Antihypertensive drugs 3

lecture-3- د.رياض الموسوي

antianginal drugs

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. these transient episodes (15 seconds to 15 minutes) of myocardial ischemia do not cause cellular death, such as occurs in myocardial infarction. three classes of drugs, used either alone or in combination, are effective in treating patients with stable angina: organic nitrates, b-blockers, and calcium-channel blockers. these agents lower the oxygen demand of the heart by affecting blood pressure, venous return, heart rate, and contractility. lifestyle and risk factor modifications, especially cessation of smoking, are also important in the treatment of angina. [note: options other than medications for treating angina include angioplasty and coronary artery bypass surgery.]

types of angina
angina pectoris has three overlapping patterns: 1) stable or typical angina, 2) unstable angina, and 3) prinzmetal s or variant angina. they are caused by varying combinations of increased myocardial demand and decreased myocardial perfusion.

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. the heart becomes vulnerable to ischemia whenever there is increased demand, such as that produced by physical activity, emotional excitement, or any other cause of increased cardiac workload. 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. in unstable angina, chest pains occur with increased frequency and are precipitated by progressively
less effort. the symptoms are not relieved by rest or nitroglycerin. unstable angina requires hospital admission and more aggressive therapy to prevent death and progression to myocardial infarction.

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. symptoms are caused by decreased blood flow to the heart muscle due to spasm of the coronary artery. although individuals with this form of angina may have significant coronary atherosclerosis, the angina attacks are unrelated to physical activity, heart rate, or blood pressure. prinzmetal s angina generally responds promptly to coronary vasodilators, such as nitroglycerin and calcium-channel blockers.

d. mixed forms of angina
patients with advanced coronary artery disease may present with angina episodes during effort as well as at rest, suggesting the presence of a fixed obstruction associated with endothelial dysfunction.

1. organic nitrates
organic nitrates (and nitrites) used in the treatment of angina pectoris are simple nitric and nitrous acid esters of glycerol. 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. these compounds cause a rapid reduction in myocardial oxygen demand, followed by rapid relief of symptoms. 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, which is also known as glyceryl trinitrate, 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).1 elevated cgmp ultimately leads to dephosphorylation of the myosin light chain, resulting in vascular smooth muscle relaxation

b. effects on the cardiovascular system
all these agents are effective, but they differ in their onset of action and rate of elimination. for prompt relief of an ongoing attack of angina precipitated by exercise or emotional stress, sublingual (or spray form) nitroglycerin is he drug of choice. 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 (venous return to the heart) 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. oral isosorbide dinitrate undergoes denitration to two mononitrates, both of which possess antianginal activity.

d. adverse effects
the most common adverse effect of nitroglycerin, as well as of the other nitrates, is headache. from 30 to 60 percent of patients receiving intermittent nitrate therapy with long-acting agents develop headaches. high doses of organic nitrates can also cause postural hypotension, facial flushing, and tachycardia. sildenafil potentiates the action of the nitrates. to preclude the dangerous hypotension that may occur, this combination is contraindicated.

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 nitrate-free intervals to restore sensitivity to the drug. this interval is typically 10 to 12 hours, usually at night, because demand on the heart is decreased at that time. nitroglycerin patches are worn for 12 hours then removed for 12 hours. however, variant angina worsens early in the morning, perhaps due to circadian catecholamine surges. therefore, the nitrate-free interval in these patients should occur in the late afternoon. patients who continue to have angina despite nitrate therapy may benefit by addition of another class of agent.


2. ?-adrenergic blockers
the b-adrenergic blocking agents decrease the oxygen demands of the myocardium by lowering both the rate and the force of contraction of the heart. they suppress the activation of the heart by blocking b1 receptors, and they reduce the work of the heart by decreasing heart rate, contractility, cardiac output, and blood pressure. with î²-blockers, the demand for oxygen by the myocardium is reduced both during exertion and at rest. propranolol is the prototype for this class of compounds, but it is not cardioselective. thus, other b-blockers, such as metoprolol or atenolol, are preferred. [note: all î²-blockers are nonselective at high doses and can inhibit b2 receptors. this is particularly important to remember in the case of asthmatics.] 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 î²-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. [note: it is important not to discontinue b-blocker therapy abruptly. the dose should be gradually tapered off over 5 to 10 days to avoid rebound angina or hypertension.]

3. calcium-channel blockers
calcium is essential for muscular contraction. calcium influx is increased in ischemia because of the membrane depolarization that hypoxia produces. in turn, this promotes the activity of several adenosine triphosphate consuming enzymes, thereby depleting energy stores and worsening the ischemia. the calciumchannel 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 he myocardium. [note: verapamil mainly affects the myocardium, whereas nifedipine exerts a greater effect on smooth muscle in the peripheral vasculature. diltiazem is intermediate in its actions.] all calcium-channel blockers lower blood pressure. they may worsen heart failure due to their negative inotropic effect. [note: variant angina caused by spontaneous coronary spasm rather than by increased myocardial oxygen requirement is controlled by organic nitrates or calcium-channel blockers î²-blockers are contraindicated.]

a. nifedipine
nifedipine, a dihydropingyridine derivative, functions mainly as an arteriolar vasodilator. this drug has minimal effect on cardiac conduction or heart rate. other members of this class, amlodipine, 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. as with all calcium-channel blockers, constipation is a problem. because it has little to no sympathetic antagonistic action, nifedipine may cause reflex tachycardia if peripheral vasodilation is marked. [note: the general consensus is that short-acting dihydropingyridines should be avoided in coronary artery disease.]

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 (the same as those for other calcium-channel blockers). interactions with other drugs are the same as those indicated for verapamil.