicorandil is not available in the US. Nicorandil causes dilation of the blood vessels and reduces the blood pressure. This reduces the oxygen requirement of the heart. Use of nicorandil has been associated with flushing, palpitation, weakness, headache, nasal congestion, mouth ulcers, nausea and vomiting and peri-anal ulcers.
Other Drugs for Angina
Several other drugs are available for long term prevention of angina. Prominent ones include ranolazine and trimetazidine. Ranolazine is believed to primarily exert its action by reducing contractility of the heart muscle. The exact mechanism is not clear action but suggested to be from blockade of sodium current that facilitates calcium entry through the sodium-calcium exchanger. Trimetazidine is believed to reduce oxygen requirement of the heart by partially inhibiting the fatty acid oxidation in the heart muscles. Energy production from fatty acid oxidation is a process that requires more oxygen. Trimetazidine is often referred to as a metabolic modulator or pFOX inhibitor.
Drugs for Different Types of Angina
Stable angina is the mildest form of the angina. It is characterized by chest pain on exertion and is also known as classical or exertional angina. Stable angina may remain stable for long time or may progress rapidly to more severe forms of ischemia. The treatment option for acute attacks of angina is limited to the nitrates. Options for prevention (prophylaxis) against angina attacks include beta adrenergic blockers, nitrates, calcium channel blockers, potassium channel openers and other drugs like ranolazine.
Vasospastic (Prinzmetal’s) angina
Vasospastic (Prinzmetal’s) or variant angina is due to spasm of the coronary arteries. The drugs useful in vasospastic angina are mainly the vasodilators. Nitrates and the vaso-selective calcium channel blockers are the most useful drugs in treating and preventing attacks of vasospastic angina. A combination therapy with drugs of both the groups can abolish attacks of vasospastic angina in most patients. Beta blockers are contraindicated in vasospastic angina.
Unstable angina is a high risk angina which can lead to more serious ischemic events like myocardial infarction and death. Unstable angina attacks occur even at rest and are more severe. It usually results from blood clot formation close to the atherosclerotic plaque. It may also result from rupture of the atherosclerotic plaque. Acute coronary syndrome [unstable angina and myocardial infarction with no ST elevation on ECG (Non-STEMI)] are managed with intravenous nitroglycerin. It reduces the workload on heart and thereby the myocardial ischemia.
Requirement of ‘clot buster’ or thrombolytic therapy and percutaneous coronary intervention (PCI) are evaluated and treated accordingly. Nitrates are also useful in the long term treatment of the unstable angina. Other standard drugs useful in long term prevention of stable angina are also useful in unstable angina. Therapy with oral nitroglycerin and beta blockers is generally considered in most patients with milder forms of unstable angina. Patients who are refractory to these drugs are also given calcium channel blockers.
Additionally, all unstable angina patients require aggressive anti-platelet therapy to prevent formation of blood clots. Intravenous heparin or subcutaneous low-molecular-weight heparin is also indicated in many patients with acute coronary syndrome (ACS) or Non-STEMI. Glycoprotein IIb/IIIa inhibitors such as abciximab should be added if percutaneous coronary intervention (PCI) with stenting is required. Lipid-lowering therapy is also initiated in most patients with unstable angina.