Katzung Chapter 12.pdf

12 C H A P T E R Vasodilators & the Treatment of Angina Pectoris...

12 C H A P T E R Vasodilators & the Treatment of Angina Pectoris ∗ Bertram G. Katzung, MD, PhD CASE STUDY A 74-year-old man presents with a history of anterior chest when he stops walking. Assuming that a diagnosis of stable pressure whenever he walks more than one block. The chest effort angina is correct, what medical treatments should be discomfort is diffuse, and he cannot localize it; sometimes it implemented to reduce the acute pain of an attack and to radiates to his lower jaw. The discomfort is more severe when prevent future attacks? he walks after meals but is relieved within 5–10 minutes Ischemic heart disease is one of the most common cardiovascular The primary cause of angina pectoris is an imbalance between disease in developed countries, and angina pectoris is the most the oxygen requirement of the heart and the oxygen supplied to it common condition involving tissue ischemia in which vasodilator via the coronary vessels. In effort angina, the imbalance occurs drugs are used. The name angina pectoris denotes chest pain when the myocardial oxygen requirement increases, especially caused by accumulation of metabolites resulting from myocardial during exercise, and coronary blood flow does not increase pro- ischemia. The organic nitrates, eg, nitroglycerin, are the mainstay portionately. The resulting ischemia usually leads to pain. In fact, of therapy for the immediate relief of angina. Another group of coronary flow reserve is frequently impaired in such patients vasodilators, the calcium channel blockers, is also important, because of endothelial dysfunction, which is associated with especially for prophylaxis, and β blockers, which are not vasodila- impaired vasodilation. As a result, ischemia may occur at a lower tors, are also useful in prophylaxis. Several newer groups of drugs level of myocardial oxygen demand. In some individuals, the isch- are under investigation, including drugs that alter myocardial emia is not always accompanied by pain, resulting in “silent” or metabolism and selective cardiac rate inhibitors. “ambulatory” ischemia. In variant angina, oxygen delivery decreases By far the most common cause of angina is atheromatous as a result of reversible coronary vasospasm. obstruction of the large coronary vessels (coronary artery disease, Unstable angina, an acute coronary syndrome, is said to be pres- CAD). Inadequate blood flow in the presence of CAD results in ent when episodes of angina occur at rest and when there is an increase effort angina, also known as classic angina. However, transient in the severity, frequency, and duration of chest pain in patients with spasm of localized portions of these vessels, which is usually associ- previously stable angina. Unstable angina is caused by episodes of ated with underlying atheromas, can also cause significant myo- increased epicardial coronary artery resistance or small platelet clots cardial ischemia and pain (vasospastic or variant angina). Variant occurring in the vicinity of an atherosclerotic plaque. In most cases, angina is also called Prinzmetal angina. formation of labile partially occlusive thrombi at the site of a fissured or ulcerated plaque is the mechanism for reduction in flow. The course and the prognosis of unstable angina are variable, but this subset of ∗ The author thanks Dr. Kanu Chatterjee, MB, FRCP, who was coauthor acute coronary syndrome is associated with a high risk of myocardial of this chapter in prior editions. infarction and death and is considered a medical emergency. 193 194 SECTION III Cardiovascular-Renal Drugs In theory, the imbalance between oxygen delivery and myocar- Determinants of Coronary Blood Flow & dial oxygen demand can be corrected by decreasing oxygen Myocardial Oxygen Supply demand or by increasing delivery (by increasing coronary flow). In effort angina, oxygen demand can be reduced by decreasing Increased demand for oxygen in the normal heart is met by aug- cardiac work or, according to some studies, by shifting myocardial menting coronary blood flow. Coronary blood flow is directly metabolism to substrates that require less oxygen per unit of ade- related to the perfusion pressure (aortic diastolic pressure) and the nosine triphosphate (ATP) produced. In variant angina, on the duration of diastole. Because coronary flow drops to negligible other hand, spasm of coronary vessels can be reversed by nitrate or values during systole, the duration of diastole becomes a limiting calcium channel-blocking vasodilators. Lipid-lowering drugs, factor for myocardial perfusion during tachycardia. Coronary especially the “statins,” have become extremely important in the blood flow is inversely proportional to coronary vascular resis- long-term treatment of atherosclerotic disease (see Chapter 35). In tance. Resistance is determined mainly by intrinsic factors— unstable angina, vigorous measures are taken to achieve both— including metabolic products and autonomic activity—and by increase oxygen delivery and decrease oxygen demand. various pharmacologic agents. Damage to the endothelium of coronary vessels has been shown to alter their ability to dilate and to increase coronary vascular resistance. PATHOPHYSIOLOGY OF ANGINA Determinants of Myocardial Oxygen Determinants of Vascular Tone Demand Peripheral arteriolar and venous tone (smooth muscle tension) both play a role in determining myocardial wall stress (Table 12–1). The major determinants of myocardial oxygen requirement are set Arteriolar tone directly controls peripheral vascular resistance and forth in Table 12–1. The effect of arterial blood pressure is medi- thus arterial blood pressure. In systole, intraventricular pressure ated through its effect on wall stress. As a consequence of its must exceed aortic pressure to eject blood; arterial blood pressure continuous activity, the heart’s oxygen needs are relatively high, thus determines the systolic wall stress in an important way. Venous and it extracts approximately 75% of the available oxygen even in tone determines the capacity of the venous circulation and con- the absence of stress. The myocardial oxygen requirement increases trols the amount of blood sequestered in the venous system versus when there is an increase in heart rate, contractility, arterial pres- the amount returned to the heart. Venous tone thereby determines sure, or ventricular volume. These hemodynamic alterations fre- the diastolic wall stress. quently occur during physical exercise and sympathetic discharge, The regulation of smooth muscle contraction and relaxation is which often precipitate angina in patients with obstructive coro- shown schematically in Figure 12–1. The mechanisms of action of nary artery disease. the major types of vasodilators are listed in Table 11–2. As shown Drugs that reduce cardiac size, rate, or force reduce cardiac in Figures 12–1 and 12–2, drugs may relax vascular smooth oxygen demand. Thus, vasodilators, β blockers, and calcium block- muscle in several ways: ers have predictable benefits in angina. A small, late component of sodium current helps to maintain the long plateau and prolong the 1. Increasing cGMP: As indicated in Figures 12–1 and 12–2, calcium current of myocardial action potentials. Drugs that block cGMP facilitates the dephosphorylation of myosin light this late sodium current can indirectly reduce calcium influx and chains, preventing the interaction of myosin with actin. Nitric oxide is an effective activator of soluble guanylyl cyclase and consequently reduce cardiac contractile force. The heart favors fatty acts mainly through this mechanism. Important molecular acids as a substrate for energy production. However, oxidation of donors of nitric oxide include nitroprusside (see Chapters 11 fatty acids requires more oxygen per unit of ATP generated than and 19) and the organic nitrates used in angina. 2+ oxidation of carbohydrates. Therefore, drugs that shift myocardial 2. Decreasing intracellular Ca : Calcium channel blockers metabolism toward greater use of glucose (fatty acid oxidation predictably cause vasodilation because they reduce intracel- inhibitors) have the potential, at least in theory, to reduce the oxy- lular Ca2+, a major modulator of the activation of myosin gen demand without altering hemodynamics. light chain kinase (Figure 12–1). Beta blockers and calcium channel blockers also reduce Ca2+ influx in cardiac muscle fibers, thereby reducing rate, contractility, and oxygen require- ment under most circumstances. TABLE 12–1 Determinants of myocardial oxygen 3. Stabilizing or preventing depolarization of the vascular consumption. smooth muscle cell membrane: The membrane potential of excitable cells is stabilized near the resting potential by increas- Wall stress ing potassium permeability. Potassium channel openers, such Intraventricular pressure as minoxidil sulfate (see Chapter 11) increase the permeability + + of K channels, probably ATP-dependent K channels. Certain Ventricular radius (volume) newer agents under investigation for use in angina (eg, nic- Wall thickness orandil) may act, in part, by this mechanism. Heart rate 4. Increasing cAMP in vascular smooth muscle cells: As shown in Figure 12–1, an increase in cAMP increases the rate of inac- Contractility tivation of myosin light chain kinase, the enzyme responsible  CHAPTER 12 Vasodilators & the Treatment of Angina Pectoris 195 Ca2+ channel Ca2+ – blockers Ca2+ K+ Calmodulin ATP + β2 agonists Ca2+ – Calmodulin complex cAMP + + MLCK* Myosin-LC kinase MLCK(PO4)2 (MLCK) + cGMP Myosin light chains Myosin-LC-PO4 Myosin-LC (myosin-LC) Actin Contraction Relaxation Vascular smooth muscle cell FIGURE 12–1 Control of smooth muscle contraction and site of action of calcium channel-blocking drugs. Contraction is triggered (red arrows) by influx of calcium (which can be blocked by calcium channel blockers) through transmembrane calcium channels. The calcium com- bines with calmodulin to form a complex that converts the enzyme myosin light-chain kinase to its active form (MLCK∗). The latter phosphory- lates the myosin light chains, thereby initiating the interaction of myosin with actin. Other proteins, calponin and caldesmon (not shown), inhibit the ATPase activity of myosin during the relaxation of smooth muscle. Interaction with the Ca2+-calmodulin complex reduces their interaction with myosin during the contraction cycle. Beta2 agonists (and other substances that increase cAMP) may cause relaxation in smooth muscle (blue arrows) by accelerating the inactivation of MLCK and by facilitating the expulsion of calcium from the cell (not shown). cGMP facilitates relaxation by the mechanism shown in Figure 12–2. for triggering the interaction of actin with myosin in these to ischemic tissue. In variant angina, these two drug groups also cells. This appears to be the mechanism of vasodilation caused increase myocardial oxygen delivery by reversing coronary artery by β2 agonists, drugs that are not used in angina (because they spasm. The newer drugs, represented by ranolazine and ivabradine, cause too much cardiac stimulation), and by fenoldopam, a D1 are discussed later. agonist used in hypertensive emergencies. BASIC PHARMACOLOGY OF NITRATES & NITRITES DRUGS USED TO TREAT ANGINA Chemistry These agents are simple nitric and nitrous acid esters of polyalco- Drug Action in Angina hols. Nitroglycerin may be considered the prototype of the group. The three drug groups traditionally used in angina (organic nitrates, Although nitroglycerin is used in the manufacture of dynamite, calcium channel blockers, and β blockers) decrease myocardial oxygen the systemic formulations used in medicine are not explosive. The requirement by decreasing the determinants of oxygen demand conventional sublingual tablet form of nitroglycerin may lose (heart rate, ventricular volume, blood pressure, and contractility). In potency when stored as a result of volatilization and adsorption to some patients, the nitrates and the calcium channel blockers may plastic surfaces. Therefore, it should be kept in tightly closed glass cause a redistribution of coronary flow and increase oxygen delivery containers. Nitroglycerin is not sensitive to light. 196 SECTION III Cardiovascular-Renal Drugs Blood vessel lumen Nitrates Nitrites Capillary Arginine Nitric oxide (NO) endothelial cells Ca2+ Interstitium Nitrates NO Nitrites Ca2+ + Vascular smooth Sildenafil – muscle cell GTP cGMP GMP Myosin light chains Myosin-LC (myosin-LC) Actin Contraction Relaxation FIGURE 12–2 Mechanism of action of nitrates, nitrites, and other substances that increase the concentration of nitric oxide (NO) in vascular smooth muscle cells. Steps leading to relaxation are shown with blue arrows. MLCK∗, activated myosin light-chain kinase (see Figure 12–1). GC∗, activated guanylyl cyclase; PDE, phosphodiesterase; eNOS, endothelial nitric oxide synthase. All therapeutically active agents in the nitrate group appear to molecule and ultimately inactivates the drug. Therefore, oral bio- have identical mechanisms of action and similar toxicities, availability of the traditional organic nitrates (eg, nitroglycerin and although susceptibility to tolerance may vary. Therefore, pharma- isosorbide dinitrate) is low (typically < 10–20%). For this rea- cokinetic factors govern the choice of agent and mode of therapy son, the sublingual route, which avoids the first-pass effect, is when using the nitrates. preferred for achieving a therapeutic blood level rapidly. Nitroglycerin and isosorbide dinitrate both are absorbed effi- H2C O NO2 ciently by this route and reach therapeutic blood levels within a HC O NO2 few minutes. However, the total dose administered by this route H2C O NO2 must be limited to avoid excessive effect; therefore, the total dura- tion of effect is brief (15–30 minutes). When much longer dura- Nitroglycerin (glyceryl trinitrate) tion of action is needed, oral preparations can be given that contain an amount of drug sufficient to result in sustained sys- temic blood levels of the parent drug plus active metabolites. Pharmacokinetics Other routes of administration available for nitroglycerin include The liver contains a high-capacity organic nitrate reductase that transdermal and buccal absorption from slow-release preparations removes nitrate groups in a stepwise fashion from the parent (described below).  CHAPTER 12 Vasodilators & the Treatment of Angina Pectoris 197 Amyl nitrite and related nitrites are highly volatile liquids. Nicorandil and several other investigational antianginal agents Amyl nitrite is available in fragile glass ampules packaged in a appear to combine the activity of nitric oxide release with potas- protective cloth covering. The ampule can be crushed with the sium channel-opening action, thus providing an additional fingers, resulting in rapid release of vapors inhalable through the mechanism for causing vasodilation. Nitroglycerin has not been cloth covering. The inhalation route provides very rapid absorp- reported to open potassium channels. tion and, like the sublingual route, avoids the hepatic first-pass effect. Because of its unpleasant odor and short duration of action, B. Organ System Effects amyl nitrite is now obsolete for angina. Nitroglycerin relaxes all types of smooth muscle regardless of the Once absorbed, the unchanged nitrate compounds have half- cause of the preexisting muscle tone (Figure 12–3). It has practi- lives of only 2–8 minutes. The partially denitrated metabolites have cally no direct effect on cardiac or skeletal muscle. much longer half-lives (up to 3 hours). Of the nitroglycerin metabolites (two dinitroglycerins and two mononitro forms), the 1. Vascular smooth muscle—All segments of the vascular 1,2-dinitro derivative has significant vasodilator efficacy and prob- system from large arteries through large veins relax in response to ably provides most of the therapeutic effect of orally administered nitroglycerin. Most evidence suggests a gradient of response, with nitroglycerin. The 5-mononitrate metabolite of isosorbide dinitrate veins responding at the lowest concentrations, arteries at slightly is an active metabolite of the latter drug and is available for oral use higher ones. The epicardial coronary arteries are sensitive, but as isosorbide mononitrate. It has a bioavailability of 100%. concentric atheromas can prevent significant dilation. On the Excretion, primarily in the form of glucuronide derivatives of other hand, eccentric lesions permit an increase in flow when the denitrated metabolites, is largely by way of the kidney. nitrates relax the smooth muscle on the side away from the lesion. Arterioles and precapillary sphincters are dilated least, partly because of reflex responses and partly because different vessels vary Pharmacodynamics in their ability to release nitric oxide from the drug. A primary direct result of an effective dose of nitroglycerin is A. Mechanism of Action in Smooth Muscle marked relaxation of veins with increased venous capacitance and After more than a century of study, the mechanism of action of decreased ventricular preload. Pulmonary vascular pressures and nitroglycerin is still not fully understood. There is general agree- heart size are significantly reduced. In the absence of heart failure, ment that the drug must be bioactivated with the release of nitric cardiac output is reduced. Because venous capacitance is increased, oxide. Unlike nitroprusside and some other direct nitric oxide orthostatic hypotension may be marked and syncope can result. donors, nitroglycerin activation requires enzymatic action. Dilation of large epicardial coronary arteries may improve oxygen Nitroglycerin can be denitrated by glutathione S-transferase in delivery in the presence of eccentric atheromas. Temporal artery smooth muscle and other cells. A mitochondrial enzyme, aldehyde pulsations and a throbbing headache associated with meningeal dehydrogenase isoform 2 (ALDH2) and possibly isoform 3, artery pulsations are common effects of nitroglycerin and amyl ALDH3, is also capable of activating nitroglycerin and releasing nitrite. In heart failure, preload is often abnormally high; the nitrates nitric oxide. The differential selectivity of glutathione S-transferase and other vasodilators, by reducing preload, may have a beneficial and ALDH2 for different organic nitrates suggests that the effect on cardiac output in this condition (see Chapter 13). ALDH2 may be the more important enzyme for nitroglycerin The indirect effects of nitroglycerin consist of those compensa- bioactivation. Free nitrite ion is released, which is then converted tory responses evoked by baroreceptors and hormonal mecha- to nitric oxide (see Chapter 19). Nitric oxide (probably com- nisms responding to decreased arterial pressure (see Figure 6–7); plexed with cysteine) combines with the heme group of soluble this often results in tachycardia and increased cardiac contractility. guanylyl cyclase, activating that enzyme and causing an increase in Retention of salt and water may also be significant, especially with cGMP. As shown in Figure 12–2, formation of cGMP represents intermediate- and long-acting nitrates. These compensatory a first step toward smooth muscle relaxation. The production of responses contribute to the development of tolerance. prostaglandin E or prostacyclin (PGI2) and membrane hyperpo- In normal subjects without coronary disease, nitroglycerin can larization may also be involved. There is no evidence that auto- induce a significant, if transient, increase in total coronary blood nomic receptors are involved in the primary nitrate response. flow. In contrast, there is no evidence that total coronary flow is However, autonomic reflex responses, evoked when hypotensive increased in patients with angina due to atherosclerotic obstruc- doses are given, are common. tive coronary artery disease. However, some studies suggest that As described in the following text, tolerance is an important redistribution of coronary flow from normal to ischemic regions consideration in the use of nitrates. Although tolerance may be may play a role in nitroglycerin’s therapeutic effect. Nitroglycerin caused in part by a decrease in tissue sulfhydryl groups, eg, on also exerts a weak negative inotropic effect on the heart via nitric cysteine, it can be only partially prevented or reversed with a oxide. sulfhydryl-regenerating agent. Increased generation of oxygen free radicals during nitrate therapy may be another important mecha- 2. Other smooth muscle organs—Relaxation of smooth nism of tolerance. Recent evidence suggests that diminished avail- muscle of the bronchi, gastrointestinal tract (including biliary ability of calcitonin gene-related peptide (CGRP, a potent system), and genitourinary tract has been demonstrated experi- vasodilator) is also associated with nitrate tolerance. mentally. Because of their brief duration, these actions of the 198 SECTION III Cardiovascular-Renal Drugs A B 10 mN 10 mN K+ NTG K+ NE NE K+ 10 min 10 mN C NE NTG 10 min 10 mN K+ Verapamil FIGURE 12–3 Effects of vasodilators on contractions of human vein segments studied in vitro. A shows contractions induced by two vaso- constrictor agents, norepinephrine (NE) and potassium (K+). B shows the relaxation induced by nitroglycerin (NTG), 4 μmol/L. The relaxation is prompt. C shows the relaxation induced by verapamil, 2.2 μmol/L. The relaxation is slower but more sustained. (Modified and reproduced, with permis- sion, from Mikkelsen E, Andersson KE, Bengtsson B: Effects of verapamil and nitroglycerin on contractile responses to potassium and noradrenaline in isolated human periph- eral veins. Acta Pharmacol Toxicol 1978;42:14.) nitrates are rarely of any clinical value. During recent decades, the corned beef. Thus, inadvertent exposure to large amounts of use of amyl nitrite and isobutyl nitrite (not nitrates) by inhalation nitrite ion can occur and may produce serious toxicity. as recreational (sex-enhancing) drugs has become popular with One therapeutic application of this otherwise toxic effect of some segments of the population. Nitrites readily release nitric oxide nitrite has been discovered. Cyanide poisoning results from com- in erectile tissue as well as vascular smooth muscle and activate plexing of cytochrome iron by the CN− ion. Methemoglobin iron guanylyl cyclase. The resulting increase in cGMP causes dephospho- has a very high affinity for CN−; thus, administration of sodium rylation of myosin light chains and relaxation (Figure 12–2), which nitrite (NaNO2) soon after cyanide exposure regenerates active enhances erection. The pharmacologic approach to erectile dys- cytochrome. The cyanmethemoglobin produced can be further function is are discussed in the Box: Drugs Used in the Treatment detoxified by the intravenous administration of sodium thiosulfate − of Erectile Dysfunction. (Na2S2O3); this results in formation of thiocyanate ion (SCN ), a less toxic ion that is readily excreted. Methemoglobinemia, if 3. Action on platelets—Nitric oxide released from nitroglycerin excessive, can be treated by giving methylene blue intravenously. stimulates guanylyl cyclase in platelets as in smooth muscle. The This antidotal procedure is now being replaced by hydroxocobala- increase in cGMP that results is responsible for a decrease in platelet min, a form of vitamin B12, which also has a very high affinity for aggregation. Unfortunately, recent prospective trials have estab- cyanide and converts it to another form of vitamin B12. lished no survival benefit when nitroglycerin is used in acute myo- cardial infarction. In contrast, intravenous nitroglycerin may be of Toxicity & Tolerance value in unstable angina, in part through its action on platelets. A. Acute Adverse Effects 4. Other effects—Nitrite ion reacts with hemoglobin (which The major acute toxicities of organic nitrates are direct extensions contains ferrous iron) to produce methemoglobin (which contains of therapeutic vasodilation: orthostatic hypotension, tachycardia, ferric iron). Because methemoglobin has a very low affinity for and throbbing headache. Glaucoma, once thought to be a con- oxygen, large doses of nitrites can result in pseudocyanosis, tissue traindication, does not worsen, and nitrates can be used safely in hypoxia, and death. Fortunately, the plasma level of nitrite result- the presence of increased intraocular pressure. Nitrates are con- ing from even large doses of organic and inorganic nitrates is too traindicated, however, if intracranial pressure is elevated. Rarely, low to cause significant methemoglobinemia in adults. In nursing transdermal nitroglycerin patches have ignited when external defi- infants, the intestinal flora is capable of converting significant brillator electroshock was applied to the chest of patients in ven- amounts of inorganic nitrate, eg, from well water, to nitrite ion. In tricular fibrillation. Such patches should be removed before use of addition, sodium nitrite is used as a curing agent for meats, eg, external defibrillators to prevent superficial burns.  CHAPTER 12 Vasodilators & the Treatment of Angina Pectoris 199 Drugs Used in the Treatment of Erectile Dysfunction Erectile dysfunction in men has long been the subject of research in the marketplace because it can be taken orally. However, (by both amateur and professional scientists). Among the sub- sildenafil is of little or no value in men with loss of potency due to stances used in the past and generally discredited are “Spanish cord injury or other damage to innervation and in men lacking Fly” (a bladder and urethral irritant), yohimbine (an α2 antago- libido. Furthermore, sildenafil potentiates the action of nitrates nist; see Chapter 10), nutmeg, and mixtures containing lead, used for angina, and severe hypotension and a few myocardial arsenic, or strychnine. Substances currently favored by practitio- infarctions have been reported in men taking both drugs. It is ners of herbal medicine but of dubious value include ginseng recommended that at least 6 hours pass between use of a nitrate and kava. and the ingestion of sildenafil. Sildenafil also has effects on color Scientific studies of the process have shown that erection vision, causing difficulty in blue-green discrimination. Two similar requires relaxation of the nonvascular smooth muscle of the cor- PDE-5 inhibitors, tadalafil and vardenafil, are available. It is pora cavernosa. This relaxation permits inflow of blood at nearly important to be aware that numerous nonprescription mail-order arterial pressure into the sinuses of the cavernosa, and it is the products that contain sildenafil analogs such as hydroxythioho- pressure of the blood that causes erection. (With regard to other mosildenafil and sulfoaildenafil have been marketed as “male aspects of male sexual function, ejaculation requires intact sym- enhancement” agents. These products are not approved by the pathetic motor function, while orgasm involves independent FDA and incur the same risk of dangerous interactions with superficial and deep sensory nerves.) Physiologic erection occurs nitrates as the approved agents. in response to the release of nitric oxide from nonadrenergic- PDE-5 inhibitors have also been studied for possible use in noncholinergic nerves (see Chapter 6) associated with parasym- other conditions. Clinical studies show distinct benefit in some pathetic discharge. Thus, parasympathetic motor innervation patients with pulmonary arterial hypertension but not in patients must be intact and nitric oxide synthesis must be active. (It with advanced idiopathic pulmonary fibrosis. The drugs have appears that a similar process occurs in female erectile tissues.) possible benefit in systemic hypertension, cystic fibrosis, and Certain other smooth muscle relaxants—eg, PGE1 analogs or α benign prostatic hyperplasia. Both sildenafil and tadalafil are cur- antagonists—if present in high enough concentration, can inde- rently approved for pulmonary hypertension. Preclinical studies pendently cause sufficient cavernosal relaxation to result in erec- suggest that sildenafil may be useful in preventing apoptosis and tion. As noted in the text, nitric oxide activates guanylyl cyclase, cardiac remodeling after ischemia and reperfusion. which increases the concentration of cGMP, and the latter sec- The drug most commonly used in patients who do not ond messenger stimulates the dephosphorylation of myosin respond to sildenafil is alprostadil, a PGE1 analog (see Chapter 18) light chains (Figure 12–2) and relaxation of the smooth muscle. that can be injected directly into the cavernosa or placed in the Thus, any drug that increases cGMP might be of value in erectile urethra as a minisuppository, from which it diffuses into the cav- dysfunction if normal innervation is present. Sildenafil (Viagra) ernosal tissue. Phentolamine can be used by injection into the acts to increase cGMP by inhibiting its breakdown by phospho- cavernosa. These drugs will cause erection in most men who do diesterase isoform 5 (PDE-5). The drug has been very successful not respond to sildenafil. B. Tolerance Tolerance does not occur equally with all nitric oxide donors. With continuous exposure to nitrates, isolated smooth muscle Nitroprusside, for example, retains activity over long periods. may develop complete tolerance (tachyphylaxis), and the intact Other organic nitrates appear to be less susceptible than nitroglyc- human becomes progressively more tolerant when long-acting erin to the development of tolerance. In cell-free systems, soluble preparations (oral, transdermal) or continuous intravenous infu- guanylate cyclase is inhibited, possibly by nitrosylation of the sions are used for more than a few hours without interruption. enzyme, only after prolonged exposure to exceedingly high nitro- The mechanisms by which tolerance develops are not completely glycerin concentrations. In contrast, treatment with antioxidants understood. As previously noted, diminished release of nitric that protect ALDH2 and similar enzymes appears to prevent or oxide resulting from reduced bioactivation may be partly respon- reduce tolerance. This suggests that tolerance is a function of sible for tolerance to nitroglycerin. Systemic compensation also diminished bioactivation of organic nitrates and to a lesser degree, plays a role in tolerance in the intact human. Initially, significant a loss of soluble guanylate cyclase responsiveness to nitric oxide. sympathetic discharge occurs, and after one or more days of Continuous exposure to high levels of nitrates can occur in the therapy with long-acting nitrates, retention of salt and water may chemical industry, especially where explosives are manufactured. reverse the favorable hemodynamic changes normally caused by When contamination of the workplace with volatile organic nitrate nitroglycerin. compounds is severe, workers find that upon starting their work 200 SECTION III Cardiovascular-Renal Drugs week (Monday), they suffer headache and transient dizziness intraventricular pressure and left ventricular volume are associ- (“Monday disease”). After a day or so, these symptoms disappear ated with decreased wall tension (Laplace relation) and decreased owing to the development of tolerance. Over the weekend, when myocardial oxygen requirement. In rare instances, a paradoxical exposure to the chemicals is reduced, tolerance disappears, so symp- increase in myocardial oxygen demand may occur as a result of toms recur each Monday. Other hazards of industrial exposure, excessive reflex tachycardia and increased contractility. including dependence, have been reported. There is no evidence Intracoronary, intravenous, or sublingual nitrate administra- that physical dependence develops as a result of the therapeutic use tion consistently increases the caliber of the large epicardial coro- of short-acting nitrates for angina, even in large doses. nary arteries except where blocked by concentric atheromas. Coronary arteriolar resistance tends to decrease, though to a lesser C. Carcinogenicity of Nitrate and Nitrite Derivatives extent. However, nitrates administered by the usual systemic Nitrosamines are small molecules with the structure R2–N–NO routes may decrease overall coronary blood flow (and myocardial formed from the combination of nitrates and nitrites with amines. oxygen consumption) if cardiac output is reduced due to decreased Some nitrosamines are powerful carcinogens in animals, appar- venous return. The reduction in oxygen consumption is the major ently through conversion to reactive derivatives. Although there is mechanism for the relief of effort angina. no direct proof that these agents cause cancer in humans, there is a strong epidemiologic correlation between the incidence of B. Nitrate Effects in Variant Angina esophageal and gastric carcinoma and the nitrate content of food Nitrates benefit patients with variant angina by relaxing the in certain cultures. Nitrosamines are also found in tobacco and in smooth muscle of the epicardial coronary arteries and relieving cigarette smoke. There is no evidence that the small doses of coronary artery spasm. nitrates used in the treatment of angina result in significant body levels of nitrosamines. C. Nitrate Effects in Unstable Angina Nitrates are also useful in the treatment of the acute coronary Mechanisms of Clinical Effect syndrome of unstable angina, but the precise mechanism for their The beneficial and deleterious effects of nitrate-induced vasodila- beneficial effects is not clear. Because both increased coronary tion are summarized in Table 12–2. vascular tone and increased myocardial oxygen demand can pre- cipitate rest angina in these patients, nitrates may exert their A. Nitrate Effects in Angina of Effort beneficial effects both by dilating the epicardial coronary arteries Decreased venous return to the heart and the resulting reduction and by simultaneously reducing myocardial oxygen demand. As of intracardiac volume are important beneficial hemodynamic previously noted, nitroglycerin also decreases platelet aggregation, effects of nitrates. Arterial pressure also decreases. Decreased and this effect may be of importance in unstable angina. Clinical Use of Nitrates TABLE 12–2 Beneficial and deleterious effects of Some of the forms of nitroglycerin and its congeners are listed in nitrates in the treatment of angina. Table 12–3. Because of its rapid onset of action (1–3 minutes), sublingual nitroglycerin is the most frequently used agent for the Effect Result immediate treatment of angina. Because its duration of action is Potential beneficial effects short (not exceeding 20–30 minutes), it is not suitable for main- Decreased ventricular volume Decreased myocardial oxygen tenance therapy. The onset of action of intravenous nitroglycerin requirement is also rapid (minutes), but its hemodynamic effects are quickly Decreased arterial pressure reversed when the infusion is stopped. Clinical use of intravenous Decreased ejection time nitroglycerin is therefore restricted to the treatment of severe, Vasodilation of epicardial cor- Relief of coronary artery spasm recurrent rest angina. Slowly absorbed preparations of nitroglyc- onary arteries erin include a buccal form, oral preparations, and several transder- Increased collateral flow Improved perfusion to ischemic myocardium mal forms. These formulations have been shown to provide blood concentrations for long periods but, as noted above, this leads to Decreased left ventricular Improved subendocardial diastolic pressure perfusion the development of tolerance. The hemodynamic effects of sublingual or chewable isosorbide Potential deleterious effects dinitrate and the oral organic nitrates are similar to those of nitro- Reflex tachycardia Increased myocardial oxygen glycerin given by the same route. The recommended dosage sched- requirement ules for commonly used long-acting nitrate preparations, along Reflex increase in contractility Increased myocardial oxygen with their durations of action, are listed in Table 12–3. Although requirement transdermal administration may provide blood levels of nitroglyc- Decreased diastolic perfusion Decreased coronary perfusion time due to tachycardia erin for 24 hours or longer, the full hemodynamic effects usually do not persist for more than 6–8 hours. The clinical efficacy of  CHAPTER 12 Vasodilators & the Treatment of Angina Pectoris 201 TABLE 12–3 Nitrate and nitrite drugs used in the treatment of angina. Drug Dose Duration of Action Short-acting Nitroglycerin, sublingual 0.15–1.2 mg 10–30 minutes Isosorbide dinitrate, sublingual 2.5–5 mg 10–60 minutes Amyl nitrite, inhalant 0.18–0.3 mL 3–5 minutes Long-acting Nitroglycerin, oral sustained-action 6.5–13 mg per 6–8 hours 6–8 hours Nitroglycerin, 2% ointment, transdermal 1–1.5 inches per 4 hours 3–6 hours Nitroglycerin, slow-release, buccal 1–2 mg per 4 hours 3–6 hours Nitroglycerin, slow-release patch, transdermal 10–25 mg per 24 hours (one patch per day) 8–10 hours Isosorbide dinitrate, sublingual 2.5–10 mg per 2 hours 1.5–2 hours Isosorbide dinitrate, oral 10–60 mg per 4–6 hours 4–6 hours Isosorbide dinitrate, chewable oral 5–10 mg per 2–4 hours 2–3 hours Isosorbide mononitrate, oral 20 mg per 12 hours 6–10 hours slow-release forms of nitroglycerin in maintenance therapy of nonfatal coronary events in patients receiving the drug. Nicorandil angina is thus limited by the development of significant tolerance. is currently approved for use in the treatment of angina in Europe Therefore, a nitrate-free period of at least 8 hours between doses and Japan and has been submitted for approval in the USA. should be observed to reduce or prevent tolerance. CALCIUM CHANNEL-BLOCKING DRUGS OTHER NITRO-VASODILATORS It has been known since the late 1800s that transmembrane cal- Nicorandil is a nicotinamide nitrate ester that has vasodilating cium influx is necessary for the contraction of smooth and cardiac properties in normal coronary arteries but more complex effects in muscle. The discovery of a calcium channel in cardiac muscle was patients with angina. Clinical studies suggest that it reduces both followed by the finding of several different types of calcium chan- preload and afterload. It also provides some myocardial protection nels in different tissues (Table 12–4). The discovery of these chan- via preconditioning by activation of cardiac KATP channels. One nels made possible the measurement of the calcium current, ICa, large trial showed a significant reduction in relative risk of fatal and and subsequently, the development of clinically useful blocking TABLE 12–4 Properties of several recognized voltage-activated calcium channels. Properties of the Type Channel Name Where Found Calcium Current Blocked By 2+ L CaV1.1–CaV1.4 Cardiac, skeletal, smooth muscle, neu- Long, large, high threshold Verapamil, DHPs, Cd , ω-aga-IIIA rons (CaV1.4 is found in retina), endocrine cells, bone 2+ T CaV3.1–CaV3.3 Heart, neurons Short, small, low threshold sFTX, flunarizine, Ni (CaV3.2 only), 1 mibefradil N CaV2.2 Neurons, sperm2 Short, high threshold Ziconotide,3 gabapentin,4 ω-CTXGVIA, ω-aga-IIIA, Cd2+ P/Q CaV2.1 Neurons Long, high threshold ω-CTX-MVIIC, ω-aga-IVA 2 R CaV2.3 Neurons, sperm Pacemaking SNX-482, ω-aga-IIIA 1 Antianginal drug withdrawn from market. 2 Channel types associated with sperm flagellar activity may be of the Catsper1–4 variety. 3 Synthetic snail peptide analgesic (see Chapter 31). 4 Antiseizure agent (see Chapter 24). DHPs, dihydropyridines (eg, nifedipine); sFTX, synthetic funnel web spider toxin; ω-CTX, conotoxins extracted from several marine snails of the genus Conus; ω-aga-IIIA and ω-aga-IVA, toxins of the funnel web spider, Agelenopsis aperta; SNX-482, a toxin of the African tarantula, Hysterocrates gigas. 202 SECTION III Cardiovascular-Renal Drugs TABLE 12–5 Clinical pharmacology of some calcium channel-blocking drugs. Oral Half-life Drug Bioavailability (%) (hours) Indication Dosage Dihydropyridines Amlodipine 65–90 30–50 Angina, hypertension 5–10 mg orally once daily Felodipine 15–20 11–16 Hypertension, Raynaud’s phenomenon 5–10 mg orally once daily Isradipine 15–25 8 Hypertension 2.5–10 mg orally twice daily Nicardipine 35 2–4 Angina, hypertension 20–40 mg orally every 8 hours Nifedipine 45–70 4 Angina, hypertension, Raynaud’s 3–10 mcg/kg IV; 20–40 mg orally every phenomenon 8 hours Nisoldipine < 10 6–12 Hypertension 20–40 mg orally once daily Nitrendipine 10–30 5–12 Investigational 20 mg orally once or twice daily Miscellaneous Diltiazem 40–65 3–4 Angina, hypertension, Raynaud’s 75–150 mcg/kg IV; 30–80 mg orally phenomenon every 6 hours Verapamil 20–35 6 Angina, hypertension, arrhythmias, 75–150 mcg/kg IV; 80–160 mg orally migraine every 8 hours drugs. Although the blockers currently available for clinical use in been recognized. Nifedipine and other dihydropyridines have cardiovascular conditions are exclusively L-type calcium channel been demonstrated to bind to one site on the α1 subunit, whereas blockers, selective blockers of other types of calcium channels are verapamil and diltiazem appear to bind to closely related but not under intensive investigation. Certain antiseizure drugs are identical receptors in another region of the same subunit. Binding thought to act, at least in part, through calcium channel (espe- of a drug to the verapamil or diltiazem receptors allosterically cially T-type) blockade in neurons (see Chapter 24). affects dihydropyridine binding. These receptor regions are ste- reoselective, since marked differences in both stereoisomer-bind- Chemistry & Pharmacokinetics ing affinity and pharmacologic potency are observed for enantiomers of verapamil, diltiazem, and optically active nife- Verapamil, the first clinically useful member of this group, was the dipine congeners. result of attempts to synthesize more active analogs of papaverine, Blockade of calcium channels by these drugs resembles that of a vasodilator alkaloid found in the opium poppy. Since then, doz- sodium channel blockade by local anesthetics (see Chapters 14 ens of agents of varying structure have been found to have the and 26). The drugs act from the inner side of the membrane and same fundamental pharmacologic action (Table 12–5). Three bind more effectively to open channels and inactivated channels. chemically dissimilar calcium channel blockers are shown in Binding of the drug reduces the frequency of opening in response Figure 12–4. Nifedipine is the prototype of the dihydropyridine to depolarization. The result is a marked decrease in transmem- family of calcium channel blockers; dozens of molecules in this brane calcium current, which in smooth muscle results in long- family have been investigated, and several are currently approved lasting relaxation (Figure 12–3) and in cardiac muscle results in in the USA for angina and other indications. Nifedipine is the reduction in contractility throughout the heart and decreases in most extensively studied of this group, but the properties of the sinus node pacemaker rate and atrioventricular node conduction other dihydropyridines can be assumed to be similar to it unless ∗ velocity. Although some neuronal cells harbor L-type calcium otherwise noted. channels, their sensitivity to these drugs is lower because the chan- The calcium channel blockers are orally active agents and are nels in these cells spend less time in the open and inactivated characterized by high first-pass effect, high plasma protein bind- states. ing, and extensive metabolism. Verapamil and diltiazem are also Smooth muscle responses to calcium influx through ligand- used by the intravenous route. gated calcium channels are also reduced by these drugs but not as markedly. The block can be partially reversed by elevating the Pharmacodynamics concentration of calcium, although the levels of calcium required A. Mechanism of Action are not easily attainable in patients. Block can also be partially The voltage-gated L-type calcium channel is the dominant type in cardiac and smooth muscle and is known to contain several ∗ At very low doses and under certain circumstances, some dihydropyri- drug receptors. It consists of α1 (the larger, pore-forming sub- dines increase calcium influx. Some special dihydropyridines, eg, Bay unit), α2, β, γ, and δ subunits. Four variant α1 subunits have K 8644, actually increase calcium influx over most of their dose range.  CHAPTER 12 Vasodilators & the Treatment of Angina Pectoris 203 H 3C CH3 H3C O O CH3 CH CH3 H3C O C CH2 CH2 CH2 N CH2 CH2 O CH3 C N Verapamil CH3 NO2 S N CH2 CH2 N O O O CH3 H3C O C C O CH3 O C CH3 O H3C CH3 N H O Nifedipine CH3 Diltiazem FIGURE 12–4 Chemical structures of several calcium channel-blocking drugs. reversed by the use of drugs that increase the transmembrane flux Important differences in vascular selectivity exist among the of calcium, such as sympathomimetics. calcium channel blockers. In general, the dihydropyridines have a Other types of calcium channels are less sensitive to blockade greater ratio of vascular smooth muscle effects relative to cardiac by these calcium channel blockers (Table 12–4). Therefore, tissues effects than do diltiazem and verapamil. The relatively smaller in which these other channel types play a major role—neurons effect of verapamil on vasodilation may be the result of simultane- and most secretory glands—are much less affected by these drugs ous blockade of vascular smooth muscle potassium channels than are cardiac and smooth muscle. Mibefradil is a selective described earlier. Furthermore, the dihydropyridines may differ in T-type calcium channel blocker that was introduced for antiar- their potency in different vascular beds. For example, nimodipine rhythmic use but has been withdrawn. Ion channels other than is claimed to be particularly selective for cerebral blood vessels. calcium channels are much less sensitive to these drugs. Potassium Splice variants in the structure of the α1 channel subunit appear channels in vascular smooth muscle are inhibited by verapamil, to account for these differences. thus limiting the vasodilation produced by this drug. Sodium channels as well as calcium channels are blocked by bepridil, an 2. Cardiac muscle—Cardiac muscle is highly dependent on cal- obsolete antiarrhythmic drug. cium influx during each action potential for normal function. Impulse generation in the sinoatrial node and conduction in the atrioventricular node—so-called slow-response, or calcium-dependent, B. Organ System Effects action potentials—may be reduced or blocked by all of the calcium 1. Smooth muscle—Most types of smooth muscle are depen- channel blockers. Excitation-contraction coupling in all cardiac cells dent on transmembrane calcium influx for normal resting tone requires calcium influx, so these drugs reduce cardiac contractility in and contractile responses. These cells are relaxed by the calcium a dose-dependent fashion. In some cases, cardiac output may also channel blockers (Figure 12–3). Vascular smooth muscle appears decrease. This reduction in cardiac mechanical function is another to be the most sensitive, but similar relaxation can be shown for mechanism by which the calcium channel blockers can reduce the bronchiolar, gastrointestinal, and uterine smooth muscle. In the oxygen requirement in patients with angina. vascular system, arterioles appear to be more sensitive than veins; Important differences between the available calcium channel orthostatic hypotension is not a common adverse effect. Blood blockers arise from the details of their interactions with cardiac ion pressure is reduced with all calcium channel blockers (see Chapter 11). channels and, as noted above, differences in their relative smooth Women may be more sensitive than men to the hypotensive action muscle versus cardiac effects. Sodium channel block is modest with of diltiazem. The reduction in peripheral vascular resistance is one verapamil, and still less marked with diltiazem. It is negligible with mechanism by which these agents may benefit the patient with nifedipine and other dihydropyridines. Verapamil and diltiazem angina of effort. Reduction of coronary artery spasm has been interact kinetically with the calcium channel receptor in a different demonstrated in patients with variant angina. manner than the dihydropyridines; they block tachycardias in 204 SECTION III Cardiovascular-Renal Drugs calcium-dependent cells, eg, the atrioventricular node, more selec- Retrospective case-control studies reported that immediate- tively than do the dihydropyridines. (See Chapter 14 for additional acting nifedipine increased the risk of myocardial infarction in details.) On the other hand, the dihydropyridines appear to block patients with hypertension. Slow-release and long-acting dihydro- smooth muscle calcium channels at concentrations below those pyridine calcium channel blockers are usually well tolerated. required for significant cardiac effects; they are therefore less depres- However, dihydropyridines, compared with angiotensin-converting sant on the heart than verapamil or diltiazem. enzyme (ACE) inhibitors, have been reported to increase the risk of adverse cardiac events in patients with hypertension with or 3. Skeletal muscle—Skeletal muscle is not depressed by the without diabetes. These results suggest that relatively short-acting calcium channel blockers because it uses intracellular pools of calcium channel blockers such as prompt-release nifedipine have calcium to support excitation-contraction coupling and does not the potential to enhance the risk of adverse cardiac events and require as much transmembrane calcium influx. should be avoided. Patients receiving β-blocking drugs are more sensitive to the cardiodepressant effects of calcium channel block- 4. Cerebral vasospasm and infarct following subarach- ers. Minor toxicities (troublesome but not usually requiring dis- noid hemorrhage—Nimodipine, a member of the dihydropyri- continuance of therapy) include flushing, dizziness, nausea, dine group of calcium channel blockers, has a high affinity for constipation, and peripheral edema. Constipation is particularly cerebral blood vessels and appears to reduce morbidity after a common with verapamil. subarachnoid hemorrhage. Nimodipine was approved for use in patients who have had a hemorrhagic stroke, but it has recently been withdrawn. Nicardipine has similar effects and is used by Mechanisms of Clinical Effects intravenous and intracerebral arterial infusion to prevent cerebral Calcium channel blockers decrease myocardial contractile force, vasospasm associated with stroke. Verapamil as well, despite its which reduces myocardial oxygen requirements. Calcium channel lack of vasoselectivity, is used by the intra-arterial route in stroke. block in arterial smooth muscle decreases arterial and intraven- Some evidence suggests that calcium channel blockers may also tricular pressure. Some of these drugs (eg, verapamil, diltiazem) reduce cerebral damage after thromboembolic stroke. also possess a nonspecific antiadrenergic effect, which may con- tribute to peripheral vasodilation. As a result of all of these effects, 5. Other effects—Calcium channel blockers minimally interfere left ventricular wall stress declines, which reduces myocardial oxy- with stimulus-secretion coupling in glands and nerve endings gen requirements. Decreased heart rate with the use of verapamil because of differences between calcium channel type and sensitivity or diltiazem causes a further decrease in myocardial oxygen in different tissues. Verapamil has been shown to inhibit insulin demand. Calcium channel-blocking agents also relieve and pre- release in humans, but the dosages required are greater than those vent focal coronary artery spasm in variant angina. Use of these used in management of angina and other cardiovascular conditions. agents has thus emerged as the most effective prophylactic treat- A significant body of evidence suggests that the calcium chan- ment for this form of angina pectoris. nel blockers may interfere with platelet aggregation in vitro and Sinoatrial and atrioventricular nodal tissues, which are mainly prevent or attenuate the development of atheromatous lesions in composed of calcium-dependent, slow-response cells, are affected animals. However, clinical studies have not established their role markedly by verapamil, moderately by diltiazem, and much less by in human blood clotting and atherosclerosis. dihydropyridines. Thus, verapamil and diltiazem decrease atrio- Verapamil has been shown to block the P-glycoprotein respon- ventricular nodal conduction and are often effective in the man- sible for the transport of many foreign drugs out of cancer (and agement of supraventricular reentry tachycardia and in decreasing other) cells (see Chapter 1); other calcium channel blockers appear ventricular responses in atrial fibrillation or flutter. Nifedipine to have a similar effect. This action is not stereospecific. Verapamil does not affect atrioventricular conduction. Nonspecific sympa- has been shown to partially reverse the resistance of cancer cells to thetic antagonism is most marked with diltiazem and much less many chemotherapeutic drugs in vitro. Some clinical results sug- with verapamil. Nifedipine does not appear to have this effect. gest similar effects in patients (see Chapter 54). Animal research Significant reflex tachycardia in response to hypotension occurs suggests possible future roles of calcium blockers in the treatment most frequently with nifedipine and less so with diltiazem and of osteoporosis, fertility disorders and male contraception, verapamil. These differences in pharmacologic effects should be immune modulation, and even schistosomiasis. Verapamil does considered in selecting calcium channel-blocking agents for the not appear to block transmembrane divalent metal ion transport- management of angina. ers such as DMT1. Toxicity Clinical Uses of Calcium The most important toxic effects reported for calcium channel Channel-Blocking Drugs blockers are direct extensions of their therapeutic action. Excessive In addition to angina, calcium channel blockers have well-documented inhibition of calcium influx can cause serious cardiac depression, efficacy in hypertension (see Chapter 11) and supraventricular including bradycardia, atrioventricular block, cardiac arrest, and tachyarrhythmias (see Chapter 14). They also show moderate heart failure. These effects have been rare in clinical use. efficacy in a variety of other conditions, including hypertrophic  CHAPTER 12 Vasodilators & the Treatment of Angina Pectoris 205 cardiomyopathy, migraine, and Raynaud’s phenomenon. Nifedipine agents decrease mortality of patients with recent myocardial infarc- has some efficacy in preterm labor but is more toxic and not as tion and improve survival and prevent stroke in patients with effective as atosiban, an investigational oxytocin antagonist (see hypertension. Randomized trials in patients with stable angina Chapter 17). have shown better outcome and symptomatic improvement with The pharmacokinetic properties of these drugs are set forth in β blockers compared with calcium channel blockers. Table 12–5. The choice of a particular calcium channel-blocking Undesirable effects of β-blocking agents in angina include an agent should be made with knowledge of its specific potential increase in end-diastolic volume and an increase in ejection time, adverse effects as well as its pharmacologic properties. Nifedipine both of which tend to increase myocardial oxygen requirement. does not decrease atrioventricular conduction and therefore can be These deleterious effects of β-blocking agents can be balanced by used more safely than verapamil or diltiazem in the presence of the concomitant use of nitrates as described below. atrioventricular conduction abnormalities. A combination of vera- Contraindications to the use of β blockers are asthma and pamil or diltiazem with β blockers may produce atrioventricular other bronchospastic conditions, severe bradycardia, atrioventric- block and depression of ventricular function. In the presence of ular blockade, bradycardia-tachycardia syndrome, and severe overt heart failure, all calcium channel blockers can cause further unstable left ventricular failure. Potential complications include worsening of failure as a result of their negative inotropic effect. fatigue, impaired exercise tolerance, insomnia, unpleasant dreams, Amlodipine, however, does not increase mortality in patients worsening of claudication, and erectile dysfunction. with heart failure due to nonischemic left ventricular systolic dys- function and can be used safely in these patients. In patients with relatively low blood pressure, dihydropyri- NEWER ANTIANGINAL DRUGS dines can cause further deleterious lowering of pressure. Verapamil and diltiazem appear to produce less hypotension and may be Because of the high prevalence of angina, new drugs are actively better tolerated in these circumstances. In patients with a history sought for its treatment. Some of the drugs or drug groups cur- of atrial tachycardia, flutter, and fibrillation, verapamil and dilti- rently under investigation are listed in Table 12–6. azem provide a distinct advantage because of their antiarrhythmic Ranolazine is a newer antianginal drug that appears to act by effects. In the patient receiving digitalis, verapamil should be used reducing a late sodium current (INa) that facilitates calcium entry with caution, because it may increase digoxin blood levels via the sodium-calcium exchanger (see Chapter 13). The resulting through a pharmacokinetic interaction. Although increases in reduction in intracellular calcium concentration reduces cardiac digoxin blood level have also been demonstrated with diltiazem contractility and work. Ranolazine is approved for use in angina and nifedipine, such interactions are less consistent than with in the USA. verapamil. Certain metabolic modulators (eg, trimetazidine) are known as In patients with unstable angina, immediate-release short- pFOX inhibitors because they partially inhibit the fatty acid oxida- acting calcium channel blockers can increase the risk of adverse tion pathway in myocardium. Because metabolism shifts to oxida- cardiac events and therefore are contraindicated (see Toxicity, tion of fatty acids in ischemic myocardium, the oxygen requirement above). However, in patients with non–Q-wave myocardial infarc- per unit of ATP produced increases. Partial inhibition of the enzyme tion, diltiazem can decrease the frequency of postinfarction angina and may be used. TABLE 12–6 New drugs or drug groups under investigation for use in angina. BETA-BLOCKING DRUGS Drugs Although they are not vasodilators (with the exception of carvedilol Amiloride and nebivolol), β-blocking drugs (see Chapter 10) are extremely Capsaicin useful in the management of effort angina. The beneficial effects of β-blocking agents are related to their hemodynamic effects— Direct bradycardic agents, eg, ivabradine decreased heart rate, blood pressure, and contractility—which Inhibitors of slowly inactivating sodium current, eg, ranolazine decrease myocardial oxygen requirements at rest and during exer- Metabolic modulators, eg, trimetazidine cise. Lower heart rate is also associated with an increase in diastolic Nitric oxide donors, eg, L-arginine perfusion time that may increase coronary perfusion. However, Potassium channel activators, eg, nicorandil reduction of heart rate and blood pressure, and consequently Protein kinase G facilitators, eg, detanonoate decreased myocardial oxygen consumption, appear to be the most important mechanisms for relief of angina and improved exercise Rho-kinase inhibitors, eg, fasudil tolerance. Beta blockers may also be valuable in treating silent or Sulfonylureas, eg, glibenclamide ambulatory ischemia. Because this condition causes no pain, it is Thiazolidinediones usually detected by the appearance of typical electrocardiographic Vasopeptidase inhibitors signs of ischemia. The total amount of “ischemic time” per day is Xanthine oxidase inhibitors, eg, allopurinol reduced by long-term therapy with a β blocker. Beta-blocking 206 SECTION III Cardiovascular-Renal Drugs required for fatty acid oxidation (long-chain 3-ketoacyl thiolase, The treatment of established angina and other manifestations LC-3KAT) appears to improve the metabolic status of ischemic tis- of myocardial ischemia includes the corrective measures previously sue. (Ranolazine was initially assigned to this group of agents.). described as well as treatment to prevent or relieve symptoms. Trimetazidine is not approved for use in angina in the USA. A much Treatment of symptoms is based on reduction of myocardial oxy- older drug, allopurinol, represents another type of metabolic gen demand and increase of coronary blood flow to the potentially modifier. Allopurinol inhibits xanthine oxidase (see Chapter 36), an ischemic myocardium to restore the balance between myocardial enzyme that contributes to oxidative stress and endothelial dysfunc- oxygen supply and demand. tion. A recent study suggests that high-dose allopurinol prolongs exercise time in patients with atherosclerotic angina. Angina of Effort So-called bradycardic drugs, relatively selective If sodium chan- Many studies have demonstrated that nitrates, calcium channel nel blockers (eg, ivabradine), reduce cardiac rate by inhibiting blockers, and β blockers increase time to onset of angina and ST the hyperpolarization-activated sodium channel in the sinoatrial depression during treadmill tests in patients with angina of effort node. No other significant hemodynamic effects have been (Figure 12–5). Although exercise tolerance increases, there is usu- reported. Ivabradine appears to reduce anginal attacks with an ally no change in the angina threshold, ie, the rate-pressure prod- efficacy similar to that of calcium channel blockers and β block- uct at which symptoms occur. ers. The lack of effect on gastrointestinal and bronchial smooth For maintenance therapy of chronic stable angina, long-acting muscle is an advantage of ivabradine, and Food and Drug nitrates, calcium channel-blocking agents, or β blockers may be Administration approval is expected. chosen; the drug of choice depends on the individual patient’s The Rho kinases comprise a family of enzymes that inhibit response. In hypertensive patients, monotherapy with either slow- vascular relaxation and diverse functions of several other cell release or long-acting calcium channel blockers or β blockers may types. Excessive activity of these enzymes has been implicated in be adequate. In normotensive patients, long-acting nitrates may coronary spasm, pulmonary hypertension, apoptosis, and other be suitable. The combination of a β blocker with a calcium chan- conditions. Drugs targeting the enzyme have therefore been nel blocker (eg, propranolol with nifedipine) or two different sought for possible clinical applications. Fasudil is an inhibitor calcium channel blockers (eg, nifedipine and verapamil) has been of smooth muscle Rho kinase and reduces coronary vasospasm shown to be more effective than individual drugs used alone. If in experimental animals. In clinical trials in patients with CAD, response to a single drug is inadequate, a drug from a different it has improved performance in stress tests. class should be added to maximize the beneficial reduction of cardiac work while minimizing undesirable effects (Table 12–7). Some patients may require therapy with all three drug groups. CLINICAL PHARMACOLOGY OF DRUGS USED TO TREAT ANGINA Because the most common cause of angina is atherosclerotic dis- HR × BP ÷ 100 ease of the coronaries (CAD), therapy must address the underly- 175 ing causes of CAD as well as the immediate symptoms of angina. In addition to reducing the need for antianginal therapy, such Control primary management has been shown to reduce major cardiac 125 120 mg/d events such as myocardial infarction. 240 mg/d 360 mg/d First-line therapy of CAD depends on modification of risk fac- tors such as smoking, hypertension (see Chapter 11), hyperlipi- 75 demia (see Chapter 35), obesity, and clinical depression. In 0 100 200 300 400 addition, antiplatelet drugs (see Chapter 34) are very important. Treadmill time (s) Specific pharmacologic therapy to prevent myocardial infarction and death consists of antiplatelet agents (aspirin, ADP receptor FIGURE 12–5 Effects of diltiazem on the double product (heart blockers, Chapter 34) and lipid-lowering agents, especially statins rate × systolic blood pressure) in a group of 20 patients with angina (Chapter 35). Aggressive therapy with statins has been shown to of effort. In a double-blind study using a standard protocol, patients reduce the incidence and severity of ischemia in patients during were tested on a treadmill during treatment with placebo and three doses of the drug. Heart rate (HR) and systolic blood pressure (BP) exercise testing and the incidence of cardiac events (including infarc- were recorded at 180 seconds of exercise (midpoints of lines) and at tion and death) in clinical trials. ACE inhibitors also reduce the risk the time of onset of anginal symptoms (rightmost points). Note that of adverse cardiac events in patients at high risk for CAD, although the drug treatment decreased the double product at all times during they have not been consistently shown to exert antianginal effects. In exercise and prolonged the time to appearance of symptoms. (Data patients with unstable angina and non-ST-segment elevation myo- from Lindenberg BS et al: Efficacy and safety of incremental doses of diltiazem for cardial infarction, aggressive therapy consisting of coronary stenting, the treatment of angina. J Am Coll Cardiol 1983;2:1129. Used with permission of the antilipid drugs, heparin, and antiplatelet agents is recommended. American College of Cardiology.)  CHAPTER 12 Vasodilators & the Treatment of Angina Pectoris 207 TABLE 12–7 Effects of nitrates alone and with a blockers or calcium channel blockers in angina pectoris. Beta Blockers or Calcium Combined Nitrates with Beta Blockers or Nitrates Alone Channel Blockers Calcium Channel Blockers 1 Heart rate Reflex increase Decrease Decrease Arterial pressure Decrease Decrease Decrease End-diastolic volume Decrease Increase None or decrease 1 Contractility Reflex increase Decrease None 1 Ejection time Decrease Increase None 1 Baroreceptor reflex. Note: Undesirable effects are shown in italics. Surgical revascularization (ie, coronary artery bypass grafting ischemia. Primary lipid-lowering and ACE-inhibitor therapy [CABG]) and catheter-based revascularization (ie, percutaneous should also be initiated. coronary intervention [PCI]) are the primary methods for promptly restoring coronary blood flow and increasing oxygen supply in unstable or medically refractory angina. TREATMENT OF PERIPHERAL ARTERY DISEASE (PAD) & INTERMITTENT Vasospastic Angina CLAUDICATION Nitrates and the calcium channel blockers are effective drugs for Atherosclerosis can result in ischemia of peripheral muscles just as relieving and preventing ischemic episodes in patients with variant coronary artery disease causes cardiac ischemia. Pain (claudication) angina. In approximately 70% of patients treated with nitrates occurs in skeletal muscles, especially in the legs, during exercise and plus calcium channel blockers, angina attacks are completely abol- disappears with rest. Although claudication is not immediately life- ished; in another 20%, marked reduction of frequency of anginal threatening, peripheral artery disease is associated with increased episodes is observed. Prevention of coronary artery spasm (with or mortality, can severely limit exercise tolerance, and may be associ- without fixed atherosclerotic coronary artery lesions) is the princi- ated with chronic ischemic ulcers and susceptibility to infection. pal mechanism for this beneficial response. All presently available Intermittent claudication results from obstruction of blood flow calcium channel blockers appear to be equally effective, and the by atheromas in large and medium arteries. Treatment is primarily choice of a particular drug should depend on the patient. Surgical directed at reversal or control of atherosclerosis and requires mea- revascularization and angioplasty are not indicated in patients surement and control of hyperlipidemia (see Chapter 35), hyper- with variant angina. tension (see Chapter 11), and obesity; cessation of smoking; and control of diabetes, if present. Physical therapy and exercise train- ing is of proven benefit. Conventional vasodilators are of no ben- Unstable Angina & Acute Coronary efit because vessels distal to the obstructive lesions are usually Syndromes already dilated at rest. Antiplatelet drugs such as aspirin or clopi- In patients with unstable angina with recurrent ischemic episodes dogrel are often used to prevent clotting in the region of plaques. at rest, recurrent platelet-rich nonocclusive thrombus formation is Two drugs are used almost exclusively for peripheral artery disease. the principal mechanism. Aggressive antiplatelet therapy with a Pentoxifylline, a xanthine derivative, is thought to act by reducing combination of aspirin and clopidogrel is indicated. Intravenous the viscosity of blood, allowing it to flow more easily through par- heparin or subcutaneous low-molecular-weight heparin is also tially obstructed areas. Cilostazol, a phosphodiesterase type 3 indicated in most patients. If percutaneous coronary intervention (PDE3) inhibitor, is poorly understood, but may have selective with stenting is required, glycoprotein IIb/IIIa inhibitors such as antiplatelet and vasodilating effects. Both drugs have been shown abciximab should be added. In addition, therapy with nitroglyc- to increase exercise tolerance in patients with severe claudication. erin and β blockers should be considered; calcium channel block- Percutaneous angioplasty with stenting is often effective in patients ers should be added in refractory cases for relief of myocardial with medically intractable signs and symptoms of ischemia. 208 SECTION III Cardiovascular-Renal Drugs SUMMARY Drugs Used in Angina Pectoris Pharmacokinetics, Toxicities, Subclass Mechanism of Action Effects Clinical Applications Interactions NITRATES Nitroglycerin Releases nitric oxide in Smooth muscle relaxation, Angina: Sublingual form for High first-pass effect, so sublingual smooth muscle, which acti- especially in vessels other acute episodes oral and dose is much smaller than oral vates guanylyl cyclase and smooth muscle is relaxed but transdermal forms for pro- high lipid solubility ensures rapid increases cGMP not as markedly vasodila- phylaxis IV form for acute absorption Toxicity: Orthostatic tion decreases venous return coronary syndrome hypotension, tachycardia