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ANGINA PATHOPHYSIOLOGY AND PHARMACOLOGIC TARGETS A common manifestation of ischemic heart disease, angina is described by patients as pressure, tightness, burning, or pain usually affecting a diffuse part of the retrosternal area and often radiating to the inner aspect of the left arm or to the jaw. The discomfort of angina is referred to the dermatomes innervated by afferent nerves that enter the spinal cord at the same level (C7-­ T4) as the sympathetic afferent fibers of the heart (1). Anginal discomfort, usually lasting between 3 and 15 minutes, is the result of an imbalance between myo­ car­ dial oxygen supply and demand. Myo­ car­ dial oxygen demand is determined by heart rate, systolic blood pressure, and contractility as well as ventricular size (wall tension is proportional to chamber size, as described by the law of Laplace). Myo­ car­ dial oxygen supply depends on perfusion pressure (related to the difference between aortic diastolic blood pressure and left ventricular diastolic pressure), re­ sis­ tance in large coronary arteries (may be affected by atherosclerosis, spasm, and other ­ factors), and arteriolar re­ sis­ tance (largely autoregulated) (2). A marked decrease in the oxygen-­ carrying capacity of the blood (e.g., hemoglobin below 7 or 8 g/dL) may reduce the oxygen supply and lead to angina. In some patients, coronary microvascular disease or malfunction may be the cause of decreased oxygen supply. Medi­ cations developed to alleviate angina derive largely from the mechanisms of angina described ­ here. As with any type of iatrogenicity, antianginal drugs may cause side effects ­ because of (a) an exaggeration of their pharmacologic effects or (b) side effects not related to dose. In general, the latter is more severe and unpredictable, but fortunately more infrequent. The following sections describe the use and iatrogenic effects of the most common classes of antianginal agents. Nitrates Nitric oxide (NO) therapy in the form of organic nitrates or nitroglycerin was one of earliest therapeutic strategies for the treatment of ischemic heart disease. This therapy was first promoted by Thomas Lauder Brunton in 1867, following his observation that amyl nitrite helped to relieve angina symptoms (3). ­ Later on, other organic nitrates including isosorbide mononitrate and dinitrate, sodium nitroprusside, and nicorandil­ were incorporated as new treatment modalities. Nitrates have a systemic vasodilatory effect on arteries and veins via cyclic guanosine monophosphate (cGMP)–­ mediated vascular smooth muscle relaxation. ­ Because the effect of ­ these agents (with the excepCHAPTER 16 Iatrogenicity and Antianginal Drugs Abel E. Moreyra and William J. Kostis Angina Pathophysiology and Pharmacologic Targets / 189 quently used for the treatment of ­ either erectile dysfunction or pulmonary hypertension in patients with concomitant ischemic heart disease.­ These drugs amplify the NO-­ mediated vasodilaton , making them pos­ si­ ble iatrogenic agents when used in patients with ischemic heart disease . The interaction of PDE-5 inhibitors with nitrates may cause life-­ threatening complications related to extreme hypotension. Patients taking nitrates must be cautioned about the risks of using PDE-5 inhibitors within 24–48 hours of being exposed to any nitrates and similarly about the risks of using nitrates within 24–48 hours of exposure to PDE-5 inhibitors. Methemoglobinemia is a rare but dangerous complication of topical anesthetic use or exposure to nitrate-­ containing substances, including prolonged administration of intravenous nitroglycerin or sodium nitroprusside. Beta-­Blockers As mentioned earlier in this chapter, angina may be due to increased myo­ car­ dial oxygen demand (classical angina on effort) or decreased oxygen supply (Prinzmetal angina, which is caused by coronary vasospasm). In many instances, fixed coronary stenosis coexists with coronary spasm (mixed angina). Beta-­ blockers usually improve angina and increase exercise tolerance by reducing cardiac work through decreased heart rate, systolic blood pressure, and contractility. As stroke volume is not a major determinant of oxygen demand, the decreased heart rate due to beta-­ blockade reduces oxygen demand without decreasing blood flow to the exercising muscles. Beta-­ blockers may also shift the hemoglobin oxygen dissociation curve to the right. They are the mainstay of angina treatment, not only­ because of the effects described ­ here, but also­ because they have been useful in decreasing mortality in patients with acute myo­ car­ dial infarction (5). Beta-­ blockers have been associated with iatrogenicity. An editorial in the British Medical Journal in 2013 entitled “Use of beta blockers during surgery may have caused 10,000 deaths in the UK” addressed the use of beta-­ blockers perioperatively rather than for treatment of angina (6). The commentary was based in part on results of Perioperative Ischemic Evaluation (POISE...


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