Drugs Used for the Treatment of Myocardial Ischemia

This chapter briefly reviews the pathophysiology underlying angina pectoris, the most common symptom of chronic ischemic heart disease. The causes of the myocardial ischemia that produces angina are defined in terms of the myocardial oxygen supplydemand relationship. Stable and unstable angina, silent ischemia, variant angina, and myocardial infarction are considered; the contributions of fixed atherosclerotic coronary narrowings, of active coronary vasospasm, and of intracoronary thrombosis in these syndromes are discussed to clarify the roles of antianginal agents. Also discussed is the angina of autonomic dysfunction, for which therapy must be specifically tailored to ameliorate the underlying problem of great fluctuations in coronary perfusion pressure, and in which conventional antianginal therapy is not efficacious. For each class of antianginal therapy (organic nitrates, Ca²⁺ channel antagonists, -adrenergic receptor antagonists, and antiplatelet/antithrombotic agents), the effects of the class and its most important agents on the factors determining myocardial oxygen demand and myocardial oxygen supply are reviewed.

The use of organic nitrates (also covered in Chapter 34: Pharmacological Treatment of Heart Failure) in sublingual, oral, buccal, and intravenous forms is discussed, with attention to the issue of nitrate tolerance and the relationship of nitrovasodilators to endogenous endothelium-derived vasodilator(s). Interactions of organic nitrates with sildenafil also are discussed. The multiple classes of Ca²⁺ channel antagonists (also discussed in Chapter 33: Antihypertensive Agents and the Drug Therapy of Hypertension) have distinct effects on vascular smooth muscle and cardiac tissue, and these effects are placed in the context of the ischemic cardiac syndromes. -Adrenergic receptor antagonists, which also are addressed in Chapters 10: Catecholamines, Sympathomimetic Drugs, and Adrenergic Receptor Antagonists, 33: Antihypertensive Agents and the Drug Therapy of Hypertension, 34: Pharmacological Treatment of Heart Failure, and 35: Antiarrhythmic Drugs, are dealt with here in terms of their ability to improve survival in ischemic heart disease as well as their efficacy in improving exercise tolerance in stable angina. Considering unstable angina as a thrombotic disease leads to a description of the role of antiplatelet therapy in ischemic heart disease (see also Chapter 55: Anticoagulant, Thrombolytic, and Antiplatelet Drugs). Agents currently under investigation and the potential role of gene-based therapy in the treatment of myocardial ischemia also are described.

History

Nitroglycerin was first synthesized in 1846 by Sobrero, who observed that a small quantity of the oily substance placed on the tongue elicited a severe headache. Constantin Hering, in 1847, developed the sublingual dosage form. In 1857, the eminent physician T. Lauder Brunton of Edinburgh administered amyl nitrite, a known vasodepressor, by inhalation and noted that anginal pain was relieved within 30 to 60 seconds. The action of amyl nitrite was transitory, however, and the dosage was difficult to adjust. Subsequently, William Murrell decided that the action of nitroglycerin mimicked that of amyl nitrite, and he established the use of sublingual nitroglycerin for relief of the acute anginal attack and as a prophylactic agent to be taken prior to exertion (Murrell, 1879). The empirical observation that organic nitrates could be used safely for the rapid, dramatic alleviation of the symptoms of angina pectoris led to their widespread acceptance by the medical profession. Basic investigations led to an understanding of the role of nitric oxide (Moncada et al., 1988) in both the vasodilation produced by nitrates and endogenous vasodilation. The importance of nitric oxide as a signaling molecule in the cardiovascular system and elsewhere was recognized by the awarding of the Nobel Prize in Medicine or Physiology to Furchgott, Ignarro, and Murad in 1998.

Chemistry

Organic nitrates are polyol esters of nitric acid, whereas organic nitrites are esters of nitrous acid (Table 321). Nitrate esters (CONO₂) and nitrite esters (CONO) are characterized by a sequence of carbonoxygennitrogen, whereas nitro compounds possess carbonnitrogen bonds (CNO₂). Thus, glyceryl trinitrate is not a nitro compound, and it is erroneously called nitroglycerin; however, this nomenclature is both widespread and official. Amyl nitrite is a highly volatile liquid that is administered by inhalation. Organic nitrates of low molecular mass (such as nitroglycerin) are moderately volatile, oily liquids, whereas the high-molecular-mass nitrate esters (e.g., erythrityl tetranitrate, pentaerythritol tetranitrate, isosorbide dinitrate) are solids. The fully nitrated polyols are lipid soluble, whereas their incompletely nitrated metabolites are more soluble in water. In the pure form (without an inert carrier such as lactose), nitroglycerin is explosive. The organic nitrates and nitrites and several other compounds that are capable of denitration to release nitric oxide (NO) have been collectively termed nitrovasodilators. Nitric oxide activates guanylyl cyclase, increasing intracellular levels of cyclic guanosine 3^',5^'-monophosphate (cyclic GMP), and thereby produces vasodilation (Murad, 1986; Molina et al., 1987; Thadani, 1992). Endogenous NO is formed when L-arginine is converted to citrulline by nitric oxide synthases. Both constitutive and inducible forms of these synthases are found in vascular endothelial and smooth muscle cells as well as in other cell types throughout the body, including the central nervous system (Lowenstein et al., 1994). In the setting of human atherosclerosis, the expression of endothelial nitric oxide synthase and the production of NO are reduced (Oemar et al., 1998).

Pharmacological Properties

Cardiovascular Effects

Hemodynamic Effects

The nitrovasodilators relax most smooth muscle, including that in arteries and veins. Low concentrations of nitroglycerin produce dilation of the veins that predominates over that of arterioles. Venodilation results in decreased left and right ventricular chamber size and end-diastolic pressures but little change in systemic vascular resistance. Systemic arterial pressure may fall slightly, and heart rate is unchanged or slightly increased reflexly. Pulmonary vascular resistance and cardiac output both are slightly reduced. Even doses of nitroglycerin that do not alter systemic arterial pressure often produce arteriolar dilation in the face and neck, resulting in a flush, or dilation of meningeal arterial vessels, causing headache. There is an enrichment of the enzyme that converts nitroglycerin to NO in venous compared to arterial smooth muscle cells, likely the basis of the partially venoselective properties of the nitrates (Bauer and Fung, 1996).

Higher doses of organic nitrates cause further venous pooling and may decrease arteriolar resistance as well, decreasing systolic and diastolic blood pressure and cardiac output and resulting in pallor, weakness, dizziness, and activation of compensatory sympathetic reflexes. The resultant tachycardia and peripheral arteriolar vasoconstriction tend to restore systemic vascular resistance; this is superimposed on sustained venous pooling. Coronary blood flow may increase transiently as a result of coronary vasodilation, but with a subsequent decrease if cardiac output and blood pressure decrease sufficiently.

In patients with autonomic dysfunction and an inability to increase sympathetic outflow (multiple-system atrophy and pure autonomic failure are the most common forms), the fall in blood pressure consequent to the venodilation produced by nitrates cannot be compensated. Nitrates may reduce arterial pressure and coronary perfusion pressure significantly and actually aggravate angina in addition to producing potentially life-threatening hypotension. The correct therapy in patients with orthostatic angina and normal coronary arteries is to correct the orthostatic hypotension by increasing volume retention (fludrocortisone and a high-sodium diet) by preventing venous pooling with fitted support garments and by the carefully titrated use of oral vasopressors. As patients with autonomic dysfunction occasionally may have coexistent coronary artery disease, the coronary anatomy should be defined before therapy is undertaken.

Effects on Total and Regional Coronary Blood Flow

Ischemia is a powerful stimulus to coronary vasodilation, and regional blood flow is adjusted by autoregulatory mechanisms. In the presence of atherosclerotic coronary narrowing, ischemia distal to the lesion is a stimulus for vasodilation, and, if the degree of narrowing is severe, much of the capacity to dilate is utilized to maintain resting blood flow. When situations arise that increase demand, further dilation may not be possible. After demonstration of direct coronary vasodilation in experimental animals, it became generally accepted that nitrates relieved anginal pain by dilating coronary arteries and thereby increasing coronary blood flow. This hypothesis was questioned by Gorlin and associates (1959), who were unable to demonstrate increases in coronary blood flow in patients with angina pectoris following the administration of nitroglycerin. However, organic nitrates do appear to cause redistribution of blood flow in the heart when the coronary circulation is partially occluded. Under these circumstances, there is a disproportionate reduction in blood flow to the subendocardial regions of the heart, which are subjected to the greatest extravascular compression during systole; organic nitrates tend to restore blood flow in these regions toward normal (Horwitz et al., 1971).

The hemodynamic mechanisms responsible for these effects are not entirely clear. Most hypotheses have focused on the ability of organic nitrates to cause dilation and prevent vasoconstriction of large epicardial vessels without impairing autoregulation in the small vessels, which are responsible for about 90% of the overall coronary vascular resistance. The vessel diameter is an important determinant of the response to nitroglycerin; vessels larger than 200 m in diameter are highly responsive, whereas those less than 100 m are minimally responsive (Sellke et al., 1990). Experimental evidence in patients undergoing coronary bypass surgery indicates that nitrates do have a relaxant effect on large coronary vessels. Collateral flow to ischemic regions also is increased (Goldstein et al., 1974). Moreover, analyses of coronary angiograms in human beings have shown that sublingual nitroglycerin can dilate epicardial stenoses and reduce the resistance to flow through such areas (Brown et al., 1981; Feldman et al., 1981). The resultant increase in blood flow would be distributed preferentially to ischemic myocardial regions as a consequence of vasodilation induced by autoregulation. An important indirect mechanism for a preferential increase in subendocardial blood flow is the nitroglycerin-induced reduction in intracavitary systolic and diastolic pressures that oppose blood flow to the subendocardium (see below). To the extent that organic nitrates decrease myocardial requirements for oxygen (see below), the increased blood flow in ischemic regions could be balanced by decreased flow in nonischemic areas, and an overall increase in coronary blood flow need not occur. Recent studies suggest that dilation of cardiac veins may result in an improvement in the perfusion of the coronary microcirculation (Darius, 1999). Redistribution of blood flow to subendocardial tissue is not typical of all vasodilators. Dipyridamole, for example, dilates resistance vessels nonselectively by distorting autoregulation; it is ineffective in patients with typical angina.

In patients with angina due to coronary spasm, the ability of organic nitrates to dilate epicardial coronary arteries, and particularly regions affected by spasm, may be the primary mechanism by which they are of benefit.

Effects on Myocardial Oxygen Requirements

By their effects on the systemic circulation, the organic nitrates also can reduce myocardial oxygen demand. The major determinants of myocardial oxygen consumption include left ventricular wall tension, heart rate, and the contractility of the myocardium. Ventricular wall tension is affected by a number of factors that may be considered under the categories of 'preload' and 'afterload.'Preload is determined by the diastolic pressure that distends the ventricle (ventricular end-diastolic pressure). Increasing end-diastolic volume augments the ventricular wall tension (by the law of Laplace, tension is proportional to pressure x radius). Increasing venous capacitance with nitrates decreases venous return to the heart, decreases ventricular end-diastolic volume, and thereby decreases oxygen consumption. An additional benefit of reducing preload is that it increases the pressure gradient for perfusion across the ventricular wall; this favors subendocardial perfusion (Parratt, 1979). Afterload is the impedance against which the ventricle must eject. In the absence of aortic valvular disease, afterload is related to peripheral resistance. Decreasing peripheral arteriolar resistance reduces afterload and thus myocardial work and oxygen consumption.

Organic nitrates do not directly alter the inotropic or chronotropic state of the heart. They do decrease both preload and afterload as a result of respective dilation of venous capacitance and arteriolar resistance vessels. Since the primary determinants of oxygen demand are reduced by the nitrates, their net effect usually is to decrease myocardial consumption of oxygen. In addition, an improvement in the lusitropic state of the heart may be seen, with more rapid early diastolic filling (Breisblatt et al., 1988). This may be secondary to the relief of ischemia, rather than primary, or may be due to a reflex increase in sympathetic activity. Nitrovasodilators also increase cyclic GMP in platelets with consequent inhibition of platelet function (De Caterina et al., 1988; Lacoste et al., 1994) and decreased deposition of platelets in animal models of arterial wall injury (Lam et al., 1988). While this may contribute to their antianginal efficacy, the effect appears to be modest and may in some settings be confounded by the potential of nitrates to alter the pharmacokinetics of heparin, reducing its antithrombotic effect.

When nitroglycerin is injected or infused directly into the coronary circulation of patients with coronary artery disease, anginal attacks (induced by electrical pacing) are not aborted, even when coronary blood flow is increased. However, sublingual administration of nitroglycerin does relieve anginal pain in the same patients (Ganz and Marcus, 1972). Furthermore, venous phlebotomy that is sufficient to reduce left ventricular end-diastolic pressure can mimic the beneficial effect of nitroglycerin.

Patients are able to exercise for considerably longer periods after the administration of nitroglycerin. Nevertheless, angina occurs, with or without nitroglycerin, at the same value of the 'triple product' (aortic pressure x heart rate x ejection time is proportional to the myocardial consumption of oxygen). The observation that angina occurs at the same level of myocardial oxygen consumption suggests that the beneficial effects of nitroglycerin are the result of a reduced cardiac oxygen demand, rather than an increase in the delivery of oxygen to ischemic regions of myocardium. However, these results do not preclude the possibility that a favorable redistribution of blood flow to ischemic subendocardial myocardium may contribute to relief of pain in a typical anginal attack, nor do they preclude the possibility that direct coronary vasodilation may be the major effect of nitroglycerin in situations where vasospasm compromises myocardial blood flow.

Mechanism of Relief of Symptoms of Angina Pectoris

Brunton ascribed the nitrate-induced relief of anginal pain to a decrease in cardiac work secondary to the fall in systemic arterial pressure. As described above, the ability of nitrates to dilate epicardial coronary arteries, even in areas of atherosclerotic stenosis, is modest, and the bulk of evidence continues to favor a reduction in myocardial work and thus in myocardial oxygen demand as their primary effect in chronic stable angina.

Paradoxically, high doses of organic nitrates may reduce blood pressure to such an extent that coronary flow is compromised; reflex tachycardia and adrenergic enhancement of contractility also occur. These effects may override the salutary action of the drugs on myocardial oxygen demand and can aggravate ischemia. Additionally, sublingual nitroglycerin administration may produce bradycardia and hypotension, probably due to activation of the Bezold-Jarisch reflex (Gibbons et al., 1999).

Other Effects

The nitrovasodilators act on almost all smooth muscle. Bronchial smooth muscle is relaxed irrespective of the cause of the preexisting tone. The muscles of the biliary tract, including those of the gallbladder, biliary ducts, and sphincter of Oddi, are effectively relaxed. Smooth muscle of the gastrointestinal tract, including that of the esophagus, can be relaxed and its spontaneous motility decreased by nitrates both in vivo and in vitro. The effect may be transient and incomplete in vivo, but abnormal 'spasm' frequently is reduced. Indeed, many incidences of atypical chest pain and 'angina' are due to biliary or esophageal spasm, and these too can be relieved by nitrates. Similarly, nitrates can relax ureteral and uterine smooth muscle, but these effects are somewhat unpredictable.

Mechanism of Action

Nitrites, organic nitrates, nitroso compounds, and a variety of other nitrogen oxidecontaining substances (including nitroprusside; see Chapter 33: Antihypertensive Agents and the Drug Therapy of Hypertension) lead to the formation of the reactive free radical nitric oxide (NO), which can activate guanylyl cyclase and increase the synthesis of cyclic GMP in smooth muscle and other tissues (see Murad, 1986; Molina et al., 1987). The exact mechanism(s) of denitration of the organic nitrates, with the subsequent liberation of NO, is controversial (Harrison and Bates, 1993). A cyclic GMPdependent protein kinase catalyzes the phosphorylation of various proteins in smooth muscle. Eventually, the light chain of myosin is dephosphorylated (Waldman and Murad, 1987). Phosphorylation of the myosin light chain regulates the maintenance of the contractile state in smooth muscle. The pharmacological and biochemical effects of the nitrovasodilators appear to be identical to those of an endothelium-derived relaxing factor, which has been shown to be NO (Moncada et al., 1988; Ignarro et al., 1987; Murad, 1996; Furchgott, 1996). The relationship of endogenous nitric oxide to its precursor, L-arginine, has been reviewed (Moncada and Higgs, 1993). Nitric oxide appears to function as a biological signal in many cell types (Lowenstein et al., 1994; Vane, 1994).

Absorption, Fate, and Excretion

The biotransformation of organic nitrates is the result of reductive hydrolysis catalyzed by the hepatic enzyme glutathioneorganic nitrate reductase. The enzyme converts the lipid-soluble organic nitrate esters into more water-soluble denitrated metabolites and inorganic nitrite. The partially denitrated metabolites are considerably less potent vasodilators than are the parent compounds. However, under certain conditions their activity may become important. Since the liver has an enormous capacity to catalyze the reduction of organic nitrates, their biotransformation is a major factor in determining oral bioavailability and duration of action. The pharmacokinetic properties of nitroglycerin and isosorbide dinitrate have been studied in the greatest detail.

Nitroglycerin

One molecule of nitroglycerin reacts with two molecules of reduced glutathione to produce 1,3- or 1,2-glyceryl dinitrate and oxidized glutathione (Needleman, 1975). A comparison of the maximal velocities of metabolism of the clinically used nitrates by this reductase indicates that erythrityl tetranitrate is degraded three times faster than is nitroglycerin, while isosorbide dinitrate and pentaerythritol tetranitrate are denitrated at one-sixth and one-tenth the rate of nitroglycerin.

In human beings, peak concentrations of nitroglycerin are found in plasma within 4 minutes of sublingual administration; the drug has a half-life of 1 to 3 minutes. The onset of action of nitroglycerin may be more rapid if it is delivered as a sublingual spray, rather than as a sublingual tablet (Ducharme et al., 1999). Dinitrate metabolites, which are about ten times less potent as vasodilators, appear to have a half-life of about 40 minutes.

Isosorbide Dinitrate

The major route of metabolism of isosorbide dinitrate in human beings is by enzymatic denitration followed by formation of glucuronide conjugates. Sublingual administration produces maximal concentrations of the drug in plasma by 6 minutes, and the fall in concentration is rapid (half-life approximately 45 minutes). The primary initial metabolites, isosorbide-2-mononitrate and isosorbide-5-mononitrate, have longer half-lives (3 to 6 hours) and are presumed to be responsible, at least in part, for the therapeutic efficacy of the drug.

Isosorbide-5-Mononitrate

This agent is available in tablet form. It has excellent bioavailability after oral administration as it does not undergo significant first-pass metabolism. It has a significantly longer half-life than does isosorbide dinitrate and has been formulated as a plain tablet and as a sustained-release preparation; both of which have longer durations of action than the corresponding dosage forms of isosorbide dinitrate.

Correlation of Plasma Concentrations of Drug and Biological Activity

Intravenous administration of nitroglycerin or the long-acting nitrates (isosorbide dinitrate, pentaerythritol tetranitrate, and erythrityl tetranitrate) in anesthetized animals produces the same transient (1 to 4 minutes) decrease in blood pressure. Relative to nitroglycerin, the potency of erythrityl tetranitrate as a vasodepressor in dogs is about 12% and that of isosorbide dinitrate 3.5%. Since denitration markedly reduces the activity of the organic nitrates, their rapid clearance from blood indicates that the transient duration of action under these conditions correlates with the concentrations of the parent compounds. The rate of hepatic denitration is characteristic of each nitrate and is influenced by hepatic blood flow or the presence of hepatic disease. In experimental animals, injection of moderate amounts of organic nitrates into the portal vein results in little or no vasodepressor activity, indicating that a substantial fraction of drug can be metabolized during its first circulation through the liver (isosorbide mononitrate is an exception).

Tolerance

Sublingual organic nitrates should be taken at the time of an anginal attack or in anticipation of exercise or stress. Such intermittent treatment results in reproducible cardiovascular effects. However, frequently repeated or continuous exposure to high doses of organic nitrates leads to a marked attenuation in the magnitude of most of their pharmacological effects (Anonymous, 1992; Thadani, 1992). The magnitude of tolerance is a function of dosage and the frequency of administration of the preparation.

Tolerance may result from an inability of the vascular smooth muscle to convert nitroglycerin to NO, 'true vascular tolerance,' or to the activation of mechanisms extraneous to the vessel wall, 'pseudotolerance' (Munzel et al., 1996). Multiple mechanisms have been proposed to account for nitrate tolerance, including volume expansion, neurohumoral activation, cellular depletion of sulfhydryl groups, and the generation of free radicals (Thadani, 1992; Rutherford, 1995; Parker and Parker 1998). The administration of organic nitrates to healthy volunteers is associated within 24 hours with the activation of the renin-angiotensin-aldosterone system and with increases in plasma norepinephrine (Parker et al., 1991). Clinical data relating to the ability of agents that modify the renin-angiotensin-aldosterone system to prevent nitrate tolerance are contradictory (Dakak et al., 1990; Muisan et al., 1993; Parker and Parker 1993; Pizzulli et al., 1996; Heitzer et al., 1998). Important factors that may influence the ability of angiotensin converting enzyme (ACE) inhibitors to prevent nitrate tolerance and that can influence the interpretation of clinical trials include the dose, treatment with the ACE inhibitors prior to the initiation of nitrates, and the tissue specificity of the agent. Despite the rationale for the depletion of sulfhydryl groups leading to impaired biotransformation of nitrates to NO and thereby resulting in nitrate tolerance, experimental results to date with sulfhydryl donors have been disappointing. A more recent proposal has linked nitroglycerin tolerance to endothelium-derived superoxide generation (Munzel et al., 1995b). In the setting of patients with congestive heart failure, administration of carvedilol, but not metoprolol, doxazosin, or placebo, has resulted in the prevention of tolerance to the effects of nitroglycerin on forearm blood flow (Watanabe et al., 1998). In addition to its properties as an - and -adrenergic receptor antagonist, carvedilol possesses antioxidant properties. A similar effect on vascular superoxide generation in the reduction of nitrate tolerance has been proposed for hydralazine (Elkayam et al., 1998). Other changes that are observed in the setting of nitroglycerin tolerance include an enhanced response to vasocontrictors such as angiotensin II, serotonin, and phenylephrine. This increased sensitivity to vasoconstrictors may result from a priming effect of endothelin-1 derived from the vasculature (Mnzel et al., 1995a). Administration of nitroglycerin is associated with plasma volume expansion, which may be reflected by a decrease in hematocrit. Although diuretic therapy with hydrochlorothiazide can improve a patient's exercise duration, appropriately designed crossover trials have failed to demonstrate an effect of diuretics on nitrate tolerance (Parker et al., 1996). In contrast to these adjunctive approaches, a more effective approach is to interrupt therapy for 8 to 12 hours each day, which allows the return of efficacy. It is usually most convenient to omit dosing at night in patients with exertional angina, either by adjusting dosing intervals of oral or buccal preparations or by removing cutaneous nitroglycerin. However, patients who have angina in a pattern suggesting its precipitation by increased left ventricular filling pressures (i.e., occurring with or near episodes of orthopnea or paroxysmal nocturnal dyspnea) may benefit from continuing nitrates at night and omitting them during a quiet period during the day. Tolerance to isosorbide dinitrate may be minimized by giving this drug two or three times daily, at 7 A.M. and noon or at 7 A.M., noon, and 5 P.M., respectively (Parker et al., 1987). Although it was thought that tolerance might be less of a problem with isosorbide-5-mononitrate, tolerance has been seen with this agent as well; an eccentric (7 or 8 A.M. and 2 or 3 P.M.) twice-daily dosing schedule appears to maintain efficacy (Parker, 1993; Thadani et al., 1994).

While these approaches appear to be effective, some patients develop an increased frequency of nocturnal angina when a nitrate-free interval is employed using nitroglycerin patches; such patients may need to receive another class of antianginal agent during this period. In addition, a phenomenon referred to as the 'zero-hour effect' has added to the complexity of designing an appropriate dosing regimen. In a 29-day study, the early morning exercise tolerance (before patch application) of patients using intermittent patch therapy was less than that of patients using placebo patches, though the antianginal efficacy of the patch itself was maintained (DeMots and Glasser, 1989). The clinical significance of this finding and its applicability to other dosage forms of nitroglycerin are not known. Tolerance does not appear to be a uniform phenomenon, as in some patients only partial tolerance seems to develop.

The problem of anginal rebound during nitrate-free intervals is especially troublesome in the treatment of unstable angina with intravenous nitroglycerin. If coverage of the interval with other agents is ineffective, an alternative approach that often is used is to increase gradually the dose of intravenous nitroglycerin in an attempt to overcome tolerance. This approach has not been studied carefully.

A special aspect of tolerance has been observed among individuals exposed to nitroglycerin in the manufacture of explosives. If protection is inadequate, workers may experience severe headaches, dizziness, and postural weakness during the first several days of employment. Tolerance then develops, but headache and other symptoms may reappear after a few days away from the jobthe 'Monday disease.' The most serious effect of chronic exposure is a form of organic nitrate dependence. Workers without demonstrable organic vascular disease have been reported to have an increase in the incidence of acute coronary syndromes during the 24- to 72-hour periods away from the work environment (Morton, 1977, Parker et al., 1995). Coronary and digital arteriospasm during withdrawal and its relaxation by nitroglycerin also have been demonstrated radiographically. Because of the potential problem of nitrate dependence, it seems prudent not to withdraw nitrates abruptly from a patient who has received such therapy chronically.

Toxicity and Untoward Responses

Untoward responses to the therapeutic use of organic nitrates are almost all secondary to actions on the cardiovascular system. Headache is common and can be severe. It usually decreases over a few days if treatment is continued and often can be controlled by decreasing the dose. Transient episodes of dizziness, weakness, and other manifestations associated with postural hypotension may develop, particularly if the patient is standing immobile, and may occasionally progress to loss of consciousness. This reaction appears to be accentuated by alcohol. It may be seen with very low doses of nitrates in patients with autonomic dysfunction. Even in the most severe nitrate syncope, positioning and other procedures to facilitate venous return are the only therapeutic measures required. It was widely believed that nitrates can increase intraocular pressure and precipitate glaucoma, but this fear appears to be unfounded (Robertson and Stevens, 1977). All of the organic nitrates occasionally can produce drug rash.

Interaction of Nitrates with Sildenafil

Erectile dysfunction is a frequently encountered problem, risk factors for which parallel those of coronary artery disease [diabetes mellitus, hypertension, known heart disease (Johannes et al., 2000) and a low level of high-density lipoprotein (Feldman et al., 1994)]. Thus, it is likely that many men requiring therapy for erectile dysfunction already may be receiving (or may require, especially if they increase physical activity) antianginal therapy. The past decade has seen remarkable advances in our understanding of the physiology of penile erection (Andersson and Wagner, 1995). Cells in the corpus cavernosum produce nitric oxide during sexual arousal in response to nonadrenergic, noncholinergic neurotransmission (Kim et al., 1991; Rajfer et al., 1992; and Burnett et al., 1992). Nitric oxide stimulates the formation of cyclic GMP, which leads to relaxation of smooth muscle of the corpus cavernosum and penile arteries. The accumulation of cyclic GMP can be enhanced by inhibition of the cyclic GMP-specific phopshophodiesterase-5 (PDE5) family (Beavo et al., 1994). Sildenafil (VIAGRA) was developed as an inhibitor of PDE5 (Boolell et al., 1996) and has been demonstrated to improve erectile function in patients with various causes of erectile dysfunction (Goldstein et al., 1998).

The side effects of sildenafil are largely predictable on the basis of its effects on PDE5. Headache, flushing, and rhinitis may be observed, as may dyspepsia due to relaxation of the lower esophageal sphincter, all thought to be consequences of the inhibition of PDE5. Sildenafil also is a weak inhibitor of PDE6, the isoenzyme involved in photoreceptor signal transduction (Beavo et al., 1994), and sildenafil has been associated with visual disturbances, most notably changes in the perception of color hue or brightness (Wallis et al., 1999; Goldstein et al., 1998). Sildenafil's most important toxicity is hemodynamic. When given alone to men with severe coronary artery disease, sildenafil has modest effects on blood pressure, producing less than a 10% fall in systolic, diastolic, and mean systemic pressures and in pulmonary artery systolic and mean pressures (Herrmann et al., 2000). However, it has a significant and potentially dangerous interaction with nitrates. As discussed above, the therapeutic actions of organic nitrates are mediated via their conversion to NO with resultant increases in cyclic GMP. In the presence of a PDE5 inhibitor, nitrates cause profound increases in cyclic GMP and can produce dramatic reductions in blood pressure. Healthy male subjects pretreated with sildenafil exhibited a much greater decrease in systolic blood pressure when treated with sublingual glyceryl trinitrate, and in many a fall of more than 25 mm Hg was detected (Webb et al., 1999). This interaction between sildenafil and nitrates is the basis for the warning that sildenafil should not be prescribed to patients receiving any form of nitrate (Cheitlen et al., 1999) and dictates that patients should be questioned about the use of sildenafil within 24 hours before nitrates are administered. A period of longer than 24 hours may be needed after sildenafil for safe use of nitrates. In the event that patients develop significant hypotension following combined administration of sildenafil and a nitrate, fluids and -adrenergic receptor agonists, if needed, should be used for support (Cheitlin et al., 1999).

Sildenafil is metabolized via CYP3A4, and its toxicity may be enhanced in patients who receive other substrates of this enzyme, including macrolide and imidazole antibiotics, some HMG-CoA reductase inhibitors, and highly active antiretroviral therapy (HAART; see Chapter 51: Antiretroviral Agents: Antiretroviral Agents) (Hall and Ahmad, 1999). Sildenafil also has been demonstrated to prolong cardiac repolarization by blocking the I_Kr (Geelen et al., 2000). Although these interactions and effects are clinically important, the overall incidence and profile of adverse events observed with sildenafil, when used without nitrates, are consistent with the expected background frequency of the same events in the treated population (Zusman et al., 1999). In patients with coronary artery disease who are not currently taking nitrates and whose exercise capacity indicates that usual sexual activity is unlikely to precipitate angina, the use of sildenafil can be considered. Such therapy needs to be individualized and appropriate warnings given about the risk of toxicity if nitrates are taken during the next 24 hours for angina. Alternative nonnitrate antianginal therapy, such as -adrenergic receptor antagonists, should be used during this time period (Cheitlin et al., 1999).

Therapeutic Uses

Angina

Diseases that predispose to angina should be treated as part of a comprehensive therapeutic program with the primary goal being to prolong life. Such conditions as hypertension, anemia, thyrotoxicosis, obesity, heart failure, cardiac arrhythmias, and acute anxiety can precipitate anginal symptoms in many patients. The patient should be asked to stop smoking and overeating, hypertension and hyperlipidemia should be corrected (see Chapters 33: Antihypertensive Agents and the Drug Therapy of Hypertension and 36: Drug Therapy for Hypercholesterolemia and Dyslipidemia), and daily aspirin (or a thienopyridine such as clopidogrel or ticlopidine, if aspirin is not tolerated; see Chapter 55: Anticoagulant, Thrombolytic, and Antiplatelet Drugs) should be prescribed. Exposure to sympathomimetic agents (e.g., those in nasal decongestants) should be avoided. The use of drugs that modify the perception of pain is a poor approach to the treatment of angina, since the underlying myocardial ischemia is not relieved. See Table 321 for preparations and dosages of the nitrites and organic nitrates. The rapidity of onset, the duration of action, and the likelihood of developing tolerance are related to the method of administration.

Sublingual Administration

Because of its rapid action, long-established efficacy, and low cost, nitroglycerin is the most useful drug among the organic nitrates that can be given sublingually. The onset of action is within 1 to 2 minutes, but the effects are undetectable by 1 hour after administration. An initial dose of 0.3 mg of nitroglycerin often will relieve pain within 3 minutes. Absorption may be limited in patients with dentures or with dry mouths. Tablets of nitroglycerin are stable but should be dispensed in glass containers and protected from moisture, light, and extremes of temperature. Active tablets usually produce a burning sensation under the tongue, but the absence of a burning sensation does not reliably predict loss of activity. Patients, especially elderly ones, differ in the ability to detect the burning sensation. Anginal pain may be prevented when the drug is used prophylactically immediately prior to exercise or stress. The smallest effective dose should be prescribed. Patients should be taught to seek medical attention immediately when three tablets taken over a 15-minute period do not relieve a sustained attack, since this situation may be indicative of myocardial infarction or another cause of the pain. The patient also should be advised that there is no virtue in trying to avoid taking sublingual nitroglycerin for anginal pain. Other nitrates that can be taken sublingually do not appear to be longer acting than nitroglycerin, as their half-lives depend only on the rate at which they are delivered to the liver. They are not more effective than nitroglycerin and often are more expensive.

Oral Administration

Oral nitrates often are used to provide prophylaxis against anginal episodes in patients who have more than occasional angina. They must be given in sufficient dosage to provide effective plasma levels after first-pass hepatic degradation. At low doses (e.g., 5 to 10 mg of isosorbide dinitrate) they are no more effective than placebo in decreasing the frequency of angina or increasing the patient's exercise tolerance. Clinical studies that have used higher doses of either isosorbide dinitrate (e.g., 20 mg or more orally every 4 hours) or sustained-release preparations of nitroglycerin indicate that such regimens decrease the frequency of attacks of angina and improve exercise tolerance. Effects peak at 60 to 90 minutes and last for 3 to 6 hours. Under these circumstances, the activities of less potent metabolites also may contribute to the therapeutic effect. Chronic oral administration of isosorbide dinitrate (120 to 720 mg daily) results in persistence of the parent compound and higher concentrations of metabolites in plasma. However, these doses are more likely to cause troublesome side effects and tolerance. Significant, prolonged (up to 4 hours) improvement of exercise tolerance also can be demonstrated with a sustained-release oral form of nitroglycerin, but high doses (e.g., 6.5 mg) of nitroglycerin are required.

Cutaneous Administration

Application of nitroglycerin ointment can relieve angina, prolong exercise capacity, and reduce ischemic ST depression with exercise for 4 hours or more. Nitroglycerin ointment (2%) is applied to the skin [2.5 to 5 cm (1 to 2 in.) as it is squeezed from the tube; it is then spread in a uniform layer]; the dosage must be adjusted for each patient. Effects are apparent within 30 to 60 minutes (although absorption is variable) and last for 4 to 6 hours. The ointment is particularly useful for controlling nocturnal angina, which commonly develops within 3 hours after the patient goes to sleep. Transdermal nitroglycerin discs utilize a nitroglycerin-impregnated polymer (bonded to an adhesive bandage) that permits gradual absorption and a continuous plasma nitrate concentration over 24 hours. The onset of action is slow, with peak effects occurring at 1 to 2 hours. To avoid tolerance and loss of the therapeutic effect, therapy should be interrupted for at least 8 hours each day. With this regimen, long-term prophylaxis of ischemic episodes often can be attained.

Transmucosal or Buccal Nitroglycerin

This formulation is inserted under the upper lip above the incisors, where it adheres to the gingiva and gradually dissolves in a uniform manner. Hemodynamic effects are seen within 2 to 5 minutes, and it is therefore useful for short-term prophylaxis of angina. Nitroglycerin continues to be released into the circulation for a prolonged period, and exercise tolerance may be enhanced for up to 5 hours.

Congestive Heart Failure

The utility of nitrovasodilators to relieve pulmonary congestion and to increase cardiac output in congestive heart failure is well established and is addressed in Chapter 34: Pharmacological Treatment of Heart Failure.

Unstable Angina

Unstable angina has been considered a single entity in most therapeutic trials; it has included patients with new-onset exertional angina, with an increase in their usual pattern of angina, and with rest angina, with or without a preceding history of exertional angina. The electrocardiogram (ECG) may show either elevation or depression of the ST segment, with variable T-wave abnormalities. In patients with left main or three-vessel disease, revascularization leads to improved survival (Multicenter Study, 1978). In the remainder of patients, and in all patients prior to determination of the coronary anatomy, appropriate medical therapy provides important benefits. The pathophysiology in most patients studied involves thrombosis overlying a ruptured atherosclerotic plaque. However, there is some variability in the anatomic substrate of unstable angina, with gradually progressive atherosclerosis accounting for some cases of new-onset exertional angina, and vasospasm occurring in minimally atherosclerotic coronary vessels accounting for some cases where rest angina has never been preceded by or associated with exertional angina. It is likely that this variability accounts for the differences in therapeutic response seen in studies with differing inclusion criteria.

Multiple agents are employed in the acute phase of treatment, although few have been demonstrated conclusively to reduce mortality. Aspirin (see below), by inhibiting platelet aggregation, has been shown clearly to improve survival (Kerins and FitzGerald, 1991). Heparin (either unfractionated or low-molecular-weight heparin) also appears to reduce angina and prevent infarction. These and related agents are discussed in detail in Chapters 27: Analgesic-Antipyretic and Antiinflammatory Agents and Drugs Employed in the Treatment of Gout and 55: Anticoagulant, Thrombolytic, and Antiplatelet Drugs. Nitrates are useful in reducing vasospasm and controlling angina; their administration should be initiated intravenously. Intravenous administration of nitroglycerin allows high concentrations of drug to be attained rapidly. As nitroglycerin is promptly degraded, the plasma concentration can be titrated quickly and safely using this route. If coronary vasospasm is present, intravenous nitroglycerin is likely to be effective, although the addition of a Ca²⁺ channel blocker is required to achieve complete control in some patients. Because of the potential risks of profound hypotension, nitrates should be withheld and alternate antianginal therapy administered if patients have consumed sildenafil within the prior 24 hours (see above).

Myocardial Infarction

Therapeutic maneuvers in myocardial infarction are directed at reducing the ultimate size of the infarct and preserving or retrieving viable tissue by reducing the oxygen demand of the myocardium. Since the proximate cause of myocardial infarction is intracoronary thrombosis, reperfusion therapies are critically important and include thrombolytic agents and direct percutaneous coronary angioplasty (Ryan et al., 1999). Thrombolytic and antiplatelet therapy are discussed in Chapter 55: Anticoagulant, Thrombolytic, and Antiplatelet Drugs. A drug that favorably alters the oxygen balance could decrease the area of myocardial damage if it were given soon after infarction.

In the past, nitroglycerin was considered to be contraindicated for use in patients with acute myocardial infarction because of its ability to induce hypotension and reflex tachycardia, although it may be highly efficacious if the infarction is due to prolonged coronary spasm. Nevertheless, evidence that nitrates improve mortality in myocardial infarction is sparse. Nitrates may be most helpful in patients in whom reperfusion does not occur, despite thrombolytic agents, and may prevent adverse remodeling. The effects of nitrates in patients with acute myocardial infarction were assessed in two large trials (GISSI-3, 1994, and ISIS-4 Collaborative Group, 1995). In the GISSI-3 study, 19,394 patients with acute myocardial infarction were randomized to receive either transdermal nitroglycerin (10 mg daily with a 10-hour nitrate-free interval overnight) or placebo for 6 weeks. There were no significant effects of nitroglycerin on mortality, reinfarction, revascularization procedures, or renal dysfunction. There was a slight reduction in postinfarction angina in the nitroglycerin-treated group (20.7% vs. 19.7%). A similar lack of benefit on mortality was observed in the ISIS-4 study of 58,050 patients, some of whom were randomized to receive an oral controlled-release form of isosorbide mononitrate, 60 mg each morning for 28 days, or placebo. In the ISIS-4 study there was no effect of the nitrate on postinfarction angina. Thus transdermal or oral nitrates are safe and well tolerated in the setting of myocardial infarction and may have a beneficial effect on pain, but they do not provide a survival advantage.

Variant (Prinzmetal's) Angina

The large coronary arteries normally contribute little to coronary resistance. However, in variant angina, coronary constriction results in reduced blood flow and ischemic pain. Multiple mechanisms have been hypothesized to be involved in the initiation of vasospasm, including endothelial cell injury (Freisinger and Robertson, 1986). It does not seem likely that abnormalities of sympathetic input are etiologic (Robertson et al., 1979), and -adrenergic receptor antagonists can be deleterious (Robertson et al., 1982). Despite the presence of abnormal coronary anatomy in all cases that have come to autopsy, it does not appear that active intravascular platelet aggregation is a precipitating factor, and aspirin does not appear to provide benefit (Robertson et al., 1981). Whereas long-acting nitrates alone are occasionally efficacious in abolishing episodes of variant angina, more often additional therapy with Ca²⁺ channel blockers is required. Because Ca²⁺ channel blockers, but not nitrates, have been shown to favorably influence mortality and the incidence of myocardial infarction in variant angina, they should be included in therapy.

History

The work in the 1960s of Fleckenstein, Godfraind, and their colleagues led to the concept that drugs can alter cardiac and smooth muscle contraction by blocking the entry of Ca²⁺ into myocytes. Godfraind and associates showed that the ability of the diphenylpiperazine analogs cinnarizine and lidoflazine to prevent vascular smooth muscle contraction induced by some agonists could be overcome by raising the concentration of Ca²⁺ in the extracellular medium; they used the term 'calcium antagonist' to describe these agents (see Godfraind and Kaba, 1972; Godfraind et al., 1986).

Hass and Hartfelder reported in 1962 that verapamil, a putative coronary vasodilator, possessed negative inotropic and chronotropic effects that were not seen with other vasodilatory agents, such as nitroglycerin. In 1967, Fleckenstein suggested that the negative inotropic effect resulted from inhibition of excitationcontraction coupling and that the mechanism involved reduction of the movement of Ca²⁺ into cardiac myocytes (see Fleckenstein, 1983). A derivative of verapamil, gallopamil, and other compounds, such as nifedipine (Kohlhardt and Fleckenstein, 1977), also were shown to block the movement of Ca²⁺ through the cardiac myocyte Ca²⁺ channel, or the slow channel (see Chapter 35: Antiarrhythmic Drugs), and thereby alter the plateau phase of the cardiac action potential. Subsequently, many drugs in several chemical classes have been shown to alter cardiac and smooth muscle contraction by blocking or 'antagonizing' the entry of Ca²⁺ through channels in the myocyte membrane.

Chemistry

The ten Ca²⁺ channel antagonists that have been approved for clinical use in the United States have diverse chemical structures. Five classes of compounds have been examined: phenylalkylamines, dihydropyridines, benzothiazepines, diphenylpiperazines, and a diarylaminopropylamine. At present, verapamil (a phenylalkylamine); diltiazem (a benzothiazepine); nicardipine, nifedipine, isradipine, amlodipine, felodipine, nisoldipine, and nimodipine (dihydropyridines); and bepridil (a diarylaminopropylamine ether) are approved for clinical use in the United States. Their structures are shown in Table 322.

Pharmacological Properties

Cardiovascular Effects

Actions in Vascular Tissue

Although there is some involvement of Na⁺ currents, depolarization of vascular smooth muscle cells is primarily dependent on the influx of Ca²⁺ (Bolton, 1979). At least three distinct mechanisms may be responsible for contraction of vascular smooth muscle cells. First, voltage-sensitive Ca²⁺ channels open in response to depolarization of the membrane, and extracellular Ca²⁺ moves down its electrochemical gradient into the cell. After closure of Ca²⁺ channels, a finite period of time is required before the channels can open again in response to a stimulus. Second, agonist-induced contractions that occur without depolarization of the membrane result from the hydrolysis of membrane phosphatidylinositol with the formation of inositol trisphosphate, which acts as a second messenger to release intracellular Ca²⁺ from the sarcoplasmic reticulum (see Berridge, 1993). This receptor-mediated release of intracellular Ca²⁺ may trigger further influx of extracellular Ca²⁺. Third, receptor-operated Ca²⁺ channels allow the entry of extracellular Ca²⁺ in response to receptor occupancy.

An increase in cytosolic Ca²⁺ results in enhanced binding of Ca²⁺ to the protein calmodulin. The Ca²⁺calmodulin complex in turn activates myosin light-chain kinase, with resultant phosphorylation of the light chain of myosin. Such phosphorylation promotes interaction between actin and myosin and contraction of smooth muscle. Ca²⁺ channel antagonists or blockers inhibit the voltage-dependent Ca²⁺ channels in vascular smooth muscle at significantly lower concentrations than are required to interfere with the release of intracellular Ca²⁺ or to block receptor-operated Ca²⁺ channels. All Ca²⁺ channel blockers relax arterial smooth muscle, but they have little effect on most venous beds and hence do not affect cardiac preload significantly.

Actions in Cardiac Cells

The mechanisms involved in excitationcontraction coupling in the heart differ from those in vascular smooth muscle in that a portion of the two inward currents is carried by Na⁺ through the fast channel in addition to that carried by Ca²⁺ through the slow channel. In the sinoatrial (SA) and atrioventricular (AV) nodes, depolarization is largely dependent on the movement of Ca²⁺ through the slow channel. Within the cardiac myocyte, Ca²⁺ binds to troponin, the inhibitory effect of troponin on the contractile apparatus is relieved, and actin and myosin interact to cause contraction. Thus, Ca²⁺ channel blockers can produce a negative inotropic effect. Although this is true of all classes of Ca²⁺ channel blockers, the greater degree of peripheral vasodilation seen with the dihydropyridines is accompanied by sufficient baroreflex-mediated increase in sympathetic tone to overcome the negative inotropic effect. Diltiazem also may inhibit mitochondrial Na⁺Ca²⁺ exchange (Schwartz, 1992).

The effect of a Ca²⁺ channel blocker on atrioventricular conduction and on the rate of the sinus node pacemaker is dependent on whether or not the agent delays the recovery of the slow channel (Henry, 1983). Although nifedipine reduces the slow inward current in a dose-dependent manner, it does not affect the rate of recovery of the slow Ca²⁺ channel (Kohlhardt and Fleckenstein, 1977). The channel blockade caused by nifedipine and related dihydropyridines also shows little dependence on the frequency of stimulation. At doses used clinically, nifedipine does not affect conduction through the node. In contrast, verapamil not only reduces the magnitude of the Ca²⁺ current through the slow channel but also decreases the rate of recovery of the channel. In addition, channel blockade caused by verapamil (and to a lesser extent by diltiazem) is enhanced as the frequency of stimulation increases, a phenomenon known as 'frequency dependence' or 'use dependence.' Verapamil and diltiazem depress the rate of the sinus node pacemaker and slow AV conduction; the latter effect is the basis for their use in the treatment of supraventricular tachyarrhythmias (see Chapter 35: Antiarrhythmic Drugs). Bepridil, like verapamil, inhibits both slow inward Ca²⁺ current and fast inward Na⁺ current. It has a direct negative inotropic effect. Its electrophysiologic properties lead to slowing of the heart rate, prolongation of the AV nodal effective refractory period, and, importantly, prolongation of the QTc interval. Particularly in the setting of hypokalemia, the last effect can be associated with torsades de pointes, a potentially lethal ventricular arrhythmia (see Chapter 35: Antiarrhythmic Drugs).

Hemodynamic Effects

All of the Ca²⁺ channel blockers that have been approved for clinical use decrease coronary vascular resistance and increase coronary blood flow. The dihydropyridines are more potent vasodilators in vivo and in vitro than is verapamil, which is more potent than diltiazem. The hemodynamic effects of each of these agents vary, depending on the route of administration and the extent of left ventricular dysfunction.

Nifedipine given intravenously increases forearm blood flow with little effect on venous pooling; this indicates a selective dilation of arterial resistance vessels. The decrease in arterial blood pressure elicits sympathetic reflexes, with resultant tachycardia and positive inotropy. Nifedipine also has direct negative inotropic effects in vitro. However, nifedipine relaxes vascular smooth muscle at significantly lower concentrations than those required for prominent direct effects on the heart. Thus, arteriolar resistance and blood pressure are lowered, contractility and segmental ventricular function are improved, and heart rate and cardiac output are increased modestly (Serruys et al., 1981; Theroux et al., 1980). After oral administration of nifedipine, arterial dilation increases peripheral blood flow; venous tone does not change.

The other dihydropyridinesnicardipine, amlodipine, isradipine, felodipine, nisoldipine, and nimodipineshare many of the cardiovascular effects of nifedipine. There may be some selectivity of nicardipine for coronary vessels compared with peripheral vessels (Pepine and Lambert, 1988); in comparative studies, nicardipine appears to produce fewer side effects, such as dizziness, than does nifedipine but has equivalent antianginal efficacy (DeWood and Wohlbach, 1990). Intravenous or oral administration of nicardipine results in decreases in systolic and diastolic blood pressure that are accompanied by an increase in cardiac output because of the reduction in afterload and compensatory increases in heart rate and ejection fraction. It also appears to reduce left ventricular diastolic dysfunction (Hanet et al., 1990). Nicardipine decreases the frequency of anginal attacks and improves exercise tolerance in patients with effort-induced angina (Pepine and Lambert, 1988). Amlodipine is a dihydropyridine that has slow absorption and a prolonged effect. With a plasma half-life of 35 to 50 hours, plasma levels and effect increase over 7 to 10 days of therapy. Amlodipine produces both peripheral arterial vasodilation and coronary dilation, with a hemodynamic profile similar to that of nifedipine. However, there is less reflex tachycardia with amlodipine, possibly because the long half-life produces minimal peaks and troughs in plasma concentrations (van Zwieten and Pfaffendorf, 1993; Taylor, 1994; Lehmann et al., 1993). Felodipine appears to have even greater vascular specificity than does nifedipine or amlodipine. At concentrations producing vasodilation, there is no negative inotropic effect. Like nifedipine, felodipine produces activation of the sympathetic nervous system, leading to an increase in heart rate (Todd and Faulds, 1992). Isradipine also produces the typical peripheral vasodilation seen with other dihydropyridines, but because of its inhibitory effect on the SA node, little or no rise in heart rate is seen. This inhibitory effect does not extend to the myocardium, however, as no cardiodepressant effect is seen. Despite the negative chronotropic effect, isradipine appears to have little effect on the AV node, so it may be used in patients with AV block or combined with a -adrenergic receptor antagonist. In general, because of their lack of myocardial depression and, to a greater or lesser extent, lack of negative chronotropic effect, dihydropyridines are less effective as monotherapy in stable angina than are verapamil, diltiazem, or a -adrenergic receptor antagonist. Nisoldipine is more than 1000-times as potent in preventing contraction of human vascular smooth muscle than in preventing contraction of human cardiac muscle in vitro, suggesting a very high degree of vascular selectivity (Godfraind et al., 1992). This selectivity has been confirmed by in vitro studies. Although nisoldipine has a short elimination half-life, a sustained-release preparation has been developed, nisoldipine coat-core, that has been demonstrated to be as effective an antianginal agent as amlodipine or diltiazem (Langtry and Spencer, 1997). Nimodipine, because of its high lipid solubility, was developed as an agent to relax the cerebral vasculature. It is effective in inhibiting cerebral vasospasm and is used primarily to treat patients with neurological defects thought to be caused by vasospasm after subarachnoid hemorrhage.

Bepridil has been demonstrated to reduce blood pressure and heart rate in patients with stable exertional angina. It also produces an increase in left ventricular performance in patients with angina, but its side-effect profile (see below) limits its use to truly refractory patients (Zusman et al., 1993; Hollingshead et al., 1992).

Verapamil is a less potent vasodilator in vivo than are the dihydropyridines. Like the latter agents, verapamil causes little effect on venous resistance vessels at concentrations that produce arteriolar dilation. With doses of verapamil sufficient to produce peripheral arterial vasodilation, there are more direct negative chronotropic, dromotropic, and inotropic effects than with the dihydropyridines. Intravenous verapamil causes a decrease in arterial blood pressure due to a decrease in vascular resistance, but the reflex tachycardia is blunted or abolished by the direct negative chronotropic effect of the drug. The intrinsic negative inotropic effect of verapamil is partially offset by both a decrease in afterload and the reflex increase in adrenergic tone. Thus, in patients without congestive heart failure, ventricular performance is not impaired and may actually improve, especially if ischemia is limiting performance. In contrast, in patients with congestive heart failure, intravenous verapamil can cause a marked decrease in contractility and left ventricular function. Oral administration of verapamil results in reduction of peripheral vascular resistance and blood pressure with no change in heart rate (Theroux et al., 1980). The relief of pacing-induced angina seen with verapamil is due primarily to a reduction in myocardial oxygen demand (Rouleau et al., 1983).

Intravenous administration of diltiazem can result initially in a marked decrease in peripheral vascular resistance and arterial blood pressure, which elicits a reflex increase in heart rate and cardiac output. Heart rate then falls below initial levels because of the direct negative chronotropic effect of the agent. Oral administration of diltiazem results in a sustained fall in both heart rate and mean arterial blood pressure (Theroux et al., 1980). Despite the fact that diltiazem and verapamil produce similar effects on the SA and AV nodes, the negative inotropic effect of diltiazem is more modest.

The effect of Ca²⁺ channel blockers on diastolic ventricular relaxation (the lusitropic state of the ventricle) is complex. The direct effect of several of these agents, assessed when they are given by the intracoronary route, is to impair relaxation (Rousseau et al., 1980; Amende et al., 1983; Serruys et al., 1983; Walsh and O'Rourke, 1985). Although several clinical studies have suggested an improvement in peak left ventricular filling rates when verapamil, nifedipine, nisoldipine, or nicardipine was given systemically (Bonow et al., 1982; Paulus et al., 1983; Rodrigues et al., 1987; DEFIANT-II Research Group, 1997), one must be cautious in extrapolating this change in filling rates to enhancement of relaxation. Indeed, in studies by Nishimura et al. (1993), verapamil increased peak filling rate but also increased left ventricular end-diastolic pressure. Because ventricular relaxation is modulated at several levels (Brutsaert et al., 1993), the effect of even a single agent may be complex. If reflex stimulation of sympathetic tone increases myocardial cyclic AMP levels, increased lusitropy will result and may outweigh a direct negative lusitropic effect. Likewise, a reduction in afterload will improve the lusitropic state. In addition, if ischemia is improved, the negative lusitropic effect of asymmetrical left ventricular contraction will be reduced. However, in any given patient, the sum total of these effects cannot be determined a priori. Thus, caution should be exercised in the use of Ca²⁺ channel blockers for this purpose; it is ideal if the end result can be determined objectively before committing the patient to therapy.

Mechanisms of Action

Increased concentrations of cytosolic Ca²⁺ cause increased contraction of cardiac and vascular smooth muscle cells. The entry of extracellular Ca²⁺ is more important in initiating the contraction of myocardial cells, while the release of Ca²⁺ from intracellular storage sites also participates in contraction of vascular smooth muscle, particularly in some vascular beds. In addition, the entry of extracellular Ca²⁺ can trigger the release of additional Ca²⁺ from intracellular stores.

Cytosolic Ca²⁺ concentrations may be increased by various contractile stimuli. Thus, many hormones and neurohormones increase Ca²⁺ influx through so-called receptor-operated channels, while high external concentrations of K⁺ and depolarizing electrical stimuli increase Ca²⁺ influx through voltage-sensitive, or 'potential-operated,' channels (Bevan et al., 1982).

Voltage-sensitive channels contain domains of homologous sequence that are arranged in tandem within a single large subunit. In addition to the major channel-forming subunit (termed ), Ca²⁺ channels contain several other associated subunits (termed , and ; see Schwartz, 1992).

Voltage-sensitive Ca²⁺ channels have been divided into at least three subtypes based on their conductances and sensitivities to voltage (Schwartz, 1992; Tsien et al., 1988). The channels best characterized to date are the L, N, and T subtypes, although P/Q and R channels have been identified. Only the L-type channel is sensitive to the dihydropyridine Ca²⁺ channel blockers. Large divalent cations such as Cd²⁺ and Mn²⁺ block a wider range of Ca²⁺ channels. All approved Ca²⁺ channel blockers bind to the subunit of the L-type calcium channel, which is the main pore-forming unit of the channel. This 200,000- to 250,000-dalton subunit is associated with a disulfide-linked subunit of approximately 140,000 daltons and an intracellular subunit of 55,000 to 72,000 daltons. The subunits share a common topology of four homologous domains (I, II, III and IV), each of which is composed of six putative transmembrane segments (S1S6). The and subunits modulate the subunit. The phenylalkylamine Ca²⁺ channel blockers bind to transmembrane segment 6 of domain IV (IVS6), the benzothiazepine Ca²⁺ channel blockers bind to the cytoplasmic bridge between domain III (IIIS) and domain IV (IVS), and the dihydropyridine Ca²⁺ channel blockers bind to transmembrane segment of both domain III (IIIS6) and domain IV (IVS6). These three separate receptor sites are allosterically linked (Hockerman et al., 1997, Abernethy and Schwartz, 1999).

The vascular and cardiac effects of some of the Ca²⁺ channel blockers are summarized below and in Table 322.

Absorption, Fate, and Excretion

Although the absorption of these agents is nearly complete after oral administration, their bioavailability is reduced, in some cases markedly, because of first-pass hepatic metabolism. The effects of these drugs are evident within 30 to 60 minutes of an oral dose, with the exception of the more slowly absorbed and longer-acting agents amlodipine, isradipine, and felodipine. For comparison, peak effects of verapamil occur within 15 minutes of its intravenous administration. These agents all are bound to plasma proteins to a significant extent (70% to 98%); their elimination half-lives are widely variable and may range from 1.3 to 64 hours. During repeated oral administration, bioavailability and half-life may increase because of saturation of hepatic metabolism. A major metabolite of diltiazem is desacetyldiltiazem, which has about one-half of diltiazem's potency as a vasodilator. N-Demethylation of verapamil results in production of norverapamil, which is biologically active but much less potent than the parent compound. The half-life of norverapamil is about 10 hours. The metabolites of the dihydropyridines are inactive or weakly active. In patients with hepatic cirrhosis, the bio availabilities and half-lives of the Ca²⁺ channel blockers may be increased, and dosage should be decreased accordingly. The half-lives of these agents also may be longer in older patients. Except for diltiazem and nifedipine, all of the Ca²⁺ channel blockers are administered as racemic mixtures (Abernethy and Schwartz, 1999).

Toxicity and Untoward Responses

The most common side effects caused by the Ca²⁺ channel antagonists, particularly the dihydropyridines, are due to excessive vasodilation. These effects may be expressed as dizziness, hypotension, headache, flushing, digital dysesthesia, and nausea. Patients also may experience constipation, peripheral edema, coughing, wheezing, and pulmonary edema. Nimodipine may produce muscular cramps when given in the large doses required for a beneficial effect in patients with subarachnoid hemorrhage. Less common side effects include rashes, somnolence, and occasional minor elevations of liver function tests. These side effects usually are benign and may abate with time or with adjustment of the dose. Aggravation of myocardial ischemia has been observed in two studies with the dihydropyridine nifedipine (Schulz et al., 1985; Egstrup and Anderson, 1993). In both of these studies, worsening of angina was observed in patients with an angiographically demonstrable coronary collateral circulation. The worsening of angina may have resulted from excessive hypotension and decreased coronary perfusion, selective coronary vasodilation in nonischemic regions of the myocardium (i.e., coronary steal, since vessels perfusing ischemic regions may already be maximally dilated), or an increase in oxygen demand owing to increased sympathetic tone and excessive tachycardia. In a study of monotherapy with an immediate-release formulation of nisoldipine, the dihydropyridine was not superior to placebo therapy and was associated with a trend toward an increased incidence of serious adverse events (Thadani et al., 1991), a process described by Waters (1991) as proischemia.

Although bradycardia, transient asystole, and exacerbation of heart failure have been reported with verapamil, these responses usually have occurred after intravenous administration of verapamil, in patients with disease of the SA node or AV nodal conduction disturbances, or in the presence of -adrenergic receptor blockade. The use of intravenous verapamil with a -adrenergic receptor antagonist is contraindicated because of the increased propensity for atrioventricular block and/or severe depression of ventricular function. Patients with ventricular dysfunction, SA or AV nodal conduction disturbances, and systolic blood pressures below 90 mm Hg should not be treated with verapamil or diltiazem, particularly intravenously. Some Ca²⁺ channel antagonists can cause an increase in the concentration of digoxin in plasma, although toxicity from the cardiac glycoside rarely develops. The use of verapamil to treat digitalis toxicity is thus contraindicated; AV nodal conduction disturbances may be exacerbated. Bepridil, because of its antiarrhythmic properties and its ability to prolong the QTc interval, can produce serious arrhythmic side effects. Especially in the setting of hypokalemia and/or bradycardia, polymorphic ventricular tachycardia (torsades de pointes), a potentially lethal arrhythmia, can be seen. Agranulocytosis also has been reported. Because of these serious side effects, this agent should be reserved for patients refractory to all other appropriate medical and surgical therapy (Hollingshead et al., 1992).

A novel Ca²⁺ channel blocker, mibefradil, is an example of an agent that inhibits both the T- and L-type Ca²⁺ channels. The T-type Ca²⁺ channel contributes to the spontaneous contractile function of smooth muscle cells (Mishra and Hermsmeyer, 1994). Mibefradil was demonstrated to be effective in reducing the frequency and duration of asymptomatic ischemic episodes in patients with stable exertional angina pectoris and asymptomatic ischemia (Braun et al., 1996) and received approval from the United States Food and Drug Administration (FDA) for use as an antianginal agent. However, it subsequently was withdrawn from the market due to adverse drug interactions, possibly due to its dual inhibition of both the P-glycoprotein and CYP3A systems (Wandel et al., 2000).

Recent observational studies and a metaanalysis have raised concerns about the long-term safety of the Ca²⁺ channel blockers, and in particular, short-acting nifedipine preparations (Psaty et al., 1995; Pahor et al., 1995; Furberg et al., 1995). Authors of a recent analysis based on a total of 100 clinical studies of Ca²⁺ channel blockers concluded that observational studies and randomized clinical trials give concordant evidence linking adverse safety effects to short-acting Ca²⁺ channel blockers, specifically to short-acting nifedipine (Opie et al., 2000). The proposed hypothesis for this adverse effect lies in abrupt vasodilation with reflex sympathetic activation. A similar conclusion was reached by Stason et al. (1999), who performed a systematic review of the literature on nifedipine and determined that adverse effects were observed in patients on monotherapy with an immediate-release formulation of nifedipine.

Therapeutic Uses

Variant Angina

Variant angina is a direct result of a reduction in flow, not the result of an increase in oxygen demand. Controlled clinical trials have demonstrated efficacy of the Ca²⁺ channel blocking agents for the treatment of variant angina (Antman et al., 1980; Severi et al., 1980). These drugs can attenuate ergonovine-induced vasospasm in patients with variant angina, which suggests that protection in variant angina is due to coronary dilation rather than to alterations in peripheral hemodynamics (Waters et al., 1981).

Exertional Angina

Ca²⁺ channel antagonists also are effective in the treatment of exertional, or exercise-induced, angina. The utility of these agents may result from an increase in blood flow due to coronary arterial dilation, from a decrease in myocardial oxygen demand (secondary to a decrease in arterial blood pressure, heart rate, or contractility), or from both. Numerous double-blind placebo-controlled studies have shown that these drugs decrease the number of anginal attacks and attenuate exercise-induced depression of the ST segment.

The 'double product,' which is calculated as heart rate x systolic blood pressure, is an indirect measure of myocardial oxygen demand. Since these agents reduce the level of the double product (or oxygen demand) at a given external work load, and the value of the double product at peak exercise is not altered, the beneficial effect of Ca²⁺ channel blockers likely is due primarily to a decrease in oxygen demand rather than to an increase in coronary flow.

As described above, Ca²⁺ channel antagonists, particularly the dihydropyridines, may aggravate anginal symptoms in some patients when used without a -adrenergic receptor antagonist. This adverse effect is not prominent with verapamil or diltiazem because of their limited ability to induce marked peripheral vasodilation and reflex tachycardia. Concurrent therapy with nifedipine and the -adrenergic receptor antagonist propranolol, or with amlodipine and any of several -adrenergic receptor antagonists, has proven more effective than either agent given alone in exertional angina, presumably because the -adrenergic receptor antagonist suppresses reflex tachycardia (Bassan et al., 1982; Lehmann et al., 1993). This concurrent drug therapy is particularly attractive, since the dihydropyridines, unlike verapamil and diltiazem, do not delay atrioventricular conduction and will not enhance the negative dromotropic effects associated with -adrenergic receptor blockade. Although concurrent administration of verapamil or diltiazem with a -adrenergic receptor antagonist also may reduce angina, the potential for atrioventricular block, severe bradycardia, and decreased left ventricular function requires that these combinations be used judiciously (Packer, 1989), especially if left ventricular function is compromised prior to therapy. Amlodipine produces less reflex tachycardia than does nifedipine, probably because of a flatter plasma concentration profile. Isradipine, approximately equivalent to nifedipine in enhancing exercise tolerance, also produces less rise in heart rate, possibly because of its slow onset of action.

Unstable Angina

Medical therapy for unstable angina involves the administration of aspirin, which reduces mortality, and nitrates, -adrenergic receptor blocking agents, and heparin, which are effective in controlling pain and ischemic episodes. Since vasospasm occurs in some patients with unstable angina (Hugenholtz et al., 1981), Ca²⁺ channel blockers offer an additional approach to the treatment of unstable angina. However, there is insufficient evidence to assess whether or not such treatment actually decreases mortality except in patients in whom the principal mechanism is vasospasm. In a randomized, double-blind, clinical trial, the short-acting dihydropyridine nifedipine was found to be less effective than was metoprolol (Muller et al., 1984), and there are no studies supporting the administration of a dihydropyridine to patients with unstable angina. One small study of 121 patients reported a benefit of intravenous diltiazem, compared to nitroglycerin, on the end-points of refractory angina or event-free survival (Gbel et al., 1995). In contrast, therapy directed toward reduction of platelet function and thrombotic episodes clearly decreases morbidity and mortality in patients with unstable angina (see Chapters 27: Analgesic-Antipyretic and Antiinflammatory Agents and Drugs Employed in the Treatment of Gout and 55: Anticoagulant, Thrombolytic, and Antiplatelet Drugs).

Myocardial Infarction

There is no evidence that Ca²⁺ channel antagonists are of benefit in the early treatment or secondary prevention of acute myocardial infarction, and in several trials, the short-acting formulation of the dihydropyridine nifedipine appears to have had a detrimental effect on mortality at higher doses (Kloner, 1995; Opie and Messerli, 1995; Yusuf, 1995; Furberg et al., 1995). Diltiazem and verapamil may reduce the incidence of reinfarction in patients with a first non-Q-wave infarction who are not candidates for a -adrenergic receptor antagonist (Ryan et al., 1999).

Other Uses

The use of Ca²⁺ channel antagonists as antiarrhythmic agents is discussed in Chapter 35: Antiarrhythmic Drugs, and their use for the treatment of hypertension is discussed in Chapter 33: Antihypertensive Agents and the Drug Therapy of Hypertension. Clinical trials are under way to evaluate the capacity of Ca²⁺ channel blockers to slow the progression of renal failure and to protect the transplanted kidney. Verapamil has been demonstrated to improve left ventricular outflow obstruction and symptoms in patients with hypertrophic cardiomyopathy. Verapamil also has been used in the prophylaxis of migraine headaches. While several studies suggest that dihydropyridines may suppress the progression of mild atherosclerosis, there is no evidence that this alters mortality or reduces the incidence of ischemic events. Nimodipine has been approved for use in patients with neurological deficits secondary to cerebral vasospasm after the rupture of a congenital intracranial aneurysm. Nifedipine, diltiazem, and felodipine have been shown to provide symptomatic relief in Raynaud's disease.

Ca²⁺ channel antagonists cause relaxation of the myometrium in vitro and markedly inhibit the amplitude of spontaneous and oxytocin-induced contractions. Clinical studies have shown Ca²⁺ channel blockers to be effective in stopping preterm uterine contractions (Murray et al., 1992; Childress and Katz, 1994; Evidence Report/Technology Assessment, 2000). In studies comparing nifedipine with the -adrenergic receptor agonist ritodrine, nifedipine has been found to be at least as effective as ritodrine in stopping contractions and to be associated with fewer maternal side effects and a lower incidence of neonatal morbidity (Koks et al., 1998; Garcia-Velasco and Gonzalez Gonzalez, 1998; Oei et al., 1999; Papatsonis et al., 2000).

The -adrenergic receptor antagonists are effective in reducing the severity and frequency of attacks of exertional angina and improve survival in patients who have had a myocardial infarction. In contrast, these agents are not useful for vasospastic angina and, if used in isolation, may worsen the condition (Robertson et al., 1982). Most -adrenergic receptor antagonists appear to be equally effective in the treatment of exertional angina (Thadani et al., 1980). Timolol, metoprolol, atenolol, and propranolol have been shown to exert cardioprotective effects. The effectiveness of -adrenergic receptor antagonists in the treatment of exertional angina is attributable primarily to a fall in myocardial oxygen consumption at rest and during exertion, although there also is some tendency for increased flow toward ischemic regions. The decrease in myocardial oxygen consumption is due to a negative chronotropic effect (particularly during exercise), a negative inotropic effect, and a reduction in arterial blood pressure (particularly systolic pressure) during exercise. Not all the actions of -adrenergic receptor antagonists are beneficial in all patients. The decrease in heart rate and contractility causes an increase in the systolic ejection period and an increase in left ventricular end-diastolic volume; this tends to increase oxygen consumption. However, the net effect of -adrenergic blockade is usually to decrease myocardial oxygen consumption, particularly during exercise. Nevertheless, in patients with limited cardiac reserve who are critically dependent on adrenergic stimulation, -adrenergic receptor blockade can result in profound decreases in left ventricular function. Despite this, several -adrenergic receptor antagonists have been shown to reduce mortality in patients with congestive heart failure (see Chapter 34: Pharmacological Treatment of Heart Failure). Numerous -adrenergic receptor antagonists are approved for clinical use in the United States. They are considered in detail in Chapter 10: Catecholamines, Sympathomimetic Drugs, and Adrenergic Receptor Antagonists.

Therapeutic Uses

Unstable Angina

-Adrenergic receptor antagonists are effective in reducing recurrent episodes of ischemia and reduce the risk of progression to acute myocardial infarction (Braunwald et al., 2000). Currently available results of clinical trials have not had sufficient statistical power to define effects of -adrenergic receptor antagonists on mortality. On the other hand, if the underlying pathophysiology is coronary vasospasm, nitrates and Ca²⁺ channel blockers will be effective, and -adrenergic receptor antagonists should not be used alone. In some patients, there is a combination of severe fixed disease and superimposed vasospasm; if adequate antiplatelet therapy and vasodilation have been provided by other agents and angina continues, the addition of a -adrenergic receptor antagonist may be helpful.

Myocardial Infarction

-Adrenergic receptor antagonists that do not have intrinsic sympathomimetic activity have been demonstrated clearly to improve mortality in myocardial infarction. They should be given early and continued for 2 to 3 years in all patients who can tolerate them (Ryan et al., 1999).

In evaluating trials in which different forms of antianginal therapy are compared, careful attention must be paid to the patient population studied, including the pathophysiology and stage of the disease. It also is important to realize that an important placebo effect may be seen in these trials. The efficacy of antianginal treatment will depend on the severity of angina, on the presence of coronary vasospasm, and on the factors underlying myocardial oxygen demand. It also is most helpful if the dose of each agent is titrated to maximum benefit.

Considering the precipitants of angina in a given patient often is helpful. In patients with normal left ventricular function who have predictable angina with exertion despite nitrate therapy, -adrenergic receptor antagonists often will be beneficial due to their effects on heart rate and blood pressure. However, in patients with impaired ventricular performance and severe coronary disease, -adrenergic receptor blockade may lead to further elevation of end-diastolic pressure and an increase in oxygen demand. Task forces from the European Society of Cardiology (Anonymous, 1997) and both the American College of Cardiology (ACC) and the American Heart Association (AHA) (Gibbons et al., 1999) have developed current guidelines that are useful in the selection of an appropriate initial form of therapy for patients with chronic stable angina pectoris. Table 323 summarizes the issues that the ACC/AHA task force considered to be relevant in choosing between -adrenergic receptor antagonists and Ca²⁺ channel blockers in patients with angina and other medical conditions. A recent metaanalysis of publications that compared two or more antianginal therapies has been conducted by Heidenreich et al., (1999). From the comparison of -adrenergic receptor antagonists with Ca²⁺ channel blockers (72 studies), the authors concluded that -adrenergic receptor antagonists were associated with fewer episodes of angina per week and a lower rate of withdrawal because of adverse events. However, there were no overall differences in effects on time to ischemia during exercise, and in the rate of adverse events when Ca²⁺ channel blockers other than nifedipine were compared with -adrenergic receptor antagonists. There were no significant differences in outcome between the studies comparing long-acting nitrates and Ca²⁺ channel blockers and the studies comparing long-acting nitrates with -adrenergic receptor antagonists.

Combination Therapy

Since the different categories of antianginal agents utilize different mechanisms of action, it has been suggested that combinations of these agents would allow the use of lower doses, increasing effectiveness and reducing the incidence of side effects. However, despite the potential advantages, combination therapy in practice rarely fully achieves this potential and may be accompanied by serious side effects.

Nitrates and -Adrenergic Receptor Antagonists

The concurrent use of organic nitrates and -adrenergic receptor antagonists can be very effective in the treatment of typical exertional angina. The additive efficacy is primarily a result of one drug blocking the adverse effects of the other agent on net myocardial oxygen consumption. -Adrenergic receptor antagonists can block the reflex tachycardia and positive inotropic effects that are sometimes associated with nitrates. Nitrates can attenuate the increase in left ventricular end-diastolic volume associated with -adrenergic blockade by increasing venous capacitance. Concurrent administration of nitrates also can alleviate the increase in coronary vascular resistance associated with blockade of -adrenergic receptors.

Ca²⁺ Channel Blockers and -Adrenergic Receptor Antagonists

When angina is not adequately controlled by nitrates and a -adrenergic receptor antagonist, additional improvement sometimes can be achieved by the addition of a Ca²⁺ channel blocker, especially if there is a component of coronary vasospasm. If the patient already is being treated with maximal doses of verapamil or diltiazem, it is difficult to demonstrate any additional benefit of -adrenergic blockade, and excessive bradycardia, heart block, or heart failure may ensue. However, in patients treated with a dihydropyridine, such as nifedipine, or with nitrates, there often is substantial reflex tachycardia that limits the effectiveness of these agents. A -adrenergic receptor antagonist may be a helpful addition in this situation, resulting in a lower heart rate and blood pressure with exercise. The efficacy of amlodipine also has been shown to be improved by combination with a -adrenergic receptor antagonist. However, in the Total Ischaemic Burden European Trial (TIBET), which compared the effects of atenolol, a sustained-release form of nifedipine, and their combination on exercise parameters and ambulatory ischemia in 608 patients with mild angina, there were no differences between the agents, either singly or in combination, on any of the measured ischemic parameters (Fox et al., 1996). On the other hand, in two studies of patients with more severe but still stable angina, atenolol and propranolol were shown to be superior to nifedipine, and the combination of propranolol and nifedipine was more effective than nifedipine alone (Fox et al., 1993). In the IMAGE trial, the combination of metoprolol and sustainedrelease nifedipine was compared to each agent alone (Savonitto et al., 1996). Although an additional effect was observed in the group of patients receiving combination therapy, this was the result of an increase in exercise tolerance in individual patients who had not exhibited an increase during monotherapy; this recruitment effect was more marked in the patients in whom metoprolol was added to nifedipine.

Fluctuations in coronary tone long have been recognized as primary in variant angina. It also is likely that increased tone superimposed on fixed disease plays a role in the variable anginal threshold seen in many patients with otherwise chronic stable angina and possibly in ischemic episodes precipitated by cold and by emotion (Zeiher et al., 1991). Increased coronary tone also may be important in the anginal episodes occurring early after myocardial infarction (Bertrand et al., 1982) and after coronary angioplasty, and it probably accounts for those patients with unstable angina who respond to dihydropyridines (Hugenholtz et al., 1981). Atherosclerotic arteries have abnormal vasomotor responses to a number of stimuli (Kaplinsky, 1992; Oemar et al., 1998), including exercise, other forms of sympathetic activation, and cholinergic agonists; in such vessels, stenotic segments actually may become more severely stenosed during exertion. This implies that the normal exercise-induced increase in coronary flow is lost in atherosclerosis. Similar exaggerated vascular contractile responses are seen in hyperlipidemia, even before anatomic evidence of atherosclerosis develops. Because of this, coronary vasodilators (nitrates and/or Ca²⁺ channel blockers) are an important part of the therapeutic program in the majority of patients with ischemic heart disease.

Ca²⁺ Channel Blockers and Nitrates

In severe exertional or vasospastic angina, the combination of a nitrate and a Ca²⁺ channel blocker may provide additional relief over that obtained with either type of agent alone. Since nitrates primarily reduce preload, whereas Ca²⁺ channel blockers reduce afterload, the net effect on reduction of oxygen demand should be additive. However, excessive vasodilation and hypotension can occur. The concurrent administration of a nitrate and nifedipine has been advocated in particular for patients with exertional angina with heart failure, the sick-sinus syndrome, or AV nodal conduction disturbances, but excessive tachycardia may be seen.

Ca²⁺ Channel Blockers, -Adrenergic Receptor Antagonists, and Nitrates

In patients with exertional angina that is not controlled by the administration of two types of antianginal agents, the use of all three may provide improvement, although the incidence of side effects increases significantly (Tolins et al., 1984; Asirvatham et al., 1998). The dihydropyridines and nitrates dilate epicardial coronary arteries; the dihydropyridines decrease afterload; the nitrates decrease preload; and the -adrenergic receptor antagonists decrease heart rate and myocardial contractility. Therefore, there is theoretical, and sometimes real, benefit with their combination. Combining verapamil or diltiazem with a -adrenergic receptor antagonist greatly increases the risk of conduction system and left ventricular dysfunction-related side effects, and should be undertaken only with extreme caution and only if no other alternatives exist.

Unlike other antianginal agents, aspirin clearly has been demonstrated to reduce mortality in patients with unstable angina, reducing the incidence of myocardial infarction and death. In addition, low doses of aspirin appear to reduce the incidence of myocardial infarction in patients with chronic stable angina, and aspirin, given in doses of 160 to 325 mg at the onset of treatment of myocardial infarction, clearly reduces mortality, presumably by inhibiting the increased platelet aggregation that accompanies thrombolytic therapy (Kerins and FitzGerald, 1991). Heparin, in its unfractionated form and as low-molecular-weight heparin, also has been shown to reduce angina and prevent infarction in unstable angina. More direct thrombin inhibitors, such as hirudin, which directly inhibit even clot-bound thrombin, are not affected by circulating inhibitors, and function independently of antithrombin III, are being investigated. A metaanalysis of the GUSTO-IIB, TIMI-9B, OASIS-1, and OASIS-2 trials showed that in patients with acute myocardial ischemia without ST segment elevation there was a modest reduction in the risk of death or myocardial infarction at 35 days when hirudin was compared with unfractionated heparin, but an increase in bleeding, with the majority of the benefit occurring in patients not receiving thrombolytic agents (OASIS-2 Investigators, 1999). Further studies seem warranted. Thrombolytic agents, on the other hand, have been shown to be of no benefit in unstable angina (Anonymous, 1992). Intravenous inhibitors of the platelet glycoprotein IIb/IIIa receptor (abciximab, tirofiban, and eptifibatide) have proven to be effective in preventing the complications of percutaneous coronary interventions and in the treatment of patients presenting with acute coronary syndromes (Bhatt and Topol, 2000). In contrast, orally active platelet glycoprotein IIb/IIIa antagonists have not proven to be effective in the chronic treatment of patients with ischemic heart disease and may result in worse outcomes. It is possible that there are subsets of patients with unstable angina who have different response profiles.

It is anticipated that new therapeutic agents in ischemic heart disease will fall into two categories. The first will include agents that modify cellular actions via cell surface or intracellular receptors but have no effect on gene expression. The second will include agents that either permanently or transiently alter gene expression, either by enhancing or inhibiting the production of a normal cell product, or by rendering the cell capable of producing an entirely new product. This gene-based therapy (see Chapter 5: Gene Therapy) will assume increasing importance in the treatment of ischemic heart disease.

Emerging agents in the nitrate category include molsidomine, a nitrate-like agent that appears to produce vascular smooth muscle relaxation utilizing mechanisms similar to those of the nitrates themselves.

A number of Ca²⁺ channel antagonists are under development in the classes of dihydropyridines (nitrendipine), phenylalkylamines (gallopamil, a verapamil derivative), and piperazines (flunarizine, which is marketed in some countries outside the United States, trimetazidine, and ranolazine). Whereas the first two agents share the general pharmacological characteristics of their classes, the piperazines exhibit some cytoprotective effects on myocardial energy metabolism and, in early studies, appear to exert an antianginal effect in the absence of significant hemodynamic effects. Although the first agent to block the T-type Ca²⁺ channel was withdrawn due to adverse drug interactions, the antianginal efficacy of this agent supports the future development of other members of this class.

K⁺ channel activators, such as cromakalim, pinacidil, and nicorandil, have been proposed for use as direct coronary vasodilators in the treatment of both vasospastic and chronic stable angina (Hamilton and Weston, 1989; Why and Richardson, 1993; Lablanche et al., 1993). Studies of nicorandil (Kukovetz et al., 1992) demonstrate that its relaxant effect on coronary arterioles is inhibited by the K⁺ channel blocker, glyburide, and thus is likely due to K⁺ channel activation, with attendant cellular hyperpolarization of vascular smooth muscle. However, this agent also exerts a nitrate-like effect, stimulating guanylyl cyclase to increase cyclic GMP, primarily in epicardial coronary arteries, including stenotic segments. The relative importance of these separate effects in human beings is not known. In studies of relatively small sample size, nicorandil had antianginal efficacy similar to that of nitrates; the -adrenergic receptor antagonists atenolol, metoprolol, and propranolol; and the Ca²⁺ channel blockers amlodipine, diltiazem, and nifedipine (Markham et al., 2000). Drugs that have their primary site of vasodilation at the arteriolar level generally are not of benefit in the treatment of angina (Anonymous, 1992). The efficacy of nicorandil may be primarily due to its nitrate-like effect.

Angiotensin converting enzyme (ACE) inhibitors (see Chapters 31, 33, and 34) are useful not only in the treatment of hypertension but also in reducing morbidity and mortality in symptomatic and asymptomatic congestive heart failure (Cohn et al., 1986; CONSENSUS Trial Study Group, 1987; Pitt, 1994). It also has been suggested that these agents may have a beneficial effect in angina pectoris over and above their effects on blood pressure, but it has been difficult to demonstrate this effect in normotensive patients. In addition to the ability of these agents to reduce blood pressure, which would be expected to have a favorable effect on ventricular wall stress, they also may reduce the coronary vascular response to angiotensin II and may prevent deleterious ventricular remodeling. Lisinopril has been suggested to reduce mortality when used in the treatment of acute infarction in the GISSI-III trial. However, if coronary perfusion pressure is lowered, ACE inhibitors have the potential to have a deleterious effect on angina; this may account for the patients who have become worse with these drugs in some trials (Vogt et al., 1993). In the HOPE trial, the ACE inhibitor rampiril resulted in a reduction in myocardial infarction and death from cardiovascular causes in patients with vascular disease or with diabetes plus one other cardiovascular risk factor, but without conventional indications for the use of an ACE inhibitor (Yusuf et al., 2000).

Our appreciation of the role of inflammation in the development and progression of atherosclerosis and of unstable coronary syndromes is evolving (Libby, 2000; Ridker et al., 2000). Clinical studies are in progress that will address the ability of antibiotics, antiinflammatory agents, and HMG-CoA reductase inhibitors to retard the atherosclerotic process and reduce cardiac events.

There has been great interest in evaluating the therapeutic utility of angiogenic factors, stem cells, and endothelial progenitor cells to facilitate growth of new vessels in areas of ischemia (Asahara et al., 2000; Isner, 2000; Kalka et al., 2000). Promising results have been achieved using vascular endothelial growth factor (VEGF) and related agents in human patients (Schumacher et al., 1998; Hendel et al., 2000).

Several problems in the treatment of myocardial ischemia lend themselves to the use of gene-based therapies. Because coronary angioplasty is so commonly followed by restenosis (30% to 40% of cases) and because conventional pharmacological therapy has not abolished this problem, the concept of altering the biology of the cellular response to angioplasty has emerged. Techniques for delivering vectors to localized segments of peripheral and coronary vessels and vein grafts have been developed, and functional genes have been transferred (Chapman et al., 1992; Lemarchand et al., 1993; Nabel, 1995; Duckers and Nabel, 2000; O'Blenes et al., 2000). In animal models, the tendency for restenosis has been significantly inhibited (Ohno et al., 1994), and clinical trials are planned. Building on the success with angiogenic factors mentioned above, studies with animals have demonstrated that transferring the gene coding for VEGF also is efficacious (Isner, 2000), and trials in human beings are under way. In an attack on one mechanism underlying the development of atherosclerosis, it recently has been shown that retroviral therapy restores apo-E levels in apo-E deficient mice and reduces the extent of atherosclerosis (Hasty et al., 1999). Alternatively, disruption of the 12/15-lipoxygenase gene also was protective in this mouse model, consistent with a role for inflammation in the atherosclerotic process (Cyrus et al., 1999). These areas of rapid progress suggest that therapy with genotypic strategies will play a significant role in the future.

For further discussion of acute myocardial infarction and ischemic heart disease see Chapters 228 and 226 in Harrison's Principles of Internal Medicine, 16th ed., McGraw-Hill, New York, 2005.