Pharmacology - An Illustrated Review

22. Antianginal Drugs

22.1 Angina

Angina or angina pectoris is characterized by sudden, temporary, substernal pain that often radiates to the left shoulder and/or neck. It results from an imbalance of the supply of oxygenated blood to cardiac muscle and the oxygen demand of the tissue (Fig. 22.1). The primary goal in the treatment of angina is to restore the balance between oxygen supply and oxygen demand.

– Classic, typical, stable angina is induced by exercise or stress and is caused by atherosclerosis of the coronary arteries (Fig. 22.2).

– Variant or unstable angina is angina that is present at rest. It is due to coronary vasospasm.

Drug Management of Angina

1. Vasodilators

2. Beta-blockers

3. Calcium channel blockers

Coronary blood flow

The major right and left coronary arteries that serve the heart tissue are the first vessels to branch off the aorta. These arteries, when healthy, maintain coronary blood flow at levels appropriate to the needs of the heart muscle. When flow through a coronary artery is reduced to the point that the myocardium it supplies becomes hypoxic, angina pectoris develops. Some individuals have angina only on exertion; others have more severe restriction of blood flow and have anginal pain at rest. If the decrease in myocardial blood flow is severe and prolonged, irreversible changes occur in the muscle, and the result is an myocardial infarction (MI). Partially occluded coronary arteries can be constricted further by vasospasm, producing MI, or, most commonly, rupture of an atherosclerotic plaque triggers the formation of a coronary-occluding clot at the site of the plaque and leads to ischemia and MI.

 

Coronary artery bypass graft

Coronary artery bypass graft (CABG) is a surgical procedure performed to bypass atherosclerotic narrowings of the coronary arteries that are the cause of anginal pain. These narrowings can eventually occlude if untreated, leading to myocardial infarction (MI). There are two main coronary arteries, left and right, and these have several branches. A CABG is denoted as single, double, triple, and so on, depending on the number of arteries that are to be bypassed. The internal thoracic artery that supplies the anterior chest wall and breasts is usually harvested to use as the bypass artery.

 

Cardiac muscle metabolism

Cardiac muscle requires an abundant supply of oxygen-rich blood, because it depends almost exclusively on aerobic metabolism to supply the ATP for its contractions. Other tissues can vary their extraction of oxygen from blood and can survive on anaerobic metabolism. Cardiac tissue has a very high fractional extraction of oxygen and can only increase its uptake of oxygen by increasing coronary blood flow. At rest the heart uses oxidation of fatty acids for its ATP; only small quantities of glucose are utilized. When cardiac workload is increased, cardiac muscle removes lactic acid from coronary blood and oxidizes it directly.

 

Myocardial infarction

Myocardial infarction (MI) is death of heart muscle. It is caused by complete occlusion of one or more coronary arteries by thrombosis. The pain of an MI is similar to that of angina but it is more severe and of longer duration. It is also accompanied by nausea, vomiting, diaphoresis (sweating), dyspnea (shortness of breath), and feeling “as if they are going to die.” Common complications of MI include arrhythmias, heart failure, hypertension, and emboli formation. ECG analysis shows ST elevation, T wave inversion, and Q waves in the leads that “look at” the infarction. Cardiac enzymes are also measured and used as a basis for diagnosis of MI. Immediate treatment of an MI involves the use of thrombolytic drugs such as streptokinase (given as soon as possible after infarction) and aspirin, as well as morphine, and nitrates. Longer-term treatment involves the use of β-blockers and ACE inhibitors. Surgical treatment is the same as for angina.

 

Cardiac enzymes

Several enzymes are released when cardiac muscle cells are damaged: troponin I, creatine kinase, myoglobin, and lactate dehydrogenase. However, troponin I is the only one that is specific for cardiac muscle damage and is routinely measured to help diagnose MI.

 

Fig. 22.1 image Oxygen supply to, and demand of, the myocardium.

Oxygen supply to the myocardium occurs during diastole and is determined by the caliber of the coronary arteries and arterioles, as well as by preload. Oxygen demand occurs during systole and is determined by heart rate, contraction velocity, and afterload. Angina occurs when there is myocardial hypoxia due to inadequate myocardial blood flow (i.e., when oxygen demand exceeds supply). Therapy for angina therefore aims to restore balance, whether by increasing oxygen supply or decreasing oxygen demand.

image

Fig. 22.2 image Pathogenesis of classic angina in coronary sclerosis.

In a healthy person, the caliber of coronary arterioles determines myocardial oxygen supply and is adjusted automatically during exercise to meet the increased demand by increasing heart rate, contraction velocity, and afterload. In a patient with atherosclerosis of the coronary arteries, there is a dilation of arterioles at rest to compensate for the flow resistance caused by the atheroma, and myocardial oxygen supply is maintained. However, during exercise, further dilation cannot occur, leading to myocardial ischemia and pain.

image

22.2 Vasodilators

Organic Nitrates: Nitroglycerin, Isosorbide Dinitrate, Isosorbide Mononitrate, and Amyl Nitrite

Mechanism of action. Organic nitrates act like the endogenous compound nitric oxide (NO). They activate guanylate cyclase to increase cyclic guanosine monophosphate in smooth muscle. This leads to relaxation of vascular smooth muscle and both arterial and venous dilation (Fig. 22.3). By reducing preload and afterload, myocardial oxygen consumption is reduced. In the presence of a fixed stenosis, coronary blood flow is not altered. The decrease in mean blood pressure produces reflex activation of the sympathetic nervous system. Increases in heart rate and contractility partially reverse the decrease in oxygen consumption produced by arterial and venous vasodilation and can be blocked by β-adrenergic receptor antagonists. In patients with variant angina, the organic nitrates can prevent or reverse coronary artery spasm. Organic nitrates are effective for the treatment of classic and variant angina.

Pharmacokinetics

– Only isosorbide mononitrate is effective with oral administration.

– Nitroglycerin and isosorbide are given sublingually and are rapidly absorbed through the oral mucosa. Their therapeutic effects are observed within 2 to 4 minutes but last for only 1 to 2 hours.

– Nitrates are well absorbed through skin from ointments and sustained-release patches. The therapeutic effects of the ointment persist for 4 to 8 hours, and the sustained-release preparation can maintain stable blood levels of nitroglycerin for 24 hours. Usefulness is limited by rapid tolerance.

Fig. 22.3 image Vasodilators: nitrates.

Nitrates cause vasodilation by acting like endogenous nitric oxide (NO), causing activation of guanylate cyclase and increased cyclic guanosine monophosphate (cGMP) levels in vascular smooth muscle cells. This vasodilation reduces cardiac work by reducing preload and afterload. Nitroglycerin and isosorbide dinitrate are both highly membrane permeable. (GTP, guanosine triphosphate; SH, sulfhydryl.)

image

— Nitroglycerin may be given as an intravenous infusion in the treatment of myocardial infarction (MI).

– Amyl nitrite is volatile and is administered by inhalation.

Side effects

– Headache (Tolerance develops with repeated use.)

– Orthostatic (postural) hypotension

Tolerance. The uninterrupted use of organic nitrates results in tolerance with subsequent doses of nitrates, producing little hemodynamic response. The use of dermal nitrates should not extend for more than 12 to 16 hours of any 24-hour period and must include a nitrate-free interval between doses.

22.3 Beta-Blockers

Beta-blockers are discussed in Chapter 20.

Specific points in relation to angina

– The β-adrenergic receptor antagonists are useful for the prophylaxis of effort-induced angina but are not effective for the acute termination of effort-induced angina or for the treatment of coronary artery spasm.

– When used in combination with organic nitrates, the drugs antagonize the increased sympathetic nervous system activity observed with the organic nitrates.

Table 22.1 compares the effects of nitrates and β-blockers on the heart.

image

22.4 Calcium Channel Blockers

Ca2+ channel blockers are discussed in Chapter 20.

Specific points in relation to angina

– In angina, calcium channel blockers act to increase coronary blood flow by dilating coronary vessels and decreasing myocardial oxygen demand by blocking Ca2+ channels on cardiac myocytes.

Table 22.2 provides a summary of the mechanisms by which antianginal drugs act.

  Table 22.2 image Summary of Mechanisms of Antianginal Drugs

Drug Class

Parameter Affected

Mechanism

Nitrates

↓ preload and afterload

↓ myocardial O2 consumption

↓ coronary artery spasm

↑ blood flow to ischemic areas of the heart

Activates guanylate cyclase to ↑ cGMP

β-blockers

↓ heart rate and contractility

↓ myocardial O2 consumption

Blocks sympathetic activation

Calcium channel blockers

↑ coronary blood flow

↓ myocardial O2 consumption

Blocks L-type Ca2+ channels to dilate blood vessels and decrease contractility of cardiac muscles

Abbreviation: cGMP, cyclic guanosine monophosphate.