Antianginal Drugs

    Antianginal Drugs
I. Overview
Angina pectoris is a characteristic sudden, severe, pressing chest pain radiating to the neck, jaw, back, and arms. It is caused by coronary blood flow that is insufficient to meet the oxygen demands of the myocardium, leading to ischemia. The imbalance between oxygen delivery and utilization may result during exertion, from a spasm of the vascular smooth muscle, or from obstruction of blood vessels caused by atherosclerotic lesions.

II. Types of Angina
A. Stable angina
Stable angina is the most common form of angina and, therefore, is called typical angina pectoris. It is characterized by a burning, heavy, or squeezing feeling in the chest. It is caused by the reduction of coronary perfusion due to a fixed obstruction produced by coronary atherosclerosis. Typical angina pectoris is promptly relieved by rest or nitroglycerin (a vasodilator).

B. Unstable angina
Unstable angina lies between stable angina on the one hand and myocardial infarction on the other. The symptoms are not  relieved by rest or nitroglycerin.

C. Prinzmetal's or variant or vasospastic angina
Prinzmetal's angina is an uncommon pattern of episodic angina that occurs at rest and is due to coronary artery spasm. Prinzmetal's angina generally responds promptly to coronary vasodilators, such as nitroglycerin and calcium-channel lockers.

D. Mixed forms of angina
Patients with advanced coronary artery disease may present with angina episodes during effort as well as at rest.


III. Organic Nitrates
They differ in their volatility. For example, isosorbide dinitrate and isosorbide mononitrate are solids at room temperature, nitroglycerin is only moderately volatile, and amyl nitrite is extremely volatile. They are effective in stable and unstable angina as well as in variant angina pectoris

A. Mechanism of action
Nitrates decrease coronary vasoconstriction or spasm and increase perfusion of the myocardium by relaxing coronary arteries. In addition, they relax veins, decreasing preload and myocardial oxygen consumption. Organic nitrates, such as nitroglycerin  are thought to relax vascular smooth muscle by their intracellular conversion to nitrite ions, and then to nitric oxide, which in turn activates guanylate cyclase and increases the cells' cyclic guanosine monophosphate (GMP) Elevated cGMP ultimately leads to dephosphorylation of the myosin light chain, resulting in vascular smooth muscle relaxation

B. Effects on the cardiovascular system
At therapeutic doses, nitroglycerin has two major effects. First, it causes dilation of the large veins, resulting in pooling of blood in the veins. This diminishes preload and reduces the work of the heart. Second, nitroglycerin dilates the coronary vasculature, providing an increased blood supply to the heart muscle. Nitroglycerin decreases myocardial oxygen consumption because of decreased cardiac work.

C. Pharmacokinetics
The time to onset of action varies from 1 minute for nitroglycerin to more than 1 hour for isosorbide  mononitrate.
Significant first-pass metabolism of nitroglycerin occurs in the liver. Therefore, it is common to take the drug either sublingually or via a transdermal patch, thereby avoiding this route of elimination. Isosorbide mononitrate owes its improved bioavailability and long duration of action to its stability against hepatic breakdown.

D. Adverse effects
The most common adverse effect of nitrates, is headache.( From 30 to 60 percent of patients ) High doses of organic nitrates can also cause postural hypotension, facial flushing, and achycardia. Sildenafil potentiates the  action of the nitrates.

E. Tolerance
Tolerance to the actions of nitrates develops rapidly. The blood vessels become desensitized to vasodilation. Tolerance can be overcome by providing a daily oenitrate-free intervalto restore sensitivity to the drug. Patients who continue to have angina despite nitrate therapy may benefit by addition of another class of agent.

IV. Adrenergic Blockers
They suppress the activation of the heart by blocking receptors, and they reduce the work of the heart by decreasing heart rate, contractility, cardiac output, and blood pressure. Propranolol is the prototype for this class of compounds, but it is not cardioselective. Thus, other blockers, such as metoprolol or atenolol, are preferred. Agents with intrinsic sympathomimetic activity (for example, pindolol) are less effective and should be avoided in angina. The B-blockers reduce the frequency and severity of angina attacks. These agents are particularly useful in the treatment of patients with myocardial infarction and have been shown to prolong survival. The B- blockers can be used with nitrates to increase exercise duration and tolerance. They are, however, contraindicated in patients with asthma, diabetes, severe bradycardia, peripheral vascular disease, or chronic obstructive pulmonary disease.

V. Calcium-Channel Blockers
The calcium channel blockers protect the tissue by inhibiting the entrance of calcium into cardiac and smooth muscle cells of the
coronary and systemic arterial beds. All calcium-channel blockers are therefore arteriolar vasodilators that cause a decrease in smooth muscle tone and vascular resistance. At clinical doses, these agents affect primarily the resistance of vascular smooth muscle and the myocardium.

A. Nifedipine
Nifedipine a dihydropyridine derivative, functions mainly as an arteriolar vasodilator. This drug has minimal effect on cardiac aconduction or heart rate. Other members of this class, mlodipine, nicardipine, and felodipine, have similar cardiovascular characteristics except for amlodipine, which does not affect heart rate or cardiac output. Nifedipine is administered orally, usually as extended-release tablets. It undergoes hepatic
metabolism to products that are eliminated in both urine and the feces. The vasodilation effect of nifedipine is useful in the treatment of variant angina caused by spontaneous coronary spasm. Nifedipine can cause flushing,headache, hypotension, and peripheral edema as side effects of its vasodilation activity. nifedipine may cause reflex tachycardia if peripheral vasodilation is marked.

B. Verapamil
The diphenylalkylamine verapamil  slows cardiac atrioventricular (AV) conduction directly, and decreases heart rate, contractility, blood pressure, and oxygen demand. Verapamil causes greater negative inotropic effects than nifedipine, but it is a weaker vasodilator. The drug is extensively metabolized by the liver;
therefore, care must be taken to adjust the dose in patients with liver dysfunction. Verapamil is contraindicated in patients with preexisting depressed cardiac function or AV conduction abnormalities. It also causes constipation. Verapamil should be used with caution in patients taking digoxin, because verapamil increases digoxin levels.


C. Diltiazem
Diltiazem has cardiovascular effects that are similar to those of verapamil. Both drugs slow AV conduction and decrease the rate of firing of the sinus node pacemaker. Diltiazem reduces the heart rate, although to a lesser extent than verapamil, and also decreases blood pressure. In addition, diltiazem can relieve coronary artery spasm and, therefore, is particularly useful in patients with variant angina. It is extensively metabolized by the liver. The incidence of adverse side effects is low . Interactions with other drugs are the same as those indicated for verapamil.