NCLEX: Antianginal Drugs

Atherosclerotic disease of the coronary arteries, also known as coronary artery disease (CAD) or ischemic heart disease (IHD), is the most common cause of mortality worldwide. Atherosclerotic lesions in coronary arteries can obstruct blood flow, leading to an imbalance in myocardial oxygen supply and demand that presents as stable angina or an acute coronary syndrome (myocardial infarction [MI] or unstable angina). Spasms of vascular smooth muscle may also impede cardiac blood flow, reducing perfusion and causing ischemia and anginal pain.

Typical angina pectoris is a characteristic sudden, severe, crushing chest pain that may radiate to the neck, jaw, back, and arms. Patients may also present with dyspnea or atypical symptoms such as indigestion, nausea, vomiting, or diaphoresis. Transient, self-limited episodes of myocardial ischemia (stable angina) do not result in cellular death; however, acute coronary syndromes and chronic ischemia can lead to deterioration of cardiac function, heart failure, arrhythmias, and sudden death.

All patients with IHD and angina should receive guideline-directed medical therapy with emphasis on lifestyle modifications (smoking cessation, physical activity, weight management) and management of modifiable risk factors (hypertension, diabetes, dyslipidemia) to reduce cardiovascular morbidity and mortality.

Antianginal Drugs

Antianginal Drugs: TYPES OF ANGINA

Focus topic: Antianginal Drugs

Angina pectoris has three patterns: 1) stable, effort-induced, classic, or typical angina; 2) unstable angina; and 3) Prinzmetal, variant, vasospastic, or rest angina. They are caused by varying combinations of increased myocardial demand and decreased myocardial perfusion.

A. Stable angina, effort-induced angina, classic or typical angina

Classic angina is the most common form of angina and, therefore, is also called typical angina pectoris. It is usually characterized by a short-lasting burning, heavy, or squeezing feeling in the chest. Some ischemic episodes may present “atypically”—with extreme fatigue, nausea, or diaphoresis—while others may not be associated with any symptoms (silent angina). Atypical presentations are more common in women, diabetic patients, and the elderly.

Classic angina is caused by the reduction of coronary perfusion due to a fixed obstruction of a coronary artery produced by atherosclerosis. Due to the fixed obstruction, the blood supply cannot increase, and the heart becomes vulnerable to ischemia whenever there is increased demand, such as that produced by physical activity, emotional stress or excitement, or any other cause of increased cardiac workload. Typical angina pectoris is promptly relieved by rest or nitroglycerin [nye-troe-GLIS-er-in]. When the pattern of the chest pains and the amount of effort needed to trigger the chest pains do not vary over time, the angina is named “stable angina.”

B. Unstable angina

Unstable angina is classified between stable angina and MI. In unstable angina, chest pain occurs with increased frequency, duration, and intensity and can be precipitated by progressively less effort. Any episode of rest angina longer than 20 minutes, any new-onset angina, any increasing (crescendo) angina, or even sudden development of shortness of breath is suggestive of unstable angina. The symptoms are not relieved by rest or nitroglycerin. Unstable angina is a form of acute coronary syndrome and requires hospital admission and more aggressive therapy to prevent progression to MI and death.

C. Prinzmetal, variant, vasospastic, or rest angina

Prinzmetal 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 from the 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 angina generally responds promptly to coronary vasodilators, such as nitroglycerin and calcium channel blockers.

D. Acute coronary syndrome

Acute coronary syndrome is an emergency that commonly results from rupture of an atherosclerotic plaque and partial or complete thrombosis of a coronary artery. Most cases occur from disruption of an atherosclerotic lesion, followed by platelet activation of the coagulation cascade and vasoconstriction. This process culminates in intraluminal thrombosis and vascular occlusion. If the thrombus occludes most of the blood vessel, and, if the occlusion is untreated, necrosis of the cardiac muscle may ensue. MI (necrosis) is typified by increases in the serum levels of biomarkers such as troponins and creatine kinase. The acute coronary syndrome may present as ST-segment elevation myocardial infarction, non–ST-segment elevation myocardial infarction, or as unstable angina. [Note: In unstable angina, no increases of biomarkers of myocardial necrosis are present.]

Antianginal Drugs


Focus topic: Antianginal Drugs

Four types of drugs, used either alone or in combination, are commonly used to manage patients with stable angina: β-blockers, calcium channel blockers, organic nitrates, and the sodium channel–blocking drug, ranolazine. These agents help to balance the cardiac oxygen supply and demand equation by affecting blood pressure, venous return, heart rate, and contractility. Figure 21.3 summarizes the treatment of angina in patients with concomitant diseases, and Figure 21.4 provides a treatment algorithm for patients with stable angina.

Antianginal Drugs: 𝛃-ADRENERGIC BLOCKERS

Focus topic: Antianginal Drugs

The β-adrenergic blockers decrease the oxygen demands of the myocardium by blocking β1 receptors, resulting in decreased heart rate, contractility, cardiac output, and blood pressure. These agents reduce myocardial oxygen demand during exertion and at rest. As such, they can reduce both the frequency and severity of angina attacks. β-Blockers can be used to increase exercise duration and tolerance in patients with effort-induced angina. β-Blockers are recommended as initial antianginal therapy in all patients unless contraindicated. [Note: The exception to this rule is vasospastic angina, in which β-blockers are ineffective and may actually worsen symptoms.] β-Blockers reduce the risk of death and MI in patients who have had a prior MI and also improve mortality in patients with hypertension and heart failure with reduced ejection fraction. Agents with intrinsic sympathomimetic activity (ISA) such as pindolol should be avoided in patients with angina and those who have had a MI. Propranolol is the prototype for this class of compounds, but it is not cardioselective. Thus, other β-blockers, such as metoprolol and atenolol, are preferred. [Note: All β-blockers are nonselective at high doses and can inhibit β2 receptors.] β-Blockers should be avoided in patients with severe bradycardia; however, they can be used in patients with diabetes, peripheral vascular disease, and chronic obstructive pulmonary disease, as long as they are monitored closely. Nonselective β-blockers should be avoided in patients with asthma. [Note: It is important not to discontinue β-blocker therapy abruptly. The dose should be gradually tapered off over 2 to 3 weeks to avoid rebound angina, MI, and hypertension.]

Antianginal Drugs

Antianginal Drugs


Focus topic: Antianginal Drugs

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 ATP-consuming enzymes, thereby depleting energy stores and worsening the ischemia. 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. These agents primarily affect the resistance of peripheral and coronary arteriolar smooth muscle. In the treatment of effort-induced angina, calcium channel blockers reduce myocardial oxygen consumption by decreasing vascular resistance, thereby decreasing afterload. Their efficacy in vasospastic angina is due to relaxation of the coronary arteries. [Note: Verapamil mainly affects the myocardium, whereas amlodipine exerts a greater effect on smooth muscle in the peripheral vasculature. Diltiazem is intermediate in its actions.] All calcium channel blockers lower blood pressure.

A. Dihydropyridine calcium channel blockers

Focus topic: Antianginal Drugs

Amlodipine [am-LOE-di-peen], an oral dihydropyridine, functions mainly as an arteriolar vasodilator. This drug has minimal effect on cardiac conduction. The vasodilatory effect of amlodipine is useful in the treatment of variant angina caused by spontaneous coronary spasm. Nifedipine [ni-FED-i-pine] is another agent in this class; it is usually administered as an extended-release oral formulation. [Note: Short-acting dihydropyridines should be avoided in CAD because of evidence of increased mortality after an MI and an increase in acute MI in hypertensive patients.]

B. Nondihydropyridine calcium channel blockers

Focus topic: Antianginal Drugs

Verapamil [ver-AP-a-mil] slows atrioventricular (AV) conduction directly and decreases heart rate, contractility, blood pressure, and oxygen demand. Verapamil has greater negative inotropic effects than amlodipine, but it is a weaker vasodilator. Verapamil is contraindicated in patients with preexisting depressed cardiac function or AV conduction abnormalities. Diltiazem [dil-TYE-a-zem] also slows AV conduction, decreases the rate of firing of the sinus node pacemaker, and is also a coronary artery vasodilator. Diltiazem can relieve coronary artery spasm and is particularly useful in patients with variant angina. Nondihydropyridine calcium channel blockers can worsen heart failure due to their negative inotropic effect, and their use should be avoided in this population.

Antianginal Drugs: ORGANIC NITRATES

Focus topic: Antianginal Drugs

These compounds cause a reduction in myocardial oxygen demand, followed by relief of symptoms. They are effective in stable, unstable, and variant angina.

A. Mechanism of action

Focus topic: Antianginal Drugs

Organic nitrates relax vascular smooth muscle by their intracellular conversion to nitrite ions and then to nitric oxide, which activates guanylate cyclase and increases the cells’ cyclic guanosine monophosphate (cGMP). Elevated cGMP ultimately leads to dephosphorylation of the myosin light chain, resulting in vascular smooth muscle relaxation. Nitrates such as nitroglycerin cause dilation of the large veins, which reduces preload (venous return to the heart) and, therefore, reduces the work of the heart. This is believed to be their main mechanism of action in the treatment of angina. Nitrates also dilate the coronary vasculature, providing an increased blood supply to the heart muscle.

Antianginal Drugs

B. Pharmacokinetics

Focus topic: Antianginal Drugs

Nitrates differ in their onset of action and rate of elimination. The onset of action varies from 1 minute for nitroglycerin to 30 minutes for isosorbide [eye-soe-SOR-bide] mononitrate (Figure 21.6). For prompt relief of an angina attack precipitated by exercise or emotional stress, sublingual (or spray form) nitroglycerin is the drug of choice. All patients suffering from angina should have nitroglycerin on hand to treat acute angina attacks. Significant first-pass metabolism of nitroglycerin occurs in the liver. Therefore, it is commonly administered via the sublingual or transdermal route (patch or ointment), thereby avoiding the hepatic first-pass effect. 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.

Antianginal Drugs

C. Adverse effects

Focus topic: Antianginal Drugs

Headache is the most common adverse effect of nitrates. High doses of nitrates can also cause postural hypotension, facial flushing, and tachycardia. Phosphodiesterase type 5 inhibitors such as sildenafil potentiate the action of the nitrates. To preclude the dangerous hypotension that may occur, this combination is contraindicated.

Tolerance to the actions of nitrates develops rapidly as the blood vessels become desensitized to vasodilation. Tolerance can be overcome by providing a daily “nitrate-free interval” to restore sensitivity to the drug. This interval of 10 to 12 hours is usually taken at night because demand on the heart is decreased at that time. Nitroglycerin patches are worn for 12 hours and 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.


Focus topic: Antianginal Drugs

Ranolazine inhibits the late phase of the sodium current (late INa), improving the oxygen supply and demand equation. Inhibition of late INa reduces intracellular sodium and calcium overload, thereby improving diastolic function. Ranolazine has antianginal as well as antiarrhythmic properties. It is indicated for the treatment of chronic angina and may be used alone or in combination with other traditional therapies. It is most often used in patients who have failed other antianginal therapies. Ranolazine is extensively metabolized in the liver, mainly by the CYP3A family and also by CYP2D6. It is also a substrate of P-glycoprotein. As such, ranolazine is subject to numerous drug interactions. In addition, ranolazine can prolong the QT interval and should be avoided with other drugs that cause QT prolongation.

Antianginal Drugs




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