Goodman and Gilman Manual of Pharmacology and Therapeutics

Section III
Modulation of Cardiovascular Function

chapter 27
Treatment of Myocardial Ischemia and Hypertension


Angina pectoris, the primary symptom of ischemic heart disease, is caused by transient episodes of myocardial ischemia that are due to an imbalance in the myocardial oxygen supply–demand relationship that may be caused by an increase in myocardial oxygen demand or by a decrease in myocardial oxygen supply or sometimes by both (Figure 27–1). Typical angina is experienced as a heavy, pressing substernal discomfort (rarely described as a “pain”), often radiating to the left shoulder, flexor aspect of the left arm, jaw, or epigastrium. However, a significant minority of patients note discomfort in a different location or of a different character. Myocardial ischemia also may be silent, with electrocardiographic, echocardiographic, or radionuclide evidence of ischemia appearing in the absence of symptoms.


Figure 27–1 Pharmacological modification of the major determinants of myocardial O2 supply. When myocardial O2 requirements exceed O2 supply, an ischemic episode results. This figure shows the primary hemodynamic sites of actions of pharmacological agents that can reduce O2 demand (left side) or enhance O2 supply (right side). Some classes of agents have multiple effects. Stents, angioplasty, and coronary bypass surgery are mechanical interventions that increase O2 supply. Both pharmacotherapy and mechanotherapy attempt to restore a dynamic balance between O2 demand and O2 supply.

This section describes the principal pharmacological agents used in the treatment of angina: nitrovasodilators, β adrenergic receptor antagonists, and Ca2+ channel antagonists. These anti-anginal agents improve the balance of myocardial O2 supply and O2 demand, increasing supply by dilating the coronary vasculature and/or decreasing demand by reducing cardiac work (see Figure 27–1).

Drugs used in typical angina function principally by reducing myocardial O2 demand by decreasing heart rate, myocardial contractility, and/or ventricular wall stress. By contrast, the principal therapeutic goal in unstable angina is to increase myocardial blood flow; strategies include the use of antiplatelet agents and heparin to reduce intracoronary thrombosis, often accompanied by efforts to restore flow by mechanical means, including percutaneous coronary interventions using coronary stents, or (less commonly) emergency coronary bypass surgery. The principal therapeutic aim in variant or Prinzmetal angina is to prevent coronary vasospasm.


These agents are prodrugs that are sources of nitric oxide (NO) (Table 27–1).

Table 27–1

Organic Nitrates


Organic nitrates are polyol esters of nitric acid, whereas organic nitrites are esters of nitrous acid. Nitrate esters (—C—O—NO2) and nitrite esters (—C—O—NO) are characterized by the sequence of carbon–oxygen–nitrogen. 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, isosorbide dinitrate, and isosorbide mononitrate) are solids. The organic nitrates and nitrites, collectively termed nitrovasodilators, must be metabolized (reduced) to produce gaseous NO, the active principle of this class of compounds. NO gas also may be administered by inhalation.


Mechanism of Action. Nitrites, organic nitrates, nitroso compounds, and a variety of other nitrogen oxide–containing substances (including nitroprusside) are basically exogenous sources of NO. NO can activate guanylyl cyclase and thereby increase the cellular level of cyclic GMP, which activates PKG and can modulate the activities of cyclic nucleotide phosphodiesterases (PDEs 2, 3, and 5) in a variety of cell types. In smooth muscle, the net result is phosphorylative activation of myosin light chain phosphatase, reduced phosphorylation of myosin light chain, reduced Ca2+ concentration in the cytosol, and relaxation. The pharmacological and biochemical effects of the nitrovasodilators appear to be identical to those of EDRF (endothelium-derived relaxing factor), now known to be NO. This NO-mediated pathway leads to relaxation of smooth muscle in the vasculature, bronchi, and GI tract, and inhibition of platelet aggregation. Chapter 3 presents details of NO biosynthesis and action.

Cardiovascular Effects; Hemodynamic Effects. Low concentrations of nitroglycerin preferentially dilate veins more than arterioles. This venodilation decreases venous return, leading to a fall in left and right ventricular chamber size and end-diastolic pressures, but usually results in little change in systemic vascular resistance. Systemic arterial pressure may fall slightly; heart rate is unchanged or may increase slightly in response to a decrease in blood pressure. Pulmonary vascular resistance and cardiac output are slightly reduced. Doses of nitroglycerin that do not alter systemic arterial pressure may still produce arteriolar dilation in the face and neck, resulting in a facial flush, or dilation of meningeal arterial vessels, causing headache.

Higher doses of organic nitrates cause further venous pooling and may decrease arteriolar resistance as well, thereby decreasing systolic and diastolic blood pressure and cardiac output and causing pallor, weakness, dizziness, and activation of compensatory sympathetic reflexes. The reflex 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 may decrease subsequently if cardiac output and blood pressure decrease sufficiently. In patients with autonomic dysfunction and an inability to increase sympathetic outflow, the physiological means to compensate for this fall in blood pressure are absent. In these clinical contexts, nitrates may reduce arterial pressure and coronary perfusion pressure significantly, producing potentially life-threatening hypotension and even aggravating angina. The appropriate therapy in patients with orthostatic angina and normal coronary arteries is to correct the orthostatic hypotension by expanding volume (fludrocortisone and a high-sodium diet), to prevent venous pooling with fitted support garments, and to carefully titrate use of oral vasopressors. Because patients with autonomic dysfunction occasionally may have coexisting coronary artery disease, the coronary anatomy should be defined before therapy is undertaken.

Effects on Coronary Blood Flow. Myocardial ischemia is a powerful stimulus to coronary vasodilation, and regional blood flow is adjusted by autoregulatory mechanisms. In the presence of atherosclerotic coronary artery narrowing, ischemia distal to the lesion stimulates vasodilation; if the stenosis is severe, much of the capacity to dilate is used to maintain resting blood flow and further dilation may not be possible when demand increases. Significant coronary stenoses disproportionately reduce 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. The hemodynamic mechanisms responsible for these effects are likely the capacity of organic nitrates to cause dilation and prevent vasoconstriction of large epicardial vessels without impairing autoregulation in the small vessels. 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).

Effects on Myocardial O2 Requirements. By their effects on the systemic circulation, the organic nitrates can reduce myocardial O2 demand. The major determinants of myocardial O2 consumption include left ventricular wall tension, heart rate, and myocardial contractility. Ventricular wall tension is affected by a number of factors that may be considered under the categories of preload and afterload. Preloadis determined by the diastolic pressure that distends the ventricle (ventricular end-diastolic pressure). Decreasing end-diastolic volume reduces ventricular wall tension (by the law of Laplace, tension is proportional to pressure times radius). Increasing venous capacitance with nitrates decreases venous return to the heart, decreases ventricular end-diastolic volume, and thereby decreases O2 consumption. An additional benefit of reducing preload is that it increases the pressure gradient for perfusion across the ventricular wall, which favors subendocardial perfusion. 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 O2consumption.

Organic nitrates decrease both preload and afterload as a result of respective dilation of venous capacitance and arteriolar resistance vessels. They do not directly alter the inotropic or chronotropic state of the heart. Since nitrates reduce the primary determinants of myocardial O2 demand, their net effect usually is to decrease myocardial O2 consumption. The effect of nitrovasodilators to inhibit platelet function may contribute to their anti-anginal efficacy, this effect appears to be modest.

Mechanism of Relief of Symptoms of Angina Pectoris. The capacity of nitrates to dilate epicardial coronary arteries, even in areas of atherosclerotic stenosis, is modest, and the preponderance of evidence continues to favor a reduction in myocardial work, and thus in myocardial O2 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 beneficial action of the drugs on myocardial O2 demand and can aggravate ischemia. Additionally, sublingual nitroglycerin administration may produce bradycardia and hypotension, probably owing to activation of the Bezold-Jarisch reflex.

OTHER EFFECTS. The nitrovasodilators act on almost all smooth muscle tissues. Bronchial smooth muscle is relaxed irrespective 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 GI 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 responses are of uncertain clinical significance.


Nitroglycerin. In humans, peak concentrations of nitroglycerin are found in plasma within 4 min of sublingual administration; the drug has a t1/2 of 1-3 min. The onset of action of nitroglycerin may be even more rapid if it is delivered as a sublingual spray rather than as a sublingual tablet. Glyceryl dinitrate metabolites, which have about one-tenth the vasodilator potency, appear to have half-lives of ~40 min.

Isosorbide Dinitrate. The major route of metabolism of isosorbide dinitrate in humans appears to be by enzymatic denitration followed by glucuronide conjugation. Sublingual administration produces maximal plasma concentrations of the drug by 6 min, and the fall in concentration is rapid (t1/2 of ~45 min). The primary initial metabolites, isosorbide-2-mononitrate and isosorbide-5-mononitrate, have longer half-lives (3-6 h) and presumably contribute to the therapeutic efficacy of the drug.

Isosorbide-5-Mononitrate. This agent is available in tablet form. It does not undergo significant first-pass metabolism and so has excellent bioavailability after oral administration. The mononitrate has a significantly longer t1/2 than does isosorbide dinitrate and has been formulated as a plain tablet and as a sustained-release preparation; both preparations have longer durations of action than the corresponding dosage forms of isosorbide dinitrate.

Inhaled NO. Nitric oxide gas administered by inhalation appears to exert most of its therapeutic effects on the pulmonary vasculature; systemically, it rapidly interacts with heme groups in hemoglobin in the blood. Inhaled NO is used to treat pulmonary hypertension in hypoxemic neonates, where inhaled NO reduces morbidity and mortality.


Sublingual organic nitrates should be taken at the time of an anginal attack or in anticipation of exercise or stress. Such intermittent treatment provides 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. The magnitude of tolerance is a function of dosage and frequency of use. Tolerance may result from a reduced capacity 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. 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. Inactivation of mitochondrial aldehyde dehydrogenase, an enzyme implicated in biotransformation of nitroglycerin, is seen in models of nitrate tolerance, potentially associated with oxidative stress. A reactive intermediate formed during the generation of NO from organic nitrates may itself damage and inactivate the enzymes of the activation pathway; tolerance could involve endothelium-derived reactive oxygen species.

An effective approach to restoring responsiveness is to interrupt therapy for 8-12 h 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 whose anginal pattern suggests its precipitation by increased left ventricular filling pressures (i.e., occurring in association with orthopnea or paroxysmal nocturnal dyspnea) may benefit from continuing nitrates at night and omitting them during a quiet period of the day. Tolerance also has been seen with isosorbide-5-mononitrate; an eccentric twice-daily dosing schedule appears to maintain efficacy. Some patients develop an increased frequency of nocturnal angina when a nitrate-free interval is employed using nitroglycerin patches; such patients may require another class of anti-anginal agent during this period. Tolerance is not universal, and some patients develop only partial tolerance. The problem of anginal rebound during nitrate-free intervals is especially problematic in the treatment of unstable angina with intravenous nitroglycerin. As tolerance develops, increasing doses are required to achieve the same therapeutic effects; eventually, despite dose escalation, the drug loses efficacy.

A special form of nitroglycerin tolerance is observed in 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 job—the “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 24-72-h periods away from the work environment. 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 progress occasionally to loss of consciousness, a reaction that appears to be accentuated by alcohol. It also may be seen with very low doses of nitrates in patients with autonomic dysfunction. Even in severe nitrate syncope, positioning and other measures that facilitate venous return are the only therapeutic measures required. All the organic nitrates occasionally can produce drug rash.

INTERACTION OF NITRATES WITH PDE5 INHIBITORS. Erectile dysfunction is a frequently encountered problem whose risk factors parallel those of coronary artery disease. Thus, many men desiring therapy for erectile dysfunction already may be receiving (or may require, especially if they increase physical activity) anti-anginal therapy. The combination of sildenafil and other phosphodiesterase 5 (PDE5) inhibitors with organic nitrate vasodilators can cause extreme hypotension.

Cells in the corpus cavernosum produce NO during sexual arousal in response to nonadrenergic, noncholinergic neurotransmission. NO stimulates the formation of cyclic GMP, which leads to relaxation of smooth muscle of the corpus cavernosum and penile arteries, engorgement of the corpus cavernosum, and erection. The accumulation of cyclic GMP can be enhanced by inhibition of the cyclic GMP–specific PDE5 family. Sildenafil (VIAGRA, REVATIO) and congeners inhibit PDE5 and have been demonstrated to improve erectile function in patients with erectile dysfunction. Not surprisingly, PDE5 inhibitors have assumed the status of widely used recreational drugs. Since the introduction of sildenafil, 3 additional PDE5 inhibitors have been developed for use in therapy of erectile dysfunction. Tadalafil (CIALIS, ADCIRCA), vardenafil (LEVITRA), and avanafil (STENDRA) share similar therapeutic efficacy and side-effect profiles with sildenafil; tadalafil has a longer time to onset of action and a longer therapeutic t1/2 than the other PDE5 inhibitors. Sildenafil has been the most thoroughly characterized of these compounds, but all 3 PDE5 inhibitors are contraindicated for patients taking organic nitrate vasodilators, and the PDE5 inhibitors should be used with caution in patients taking α or β adrenergic receptor antagonists (see Chapter 12).

The side effects of sildenafil and other PDE5 inhibitors are largely predictable on the basis of their effects on PDE5. Headache, flushing, and rhinitis may be observed, as well as dyspepsia owing to relaxation of the lower esophageal sphincter. Sildenafil and vardenafil also weakly inhibit PDE6, the enzyme involved in photoreceptor signal transduction (see Chapters 3 and 64), and can produce visual disturbances, most notably changes in the perception of color hue or brightness. In addition to visual disturbances, sudden one-sided hearing loss has also been reported. Tadalafil inhibits PDE11, a widely distributed PDE isoform, but the clinical importance of this effect is not clear. The most important toxicity of all these PDE5 inhibitors is hemodynamic. When given alone to men with severe coronary artery disease, these drugs have modest effects on blood pressure, producing >10% fall in systolic, diastolic, and mean systemic pressures and in pulmonary artery systolic and mean pressures. However, sildenafil, tadalafil, and vardenafil all have a significant and potentially dangerous interaction with organic nitrates, which act therapeutically via enhancing cyclic GMP production in smooth muscle. In the presence of a PDE5 inhibitor, nitrates cause profound increases in cyclic GMP and can produce dramatic reductions in blood pressure. This drug class toxicity is the basis for the warning that PDE5 inhibitors should not be prescribed to patients receiving any form of nitrate and dictates that patients should be warned about the prior use of PDE5 inhibitors within 24 h of administration of nitrates. A period of longer than 24 h may be needed following administration of a PDE5 inhibitor for safe use of nitrates, especially with tadalafil because of its prolonged t1/2. In the event that patients develop significant hypotension following combined administration of sildenafil and a nitrate, fluids and α adrenergic receptor agonists, if needed, should be used for support. These same hemodynamic responses to PDE5 inhibition also may underlie the efficacy of sildenafil in the treatment of patients with primary pulmonary hypertension, in whom chronic treatment with the drug appears to result in enhanced exercise capacity associated with a decrease in pulmonary vascular resistance. PDE5 inhibitors also are being studied in patients with congestive heart failure and cardiac hypertrophy (see Chapter 28).

Sildenafil, tadalafil, vardenafil, and avanafil are metabolized via CYP3A4, and their toxicity may be enhanced in patients who receive other substrates of this enzyme, including macrolide and imidazole antibiotics, some statins, and antiretroviral agents (see individual chapters and Chapter 6). PDE5 inhibitors also may prolong cardiac repolarization by blocking the IKr. In patients with coronary artery disease whose exercise capacity indicates that sexual activity is unlikely to precipitate angina and who are not currently taking nitrates, the use of PDE5 inhibitors can be considered. Such therapy needs to be individualized, and appropriate warnings must be given about the risk of toxicity if nitrates are taken subsequently for angina. Alternative non-nitrate anti-anginal therapy, such as β adrenergic receptor antagonists, should be used during these time periods.


ANGINA. Diseases that predispose to angina should be treated as part of a comprehensive therapeutic program with the primary goal being to prolong life. Conditions such as hypertension, anemia, thyrotoxicosis, obesity, heart failure, cardiac arrhythmias, and acute anxiety can precipitate anginal symptoms in many patients. Patients should be counseled to stop smoking, lose weight, and maintain a low-fat, high-fiber diet; hypertension and hyperlipidemia should be corrected; and daily aspirin (or clopidogrel if aspirin is not tolerated) (see Chapter 30) should be prescribed. Exposure to sympathomimetic agents (e.g., those in nasal decongestants and other sources) probably should be avoided. The use of drugs that modify the perception of pain is a poor approach to the treatment of angina because the underlying myocardial ischemia is not relieved. Table 27–1 lists the preparations and dosages of the nitrites and organic nitrates.

Sublingual Administration. Because of its rapid action, long-established efficacy, and low cost, nitroglycerin is the most useful drug of the organic nitrates given sublingually. The onset of action is within 1-2 min, but the effects are undetectable by 1 h after administration.

Oral Administration. Oral nitrates often are used to provide prophylaxis against anginal episodes. Higher doses of either isosorbide dinitrate (e.g., 20 mg or more orally every 4 h) or sustained-release preparations of nitroglycerin decrease the frequency of anginal attacks and improve exercise tolerance. Effects peak at 60-90 min and last for 3-6 h. Administration of isosorbide mononitrate (typically starting at 20 mg) once or twice daily (in the latter case, with the doses administered 7 h apart) is efficacious in the treatment of chronic angina, and once-daily dosing or an eccentric twice-daily dosing schedule can minimize the development of tolerance.

Cutaneous Administration. Nitroglycerin ointment (2%) is applied to the skin (2.5-5 cm); the dosage must be adjusted for each patient. Effects are apparent within 30-60 min (although absorption is variable) and last for 4-6 h. The ointment is particularly useful for controlling nocturnal angina, which commonly develops within 3 h after the patient goes to sleep. To avoid tolerance, therapy should be interrupted for at least 8 h each day.

Transmucosal or Buccal Nitroglycerin. This formulation is inserted under the upper lip above the incisors, where it adheres to the gingiva and dissolves gradually in a uniform manner. Hemodynamic effects are seen within 2-5 min, and it is therefore useful for short-term prophylaxis of angina.

CONGESTIVE HEART FAILURE. The utility of nitrovasodilators to relieve pulmonary congestion and to increase cardiac output in congestive heart failure is addressed in Chapter 28.

UNSTABLE ANGINA PECTORIS AND NON-ST-SEGMENT–ELEVATION MYOCARDIAL INFARCTION. The term unstable angina pectoris has been used to describe a broad spectrum of clinical entities characterized by an acute or subacute worsening in a patient’s anginal symptoms. The variable prognosis of unstable angina reflects the broad range of clinical entities subsumed by the term. Efforts have been directed toward identifying patients with unstable angina on the basis of their risks for subsequent adverse outcomes such as MI or death. The term acute coronary syndrome has been useful in this context: Common to most clinical presentations of acute coronary syndrome is disruption of a coronary plaque, leading to local platelet aggregation and thrombosis at the arterial wall, with subsequent partial or total occlusion of the vessel. There is some variability in the pathogenesis of unstable angina, with gradually progressive atherosclerosis accounting for some cases of new-onset exertional angina. Less commonly, vasospasm in minimally atherosclerotic coronary vessels may account for some cases where rest angina has not been preceded by symptoms of exertional angina. For the most part, the pathophysiological principles that underlie therapy for exertional angina—which are directed at decreasing myocardial oxygen demand—have limited efficacy in the treatment of acute coronary syndromes characterized by an insufficiency of myocardial oxygen (blood) supply.

OTHER AGENTS; DRUG COMBINATIONS. Drugs that reduce myocardial O2 consumption by reducing ventricular preload (nitrates) or by reducing heart rate and ventricular contractility (β adrenergic receptor antagonists) are efficacious, but additional therapies are directed at an atherosclerotic plaque and the consequences (or prevention) of its rupture. These therapies include combinations of:

• Antiplatelet agents, including aspirin and thioenopyridines such as clopidogrel or prasugrel

• Antithrombin agents such as heparin and the thrombolytics anti-integrin therapies that directly inhibit platelet aggregation mediated by glycoprotein (GP)IIb/IIIa mechano-pharmacological approaches with percutaneously deployed intracoronary stents

• Coronary bypass surgery for selected patients

Along with nitrates and β adrenergic receptor antagonists, antiplatelet agents represent the cornerstone of therapy for acute coronary syndrome. Aspirin inhibits platelet aggregation and improves survival. Heparin (either unfractionated or low-molecular-weight) also appears to reduce angina and prevent infarction. These and related agents are discussed in detail in Chapters 30 and 34. Anti-integrin agents directed against the platelet integrin GPIIb/IIIa (including abciximab, tirofiban, and eptifibatide) are effective in combination with heparin, as discussed later. Nitrates are useful both in reducing vasospasm and in reducing myocardial O2 consumption by decreasing ventricular wall stress. Intravenous administration of nitroglycerin allows high concentrations of drug to be attained rapidly. Because nitroglycerin is degraded rapidly, the dose can be titrated quickly and safely using intravenous administration. If coronary vasospasm is present, intravenous nitroglycerin is likely to be effective, although the addition of a Ca2+ channel blocker may be required to achieve complete control.

ACUTE MYOCARDIAL INFARCTION. Therapeutic maneuvers in MI are directed at reducing the size of the infarct, preserving or retrieving viable tissue by reducing the O2demand of the myocardium, and preventing ventricular remodeling that could lead to heart failure.

Nitroglycerin is commonly administered to relieve ischemic pain in patients presenting with MI, but evidence that nitrates improve mortality in MI is sparse. Because they reduce ventricular preload through vasodilation, nitrates are effective in relief of pulmonary congestion. A decreased ventricular preload should be avoided in patients with right ventricular infarction because higher right-sided heart filling pressures are needed in this clinical context. Nitrates are relatively contraindicated in patients with systemic hypotension. According to the American Heart Association/American College of Cardiology (AHA/ACC) guidelines, “nitrates should not be used if hypotension limits the administration of β blockers, which have more powerful salutary effects.” Because the proximate cause of MI is intracoronary thrombosis, reperfusion therapies are critically important, employing, when possible, direct percutaneous coronary interventions (PCIs) for acute MI, usually using drug-eluting intracoronary stents. Thrombolytic agents are administered at hospitals where emergency PCI is not performed, but outcomes are better with direct PCI than with thrombolytic therapy.

VARIANT (PRINZMETAL) 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. Whereas long-acting nitrates alone are occasionally efficacious in abolishing episodes of variant angina, additional therapy with Ca2+ channel blockers usually is required.


Voltage-sensitive Ca2+ channels (L-type or slow channels) mediate the entry of extracellular Ca2+ (~1.25 mM) into smooth muscle and cardiac myocytes and sinoatrial (SA) and atrioventricular (AV) nodal cells (cytosolic concentration in resting cell, ~100 nM) in response to electrical depolarization. In both smooth muscle and cardiac myocytes, Ca2+ is a trigger for contraction, albeit by different mechanisms. Ca2+ channel antagonists, also called Ca2+ entry blockers, inhibit Ca2+ channel function. In vascular smooth muscle, this leads to relaxation, especially in arterial beds. In the heart, these drugs can produce negative inotropic and chronotropic effects.

Clinically used Ca2+ channel antagonists include the phenylalkylamine compound verapamil, the benzothiazepine diltiazem, and numerous dihydropyridines, including nifedipine, amlodipine, felodipine, isradipine, nicardipine, nisoldipine, and nimodipine. The specificities of several of these drugs are shown in Table 27–2. Although these drugs are commonly grouped together as “Ca2+ channel blockers,” there are fundamental differences among verapamil, diltiazem, and the dihydropyridines, especially with respect to pharmacological characteristics, drug interactions, and toxicities.

Table 27–2

Comparative CV Effectsa of Ca2+ Channel Blockers


Mechanisms of Action. An increased concentration of cytosolic Ca2+ causes increased contraction in both cardiac and vascular smooth muscle cells. The entry of extracellular Ca2+ initiates contraction of cardiac myocytes (Ca2+-induced Ca2+ release, where the bulk of contractile Ca2+ is from the sarcoplasmic reticulum) and provides a major source of contractile Ca2+ in smooth muscle (in which the release of Ca2+ from IP3-sensitive intracellular storage vesicles and Ca2+ entry via receptor-operated channels can also contribute to contraction, particularly in some vascular beds). The Ca2+ channel antagonists produce their effects by binding to the α1 subunit of the L-type Ca2+ channels and reducing Ca2+ flux through the channel. The vascular and cardiac effects of some of the Ca2+ channel blockers are summarized in the next section and in Table 27–2.



Vascular Tissue. At least 3 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. Second, agonist-induced contractions that occur without depolarization of the membrane result from stimulation of the Gq–PLC–IP3 pathway, resulting in the release of intracellular Ca2+ from the sarcoplasmic reticulum (see Chapter 3). Third, receptor-operated Ca2+ channels allow the entry of extracellular Ca2+ in response to receptor occupancy.

Ca2+ channel antagonists 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 a less pronounced effect on most venous beds and hence do not affect cardiac preload significantly.

Cardiac Cells. In the SA and AV nodes, depolarization largely depends on the movement of Ca2+ through the slow channel. The effect of a Ca2+ channel blocker on AV conduction and on the rate of the sinus node pacemaker depends on whether or not the agent delays the recovery of the slow channel. 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. 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 AV 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 29). Bepridil, like verapamil, inhibits both slow inward Ca2+ current and fast inward Na+ current. It has a direct negative inotropic effect. Its electrophysiological 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 withtorsade de pointes, a potentially lethal ventricular arrhythmia (see Chapter 29).

In cardiac myocytes, initiation of Ca2+-induced Ca2+ release relies on entry Ca2+ of through the L-type channel in response to depolarization. By reducing this entry, Ca2+ channel blockers can produce a negative inotropic effect.

Hemodynamic Effects. All the Ca2+ channel blockers approved for clinical use decrease coronary vascular resistance and can lead to an increase in coronary blood flow. The dihydropyridines are more potent vasodilator than verapamil, which is more potent than diltiazem. The hemodynamic effects of these agents vary depending on the route of administration and the extent of left ventricular dysfunction. Drugs that significantly lower mean pressure will elicit a baroreceptor reflex response.

Nifedipine, the prototypical dihydropyridine, selectively dilates arterial resistance vessels. The decrease in arterial blood pressure elicits sympathetic reflexes, with resulting tachycardia and positive inotropy. Nifedipine has direct negative inotropic effects in vitro but 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. After oral administration of nifedipine, arterial dilation increases peripheral blood flow; venous tone does not change. The other dihydropyridines—amlodipine, felodipine, isradipine, nicardipine, nisoldipine, nimodipine, and clevidipine—share many of the cardiovascular effects of nifedipine.

Amlodipine has a slow absorption and a prolonged effect. Amlodipine produces both peripheral arterial vasodilation and coronary dilation. There is less reflex tachycardia with amlodipine than with nifedipine, possibly because the long t1/2 (35-50 h) produces minimal peaks and troughs in plasma concentrations. Felodipine may have even greater vascular specificity than does nifedipine or amlodipine. At concentrations producing vasodilation, there is no negative inotropic effect. Nicardipine has anti-anginal properties similar to those of nifedipine and may have selectivity for coronary vessels. 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. 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 β 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 β adrenergic receptor antagonist. Nisoldipine is more than 1000 times more potent in preventing contraction of human vascular smooth muscle than in preventing contraction of human cardiac muscle in vitro, suggesting a high degree of vascular selectivity. Although nisoldipine has a short elimination t1/2, a sustained-release preparation that is efficacious as an anti-anginal agent has been developed. Nimodipine has high lipid solubility and is effective in inhibiting cerebral vasospasm and has been used primarily to treat patients with neurological defects associated with cerebral vasospasm after subarachnoid hemorrhage.

Clevidipine is a novel dihydropyridine L-type Ca2+ channel blocker—available for intravenous administration—that has a very rapid (t1/2 ~2 min) onset and offset of action. It is metabolized by esterases in blood, similar to the fate of esmolol. Clevidipine preferentially affects arterial smooth muscle compared to targeting veins or the heart. Infusions are typically started at a rate of 1-2 μg/kg/min and titrated to the desired effect on blood pressure.

Verapamil is a less potent vasodilator the dihydropyridines. Like dihydropyridines, 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 owing to a decrease in vascular resistance, but the reflex tachycardia is blunted or abolished by the direct negative chronotropic effect of the drug. This intrinsic negative inotropic effect 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 actually may improve, especially if ischemia limits 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 reduces peripheral vascular resistance and blood pressure, often with minimal changes in heart rate. The relief of pacing-induced angina seen with verapamil is due primarily to a reduction in myocardial oxygen demand.

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 decreases both heart rate and mean arterial blood pressure. While diltiazem and verapamil produce similar effects on the SA and AV nodes, the negative inotropic effect of diltiazem is more modest.

ADME. Although the absorption of these agents is nearly complete after oral administration, their bioavailability is reduced, in some cases markedly, by first-pass hepatic metabolism. The effects of these drugs are evident within 30-60 min of an oral dose, with the exception of the more slowly absorbed and longer-acting agents amlodipine, isradipine, and felodipine. These agents all are bound extensively to plasma proteins (70-98%); their elimination half-lives vary widely, from 1.3 to 64 h. During repeated oral administration, bioavailability and t1/2 may increase because of saturation of hepatic metabolism. The bioavailability of some of these drugs may be increased by grapefruit juice, likely through inhibition of enzyme CYP3A4. 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 t1/2 of norverapamil is ~10 h. The metabolites of the dihydropyridines are inactive or weakly active. In patients with hepatic cirrhosis, the bioavailabilities and half-lives of the Ca2+ channel blockers may be increased, and dosage should be adjusted. The half-lives of these agents also may be longer in older patients. Except for diltiazem and nifedipine, all the Ca2+ channel blockers are administered as racemic mixtures.

Toxicity and Untoward Responses. The profile of adverse reactions to the Ca2+ channel blockers varies among the drugs in this class. Patients receiving immediate-release capsules of nifedipine develop headache, flushing, dizziness, and peripheral edema. Dizziness and flushing are much less of a problem with the sustained-release formulations and with the dihydropyridines having a long t1/2 and relatively constant concentrations of drug in plasma. Peripheral edema may occur in some patients with Ca2+ channel blockers; it most likely results from increased hydrostatic pressure in the lower extremities owing to precapillary dilation and reflex postcapillary constriction. Some other adverse effects of these drugs are due to actions in nonvascular smooth muscle. Contraction of the lower esophageal sphincter is inhibited by the Ca2+ channel blockers. Ca2+ channel blockers can cause or aggravate gastroesophageal reflux. Constipation is a common side effect of verapamil, but it occurs less frequently with other Ca2+ channel blockers. Uncommon adverse effects include urinary retention, rash, and elevations of liver enzymes.

Worsened myocardial ischemia has been observed with nifedipine from excessive hypotension and decreased coronary perfusion, selective coronary vasodilation in nonischemic regions of the myocardium in a setting where vessels perfusing ischemic regions were already maximally dilated (i.e., coronary steal), or an increase in O2 demand owing to increased sympathetic tone and excessive tachycardia. 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 β blockade. The use of intravenous verapamil with an intravenous β adrenergic receptor antagonist is contraindicated because of the increased propensity for AV block and/or severe depression of ventricular function. Patients with ventricular dysfunction, SA or AV nodal conduction disturbances, and systolic blood pressures < 90 mm Hg should not be treated with verapamil or diltiazem, particularly intravenously. Some Ca2+ channel antagonists such as verapamil can cause an increase in the concentration of digoxin in plasma; resulting toxicity from the cardiac glycoside rarely develops, but the use of verapamil to treat digitalis toxicity thus is contraindicated; AV nodal conduction disturbances may be exacerbated.

Drug Interactions. Verapamil blocks the P-glycoprotein drug transporter. Both the renal and hepatic disposition of digoxin occurs via this transporter. Accordingly, verapamil inhibits the elimination of digoxin and other drugs that are cleared from the body by the P-glycoprotein (see Chapter 5). When used with quinidine, Ca2+ channel blockers may cause excessive hypotension, particularly in patients with idiopathic hypertrophic subaortic stenosis.


VARIANT ANGINA. Variant angina results from reduced blood flow rather than increased oxygen demand. Ca2+ channel blocking agents have proven efficacy for the treatment of variant angina. 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.

EXERTIONAL ANGINA. Ca2+ channel antagonists also are effective in the treatment of exertional, or exercise-induced, angina. Their utility may result from an increase in blood flow owing to coronary arterial dilation, from a decrease in myocardial oxygen demand (secondary to a decrease in arterial blood pressure, heart rate, or contractility), or both. These drugs decrease the number of anginal attacks and attenuate exercise-induced ST-segment depression.

Ca2+ channel antagonists, particularly the dihydropyridines, may aggravate anginal symptoms in some patients when used without a β 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 β receptor antagonist propranolol or with amlodipine and any of several β receptor antagonists has proven more effective than either agent given alone in exertional angina, presumably because the β antagonist suppresses reflex tachycardia. This concurrent drug therapy is particularly attractive because the dihydropyridines, unlike verapamil and diltiazem, do not delay AV conduction and will not enhance the negative dromotropic effects associated with β receptor blockade. Although concurrent administration of verapamil or diltiazem with a β receptor antagonist also may reduce angina, the potential for AV block, severe bradycardia, and decreased left ventricular function requires that these combinations be used judiciously, 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 slower onset of action.

Unstable Angina. Medical therapy for unstable angina involves the administration of aspirin, which reduces mortality, nitrates, β adrenergic receptor blocking agents, and heparin. Because vasospasm occurs in some patients with unstable angina, Ca2+ channel blockers may offer an additional approach to this condition.

Myocardial Infarction. There is no evidence that Ca2+ channel antagonists are of benefit in the early treatment or secondary prevention of acute MI. Diltiazem and verapamil may reduce the incidence of reinfarction in patients with MI who are not candidates for a β adrenergic receptor antagonist, but β adrenergic receptor antagonists remain the drugs of first choice.

Other Uses. Ca2+ channel antagonists are also used as anti-arrhythmic agents, for the treatment of hypertension, and for the treatment of heart failure. 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, amlodipine, and felodipine appear to provide symptomatic relief in Raynaud disease. The Ca2+ channel antagonists cause relaxation of the myometrium in vitro and may be effective in stopping preterm uterine contractions in preterm labor (see Chapter 66).


β Adrenergic receptor antagonists are effective in reducing the severity and frequency of attacks of exertional angina and in improving survival in patients who have had an MI. In contrast, these agents are not useful for vasospastic angina and, if used in isolation, may worsen the condition. Timolol, metoprolol, atenolol, and propranolol exert cardioprotective effects. The effectiveness of β adrenergic receptor antagonists in the treatment of exertional angina is attributable primarily to a fall in myocardial O2 consumption at rest and during exertion; there also is some tendency for increased flow toward ischemic regions. The decrease in myocardial O2 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 actions of β adrenergic receptor antagonists are beneficial in all patients. The decreases in heart rate and contractility cause increases in the systolic ejection period and left ventricular end-diastolic volume; these alterations tend to increase O2 consumption. However, the net effect of β receptor blockade usually is to decrease myocardial O2 consumption, particularly during exercise. In patients with limited cardiac reserve who are critically dependent on adrenergic stimulation, β receptor blockade can result in profound decreases in left ventricular function. Despite this, several β adrenergic receptor antagonists have been shown to reduce mortality in patients with congestive heart failure (see Chapters 12 and 28). Numerous β receptor antagonists are approved for clinical use in the U.S. (see Chapter 12).


UNSTABLE ANGINA. β Adrenergic receptor antagonists are effective in reducing recurrent episodes of ischemia and the risk of progression to acute MI. Clinical trials have lacked sufficient statistical power to demonstrate beneficial effects of β receptor antagonists on mortality. If the underlying pathophysiology is coronary vasospasm, nitrates and Ca2+ channel blockers may be effective, and β receptor antagonists should be used with caution. 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 β receptor antagonist may be helpful.

MYOCARDIAL INFARCTION. β Adrenergic receptor antagonists that do not have intrinsic sympathomimetic activity improve mortality in MI. They should be given early and continued indefinitely in patients who can tolerate them.


In evaluating trials in which different forms of anti-anginal therapy are compared, one must pay careful attention to the patient population studied and to the pathophysiology and stage of the disease. An important placebo effect may be seen in these trials. The efficacy of anti-anginal treatment will depend on the severity of angina, the presence of coronary vasospasm, and myocardial O2 demand. Optimally, the dose of each agent should be titrated to maximum benefit.

Task forces from the ACC and the AHA have published guidelines that are useful in the selection of appropriate initial therapy for patients with chronic stable angina pectoris. Patients with coronary artery disease should be treated with aspirin and a β receptor blocking drug (particularly if there is a history of prior MI). The guidelines also note that solid data support the use of ACE inhibitors in patients with coronary artery disease who also have left ventricular dysfunction and/or diabetes. Therapy of hypercholesterolemia also is indicated. Nitrates, for treatment of angina symptoms, and Ca2+ antagonists also may be used. Table 27–3 summarizes the issues that the ACC/AHA task force considered to be relevant in choosing between β receptor antagonists and Ca2+ channel blockers in patients with angina and other medical conditions. Comparison of β adrenergic receptor antagonists with Ca2+ channel blockers showed that β receptor antagonists are associated with fewer episodes of angina per week and a lower rate of withdrawal because of adverse events. However, there were no differences in time to ischemia during exercise or in the frequency of adverse events when Ca2+ channel blockers other than nifedipine were compared with β 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 β receptor antagonists.

COMBINATION THERAPY AND NEW ANTI-ANGINAL DRUGS. Because the different categories of anti-anginal agents have 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. Despite the predicted advantages, combination therapy rarely achieves this potential and may be accompanied by serious side effects. The new anti-anginal agent ranolazine elicits its therapeutic effects by different and incompletely understood mechanisms that distinguish this new drug from the “classical” classes of anti-anginal drugs (organic nitrates, β adrenergic blockers and Ca2+ channel blockers). Ranolazine may have additional efficacy in combination with other anti-anginal agents, and the effects of ranolazine on cardiac arrhythmias and glucose metabolism may identify indications for this drug independent of its role as an anti-anginal agent. Table 27–3 shows some of the important indications and contraindications for use of anti-anginal agents in the context of other disease states.

Table 27–3

Recommended Drug Therapy for Angina in Patients with Other Medical Conditions


Nitrates and β Adrenergic Receptor Antagonists. The concurrent use of organic nitrates and β adrenergic receptor antagonists can be very effective in the treatment of typical exertional angina. The additive efficacy primarily is a result of the blockade by one drug of a reflex effect elicited by the other. β Adrenergic receptor antagonists can block the baroreceptor-mediated reflex tachycardia and positive inotropic effects that are sometimes associated with nitrates, whereas nitrates, by increasing venous capacitance, can attenuate the increase in left ventricular end-diastolic volume associated with β receptor blockade. Concurrent administration of nitrates also can alleviate the increase in coronary vascular resistance associated with blockade of β adrenergic receptors.

Ca2+ Channel Blockers and β Receptor Antagonists. Because there is a proven mortality benefit from the use of β adrenergic receptor antagonists in patients with heart disease, this class of drugs represents the first line of therapy. However, when angina is not controlled adequately by a β receptor antagonist plus nitrates, additional improvement sometimes can be achieved by the addition of a Ca2+ channel blocker, especially if there is a component of coronary vasospasm. The differences among the chemical classes of Ca2+ channel blockers can lead to important adverse or salutary drug interactions with β receptor antagonists. If the patient already is being treated with maximal doses of verapamil or diltiazem, it is difficult to demonstrate any additional benefit of β receptor blockade, and excessive bradycardia, heart block, or heart failure may ensue. However, in patients treated with a dihydropyridine such as nifedipine or with nitrates, substantial reflex tachycardia often limits the effectiveness of these agents. A β receptor antagonist may be a helpful addition in this situation, resulting in a lower heart rate and blood pressure with exercise.

Relative contraindications to the use of β receptor antagonists for treatment of angina—bronchospasm, Raynaud syndrome, or Prinzmetal angina—may lead to a choice to initiate therapy with a Ca2+channel blocker. Fluctuations in coronary tone are important determinants of variant angina. It is likely that episodes of increased tone, such as those precipitated by cold and by emotion, superimposed on fixed disease have a role in the variable anginal threshold seen in some patients with otherwise chronic stable angina. Increased coronary tone also may be important in the anginal episodes occurring early after MI and after coronary angioplasty, and it probably accounts for those patients with unstable angina who respond to dihydropyridines. Atherosclerotic arteries have abnormal vasomotor responses to a number of stimuli, 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 anatomical 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. Because nitrates primarily reduce preload, whereas Ca2+ channel blockers reduce afterload, the net effect on reduction of O2 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, β Receptor Antagonists, and Nitrates. In patients with exertional angina that is not controlled by the administration of 2 types of anti-anginal agents, the use of all 3 may provide improvement, although the incidence of side effects increases significantly. The dihydropyridines and nitrates dilate epicardial coronary arteries, the dihydropyridines decrease afterload, the nitrates decrease preload, and the β receptor antagonists decrease heart rate and myocardial contractility. Combining verapamil or diltiazem with a β receptor antagonist greatly increases the risk of conduction system and left ventricular dysfunction–related side effects and should be undertaken only with extreme caution.


Aspirin reduces the incidence of MI and death in patients with unstable angina. In addition, low doses of aspirin appear to reduce the incidence of MI in patients with chronic stable angina. Aspirin, given in doses of 160-325 mg at the onset of treatment of MI, reduces mortality in patients presenting with unstable angina. The addition of the clopidogrel to aspirin therapy reduces mortality in patients with acute coronary syndromes; a related thienopyridine, prasugrel, has been approved for treatment of acute coronary syndromes. Heparin, in its unfractionated form and as low-molecular-weight heparin, also reduces symptoms and prevents infarction in unstable angina. Thrombin inhibitors, such as hirudin or bivalirudin, directly inhibit even clot-bound thrombin, are not affected by circulating inhibitors, and function independently of antithrombin III. Thrombolytic agents, on the other hand, are of no benefit in unstable angina. Intravenous inhibitors of the platelet GPIIb/IIIa receptor (abciximab, tirofiban, and eptifibatide) are effective in preventing the complications of PCIs and in the treatment of some patients presenting with acute coronary syndromes.


Most patients with peripheral vascular disease also have coronary artery disease, and the therapeutic approaches for peripheral and coronary arterial diseases overlap. Mortality in patients with peripheral vascular disease is most commonly due to cardiovascular disease, and treatment of coronary disease remains the central focus of therapy. Many patients with advanced peripheral arterial disease are more limited by the consequences of peripheral ischemia than by myocardial ischemia. In the cerebral circulation, arterial disease may be manifest as stroke or transient ischemic attacks. The painful symptoms of peripheral arterial disease in the lower extremities (claudication) typically are provoked by exertion, with increases in skeletal muscle O2 demand exceeding blood flow impaired by proximal stenoses. When flow to the extremities becomes critically limiting, peripheral ulcers and rest pain from tissue ischemia can become debilitating.

Most of the therapies that are efficacious for treatment of coronary artery disease also have a salutary effect on progression of peripheral artery disease. Reductions in cardiovascular morbidity and mortality in patients with peripheral arterial disease have been documented with antiplatelet therapy using aspirin, clopidogrel, ticlopidine, ACE inhibitors, and treatment of hyperlipidemia. Interestingly, neither intensive treatment of diabetes mellitus nor antihypertensive therapy appears to alter the progression of symptoms of claudication. Other risk factor and lifestyle modifications remain cornerstones of therapy for patients with claudication: physical exercise, rehabilitation, and smoking cessation have proven efficacy.

Drugs used specifically in the treatment of lower-extremity claudication include pentoxifylline and cilostazol. Pentoxifylline is a methylxanthine derivative that is called a rheologic modifier for its effects on increasing the deformability of red blood cells. The effects of pentoxifylline on lower-extremity claudication appear to be modest. Cilostazol is an inhibitor of PDE3 and promotes accumulation of intracellular cyclic AMP in many cells, including blood platelets. Cilostazol-mediated increases in cyclic AMP inhibit platelet aggregation and promote vasodilation. The drug is metabolized by CYP3A4 and has important drug interactions with other drugs metabolized via this pathway (see Chapter 6). Cilostazol treatment improves symptoms of claudication but has no effect on cardiovascular mortality. As a PDE3 inhibitor, cilostazol is in the same drug class as milrinone, which had been used orally as an inotropic agent for patients with heart failure. Milrinone therapy was associated with an increase in sudden cardiac death, and the oral form of the drug was withdrawn from the market. Concerns about several other inhibitors of PDE3 (inamrinone, flosequinan) followed. Cilostazol, therefore, is labeled as being contraindicated in patients with heart failure, although it is not clear that cilostazol itself leads to increased mortality in such patients. Cilostazol has been reported to increase nonsustained ventricular tachycardia; headache is the most common side effect. Other treatments for claudication, including naftidrofuryl, propionyl levocarnitine, and prostaglandins, may also be efficacious.


Intracoronary stents can ameliorate angina and reduce adverse events in patients with acute coronary syndromes. However, the long-term efficacy of intracoronary stents is limited by subacute luminal restenosis within the stent, which occurs in a substantial minority of patients. The pathways that lead to “in-stent restenosis” are complex, but smooth muscle proliferation within the lumen of the stented artery is a common pathological finding.

Two drugs are currently being used on intravascular stents as localized anti-proliferative therapy: paclitaxel and sirolimus. Paclitaxel is a tricyclic diterpene that inhibits cellular proliferation by binding to and stabilizing polymerized microtubules. Sirolimus is a hydrophobic macrolide that binds to the cytosolic immunophilin FKBP12; the FKBP12–sirolimus complex inhibits the mammalian kinase target of rapamycin (mTOR), thereby inhibiting cell-cycle progression (see Chapter 62). Stent-induced damage to the vascular endothelial cell layer can lead to thrombosis; patients typically are treated with antiplatelet agents, including clopidogrel (for up to 6 months) and aspirin (indefinitely), sometimes in conjunction with intravenous heparin and/or GPIIb/IIIa inhibitors. The inhibition of cellular proliferation by paclitaxel and sirolimus not only affects vascular smooth muscle cell proliferation but also attenuates the formation of an intact endothelial layer within the stented artery. Therefore, antiplatelet therapy is continued for several months after intracoronary stenting with drug-eluting stents. The rate of restenosis with drug-eluting stents is reduced markedly compared with “bare metal” stents. Stent thrombosis can occur even many months after placement of the stent, sometimes temporally associated with discontinuation of antiplatelet therapy.


Hypertension is the most common cardiovascular disease; its prevalence increases with advancing age. Elevated arterial pressure causes pathological changes in the vasculature and hypertrophy of the left ventricle. Hypertension is the principal cause of stroke, a major risk factor for coronary artery disease and its complications, and a major contributor to cardiac failure, renal insufficiency, and dissecting aneurysm of the aorta.

Hypertension is defined conventionally as a sustained increase in blood pressure ≥140/90 mm Hg, a criterion that characterizes a group of patients whose risk of hypertension-related cardiovascular disease is high enough to merit medical attention. Actually, the risk of both fatal and nonfatal cardiovascular disease in adults is lowest with systolic blood pressures of <120 mm Hg and diastolic BP <80 mm Hg; these risks increase progressively with higher systolic and diastolic blood pressures (Table 27–4). Isolated systolic hypertension (sometimes defined as systolic BP > 140-160 mm Hg with diastolic BP <90 mm Hg) is largely confined to people older than 60 years of age. At very high blood pressures (systolic ≥210 mm Hg and/or diastolic ≥120 mm Hg), a subset of patients develops fulminant arteriopathy characterized by endothelial injury and a marked proliferation of cells in the intima, leading to intimal thickening and ultimately to arteriolar occlusion. This is associated with rapidly progressive microvascular occlusive disease in the kidney (with renal failure), brain (hypertensive encephalopathy), congestive heart failure, and pulmonary edema. These patients typically require in-hospital management on an emergency basis for prompt lowering of blood pressure. Pharmacological treatment of patients with hypertension decreases morbidity and mortality from cardiovascular disease.

Table 27–4

Criteria for Hypertension in Adults


PRINCIPLES OF ANTIHYPERTENSIVE THERAPY. Nonpharmacological therapy is an important component of treatment of all patients with hypertension. In some stage 1 hypertensives, blood pressure may be adequately controlled by a combination of weight loss (in overweight individuals), restricting sodium intake, increasing aerobic exercise, and moderating consumption of alcohol. These lifestyle changes may facilitate pharmacological control of blood pressure.

Antihypertensive drugs can be classified according to their sites or mechanisms of action (Table 27–5). Drugs lower blood pressure by actions on peripheral resistance, cardiac output, or both (recall that arterial pressure is the product of cardiac output and peripheral vascular resistance). Drugs may decrease the cardiac output by inhibiting myocardial contractility or by decreasing ventricular filling pressure. Reduction in ventricular filling pressure may be achieved by actions on the venous tone or on blood volume via renal effects. Drugs can decrease peripheral resistance by acting on smooth muscle to cause relaxation of resistance vessels or by interfering with the activity of systems that produce constriction of resistance vessels. In patients with isolated systolic hypertension, complex hemodynamics in a rigid arterial system contribute to increased blood pressure; drug effects may be mediated by changes in peripheral resistance but also via effects on large artery stiffness.

Table 27–5

Classification of Antihypertensive Drugs by Primary Site or Mechanism of Action


The concurrent use of drugs from different classes is a strategy for achieving effective control of blood pressure while minimizing dose-related adverse effects. Hemodynamic consequences of longterm antihypertensive therapy provide a rationale for multidrug therapy (Table 27–6).

Table 27–6

Hemodynamic Effects of Long-Term Administration of Antihypertensive Agents



Diuretic agents (see Chapter 25) have antihypertensive effects when used alone, and they enhance the efficacy of virtually all other antihypertensive drugs.

The exact mechanism for reduction of arterial blood pressure by diuretics is not certain. The drugs decrease extracellular volume by inhibiting the NaCl co-transporter (NCC) in the distal convoluted tubule, enhancing Na+ excretion in the urine, and leading to a fall in cardiac output. However, the hypotensive effect is maintained during long-term therapy due to decreased vascular resistance; cardiac output returns to pretreatment values and extracellular volume returns almost to normal due to compensatory responses such as activation of the RAS. Hydrochlorothiazide may open Ca2+-activated K+ channels, leading to hyperpolarization of vascular smooth muscle cells, which leads in turn to closing of L-type Ca2+ channels and lower probability of opening, resulting in decreased Ca2+ entry and reduced vasoconstriction.

BENZOTHIADIAZIDES AND RELATED COMPOUNDS. Benzothiadiazides (“thiazides”) and related diuretics are the most frequently used class of antihypertensive agents in the U.S. Following the discovery of chlorothiazide, a number of oral diuretics were developed that have an arylsulfonamide structure and block the NaCl co-transporter. Some of these are not benzothiadiazines but have structural features and molecular functions that are similar to the original benzothiadiazine compounds; consequently, they are designated as members of the thiazide class of diuretics. For example, chlorthalidone, one of the non-benzothiadiazines, is widely used in the treatment of hypertension, as is indapamide.

Regimen for Administration of the Thiazide-Class Diuretics in Hypertension. Antihypertensive effects can be achieved in many patients with as little as 12.5 mg daily of chlorthalidone or hydrochlorothiazide. Furthermore, when used as monotherapy, the maximal daily dose of thiazide-class diuretics usually should not exceed 25 mg of hydrochlorothiazide or chlorthalidone (or equivalent). Higher doses are not generally more efficacious in lowering blood pressure in patients with normal renal function. Urinary K+ loss can be a problem with thiazides. ACE inhibitors and angiotensin receptor antagonists will attenuate diuretic-induced loss of K+ to some degree, and this is a consideration if a second drug is required to achieve further blood pressure reduction beyond that attained with the diuretic alone. Because the diuretic and hypotensive effects of these drugs are greatly enhanced when they are given in combination, care should be taken to initiate combination therapy with low doses of each of these drugs. Administration of ACE inhibitors or angiotensin receptor antagonists together with other K+-sparing agents or with K+ supplements requires great caution; combining K+-sparing agents with each other or with K+ supplementation can cause potentially dangerous hyperkalemia in some patients.

Treatment of severe hypertension that is unresponsive to 3 or more drugs may require larger doses of the thiazide-class diuretics. Hypertensive patients may become refractory to drugs that block the sympathetic nervous system or to vasodilator drugs, because these drugs engender a state in which the blood pressure is very volume-dependent. Therefore, it is appropriate to consider the use of thiazide-class diuretics in doses of 50 mg of daily hydrochlorothiazide equivalent when treatment with appropriate combinations and doses of 3 or more drugs fails to yield adequate control of the blood pressure. Alternatively, there may be a need to use higher-capacity diuretics such as furosemide, especially if renal function is not normal, in some of these patients. Dietary Na+ restriction is a valuable adjunct to the management of such refractory patients and will minimize the dose of diuretic that is required. Because the degree of K+ loss relates to the amount of Na+ delivered to the distal tubule, such restriction of Na+ can minimize the development of hypokalemia and alkalosis. The effectiveness of thiazides as diuretics or antihypertensive agents is progressively diminished when the glomerular filtration rate falls below 30 mL/min. One exception is metolazone, which retains efficacy in patients with this degree of renal insufficiency.

Most patients will respond to thiazide diuretics with a reduction in blood pressure within about 4-6 weeks. Therefore, doses should not be increased more often than every 4-6 weeks. Because the effect of thiazide diuretics is additive with that of other antihypertensive drugs, combination regimens that include these diuretics are common and rational. A wide range of fixed-dose combination products containing a thiazide are marketed for this purpose. Diuretics also have the advantage of minimizing the retention of salt and water that is commonly caused by vasodilators and some sympatholytic drugs. Omitting or underutilizing a diuretic is a frequent cause of “resistant hypertension.”

Adverse Effects and Precautions. The adverse effects of diuretics are discussed in Chapter 25. Erectile dysfunction is a troublesome adverse effect of the thiazide-class diuretics. Gout may be a consequence of the hyperuricemia induced by these diuretics. Precipitation of acute gout is relatively uncommon with low doses of diuretics. Hydrochlorothiazide may cause rapidly developing, severe hyponatremia in some patients. Thiazides inhibit renal Ca2+ excretion, occasionally leading to hypercalcemia; although generally mild, this can be more severe in patients with primary hyperparathyroidism. The thiazide-induced decreased Ca2+ excretion may be used therapeutically in patients with osteoporosis or hypercalciuria.

Two types of ventricular arrhythmias may be enhanced by K+ depletion. One of these is polymorphic ventricular tachycardia (torsade de pointes), which is induced by a number of drugs, including quinidine. Because K+ currents normally mediate repolarization, drugs that produce K+ depletion potentiate polymorphic ventricular tachycardia. The second is ischemic ventricular fibrillation, the leading cause of sudden cardiac death and a major contributor to cardiovascular mortality in treated hypertensive patients. There is a positive correlation between diuretic dose and sudden cardiac death, and an inverse correlation between the use of adjunctive K+-sparing agents and sudden cardiac death. All of the thiazide-like drugs cross the placenta but they have not been shown to have direct adverse effects on the fetus. If administration of a thiazide is begun during pregnancy, there is a risk of transient volume depletion that may result in placental hypoperfusion. Because the thiazides appear in breast milk, they should be avoided by nursing mothers.

OTHER DIURETIC ANTIHYPERTENSIVE AGENTS. The thiazide diuretics are more effective antihypertensive agents than are the loop diuretics, such as furosemide and bumetanide in patients who have normal renal function. This differential effect likely relates to the short duration of action of loop diuretics, such that a single daily dose does not cause a significant net loss of Na+ for an entire 24-h period. Indeed, loop diuretics are frequently and inappropriately prescribed as a once-daily medication in the treatment of hypertension, congestive heart failure, and ascites. The spectacular efficacy of the loop diuretics in producing a rapid and profound natriuresis can be detrimental for the treatment of hypertension. When a loop diuretic is given twice daily, the acute diuresis can be excessive and lead to more side effects than with a slower-acting, milder thiazide diuretic. Loop diuretics may be particularly useful in patients with azotemia or with severe edema associated with a vasodilator such as minoxidil.

Amiloride is a K+-sparing diuretic that has some efficacy in lowering blood pressure in patients with hypertension. Spironolactone lowers blood pressure but has some significant adverse effects, especially in men (e.g., erectile dysfunction, gynecomastia, benign prostatic hyperplasia). Eplerenone is a newer aldosterone receptor antagonist that does not have the sexually related adverse effects. Triamterene is a K+-sparing diuretic that decreases the risk of hypokalemia in patients treated with a thiazide diuretic but does not have efficacy in lowering blood pressure by itself. These agents should be used cautiously with frequent measurements of K+ concentrations in plasma in patients predisposed to hyperkalemia. Patients should be cautioned regarding the concurrent use of K+-containing salt substitutes. Renal insufficiency is a relative contraindication to the use of K+-sparing diuretics. Concomitant use of an ACE inhibitor or an angiotensin receptor antagonist magnifies the risk of hyperkalemia with these agents.

DIURETIC-ASSOCIATED DRUG INTERACTIONS. The K+- and Mg2+-depleting effects of the thiazides and loop diuretics can potentiate arrhythmias that arise from digitalis toxicity. Corticosteroids can amplify the hypokalemia produced by the diuretics. All diuretics can decrease the clearance of Li+, resulting in increased plasma concentrations of Li+ and potential toxicity. NSAIDs (see Chapter 34), including selective COX-2 inhibitors, that inhibit the synthesis of prostaglandins reduce the antihypertensive effects of diuretics. NSAIDs, β receptor antagonists, and ACE inhibitors reduce plasma concentrations of aldosterone and can potentiate the hyperkalemic effects of a K+-sparing diuretic.


Antagonists of α and β adrenergic receptors are mainstays of antihypertensive therapy (see Table 27–5).


β Adrenergic receptor antagonists have antihypertensive effects. Antagonism of β adrenergic receptors affects the regulation of the circulation through a number of mechanisms, including a reduction in myocardial contractility, heart rate, and cardiac output. An important consequence is blockade of the β1 receptors of the juxtaglomerular complex, reducing renin secretion and thereby diminishing production of circulating AngII. Some β receptor antagonists may lower blood pressure by other mechanisms. For example, labetalol is also an α1 receptor antagonist, and nebivolol promotes endothelium-dependent vasodilation via activation of the NO pathway.

Pharmacological Effects. The β adrenergic blockers vary in their selectivity for the β1 receptor subtype, presence of partial agonist or intrinsic sympathomimetic activity, and vasodilating capacity. These differences do influence the clinical pharmacokinetics and spectrum of adverse effects of the various drugs. Drugs without intrinsic sympathomimetic activity produce an initial reduction in cardiac output and a reflex-induced rise in peripheral resistance, generally with no net change in arterial pressure. Persistently reduced cardiac output and possibly decreased peripheral resistance accounts for the reduction in arterial pressure. Drugs with intrinsic sympathomimetic activity produce lesser decreases in resting heart rate and cardiac output; the fall in arterial pressure correlates with a fall in vascular resistance below pretreatment levels, possibly because of stimulation of vascular β2 receptors that mediate vasodilation.

Adverse Effects and Precautions. The adverse effects of β adrenergic blocking agents are discussed in Chapter 12. These drugs should be avoided in patients with asthma or with SA or AV nodal dysfunction or in combination with other drugs that inhibit AV conduction, such as verapamil. The risk of hypoglycemic reactions may be increased in diabetics taking insulin. β Receptor antagonists without intrinsic sympathomimetic activity increase concentrations of triglycerides in plasma and lower those of HDL cholesterol without changing total cholesterol concentrations. β receptor blocking agents with intrinsic sympathomimetic activity have little or no effect on blood lipids or increase HDL cholesterol.

Sudden discontinuation of β adrenergic blockers can produce a withdrawal syndrome that is likely due to upregulation of β receptors causing enhanced tissue sensitivity to endogenous catecholamines; this can exacerbate the symptoms of coronary artery disease or cause rebound hypertension. Thus, β adrenergic blockers should be tapered gradually over 10-14 days.

NSAIDs such as indomethacin can blunt the antihypertensive effect of propranolol and probably other β receptor antagonists. This effect may be related to inhibition of vascular synthesis of prostacyclin, as well as to retention of Na+.

Epinephrine can produce severe hypertension and bradycardia when a nonselective β antagonist is present due to the unopposed stimulation of α adrenergic receptors when vascular β2 receptors are blocked. The bradycardia is the result of reflex vagal stimulation. Such hypertensive responses to β receptor antagonists have been observed in patients with hypoglycemia or pheochromocytoma, during withdrawal from clonidine, following administration of epinephrine as a therapeutic agent, or in association with the illicit use of cocaine.

Therapeutic Uses. The β receptor antagonists provide effective therapy for all grades of hypertension. The antihypertensive effect of all the β blockers is of sufficient duration to permit once- or twice-daily administration. Populations that tend to have a lesser antihypertensive response to β blocking agents include the elderly and African Americans. However, intra-individual differences in antihypertensive efficacy are generally much larger than differences between racial or age-related groups. The β receptor antagonists usually do not cause retention of salt and water, but do have additive antihypertensive effects when combined with diuretics. β receptor antagonists are preferred drugs for hypertensive patients with conditions such as MI, ischemic heart disease, or congestive heart failure.


Drugs that selectively block α1 adrenergic receptors without affecting α2 adrenergic receptors are used in hypertension. Prazosin, terazosin, and doxazosin are the agents that are available for the treatment of hypertension.

Pharmacological Effects. Initially, α1 adrenergic receptor antagonists reduce arteriolar resistance and increase venous capacitance; this causes a sympathetically mediated reflex increase in heart rate and plasma renin activity. During long-term therapy, vasodilation persists, but cardiac output, heart rate, and plasma renin activity return to normal. Renal blood flow is unchanged during therapy. The α1adrenergic blockers cause a variable amount of postural hypotension, depending on the plasma volume. Retention of salt and water occurs in many patients during continued administration, and this attenuates the postural hypotension. α1 Receptor antagonists reduce plasma concentrations of triglycerides and total LDL cholesterol and increase HDL cholesterol. These potentially favorable effects on lipids persist when a thiazide-type diuretic is given concurrently. The long-term consequences of these small, drug-induced changes in lipids are unknown.

Adverse Effects. The use of doxazosin as monotherapy for hypertension increases the risk for developing congestive heart failure. This may be an adverse effect of all of the α1 receptor antagonists. A major precaution regarding the use of the α1 receptor antagonists for hypertension is the so-called first-dose phenomenon, in which symptomatic orthostatic hypotension occurs within 30-90 min (or longer) of the initial dose of the drug or after a dosage increase. This effect may occur in up to 50% of patients, especially in patients who are already receiving a diuretic or an α receptor antagonist. After the first few doses, patients develop a tolerance to this marked hypotensive response.

Therapeutic Uses. α1 Receptor antagonists are not recommended as monotherapy for hypertensive patients but are used primarily in conjunction with diuretics, β blockers, and other antihypertensive agents. β Receptor antagonists enhance the efficacy of the α1 blockers. α1 Receptor antagonists are not the drugs of choice in patients with pheochromocytoma, because a vasoconstrictor response to epinephrine can still result from activation of unblocked vascular α2 adrenergic receptors. α1 Receptor antagonists improve urinary symptoms in hypertensive patients with benign prostatic hyperplasia.


Labetalol (see Chapter 12) is an equimolar mixture of 4 stereoisomers. One isomer is an α1 antagonist (like prazosin), another is a nonselective β antagonist with partial agonist activity (like pindolol), and the other 2 isomers are inactive. Because of its capacity to block α1 adrenergic receptors, labetalol given intravenously can reduce blood pressure sufficiently rapidly to be useful for the treatment of hypertensive emergencies. Labetalol has efficacy and adverse effects that would be expected with any combination of β and α1receptor antagonists.

Carvedilol (see Chapter 12) is a β receptor antagonist with α1 receptor antagonist activity. The drug has been approved for the treatment of hypertension and symptomatic heart failure. The ratio of α1 to β receptor antagonist potency for carvedilol is approximately 1:10. Carvedilol is oxidized by hepatic CYP2D6 and then glucuronidated. Carvedilol reduces mortality in patients with congestive heart failure associated with systolic dysfunction when used as an adjunct to therapy with diuretics and ACE inhibitors. It should not be given to those patients with decompensated heart failure who are dependent on sympathetic stimulation. As with labetalol, the side effects of carvedilol in hypertension are predictable based on its properties as a β and α1 adrenergic receptor antagonist.

Nebivolol is a β1-selective adrenergic antagonist that also promotes vasodilatation; nebivolol augments arterial smooth muscle relaxation via NO, and has agonist activity at β3receptors, although the clinical significance of this effect is not known.


Methyldopa is a centrally acting antihypertensive agent. It is a prodrug that exerts its antihypertensive action via an active metabolite. Methyldopa’s significant adverse effects limit its current use largely to treatment of hypertension in pregnancy, where it has a record for safety.

Methyldopa is metabolized by the L-aromatic amino acid decarboxylase in adrenergic neurons to α-methyldopamine, which then is converted to α-methylnorepinephrine (α-CH3-NE). α-CH3-NE is stored in the secretory vesicles of adrenergic neurons, substituting for NE. Thus, when the adrenergic neuron discharges its neurotransmitter, α-CH3-NE is released instead of NE. α-CH3-NE acts in the CNS to inhibit adrenergic neuronal outflow from the brainstem and probably acts as an agonist at presynaptic α2 adrenergic receptors in the brainstem, attenuating NE release and thereby reducing the output of vasoconstrictor adrenergic signals to the peripheral sympathetic nervous system.

ADME. Because methyldopa is a prodrug that is metabolized in the brain to the active form, its concentration in plasma has less relevance for its effects than that for many other drugs. Peak concentrations in plasma occur after 2-3 h. The drug is eliminated with a t1/2 of ~2 h but is prolonged to 4-6 h in patients with renal failure. The peak effect of methyldopa is delayed for 6-8 h, even after intravenous administration, and the duration of action of a single dose is usually about 24 h; this permits once- or twice-daily dosing. The discrepancy between the effects of methyldopa and the measured concentrations of the drug in plasma is most likely related to the time required for transport into the CNS, conversion to the active metabolite, storage of α-CH3-NE and its subsequent release at relevant α2 receptors in the CNS.

Adverse Effects and Precautions. Methyldopa produces sedation that is largely transient; depression occurs occasionally. Methyldopa may produce dryness of the mouth, diminished libido, parkinsonian signs, and hyper-prolactinemia that may become sufficiently pronounced to cause gynecomastia and galactorrhea. Methyldopa may precipitate severe bradycardia and sinus arrest. Hepatotoxicity, sometimes associated with fever, is an uncommon but potentially serious toxic effect of methyldopa. At least 20% of patients who receive methyldopa for a year develop a positive Coombs test (antiglobulin test) that is due to autoantibodies directed against the Rh antigen on erythrocytes; 1-5% of these patients will develop a hemolytic anemia that requires prompt discontinuation of the drug. The Coombs test may remain positive for as long as a year after discontinuation of methyldopa, but the hemolytic anemia usually resolves within a matter of weeks. Severe hemolysis may be attenuated by treatment with glucocorticoids. Rarer adverse effects include leukopenia, thrombocytopenia, red cell aplasia, lupus erythematosus–like syndrome, lichenoid and granulomatous skin eruptions, myocarditis, retroperitoneal fibrosis, pancreatitis, diarrhea, and malabsorption.

Therapeutic Uses. Methyldopa is a preferred drug for treatment of hypertension during pregnancy based on its effectiveness and safety for both mother and fetus. The usual initial dose of methyldopa is 250 mg twice daily, and there is little additional effect with doses >2 g/day.


The detailed pharmacology of the α2 adrenergic agonists clonidine, guanabenz, and guanfacine is discussed in Chapter 12. These drugs stimulate the α2A subtype of α2 adrenergic receptors in the brainstem, resulting in a reduction in sympathetic outflow from the CNS. Patients who have had a spinal cord transection above the level of the sympathetic outflow tracts do not display a hypotensive response to clonidine. At doses higher than those required to stimulate central α2A receptors, these drugs can activate α2 receptors of the α2B subtype on vascular smooth muscle cells. This effect accounts for the initial vasoconstriction that is seen when overdoses of these drugs are taken, and may be responsible for the loss of therapeutic effect that is observed with high doses.

Pharmacological Effects. The α2 adrenergic agonists lower arterial pressure by an effect on both cardiac output and peripheral resistance. In the supine position, when the sympathetic tone to the vasculature is low, the major effect is to reduce both heart rate and stroke volume; however, in the upright position, when sympathetic outflow to the vasculature is normally increased, these drugs reduce vascular resistance and may lead to postural hypotension. The decrease in cardiac sympathetic tone leads to a reduction in myocardial contractility and heart rate that could promote congestive heart failure in susceptible patients.

Adverse Effects and Precautions. Sedation and xerostomia are prominent adverse effects. The xerostomia may be accompanied by dry nasal mucosa, dry eyes, and parotid gland swelling and pain. Postural hypotension and erectile dysfunction may be prominent in some patients. Clonidine may produce a lower incidence of dry mouth and sedation when given transdermally. Less common CNS side effects include sleep disturbances with vivid dreams or nightmares, restlessness, and depression. Cardiac effects related to the sympatholytic action of these drugs include symptomatic bradycardia and sinus arrest in patients with dysfunction of the SA node and AV block in patients with AV nodal disease or in patients taking other drugs that depress AV conduction. Some 15-20% of patients who receive transdermal clonidine may develop contact dermatitis.

Sudden discontinuation of clonidine and related α2 adrenergic agonists may cause a withdrawal syndrome consisting of headache, apprehension, tremors, abdominal pain, sweating, and tachycardia. The arterial blood pressure may rise to levels above those that were present prior to treatment. Symptoms typically occur 18-36 h after the drug is stopped and are associated with increased sympathetic discharge. The withdrawal syndrome is likely dose related and more dangerous in patients with poorly controlled hypertension. In the absence of life-threatening target organ damage, patients can be treated by restoring the use of clonidine. If a more rapid effect is required, sodium nitroprusside or a combination of an α and β adrenergic blocker is appropriate. β Adrenergic blocking agents should not be used alone in this setting, because they may accentuate the hypertension by allowing unopposed α adrenergic vasoconstriction caused by activation of the sympathetic nervous system.

Surgical patients who are being treated with an α2 adrenergic agonist either should be switched to another drug prior to elective surgery or should receive their morning dose and/or transdermal clonidine prior to the procedure. All patients who receive one of these drugs should be warned of the potential danger of discontinuing the drug abruptly, and patients suspected of being noncompliant with medications should not be given α2 adrenergic agonists for hypertension. Adverse drug interactions with α2 adrenergic agonists are rare. Diuretics predictably potentiate the hypotensive effect of these drugs. Tricyclic antidepressants may inhibit the antihypertensive effect of clonidine, but the mechanism of this interaction is not known.

Therapeutic Uses. The CNS effects are such that this class of drugs is not a leading option for monotherapy of hypertension. They effectively lower blood pressure in some patients who have not responded adequately to combinations of other agents.


Guanadrel specifically inhibits the function of peripheral postganglionic adrenergic neurons. It is an exogenous false neurotransmitter that is accumulated, stored, and released like NE but is inactive at adrenergic receptors. In the neuron, guanadrel is concentrated within the adrenergic storage vesicle, where it replaces NE. Because guanadrel can promote NE release from pheochromocytomas, it is contraindicated in those patients.

Pharmacological Effects. The antihypertensive effect is achieved by a reduction in peripheral vascular resistance that results from inhibition of α receptor–mediated vasoconstriction. Arterial pressure is reduced modestly in the supine position when sympathetic activity is usually low, but the pressure can fall to a greater extent during situations in which reflex sympathetic activation is an important mechanism for maintaining arterial pressure, particularly when standing.

ADME. The maximum effect on blood pressure is not seen until 4-5 h. The t1/2 of the pharmacological effect of guanadrel is determined by the drug’s persistence in this neuronal pool and is at least 10 h.

Adverse Effects. Guanadrel produces undesirable effects that are related to sympathetic blockade such as symptomatic hypotension during standing, exercise, ingestion of alcohol, or in hot weather. A general feeling of fatigue and lassitude is partially related to postural hypotension. Sexual dysfunction usually presents as delayed or retrograde ejaculation. Diarrhea also may occur. Drugs that block or compete for the catecholamine transporter on the presynaptic membrane (e.g., tricyclic antidepressants cocaine, chlorpromazine, ephedrine, phenylpropanolamine, and amphetamine; see Chapter 8) also will inhibit the effect of guanadrel.

Therapeutic Uses. Because of the availability of a number of drugs that lower blood pressure without producing similar adverse effects, guanadrel is used very rarely; the drug is no longer marketed in the U.S.


Reserpine is an alkaloid extracted from the root of Rauwolfia serpentina. Reserpine inhibits the vesicular catecholamine transporter, VMAT2, so that nerve endings lose their capacity to concentrate and store NE and dopamine. Catecholamines leak into the cytoplasm, where they are metabolized. Consequently, little or no active transmitter is released from nerve endings, resulting in a pharmacological sympathectomy. Recovery of sympathetic function requires synthesis of new storage vesicles, which takes days to weeks after discontinuation of the drug. Reserpine depletes amines in the CNS as well as in the peripheral adrenergic neuron and its antihypertensive effects may be related to both central and peripheral actions.

Pharmacological Effects. Both cardiac output and peripheral vascular resistance are reduced during long-term therapy with reserpine.

ADME. Data available on the pharmacokinetic properties of reserpine are limited because of the lack of an assay capable of detecting low concentrations of the drug or its metabolites. Since reserpine binding is irreversible, the amount of drug in plasma is unlikely to bear any consistent relationship to drug concentration at the site of action. Free reserpine is entirely metabolized.

Toxicity and Precautions. Most adverse effects of reserpine are due to its effect on the CNS. Sedation and inability to concentrate or perform complex tasks are the most common adverse effects. More serious is the occasional psychotic depression that can lead to suicide. Reserpine must be discontinued at the first sign of depression; reserpine-induced depression may last several months after the drug is discontinued. The risk of depression is likely dose related and is uncommon with doses of 0.25 mg/day or less. Other adverse effects include nasal stuffiness and exacerbation of peptic ulcer disease, which is uncommon with small oral doses.

Therapeutic Uses. The use of reserpine has diminished because of its CNS side effects. Reserpine is used once daily with a diuretic, and several weeks are necessary to achieve a maximum effect. The daily dose should be limited to 0.25 mg or less, and as little as 0.05 mg/day may be efficacious when a diuretic is also used.


Metyrosine (DEMSER), α-methyl-L-tyrosine, inhibits tyrosine hydroxylase, the enzyme that catalyzes the conversion of tyrosine to DOPA and the rate-limiting step in catecholamine biosynthesis (see Chapter 8).

At a dose of 1-4 g/day, metyrosine decreases catecholamine biosynthesis by 35-80% in patients with pheochromocytoma. The maximal decrease in synthesis occurs only after several days and may be assessed by measurements of urinary catecholamines and their metabolites. Metyrosine is used as an adjuvant to phenoxybenzamine and other α adrenergic blocking agents for the management of pheochromocytoma and in the preoperative preparation of patients for resection of pheochromocytoma. Metyrosine carries a risk of crystalluria, which can be minimized by maintaining a daily urine volume of >2 L. Other adverse effects include orthostatic hypotension, sedation, extrapyramidal signs, diarrhea, anxiety, and psychic disturbances. Doses must be titrated carefully to minimize these side effects.


Ca2+ channel blocking agents are important drugs for the treatment of hypertension. The pharmacology of these drugs is presented earlier in this chapter. Because contraction of vascular smooth muscle is dependent on the free intracellular concentration of Ca2+, inhibition of transmembrane movement of Ca2+ through voltage-sensitive Ca2+ channels can decrease the total amount of Ca2+ that reaches intracellular sites. Ca2+ channel blockers lower blood pressure by relaxing arteriolar smooth muscle and decreasing peripheral vascular resistance; however, this evokes a baroreceptor-mediated sympathetic discharge. With dihydropyridines, tachycardia may occur from the adrenergic stimulation of the SA node. Tachycardia is typically minimal to absent with verapamil and diltiazem because of the direct negative chronotropic effect of these 2 drugs. Indeed, the concurrent use of a β receptor antagonist drug may magnify negative chronotropic effects of these drugs or cause heart block in susceptible patients.

Ca2+ channel blockers are effective when used alone or in combination with other drugs for the treatment of hypertension. However, there is no place in the treatment of hypertension for the use of nifedipine or other dihydropyridine Ca2+ channel blockers with short half-lives, administered in a standard (immediate-release) formulation, because of the oscillation in blood pressure and concurrent surges in sympathetic reflex activity within each dosage interval. Parenteral administration of the dihydropyridine clevidipine may be useful in treating severe or perioperative hypertension. Compared with other classes of antihypertensive agents, there may be a greater frequency of achieving blood pressure control with Ca2+ channel blockers as monotherapy in elderly subjects and in African Americans, population groups in which the low renin status is more prevalent. Ca2+ channel blockers are effective in lowering blood pressure and decreasing cardiovascular events in the elderly with isolated systolic hypertension.


Angiotensin II is an important regulator of cardiovascular function (see Chapter 26). ACE inhibitors include captopril, enalapril, lisinopril, quinapril, ramipril, benazepril, moexipril, fosinopril, trandolapril, and perindopril. Chapter 26 presents the pharmacology of ACE inhibitors in detail. The ACE inhibitors appear to confer a special advantage in the treatment of patients with diabetes, slowing the development and progression of diabetic glomerulopathy. They also are effective in slowing the progression of other forms of chronic renal disease, such as glomerulosclerosis; many of these patients also have hypertension. An ACE inhibitor is the preferred initial agent in these patients. Patients with hypertension and ischemic heart disease are candidates for treatment with ACE inhibitors; administration of ACE inhibitors in the immediate post-MI period has been shown to improve ventricular function and reduce morbidity and mortality (see Chapter 28).

Because ACE inhibitors blunt the rise in aldosterone concentrations in response to Na+ loss, the normal role of aldosterone to oppose diuretic-induced natriuresis is diminished. Consequently, ACE inhibitors tend to enhance the efficacy of diuretic drugs. Thus, even very small doses of diuretics may substantially improve the antihypertensive efficacy of ACE inhibitors; conversely, the use of high doses of diuretics together with ACE inhibitors may lead to excessive reduction in blood pressure and Na+ loss. The attenuation of aldosterone production by ACE inhibitors also influences K+ homeostasis; substantial retention of K+ can occur in some patients with renal insufficiency. Furthermore, the potential for developing hyperkalemia should be considered when ACE inhibitors are used with other drugs that can cause K+ retention, including the K+-sparing diuretics (amiloride, triamterene, and spironolactone), NSAIDs, K+ supplements, and β receptor antagonists. Patients with diabetic nephropathy may be at greater risk of hyperkalemia. Angioedema is a rare but serious and potentially fatal adverse effect of the ACE inhibitors. ACE inhibitors are contraindicated during pregnancy.

In most patients, there is no appreciable change in glomerular filtration rate following the administration of ACE inhibitors. However, in renovascular hypertension, the glomerular filtration rate is generally maintained as the result of increased resistance in the postglomerular arteriole caused by AngII. Accordingly, in patients with bilateral renal artery stenosis or stenosis in a sole kidney, the administration of an ACE inhibitor will reduce the filtration fraction and cause a substantial reduction in glomerular filtration rate.

ACE inhibitors lower the blood pressure to some extent in most patients with hypertension. Following the initial dose of an ACE inhibitor, there may be a considerable fall in blood pressure in some patients; this response to the initial dose is a function of plasma renin activity prior to treatment. The potential for a large initial drop in blood pressure is the reason for using a low dose to initiate therapy, especially in patients who may have a very active RAS supporting blood pressure, such as patients with diuretic-induced volume contraction or congestive heart failure. With continuing treatment, there usually is a progressive fall in blood pressure that in most patients does not reach a maximum for several weeks. The blood pressure seen during chronic treatment is not strongly correlated with the pretreatment plasma renin activity. While most ACE inhibitors are approved for once-daily dosing for hypertension, a significant fraction of patients has a response that lasts <24 h and may require twice-daily dosing for adequate control of blood pressure.


Nonpeptide antagonists of the AT1 AngII receptor approved for treatment of hypertension include losartan, candesartan, irbesartan, valsartan, telmisartan, olmesartan, eprosartan, and azilsartan. The pharmacology of AT1 receptor antagonists is presented in detail in Chapter 26. By antagonizing the effects of AngII, these agents permit relaxation of smooth muscle and vasodilation, increase renal salt and water excretion, reduce plasma volume, and decrease cellular hypertrophy.

There are 2 distinct subtypes of AngII receptors, AT1 and AT2. Because the AT1 receptor mediates feedback inhibition of renin release, renin and AngII concentrations are increased during AT1 receptor antagonism. The clinical consequences of increased AngII effects on an uninhibited AT2 receptor are unknown; however, emerging data suggest that the AT2 receptor may elicit antigrowth and antiproliferative responses.

Adverse Effects and Precautions. Adverse effects of ACE inhibitors that result from inhibiting AngII-related functions (see above and Chapter 26) also occur with AT1 receptor antagonists. These include hypotension, hyperkalemia, and reduced renal function, including that associated with bilateral renal artery stenosis and stenosis in the artery of a solitary kidney. Cough, an adverse effect of ACE inhibitors, is less frequent with AT1 receptor antagonists. Angioedema occurs very rarely.

Therapeutic Uses. When given in adequate doses, the AT1 receptor antagonists appear to be as effective as ACE inhibitors in the treatment of hypertension. The full effect of AT1 receptor antagonists on blood pressure typically is not observed until about 4 weeks after the initiation of therapy. If blood pressure is not controlled by an AT1 receptor antagonist alone, a second drug acting by a different mechanism (e.g., a diuretic or Ca2+ channel blocker) may be added. The combination of an ACE inhibitor and an AT1 receptor antagonist is not recommended.


Aliskiren is an orally effective direct renin inhibitor that lowers blood pressure in patients with hypertension. The detailed pharmacology of aliskiren is covered in Chapter 26.

Pharmacological Effects. Aliskiren directly and competitively inhibits the catalytic activity of renin, which leads to diminished production of AngI—and ultimately AngII and aldosterone—with a resulting fall in blood pressure. Aliskiren along with ACE inhibitors and AT1 receptor antagonists lead to an adaptive increase in the plasma concentrations of renin; however, because aliskiren inhibits renin activity, plasma renin activity does not increase as occurs with these other classes of drugs (see Table 26–1).

Absorption, Metabolism, and Excretion. Aliskiren is poorly absorbed; bioavailability is <3%. High-fat meal may substantially decrease plasma concentrations of the drug. The t1/2 is at least 24 h. Elimination of the drug may be primarily through hepatobiliary excretion with limited metabolism via CYP3A4.

Therapeutic Uses. Aliskiren (TEKTURNA) is effective as monotherapy in treating patients with hypertension with dose-dependent increasing efficacy at 150-300 mg/day. The combination of aliskiren with hydrochlorothiazide has a greater lowering effect on blood pressure than either drug alone. Aliskiren appears to have greater efficacy when added to other agents in the treatment of hypertension, including ACE inhibitors, AT1 receptor antagonists, and Ca2+ channel blockers. Combination therapy of aliskiren with ACE inhibitors or ARBs is contraindicated in patients with diabetes or kidney impairment due to increased risk of hyperkalemia, hypotension, and renal complications. Overall, aliskiren appears to be well tolerated.



Hydralazine directly relaxes arteriolar smooth muscle. The molecular mechanisms mediating this action are not clear but may ultimately involve a fall in intracellular Ca2+concentrations. The drug does not relax venous smooth muscle. Hydralazine-induced vasodilation is associated with powerful stimulation of the sympathetic nervous system, likely due to baroreceptor-mediated reflexes, which results in increased heart rate and contractility, and increased plasma renin activity; all of these effects tend to counteract the antihypertensive effect of hydralazine.

The decrease in blood pressure after administration of hydralazine is associated with a selective decrease in vascular resistance in the coronary, cerebral, and renal circulations, with a smaller effect in skin and muscle. Because of preferential dilation of arterioles over veins, postural hypotension is not a common problem; hydralazine lowers blood pressure similarly in the supine and upright positions.

Absorption, Metabolism, and Excretion. Hydralazine is well absorbed through the GI tract, but the systemic bioavailability is low (16% in fast acetylators and 35% in slow acetylators). Hydralazine is N-acetylated in the bowel and/or the liver. Although its t1/2 in plasma is ~1 h, the duration of the hypotensive effect of hydralazine can last up to 12 h. Systemic clearance of the drug is ~50 mL/kg/min. The rate of acetylation is genetically determined; about half of the U.S. population acetylates rapidly, and half do so slowly. The acetylated compound is inactive; thus, the dose necessary to produce a systemic effect is larger in fast acetylators (acetylation rate is genetically determined; see Figure 56–4). The peak concentration of hydralazine in plasma and the peak hypotensive effect of the drug occur within 30-120 min of ingestion.

Toxicity and Precautions. Adverse effects of the drug, include headache, nausea, flushing, hypotension, palpitations, tachycardia, dizziness, and angina pectoris. Myocardial ischemia can occur on account of increased O2 demand induced by the baroreceptor reflex-induced stimulation of the sympathetic nervous system. Following parenteral administration to patients with coronary artery disease, the myocardial ischemia may be sufficiently severe and protracted to cause frank MI. For this reason, parenteral administration of hydralazine is not advisable in hypertensive patients with coronary artery disease, hypertensive patients with multiple cardiovascular risk factors, or older patients. In addition, if the drug is used alone, there may be salt retention with development of high-output congestive heart failure. When combined with a β adrenergic receptor blocker and a diuretic, hydralazine is better tolerated.

Other adverse effects are caused by immunological reactions, of which the drug-induced lupus syndrome is the most common. Hydralazine also can result in an illness that resembles serum sickness, hemolytic anemia, vasculitis, and rapidly progressive glomerulonephritis. The mechanism of these autoimmune reactions is unknown. The drug-induced lupus syndrome usually occurs after at least 6 months of continuous treatment with hydralazine, and its incidence is related to dose, sex, acetylator phenotype, and race. Discontinuation of the drug is all that is necessary for most patients with the hydralazine-induced lupus syndrome, but symptoms may persist in a few patients, and administration of corticosteroids may be necessary. Hydralazine also can produce a pyridoxine-responsive polyneuropathy. The mechanism appears to be related to the ability of hydralazine to combine with pyridoxine to form a hydrazone. This side effect is very unusual with doses ≤200 mg/day.

Therapeutic Uses. Due to its relatively unfavorable adverse-effect profile, hydralazine is no longer a first-line drug in the treatment of hypertension. The drug is marketed as a combination pill containing isosorbide dinitrate (BiDil) that is used for the treatment of heart failure (see Chapter 28). Hydralazine may have utility in the treatment of some patients with congestive heart failure (in combination with nitrates for patients who cannot tolerate ACE inhibitors or AT1 receptor antagonists), and may be useful in the treatment of hypertensive emergencies in pregnant women (especially preeclampsia). Hydralazine should be used with the great caution in elderly patients and in hypertensive patients with coronary artery disease because of the possibility of precipitation of myocardial ischemia due to reflex tachycardia. The usual oral dosage of hydralazine is 25-100 mg twice daily. The maximum recommended dose of hydralazine is 200 mg/day to minimize the risk of drug-induced lupus syndrome.


Minoxidil is efficacious in patients with the most severe and drug-resistant forms of hypertension. Minoxidil is metabolized by hepatic sulfotransferase to the active molecule, minoxidil N-O sulfate. Minoxidil sulfate activates the ATP-modulated K+ channel. By opening K+ channels in smooth muscle and thereby permitting K+ efflux, it causes hyperpolarization and relaxation of smooth muscle. Minoxidil produces arteriolar vasodilation with essentially no effect on the capacitance vessels.

Minoxidil increases blood flow to skin, skeletal muscle, the gastrointestinal tract, and the heart. The disproportionate increase in blood flow to the heart may have a metabolic basis, in that administration of minoxidil is associated with a reflex increase in myocardial contractility and in cardiac output. The cardiac output can increase markedly, as much as 3- to 4-fold. The increased venous return probably results from enhancement of flow in the regional vascular beds, with a fast time constant for venous return to the heart. The adrenergic increase in myocardial contractility contributes to the increased cardiac output but is not the predominant causal factor. Minoxidil is a renal artery vasodilator, but systemic hypotension produced by the drug occasionally can decrease renal blood flow. Renal function usually improves in patients who take minoxidil for the treatment of hypertension, especially if renal dysfunction is secondary to hypertension. Minoxidil is a very potent stimulator of renin secretion; this effect is mediated by a renal sympathetic stimulation and activation of the intrinsic renal mechanisms for regulation of renin release.

ADME. Minoxidil is well absorbed from the GI tract. Although peak concentrations of minoxidil in blood occur 1 h after oral administration, the maximal hypotensive effect of the drug occurs later, possibly because formation of the active metabolite is delayed. The bulk of the absorbed drug is eliminated by hepatic metabolism; ~20% is excreted unchanged in the urine. Minoxidil has a plasma t1/2 of 3-4 h, but its duration of action is 24 h or longer.

Adverse Effects and Precautions. The adverse effects of minoxidil can be severe and are divided into 3 major categories: fluid and salt retention, cardiovascular effects, and hypertrichosis.

Retention of salt and water results from increased proximal renal tubular reabsorption, which is in turn secondary to reduced renal perfusion pressure and to reflex stimulation of renal tubular α adrenergic receptors. Similar antinatriuretic effects can be observed with the other arteriolar dilators (e.g., diazoxide and hydralazine). Although administration of minoxidil causes increased secretion of renin and aldosterone, this is not an important mechanism for retention of salt and water in this case. Fluid retention usually can be controlled by the administration of a diuretic. However, thiazides may not be sufficiently efficacious, and it may be necessary to use a loop diuretic, especially if the patient has any degree of renal dysfunction.

The cardiac consequences of the baroreceptor-mediated activation of the sympathetic nervous system during minoxidil therapy include increases in heart rate, myocardial contractility, and myocardial O2consumption. Thus, myocardial ischemia can be induced by minoxidil in patients with coronary artery disease. The cardiac sympathetic responses are attenuated by concurrent administration of a β adrenergic blocker. The adrenergically-induced increase in renin secretion also can be ameliorated by a β receptor antagonist or an ACE inhibitor.

Minoxidil has particularly adverse consequences in those hypertensive patients who have left ventricular hypertrophy and diastolic dysfunction. Such poorly compliant ventricles respond suboptimally to increased volume loads, with a resulting increase in left ventricular filling pressure. This likely contributes to the increased pulmonary artery pressure seen with minoxidil therapy in hypertensive patients and is compounded by the retention of salt and water. Cardiac failure can result from minoxidil therapy in such patients; the potential for this complication can be reduced but not prevented by effective diuretic therapy. Pericardial effusion is an uncommon but serious complication of minoxidil. Although more commonly described in patients with cardiac and renal failure, pericardial effusion can occur in patients with normal cardiovascular and renal function. Mild and asymptomatic pericardial effusion is not an indication for discontinuing minoxidil, but the situation should be monitored closely to avoid progression to tamponade. Effusions usually clear when the drug is discontinued but can recur if treatment with minoxidil is resumed.

Flattened and inverted T waves frequently are observed in the electrocardiogram following the initiation of minoxidil treatment. These are not ischemic in origin and are seen with other drugs that activate K+ channels. Openers of the ATP-modulated K+ channel accelerate myocardial repolarization, shorten the refractory period, and one of them, pinacidil, lowers the ventricular fibrillation threshold and increases spontaneous ventricular fibrillation in the setting of myocardial ischemia. Hypertrichosis occurs in patients who receive minoxidil for an extended period and is probably a consequence of K+channel activation. Growth of hair occurs on the face, back, arms, and legs and is particularly offensive to women. Topical minoxidil (ROGAINE) is used for male pattern baldness: It may have cardiovascular effects in some individuals. Other side effects of the drug are rare and include rashes, Stevens-Johnson syndrome, glucose intolerance, serosanguineous bullae, formation of antinuclear antibodies, and thrombocytopenia.

Therapeutic Uses. Systemic minoxidil is best reserved for the treatment of severe hypertension that responds poorly to other antihypertensive medications, especially in male patients with renal insufficiency. Minoxidil should be given concurrently with a diuretic to avoid fluid retention and with a sympatholytic drug (usually a β receptor antagonist) to control reflex cardiovascular effects. The initial daily dose of minoxidil may be as little as 1.25 mg, which can be increased gradually to 40 mg in 1 or 2 daily doses.


Nitroprusside is a nitrovasodilator that acts by releasing NO that stimulates the guanylyl cyclase–cyclic GMP–PKG pathway, leading to vasodilation. Tolerance develops tonitroglycerin but not to nitroprusside. Nitroprusside dilates both arterioles and venules, and the hemodynamic response to its administration results from a combination of venous pooling and reduced arterial impedance. In subjects with normal left ventricular function, venous pooling affects cardiac output more than does the reduction of afterload; cardiac output tends to fall. In contrast, in patients with severely impaired left ventricular function and diastolic ventricular distention, the reduction of arterial impedance is the predominant effect, leading to a rise in cardiac output (see Chapter 28).


Sodium nitroprusside is a nonselective vasodilator, and regional distribution of blood flow is little affected by the drug. In general, renal blood flow and glomerular filtration are maintained, and plasma renin activity increases. Sodium nitroprusside usually causes only a modest increase in heart rate and an overall reduction in myocardial O2 demand.

Absorption, Metabolism, and Excretion. Sodium nitroprusside is an unstable molecule that must be protected from light and given by continuous intravenous infusion to be effective. Its onset of action is within 30 sec; the peak hypotensive effect occurs within 2 min, and the effect disappears within 3 min after infusion is stopped. The metabolism of nitroprusside by smooth muscle is initiated by its reduction, which is followed by the release of cyanide and then NO. Cyanide is further metabolized by liver rhodanese to form thiocyanate, which is eliminated almost entirely in the urine. The mean elimination t1/2 for thiocyanate is 3 days in patients with normal renal function, and it can be much longer in patients with renal insufficiency.

Therapeutic Uses. Sodium nitroprusside is used primarily to treat hypertensive emergencies but also can be used in many situations when short-term reduction of cardiac preload and/or afterload is desired. Nitroprusside has been used to lower blood pressure during acute aortic dissection; improve cardiac output in congestive heart failure, especially in hypertensive patients with pulmonary edema that does not respond to other treatment (see Chapter 28); and decrease myocardial oxygen demand after acute MI. In addition, nitroprusside is used to induce controlled hypotension during anesthesia in order to reduce bleeding in surgical procedures. In the treatment of acute aortic dissection, it is important to administer a β adrenergic receptor antagonist with nitroprusside, because reduction of blood pressure with nitroprusside alone can increase the rate of rise in pressure in the aorta as a result of increased myocardial contractility, thereby enhancing propagation of the dissection.

Sodium nitroprusside is available in vials that contain 50 mg. The contents of the vial should be dissolved in 2-3 mL of 5% dextrose in water. Addition of this solution to 250-1000 mL of 5% dextrose in water produces a concentration of 50-200 μg/mL. Because the compound decomposes in light, only fresh solutions should be used, and the bottle should be covered with an opaque wrapping. The drug must be administered as a controlled continuous infusion, and the patient must be closely observed. Most hypertensive patients respond to an infusion of 0.25-1.5 μ/kg/min. Higher rates of infusion are necessary to produce controlled hypotension in normotensive patients under surgical anesthesia. Patients who are receiving other antihypertensive medications usually require less nitroprusside to lower blood pressure. If infusion rates of 10 μg/kg/min do not produce adequate reduction of blood pressure within 10 min, the rate of administration of nitroprusside should be reduced to minimize potential toxicity.

Toxicity and Precautions. The short-term adverse effects of nitroprusside are due to excessive vasodilation. Close monitoring of blood pressure and the use of a continuous variable-rate infusion pump will prevent an excessive hemodynamic response to the drug. Less commonly, toxicity may result from conversion of nitroprusside to cyanide and thiocyanate. Toxic accumulation of cyanide leading to severe lactic acidosis usually occurs when sodium nitroprusside is infused at a rate >5 μg/kg/min but also can occur in some patients receiving doses ~2 μg/kg/min for a prolonged period. The concomitant administration of sodium thiosulfate can prevent accumulation of cyanide in patients who are receiving higher-than-usual doses of sodium nitroprusside. The risk of thiocyanate toxicity increases when sodium nitroprusside is infused for more than 24-48 h, especially if renal function is impaired. Signs and symptoms of thiocyanate toxicity include anorexia, nausea, fatigue, disorientation, and toxic psychosis. The plasma concentration of thiocyanate should be monitored during prolonged infusions of nitroprusside and should not be allowed to exceed 0.1 mg/mL. Rarely, excessive concentrations of thiocyanate may cause hypothyroidism by inhibiting iodine uptake by the thyroid gland. In patients with renal failure, thiocyanate can be removed readily by hemodialysis.

Nitroprusside can worsen arterial hypoxemia in patients with chronic obstructive pulmonary disease because the drug interferes with hypoxic pulmonary vasoconstriction and therefore promotes mismatching of ventilation with perfusion.


Nonpharmacological approaches to the treatment of hypertension may be sufficient in patients with modestly elevated blood pressure and can augment the effects of antihypertensive drugs in patients with more marked initial elevations in blood pressure.

• Reduction in body weight for people who are modestly overweight or frankly obese may be useful.

• Restricting Na+ consumption lowers blood pressure in some patients. The Dietary Approaches to Stop Hypertension (DASH) diet may be particularly useful.

• For some patients, restriction of ethanol intake to modest levels may lower blood pressure.

• Increased physical activity may improve control of hypertension.


National guidelines recommend diuretics as preferred initial therapy for most patients with uncomplicated stage 1 hypertension (see Table 27–4) who are unresponsive to nonpharmacological measures. Patients also are commonly treated with other drugs: β receptor antagonists, ACE inhibitors/AT1 receptor antagonists, and Ca2+ channel blockers. Patients with uncomplicated stage 2 hypertension will likely require the early introduction of a diuretic and another drug from a different class. Subsequently, doses can be titrated upward and additional drugs added to achieve goal blood pressures (blood pressure <140/90 mm Hg in uncomplicated patients).

An important and high-risk group of patients with hypertension are those with compelling indications for specific drugs on account of other underlying serious cardiovascular disease (heart failure, post-MI, or with high risk for coronary artery disease), chronic kidney disease, or diabetes. For example, a hypertensive patient with congestive heart failure ideally should be treated with a diuretic, β receptor antagonist, ACE inhibitor/AT1 receptor antagonist, and (in selected patients) spironolactone because of the benefit of these drugs in congestive heart failure, even in the absence of hypertension (see Chapter 28). Similarly, ACE inhibitors/AT1 receptor antagonists should be first-line drugs in the treatment of diabetics with hypertension in view of these drugs’ well-established benefits in diabetic nephropathy.

Other patients may have less serious underlying diseases that could influence choice of antihypertensive drugs. For example, a hypertensive patient with symptomatic benign prostatic hyperplasia might benefit from having an α1 receptor antagonist as part of his or her therapeutic program, because α1 antagonists are efficacious in both diseases. Similarly, a patient with recurrent migraine attacks might particularly benefit from use of a β receptor antagonist because a number of drugs in this class are efficacious in preventing migraine attacks. Patients with isolated systolic hypertension benefit particularly from diuretics and also from Ca2+ channel blockers and ACE inhibitors. These should be first-line drugs in these patients in terms of efficacy, but compelling indications as noted earlier need to be taken into account.