Chapter 27: Treatment of Myocardial Ischemia and Hypertension

Coronary artery bypass surgery and percutaneous coronary interventions such as angioplasty and coronary artery stent deployment can complement pharmacological treatment. In some subsets of patients, percutaneous or surgical revascularization may have a survival advantage over medical treatment alone. Intracoronary drug delivery using drug-eluting coronary stents represents an intersection of mechanical and pharmacological approaches in the treatment of coronary artery disease. Novel therapies that modify the expression of vascular or myocardial cell genes eventually may become an important part of the therapy of ischemic heart disease.

History. Nitroglycerin was first synthesized in 1846 by Sobrero, who observed that a small quantity placed on the tongue elicited a severe headache. The explosive properties of nitroglycerin also were soon noted, and control of this unstable compound for military and industrial use was not realized until Alfred Nobel devised a process to stabilize the nitroglycerin and patented a specialized detonator in 1863. The vast fortune that Nobel accrued from the nitroglycerin detonator patent provided the funds later used to establish the Nobel prizes. In 1857, T. Lauder Brunton of Edinburgh administered amyl nitrite, a known vasodepressor, by inhalation and noted that anginal pain was relieved within 30- 60 seconds. The action of amyl nitrite was transitory, however, and the dosage was difficult to adjust. Subsequently, William Murrell surmised that the action of nitroglycerin mimicked that of amyl nitrite and established the use of sublingual nitroglycerin for relief of the acute anginal attack and as a prophylactic agent to be taken prior to exertion. The empirical observation that organic nitrates could dramatically and safely alleviate the symptoms of angina pectoris led to their widespread acceptance by the medical profession. Indeed, Alfred Nobel himself was prescribed nitroglycerin by his physicians when he developed angina in 1890. Basic investigations defined the role of NO in both the vasodilation produced by nitrates and endogenous vasodilation. The importance of NO as a signaling molecule in the cardiovascular system and elsewhere was recognized by the awarding of the 1998 Nobel Prize in medicine/physiology to the pharmacologists Robert Furchgott, Louis Ignarro, and Ferid Murad.

Chemistry. Organic nitrates are polyol esters of nitric acid, whereas organic nitrites are esters of nitrous acid (Table 27–1). Nitrate esters (—C—O—NO₂) and nitrite esters (—C—O—NO) are characterized by a sequence of carbon–oxygen–nitrogen, whereas nitro compounds possess carbon–nitrogen bonds (C—NO₂). Thus glyceryl trinitrate is not a nitro compound, and it is erroneously called nitroglycerin; however, this nomenclature is both widespread and official. Amyl nitrite is a highly volatile liquid that must be administered by inhalation and is of limited therapeutic utility. 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. In the pure form (without an inert carrier such as lactose), nitroglycerin is explosive. The organic nitrates and nitrites, collectively termed nitrovasodilators, must be metabolized (reduced) to produce gaseous NO, which appears to be the active principle of this class of compounds. Nitric oxide gas also can be directly administered by inhalation (Bloch et al., 2007).

In patients with autonomic dysfunction and an inability to increase sympathetic outflow (multiple-system atrophy and pure autonomic failure are the most common forms, much less commonly seen in the autonomic dysfunction associated with diabetes), the fall in blood pressure consequent to the venodilation produced by nitrates cannot be compensated. 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.

The hemodynamic mechanisms responsible for these effects are not entirely clear. Most hypotheses have focused on the ability of organic nitrates to cause dilation and prevent vasoconstriction of large epicardial vessels without impairing autoregulation in the small vessels, which are responsible for ~90% of the overall coronary vascular resistance. The vessel diameter is an important determinant of the response to nitroglycerin; vessels >200 μm in diameter are highly responsive, whereas those >100 μm respond minimally. Experimental evidence in patients undergoing coronary bypass surgery indicates that nitrates do have a relaxant effect on large coronary vessels. Collateral flow to ischemic regions also is increased. Moreover, analyses of coronary angiograms in humans have shown that sublingual nitroglycerin can dilate epicardial stenoses and reduce the resistance to flow through such areas (Brown et al., 1981; Feldman et al., 1981). The resulting increase in blood flow would be distributed preferentially to ischemic myocardial regions as a consequence of vasodilation induced by autoregulation. An important indirect mechanism for a preferential increase in subendocardial blood flow is the nitroglycerin-induced reduction in intracavitary systolic and diastolic pressures that oppose blood flow to the subendocardium (see below). To the extent that organic nitrates decrease myocardial requirements for O₂ (see the next section), the increased blood flow in ischemic regions could be balanced by decreased flow in nonischemic areas, and an overall increase in coronary artery blood flow need not occur. Dilation of cardiac veins may improve the perfusion of the coronary microcirculation. Such redistribution of blood flow to subendocardial tissue is not typical of all vasodilators. Dipyridamole, e.g., dilates resistance vessels nonselectively by distorting autoregulation and is ineffective in patients with typical angina.

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.

Absorption, Fate, and Excretion. More than a century after the first use of organic nitrates to treat angina pectoris, their biotransformation remains the subject of active investigation. Studies in the 1970s suggested that nitroglycerin is reductively hydrolyzed by hepatic glutathione–organic nitrate reductase. More recent studies have implicated a mitochondrial aldehyde dehydrogenase enzyme in the biotransformation of nitroglycerin (Chen et al., 2002). Other enzymatic and nonenzymatic pathways also may contribute to the biotransformation of nitrovasodilators. Despite uncertainties about the quantitative importance of the various pathways involved in nitrovasodilator metabolism, the pharmacokinetic properties of nitroglycerin and isosorbide dinitrate have been studied in some detail (Parker and Parker, 1998).

Preparations

Nitroglycerin. In humans, peak concentrations of nitroglycerin are found in plasma within 4 minutes of sublingual administration; the drug has a t_1/2 of 1-3 minutes. 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 minutes.

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 minutes, and the fall in concentration is rapid (t_1/2 of ~45 minutes). The primary initial metabolites, isosorbide-2-mononitrate and isosorbide-5-mononitrate, have longer half-lives (3-6 hours) and are presumed to 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 t_1/2 than does isosorbide dinitrate and has been formulated as a plain tablet and as a sustained-release preparation; both 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 because of the rapid inactivation of NO by hemoglobin in the blood. The selective pulmonary vasodilation observed when NO is administered by inhalation has formed the basis for the widespread use of inhaled NO to treat pulmonary hypertension in hypoxemic neonates, where inhaled NO has been shown to significantly reduce morbidity and mortality (Bloch et al., 2007). The efficacy of inhaled NO in adults for other clinical situations that are characterized by elevated pulmonary vascular pressures (acute lung injury and primary pulmonary hypertension, among other disease states) has not yet been established, and therapies using inhaled NO remain under active investigation.

Correlation of Plasma Concentrations of Drug and Biological Activity. Intravenous administration of nitroglycerin or long-acting organic nitrates in anesthetized animals produces the same transient (1-4 minutes) decrease in blood pressure. Because denitration markedly reduces the activity of the organic nitrates, their rapid clearance from blood indicates that the transient duration of action under these conditions correlates with the concentrations of the parent compounds. The rate of hepatic denitration is characteristic of each nitrate and is influenced by hepatic blood flow or the presence of hepatic disease. In experimental animals, injection of moderate amounts of organic nitrates into the portal vein results in little or no vasodepressor activity, indicating that a substantial fraction of drug can be inactivated by first-pass metabolism in the liver (isosorbide mononitrate is an exception).

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 (Münzel et al., 1995). 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 (Parker and Parker, 1998). Inactivation of mitochondrial aldehyde dehydrogenase, an enzyme implicated in biotransformation of nitroglycerin, is seen in models of nitrate tolerance (Sydow et al., 2004), potentially associated with oxidative stress (Parker, 2004). 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 (Münzel et al., 1995; Parker 2004). Clinical data relating to the ability of agents that modify the renin–angiotensin–aldosterone system to prevent nitrate tolerance are contradictory (Parker and Parker, 1998). Important to the interpretation of clinical trials, factors that may influence the ability of such modification to prevent nitrate tolerance include the dose, whether the ACE inhibitors or angiotensin receptor antagonists were administered prior to the initiation of nitrates, and the tissue specificity of the agent. Despite experimental evidence that depletion of sulfhydryl groups may lead to impaired biotransformation of nitrates to NO and thereby result in nitrate tolerance, experimental results to date with sulfhydryl donors have been disappointing. Other changes that are observed in the setting of nitroglycerin tolerance include an enhanced response to vasoconstrictors such as angiotensin II (AngII), serotonin, and phenylephrine. Administration of nitroglycerin is associated with plasma volume expansion, which may be reflected by a decrease in hematocrit. Although diuretic therapy with hydrochlorothiazide can improve a patient's exercise duration, appropriately designed crossover trials have failed to demonstrate an effect of diuretics on nitrate tolerance (Parker et al., 1996).

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-hour periods away from the work environment (Parker et al., 1995). Coronary and digital arteriospasm during withdrawal and its relaxation by nitroglycerin also have been demonstrated radiographically. Because of the potential problem of nitrate dependence, it seems prudent not to withdraw nitrates abruptly from a patient who has received such therapy chronically.

Cells in the corpus cavernosum produce NO during sexual arousal in response to nonadrenergic, noncholinergic neurotransmission (Burnett et al., 1992). 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, two additional PDE5 inhibitors have been developed for use in therapy of erectile dysfunction. Tadalafil (cialis, adcirca) and vardenafil (levitra) share similar therapeutic efficacy and side-effect profiles with sildenafil; tadalafil has a longer time to onset of action and a longer therapeutic t_1/2 than the other PDE5 inhibitors. Sildenafil has been the most thoroughly characterized of these compounds, but all three 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 (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 (Herrmann et al., 2000). However, sildenafil, tadalafil, and vardenafil all have a significant and potentially dangerous interaction with organic nitrates, the therapeutic actions of which are mediated via their conversion to NO with resulting increases in cyclic GMP. In the presence of a PDE5 inhibitor, nitrates cause profound increases in cyclic GMP and can produce dramatic reductions in blood pressure. Compared with controls, healthy male subjects pretreated with sildenafil or the other PDE5 inhibitors exhibit a much greater decrease in systolic blood pressure when treated with sublingual glyceryl trinitrate, and in many subjects a fall of more than 25 mm Hg was detected. This drug class toxicity is the basis for the warning that PDE5 inhibitors should not be prescribed to patients receiving any form of nitrate (Cheitlin et al., 1999) and dictates that patients should be questioned about the use of PDE5 inhibitors within 24 hours before nitrates are administered. A period of longer than 24 hours may be needed following administration of a PDE5 inhibitor for safe use of nitrates, especially with tadalafil because of its prolonged t_1/2. 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 (Cheitlin et al., 1999). 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 (Tsai and Kass, 2009). PDE5 inhibitors also are being studied in patients with congestive heart failure and cardiac hypertrophy (see Chapter 28).

Sildenafil, tadalafil, and vardenafil 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 I_Kr. Although these interactions and effects are important clinically, the overall incidence and profile of adverse events observed with PDE5 inhibitors, when used without nitrates, are consistent with the expected background frequency of the same events in the treated population. 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; this drug interaction may persist for approximately 24 hours for sildenafil and vardenafil and for considerably longer with tadalafil. Alternative nonnitrate anti-anginal therapy, such as β adrenergic receptor antagonists, should be used during these time periods (Cheitlin et al., 1999).

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 minutes, but the effects are undetectable by 1 hour after administration. An initial dose of 0.3 mg nitroglycerin often relieves pain within 3 minutes. Absorption may be limited in patients with dentures or with dry mouths. Nitroglycerin tablets are stable but should be dispensed in glass containers and protected from moisture, light, and extremes of temperature. Active tablets usually produce a burning sensation under the tongue, but the absence of this sensation does not reliably predict loss of activity; elderly patients especially may be unable to detect the burning sensation. Anginal pain may be prevented when the drug is used prophylactically immediately prior to exercise or stress. The smallest effective dose should be prescribed. Patients should be instructed to seek medical attention immediately if three tablets taken over a 15-minute period do not relieve a sustained attack because this situation may be indicative of myocardial infarction (MI), unstable angina, or another cause of the pain. Patients also should be advised that there is no virtue in trying to avoid taking sublingual nitroglycerin for anginal pain. Other nitrates that can be taken sublingually do not appear to be longer acting than nitroglycerin because their half-lives depend only on the rate at which they are delivered to the liver. They are no more effective than nitroglycerin and often are more expensive.

Oral Administration. Oral nitrates often are used to provide prophylaxis against anginal episodes in patients who have more than occasional angina. They must be given in sufficient dosage to provide effective plasma levels after first-pass hepatic degradation. Low doses (e.g., 5-10 mg isosorbide dinitrate) are no more effective than placebo in decreasing the frequency of anginal attacks or increasing exercise tolerance. Higher doses of either isosorbide dinitrate (e.g., 20 mg or more orally every 4 hours) or sustained-release preparations of nitroglycerin decrease the frequency of anginal attacks and improve exercise tolerance. Effects peak at 60-90 minutes and last for 3-6 hours. Under these circumstances, the activities of less potent metabolites also may contribute to the therapeutic effect. Chronic oral administration of isosorbide dinitrate (120-720 mg daily) results in persistence of the parent compound and higher plasma concentrations of metabolites. However, these doses are more likely to cause troublesome side effects and lead to tolerance. Administration of isosorbide mononitrate (typically starting at 20 mg) once or twice daily (in the latter case, with the doses administered 7 hours 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. Application of nitroglycerin ointment can relieve angina, prolong exercise capacity, and reduce ischemic ST-segment depression with exercise for 4 hours or more. Nitroglycerin ointment (2%) is applied to the skin (2.5-5 cm) as it is squeezed from the tube and then spread in a uniform layer; the dosage must be adjusted for each patient. Effects are apparent within 30-60 minutes (although absorption is variable) and last for 4-6 hours. The ointment is particularly useful for controlling nocturnal angina, which commonly develops within 3 hours after the patient goes to sleep. Transdermal nitroglycerin disks use a nitroglycerin-impregnated polymer (bonded to an adhesive bandage) that permits gradual absorption and a continuous plasma nitrate concentration over 24 hours. The onset of action is slow, with peak effects occurring at 1-2 hours. To avoid tolerance, therapy should be interrupted for at least 8 hours each day. With this regimen, long-term prophylaxis of ischemic episodes often can be attained.

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

Notably, the degree of coronary stenosis correlates poorly with the likelihood of plaque rupture. Drugs that reduce myocardial O₂ consumption by reducing ventricular preload (nitrates) or by reducing heart rate and ventricular contractility (using β adrenergic receptor antagonists) are efficacious, but additional therapies are directed at the atherosclerotic plaque itself and the consequences (or prevention) of its rupture. As discussed later, these therapies include combinations of:

• anti-platelet agents, including aspirin and thioenopyridines such as clopidogrel or prasugrel

• anti-thrombin 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 (Hillis and Lange, 2009). Aspirin (see later in the chapter) inhibits platelet aggregation and improves survival (Yeghiazarians et al., 2000). 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 34 and 30. 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 in some patients. Because of the potential risk of profound hypotension, nitrates should be withheld and alternate anti-anginal therapy administered if patients have consumed a PDE5 inhibitor within 24 hours (discussed earlier).

History. The work in the 1960s of Fleckenstein, Godfraind, and their colleagues led to the concept that drugs can alter cardiac and smooth muscle contraction by blocking the entry of Ca²⁺ into myocytes. Godfraind and associates showed that the effect of the diphenylpiperazine analoges in preventing agonist-induced vascular smooth muscle contraction could be overcome by raising the concentration of Ca²⁺ in the extracellular medium (Godfraind et al., 1986).

Hass and Hartfelder reported in 1962 that verapamil, a coronary vasodilator, possessed negative inotropic and chronotropic effects that were not seen with other vasodilatory agents, such as nitroglycerin. In 1967, Fleckenstein suggested that the negative inotropic effect resulted from inhibition of excitation–contraction coupling and that the mechanism involved reduced movement of Ca²⁺ into cardiac myocytes. Verapamil was the first clinically available calcium-channel blocker; it is a congener of papaverine. Many other calcium entry blockers with a wide range of structures are now available. Other compounds, such as nifedipine and diltiazem, also were shown to block the movement of Ca²⁺ through the cardiac myocyte Ca²⁺ channel, or the slow channel (see Chapter 29), and thereby alter the plateau phase of the cardiac action potential. Subsequently, drugs in several chemical classes have been shown to alter cardiac and smooth muscle contraction by blocking or "antagonizing" the entry of Ca²⁺ through channels in the myocyte membrane.

Chemistry. The multiple Ca²⁺ channel antagonists that are approved for clinical use in the U.S. have diverse chemical structures. 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 structures and specificities of several of these drugs are shown in Table 27–2. Although these drugs are commonly grouped together as "calcium channel blockers," there are fundamental differences among verapamil, diltiazem, and the dihydropyridines, especially with respect to pharmacological characteristics, drug interactions, and toxicities.

Voltage-sensitive channels contain domains of homologous sequence that are arranged in tandem within a single large subunit. In addition to the major channel-forming subunit (termed α₁), Ca²⁺ channels contain several other associated subunits (termed α₂, β, γ, and δ) (Schwartz, 1992). Voltage-sensitive Ca²⁺ channels have been divided into at least three subtypes based on their conductances and sensitivities to voltage (Schwartz, 1992; Tsien et al., 1988). The channels best characterized to date are the L, N, and T subtypes. Only the L-type channel is sensitive to the dihydropyridine Ca²⁺ channel blockers. All approved Ca²⁺ channel blockers bind to the α₁ subunit of the L-type Ca²⁺ channel, which is the main pore-forming unit of the channel. This ~250,000-Da subunit is associated with a disulfide-linked α₂δ subunit of ~140,000 Da and a smaller intracellular β subunit. The α₁ subunits share a common topology of four homologous domains, each of which is composed of six putative transmembrane segments (S1–S6). The α₂, δ, and β subunits modulate the α₁ subunit (see Figure 14–2). The phenylalkylamine Ca²⁺ channel blocker verapamil binds to transmembrane segment 6 of domain IV (IVS6), the benzothiazepine Ca²⁺ channel blocker diltiazem binds to the cytoplasmic bridge between domain III (IIIS) and domain IV (IVS), and the dihydropyridine Ca²⁺ channel blockers (nifedipine and several others) bind to transmembrane segments of both domains III and IV. These three separate receptor sites are linked allosterically.

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 (Schwarz, 1992). 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 with torsades de pointes, a potentially lethal ventricular arrhythmia (see Chapter 29).

Amlodipine is a dihydropyridine that has a slow absorption and a prolonged effect. With a plasma t_1/2 of 35-50 hours, plasma levels and effect increase over 7-10 days of daily administration of a constant dose. Amlodipine produces both peripheral arterial vasodilation and coronary dilation, with a hemodynamic profile similar to that of nifedipine. However, there is less reflex tachycardia with amlodipine, possibly because the long t_1/2 produces minimal peaks and troughs in plasma concentrations (van Zwieten and Pfaffendorf, 1993). Felodipine may have even greater vascular specificity than does nifedipine or amlodipine. At concentrations producing vasodilation, there is no negative inotropic effect. Like nifedipine, felodipine indirectly activates the sympathetic nervous system, leading to an increase in heart rate. 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. This inhibitory effect does not extend to the cardiac myocytes, however, because no cardiodepressant effect is seen.

Despite the negative chronotropic effect, isradipine appears to have little effect on the AV node, so it may be used in patients with AV block or combined with a 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 (Godfraind et al., 1992). Although nisoldipine has a short elimination t_1/2, a sustained-release preparation that is efficacious as an anti-anginal agent has been developed. Nimodipine has high lipid solubility and was developed as an agent to relax the cerebral vasculature. It 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 (t_1/2 ~2 minutes) 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. It may be useful in controlling blood pressure in severe or perioperative hypertension when oral therapy is not possible or desirable. Infusions are typically started at a rate of 1-2 μg/kg/min and titrated to the desired effect on blood pressure. Cumulative experience with the drug in clinical settings is relatively limited.

The effects of Ca²⁺ channel blockers on diastolic ventricular relaxation (the lusitropic state of the ventricle) are complex. The direct effect of several of these agents, especially when given into the coronary arteries, is to impair relaxation (Walsh and O'Rourke, 1985). Clinical studies suggest an improvement in peak left ventricular filling rates when verapamil, nifedipine, nisoldipine, or nicardipine are given systemically, but one must be cautious in extrapolating this change in filling rates to enhancement of relaxation. Because ventricular relaxation is so complex, the effect of even a single agent may be pleiotropic. If reflex stimulation of sympathetic tone increases cyclic AMP levels in myocytes, increased lusitropy will result that may outweigh a direct negative lusitropic effect. Likewise, a reduction in afterload will improve the lusitropic state. In addition, if ischemia is improved, the negative lusitropic effect of asymmetrical left ventricular contraction will be reduced. The sum total of these effects in any given patient cannot be determined a priori. Thus, caution should be exercised in the use of Ca²⁺ channel blockers for this purpose; the ideal is to determine the end result objectively before committing the patient to therapy.

These agents all are bound extensively to plasma proteins (70-98%); their elimination half-lives vary widely and range from 1.3-64 hours. During repeated oral administration, bioavailability and t_1/2 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 expressed in the small bowel. 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 t_1/2 of norverapamil is ~10 hours. 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 decreased accordingly. 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 (Abernethy and Schwartz, 1999).

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. However, short-acting formulations of nifedipine are not appropriate in the long-term treatment of angina or hypertension. Dizziness and flushing are much less of a problem with the sustained-release formulations and with the dihydropyridines having a long t_1/2 and relatively constant concentrations of drug in plasma. Peripheral edema may occur in some patients with Ca²⁺ channel blockers but is not the result of generalized fluid retention; it most likely results from increased hydrostatic pressure in the lower extremities owing to precapillary dilation and reflex postcapillary constriction (Epstein and Roberts, 2009). 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. For example, 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. Urinary retention is a rare adverse effect. Uncommon adverse effects include rash and elevations of liver enzymes. Worsened myocardial ischemia has been observed with nifedipine (Egstrup and Andersen, 1993). Worsening of angina was observed in patients with an angiographically demonstrable coronary collateral circulation. The worsening of angina may have resulted from excessive hypotension and decreased coronary perfusion, selective coronary vasodilation in nonischemic regions of the myocardium 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. In a study of monotherapy with an immediate-release formulation of nisoldipine, the dihydropyridine was not superior to placebo and was associated with a trend toward an increased incidence of serious adverse events, a process termed proischemia (Waters, 1991).

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 below 90 mm Hg should not be treated with verapamil or diltiazem, particularly intravenously. Some Ca²⁺ channel antagonists can cause an increase in the concentration of digoxin in plasma, although toxicity from the cardiac glycoside rarely develops. The use of verapamil to treat digitalis toxicity thus is contraindicated; AV nodal conduction disturbances may be exacerbated.

Several studies have raised concerns about the long-term safety of short-acting nifedipine (Opie et al., 2000). The proposed mechanism for this adverse effect lies in abrupt vasodilation with reflex sympathetic activation. There does not appear to be either significant reflex tachycardia or long-term adverse outcomes from treatment with sustained-release forms of nifedipine or with the dihydropyridine Ca²⁺ blockers such as amlodipine or felodipine, which have more favorable (slower) pharmacokinetics.

Important drug–drug interactions may be encountered with Ca²⁺ channel blockers. 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.

As described earlier, 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 (Gibbons et al., 2003). 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.

Other Uses. The use of Ca²⁺ channel antagonists as antiarrhythmic agents is discussed in Chapter 29; their use for the treatment of hypertension is discussed later; and use of amlodipine in the treatment of heart failure is reviewed in Chapter 28. Clinical trials are under way to evaluate the capacity of Ca²⁺ channel blockers to slow the progression of renal failure and to protect the transplanted kidney. Verapamil has been demonstrated to improve left ventricular outflow obstruction and symptoms in patients with hypertrophic cardiomyopathy. Verapamil also has been used in the prophylaxis of migraine headaches. While several studies suggest that dihydropyridines may suppress the progression of mild atherosclerosis, there is no evidence that this alters mortality or reduces the incidence of ischemic events. Nimodipine has been approved for use in patients with neurological deficits secondary to cerebral vasospasm after the rupture of a congenital intracranial aneurysm. Nifedipine, diltiazem, amlodipine, and felodipine appear to provide symptomatic relief in Raynaud's 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).

Relative contraindications to the use of β receptor antagonists for treatment of angina—bronchospasm, Raynaud's 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 (Dudzinski et al., 2006), 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.

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, have been explored in clinical trials, and there is some evidence that some of these therapies may be efficacious.

An important caveat in the use of drug-eluting stents is that stent thrombosis can occur even many months after placement of the stent, sometimes temporally associated with discontinuation of antiplatelet therapy with clopidogrel (Hillis and Lange, 2009). Long-term therapy with clopidogrel added to lifelong therapy with aspirin may be considered for many patients with drug-eluting stents; such long-term therapy carries an increased risk of bleeding. In some patients, the risk-benefit ratio between bare metal and drug-eluting stents may lead to the choice of a bare metal stent. The relative efficacy, morbidity, and morbidity of percutaneous coronary revascularization versus surgical coronary artery bypass grafting are topics of active investigation and debate, well beyond the scope of this chapter. Mechano-pharmaclogical therapies influence this important ongoing discussion.

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 the pathological basis of the syndrome of immediately life-threatening hypertension, which 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. Interestingly, isolated retinal changes with papilledema in an otherwise asymptomatic patient with very high blood pressure (formerly called "malignant hypertension") may benefit from a more gradual lowering of blood pressure over days rather than hours.

The presence of pathological changes in certain target organs heralds a worse prognosis than the same level of blood pressure in a patient lacking these findings. Consequently, retinal hemorrhages, exudates, and papilledema in the eyes indicate a far worse short-term prognosis for a given level of blood pressure. Left ventricular hypertrophy defined by electrocardiogram, or more sensitively by echocardiography, is associated with a substantially worse long-term outcome that includes a higher risk of sudden cardiac death. The risk of cardiovascular disease, disability, and death in hypertensive patients also is increased markedly by concomitant cigarette smoking, diabetes, or elevated low-density lipoprotein; the coexistence of hypertension with these risk factors increases cardiovascular morbidity and mortality to a degree that is compounded by each additional risk factor. Because the purpose of treating hypertension is to decrease cardiovascular risk, other dietary and pharmacological interventions may be required to treat these conditions.

It generally is not possible to predict the responses of individuals with hypertension to any specific drug. For example, for some antihypertensive drugs, on average about two-thirds of patients will have a meaningful clinical response, whereas about one-third of patients will not respond to the same drug. Racial origin and age may have modest influence on the likelihood of a favorable response to a particular class of drugs. There is considerable interest in identifying genetic variation to improve selection of antihypertensive drugs in individual patients. Polymorphisms in a number of genes involved in the metabolism of antihypertensive drugs have been identified, for example in the CYP family (phase I metabolism) and in phase II metabolism, such as catechol-O-methyltransferase (see Chapters 6 and 7). While these polymorphisms change the pharmacokinetics of specific drugs, it is not clear that there will be substantial differences in efficacy given the dose range available clinically for these drugs. Consequently, identification of polymorphisms that influence pharmacodynamic responses to antihypertensive drugs are of considerable interest. Polymorphisms influencing the actions of a number of classes of antihypertensive drugs, including ACE inhibitors and diuretics, have been identified; so far, individual genes have not been found to have a major impact on pharmacodynamic responses. Genome-wide scanning may lead to identification of novel genes that are more clinically significant. Likewise, treatment may benefit from an increased understanding of the molecular and genetic bases of hypertension (Charchar et al., 2008; Shih and O'Connor, 2008).

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. Hydrochlorothiazide also inhibits vascular carbonic anhydrase, which hypothetically may alter smooth-cell systolic pH and thereby cause opening of Ca²⁺-activated K⁺ channels with the consequences noted above (Pickkers et al., 1999). The relevance of these findings—largely assessed in vitro—to the observed antihypertensive effects of thiazides is speculative. The major action of these drugs on SLC12A3—expressed predominantly in the distal convoluted tubules and not in vascular smooth muscle or the heart—has contributed to repeated suggestions that these drugs decrease peripheral resistance as an indirect effect of negative sodium balance. That thiazides lose efficacy in treating hypertension in patients with co-existing renal insufficiency is compatible with this hypothesis. Moreover, carriers of rare functional mutations in SLC12A3 that decrease renal Na⁺ reabsorption have lower blood pressure than appropriate controls (Ji et al., 2008); in a sense, this is an experiment of nature that may mimic the therapeutic effect of thiazides. Nonetheless, sorting out direct versus indirect actions of thiazides in promoting decreased peripheral resistance requires further experimental testing (Ellison and Loffing, 2009).

When a thiazide-class diuretic is utilized as the sole antihypertensive drug (monotherapy), its dose-response curve for lowering blood pressure in patients with hypertension should be kept in mind. 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). Even though more diuresis can be achieved with higher doses of these diuretics, some evidence suggests that doses higher than this are not generally more efficacious in lowering blood pressure in patients with normal renal function. For example, a large study comparing 25 and 50 mg of hydrochlorothiazide daily in an elderly population did not show a greater decrease in blood pressure with the larger dose (Medical Research Council Working Party, 1987). However, these conclusions are based on conventional rather than ambulatory blood pressure measurements. Other studies suggest that low doses of hydrochlorothiazide have inadequate effects on blood pressure when monitored in this more detailed manner (Lacourcière et al., 1995). In summary, recent critical attention has been focused on whether low doses of hydrochlorothiazide are as efficacious as low doses of chlorthalidone and whether low doses of hydrochlorothiazide are efficacious as monotherapy in protecting against the cardiovascular complications of hypertension. Relatively low doses of either thiazide are not at the top of the dose-response curve for adverse effects such as K⁺ wasting and inhibition of uric acid excretion, emphasizing the importance of knowledge about the dose-response relationships for both beneficial and adverse effects.

In the clinical trials of antihypertensive therapy in the elderly that demonstrated the best outcomes in cardiovascular morbidity and mortality, 25 mg of hydrochlorothiazide or chlorthalidone was the maximum dose given; if this dose did not achieve the target blood pressure reduction, treatment with a second drug was initiated (SHEP Cooperative Research Group, 1991; Dahlöf et al., 1991; Medical Research Council Working Party, 1992). With respect to safety, a case-control study (Siscovick et al., 1994) found a dose-dependent increase in the occurrence of sudden death at doses of hydrochlorothiazide >25 mg daily. This finding supports the hypothesis proposed by the Multiple Risk Factor Intervention Trial Research Group (1982), suggesting that increased cardiovascular mortality is associated with higher diuretic doses. Taken together, clinical studies indicate that if adequate blood pressure reduction is not achieved with the 25-mg daily dose of hydrochlorothiazide or chlorthalidone, a second drug should be added rather than increasing the dose of diuretic. There is some concern that thiazide diuretics, especially at higher doses and in the absence of K⁺-sparing diuretics or K⁺ supplements, may increase the risk of sudden death. However, their overall therapeutic benefits are well established.

Erectile dysfunction is a troublesome adverse effect of the thiazide-class diuretics, and physicians should inquire specifically regarding its occurrence in conjunction with treatment with these drugs. Gout may be a consequence of the hyperuricemia induced by these diuretics. The occurrence of either of these adverse effects is a reason for considering alternative approaches to therapy. However, 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 subject to hypercalcemia, such as those with primary hyperparathyroidism. The thiazide-induced decreased Ca²⁺ excretion may be used therapeutically in patients with osteoporosis or hypercalciuria.

Some other effects of thiazide diuretics are laboratory observations that are of concern primarily because they are putative surrogate markers for adverse drug effects on morbidity and mortality. The effects of diuretic drugs on several surrogate markers for adverse outcomes merit consideration. The K⁺ depletion produced by thiazide-class diuretics is dose dependent and is variable among individuals, such that a subset of patients may become substantially K⁺ depleted on diuretic drugs. Given chronically, even small doses lead to some K⁺ depletion.

There are two types of ventricular arrhythmias that are thought to be enhanced by K⁺ depletion. One of these is polymorphic ventricular tachycardia (torsades de pointes), which is induced by a number of drugs, including quinidine. Drug-induced polymorphic ventricular tachycardia is initiated by abnormal ventricular repolarization; because K⁺ currents normally mediate repolarization, drugs that produce K⁺ depletion potentiate polymorphic ventricular tachycardia. Accordingly, thiazide diuretics should not be given together with drugs that can cause polymorphic ventricular tachycardia (see Chapter 29).

The most important concern regarding K⁺ depletion is its influence on ischemic ventricular fibrillation, the leading cause of sudden cardiac death and a major contributor to cardiovascular mortality in treated hypertensive patients. Studies in experimental animals have demonstrated that K⁺ depletion lowers the threshold for electrically induced ventricular fibrillation in the ischemic myocardium and also increases spontaneous ischemic ventricular fibrillation (Curtis and Hearse, 1989). 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 (Siscovick et al., 1994). One controlled clinical trial demonstrated a significantly greater occurrence of sudden cardiac death in patients treated with 50 mg of hydrochlorothiazide daily in comparison with the β receptor antagonist metoprolol (Medical Research Council Working Party, 1992).

Thiazide diuretics have been associated with changes in plasma lipids and glucose tolerance that have led to some concern. The clinical significance of the changes has been disputed. Nonetheless, clinical studies demonstrate the efficacy of the thiazide diuretics in reducing cardiovascular risk (ALLHAT Officers, 2002).

All of the thiazide-like drugs cross the placenta, but they have not been shown to have direct adverse effects on the fetus. However, 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.

The clinical significance, if any, of these differences is uncertain. However, there is increasing concern that some β receptor blockers, particularly atenolol, may have less efficacy as monotherapy for hypertension than some other drug classes in terms of decreasing risk of adverse cardiovascular consequences of hypertension, particularly due to stroke and coronary artery disease (Carlberg et al., 2004; Kaplan, 2008; Pedersen and Cockcroft, 2009). Particular interest has focused on evidence suggesting that atenolol-based therapy may not lower central (aortic) blood pressure as effectively as it appears when conventionally measured in the brachial artery using a standard arm cuff (CAFE Investigators, 2006). However, teasing out the comparative efficacy of the various classes of antihypertensive drugs represents a complex undertaking. Results of a detailed meta-analysis of 147 randomized trials of blood pressure reduction showed that, regardless of blood pressure before treatment, lowering systolic blood pressure by 10 mm Hg or diastolic blood pressure by 5 mm Hg using any of the main classes of antihypertensive drugs significantly reduces coronary events and stroke without an increase in nonvascular mortality (Law et al., 2009).

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 reactive airway disease (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. The long-term consequences of these effects are unknown.

Sudden discontinuation of β adrenergic blockers can produce a withdrawal syndrome that is likely due to upregulation of β receptors during blockade, causing enhanced tissue sensitivity to endogenous catecholamines; this can exacerbate the symptoms of coronary artery disease. The result, especially in active patients, can be rebound hypertension. Thus, β adrenergic blockers should not be discontinued abruptly except under close observation; dosage should be tapered gradually over 10-14 days prior to discontinuation.

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⁺ (Beckmann et al., 1988).

Epinephrine. can produce severe hypertension and bradycardia when a nonselective β antagonist is present. The hypertension is 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 paradoxical 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.

Adverse Effects. The use of doxazosin as monotherapy for hypertension increased the risk for developing congestive heart failure (ALLHAT Officers, 2002). This may be a class effect that represents an adverse effect of all of the α₁ receptor antagonists. However, this interpretation of the outcome of the ALLHAT study is controversial.

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 minutes (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.

Methyldopa (α-methyl-3,4-dihydroxy-l-phenylalanine), an analog of 3,4-dihydroxyphenylalanine (DOPA), is metabolized by the l-aromatic amino acid decarboxylase in adrenergic neurons to α-methyldopamine, which then is converted to α-methylnorepinephrine. α-Methylnorepinephrine is stored in the secretory vesicles of adrenergic neurons, substituting for norepinephrine (NE) itself. Consequently, when the adrenergic neuron discharges its neurotransmitter, α-methylnorepinephrine is released instead of norepinephrine. α-Methylnorepinephrine acts in the central nervous system (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.

Absorption, Metabolism, and Excretion. 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 hours. The drug is eliminated with a t_1/2 of ~2 hours. Methyldopa is excreted in the urine primarily as the sulfate conjugate (50-70%) and as the parent drug (25%). The remaining fraction is excreted as other metabolites, including methyldopamine, methylnorepinephrine, and O-methylated products of these catecholamines. The t_1/2 of methyldopa is prolonged to 4-6 hours in patients with renal failure.

In spite of its rapid absorption and short t_1/2, the peak effect of methyldopa is delayed for 6-8 hours, even after intravenous administration, and the duration of action of a single dose is usually about 24 hours; 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-methylnorepinephrine and its subsequent release in the vicinity of relevant α₂ receptors in the CNS. This is a good example of the potential for a complex relationship between a drug's pharmacokinetics and its pharmacodynamics. Patients with renal failure are more sensitive to the antihypertensive effect of methyldopa, but it is not known if this is due to alteration in excretion of the drug or to an increase in transport into the CNS.

Adverse Effects and Precautions. Methyldopa produces sedation that is largely transient. A diminution in psychic energy may persist in some patients, and depression occurs occasionally. Methyldopa may produce dryness of the mouth. Other adverse effects include diminished libido, parkinsonian signs, and hyperprolactinemia that may become sufficiently pronounced to cause gynecomastia and galactorrhea. Methyldopa may precipitate severe bradycardia and sinus arrest.

Methyldopa also produces some adverse effects that are not related to its pharmacological action. 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. The development of a positive Coombs test is not necessarily an indication to stop treatment with methyldopa; 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. Adverse effects that are even more rare 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. Administration of a single daily dose of methyldopa at bedtime minimizes sedative effects, but administration twice daily is required for some patients.

Adverse Effects and Precautions. Many patients experience annoying and sometimes intolerable adverse effects with these drugs. 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, perhaps because high peak concentrations are avoided. 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, but the syndrome may occur in the absence of an overshoot in pressure. Symptoms typically occur 18-36 hours after the drug is stopped and are associated with increased sympathetic discharge, as evidenced by elevated plasma and urine concentrations of catecholamines. The exact incidence of the withdrawal syndrome is not known, but it is likely dose related and more dangerous in patients with poorly controlled hypertension. Rebound hypertension also has been seen after discontinuation of transdermal administration of clonidine (Metz et al., 1987).

Treatment of the withdrawal syndrome depends on the urgency of reducing the arterial blood pressure. 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 and elevated circulating catecholamines.

Because perioperative hypertension has been described in patients in whom clonidine was withdrawn the night before surgery, 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.

Clonidine has been used in hypertensive patients for the diagnosis of pheochromocytoma. The lack of suppression of the plasma concentration of NE to >500 pg/mL 3 hours after an oral dose of 0.3 mg of clonidine suggests the presence of such a tumor. A modification of this test, wherein overnight urinary excretion of NE and epinephrine is measured after administration of a 0.3-mg dose of clonidine at bedtime, may be useful when results based on plasma NE concentrations are equivocal. Other uses for α₂ adrenergic agonists are discussed in Chapters 12, 13, and 23.

Locus and Mechanism of Action. Guanadrel is an exogenous false neurotransmitter that is accumulated, stored, and released like NE but is inactive at adrenergic receptors. The drug reaches its site of action by active transport into the neuron by the same transporter that is responsible for the reuptake of NE (see Chapter 8). In the neuron, guanadrel is concentrated within the adrenergic storage vesicle, where it replaces NE. During chronic administration, guanadrel acts as a "false neurotransmitter": It is present in storage vesicles, depletes the normal transmitter, and can be released by stimuli that normally release NE, but is inactive at adrenergic receptors. This replacement of NE with an inactive transmitter is probably the principal mechanism of action of guanadrel. Because guanadrel can promote NE release from pheochromocytomas, it is contraindicated in those patients.

Pharmacological Effects. Essentially all of the therapeutic and adverse effects of guanadrel result from functional sympathetic blockade. The antihypertensive effect is achieved by a reduction in peripheral vascular resistance that results from inhibition of α receptor– mediated vasoconstriction. Consequently, 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.

Absorption, Distribution, Metabolism, and Excretion. Because guanadrel must be transported into and accumulate in adrenergic neurons, the maximum effect on blood pressure is not seen until 4-5 hours. The t_1/2 of the pharmacological effect of guanadrel is determined by the drug's persistence in this neuronal pool and is probably at least 10 hours.

Adverse Effects. Guanadrel produces undesirable effects that are related to sympathetic blockade. Symptomatic hypotension during standing, exercise, ingestion of alcohol, or in hot weather is the result of the lack of sympathetic compensation for these stresses. A general feeling of fatigue and lassitude is partially, but not entirely, related to postural hypotension. Sexual dysfunction usually presents as delayed or retrograde ejaculation. Diarrhea also may occur.

Because guanadrel is actively transported to its site of action, drugs that block or compete for the catecholamine transporter on the presynaptic membrane will inhibit the effect of guanadrel. Such drugs include the tricyclic antidepressants cocaine, chlorpromazine, ephedrine, phenylpropanolamine, and amphetamine (see Chapter 8).

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. The usual starting dose is 10 mg daily, and side effects can be minimized by not exceeding 20 mg daily.

Reserpine is an alkaloid extracted from the root of Rauwolfia serpentina, a climbing shrub indigenous to India. Ancient Hindu Ayurvedic writings describe medicinal uses of the plant; Sen and Bose described its use in the Indian biomedical literature. However, rauwolfia alkaloids were not used in western medicine until the mid-1950s.

Locus and Mechanism of Action. Reserpine binds tightly to adrenergic storage vesicles in central and peripheral adrenergic neurons and remains bound for prolonged periods of time. The interaction 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. Because reserpine depletes amines in the CNS as well as in the peripheral adrenergic neuron, it is probable that its antihypertensive effects are related to both central and peripheral actions.

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

Absorption, Metabolism, and Excretion. Few data are available on the pharmacokinetic properties of reserpine because of the lack of an assay capable of detecting low concentrations of the drug or its metabolites. Reserpine that is bound to isolated storage vesicles cannot be removed by dialysis, indicating that the binding is not in equilibrium with the surrounding medium. Because of the irreversible nature of reserpine binding, 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; none of the parent drug is excreted unchanged.

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. Depression usually appears insidiously over many weeks or months and may not be attributed to the drug because of the delayed and gradual onset of symptoms. 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. Depression appears to be uncommon, but not unknown, with doses of 0.25 mg/day or less. The drug should never be given to patients with a history of depression. Other adverse effects include nasal stuffiness and exacerbation of peptic ulcer disease, which is uncommon with small oral doses.

Therapeutic Uses. With the availability of newer drugs that are both effective and well tolerated, the use of reserpine has diminished because of its CNS side effects. Nonetheless, there has been some recent interest in using reserpine at low doses, in combination with diuretics, in the treatment of hypertension, especially in the elderly. 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. One advantage of reserpine is that it is considerably less expensive than other antihypertensive drugs; thus, it is still used in developing nations.

Metyrosine (demser) is (–)-α-methyl-l-tyrosine. Metyrosine 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 achieve significant inhibition of catecholamine biosynthesis and yet minimize these substantive side effects.

Oral administration of nifedipine as an approach to urgent reduction of blood pressure has been abandoned. Sublingual administration does not achieve the maximum plasma concentration any more quickly than does oral administration. Moreover, in the absence of deleterious consequences of high arterial pressure, data do not support the rapid lowering of blood pressure. There is no place in the treatment of hypertension for the use of nifedipine or other dihydropyridine Ca²⁺ channel blockers with short half-lives when 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. As noted earlier, parenteral administration of the novel 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. However, intrasubject variability is more important than relatively small differences between population groups. Ca²⁺ channel blockers are effective in lowering blood pressure and decreasing cardiovascular events in the elderly with isolated systolic hypertension (Staessen et al., 1997). Indeed, these drugs may be a preferred treatment in patients with isolated systolic hypertension.

There are several cautions in the use of ACE inhibitors in patients with hypertension. Angioedema is a rare but serious and potentially fatal adverse effect of the ACE inhibitors. Patients starting treatment with these drugs should be explicitly warned to discontinue their use with the advent of any signs of angioedema. Due to the risk of severe fetal adverse effects, ACE inhibitors are contraindicated during pregnancy, a fact that should be communicated to women of childbearing age.

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. In some patients with preexisting renal disease, the glomerular filtration may decrease with an ACE inhibitor. More information is needed on how to balance the potential risk of reversible drug-induced impairment of glomerular filtration rate versus inhibition of the progression of kidney disease.

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. Young and middle-aged Caucasian patients have a higher probability of responding to ACE inhibitors; elderly African-American patients as a group are more resistant to the hypotensive effect of these drugs. While most ACE inhibitors are approved for once-daily dosing for hypertension, a significant fraction of patients has a response that lasts <24 hours and may require twice-daily dosing for adequate control of blood pressure.

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. Hypotension is most likely to occur in patients in whom the blood pressure is highly dependent on AngII, including those with volume depletion (e.g., with diuretics), renovascular hypertension, cardiac failure, and cirrhosis; in such patients, initiation of treatment with low doses and attention to blood volume are essential. Hyperkalemia may occur in conjunction with other factors that alter K⁺ homeostasis, such as renal insufficiency, ingestion of excess K⁺, and the use of drugs that promote K⁺ retention. Cough, an adverse effect of ACE inhibitors, is less frequent with AT₁ receptor antagonists. Angioedema occurs very rarely.

ACE inhibitors and AT₁ receptor antagonists should not be administered during pregnancy and should be discontinued as soon as pregnancy is detected.

Aliskiren has been shown to lower blood pressure in patients with hypertension. However, its efficacy in preventing adverse cardiovascular outcomes, especially in comparison with other more established drugs, awaits the results of large-scale clinical trials or other types of epidemiological inquiry. Until that information becomes available, aliskiren has a place as an add-on drug in patients with hypertension, rather than as a replacement for other successful therapies. The detailed pharmacology of aliskiren is covered in Chapter 26.

Locus and Mechanism of Action. The initial renin inhibitors were peptide analogs of sequences either in renin itself or included the renin cleavage site in angiotensinogen (Staessen et al., 2006). While effective in inhibiting renin and lowering blood pressure, these peptide analogs were effective only parenterally. However, aliskiren is effective following oral administration; it directly and competitively inhibits the catalytic activity of renin.

Pharmacological Effects. Aliskiren's inhibition of renin 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 (Table 26–1).

Absorption, Metabolism, and Excretion. Aliskiren is poorly absorbed, with a bioavailability of <3% (Frampton and Curran, 2007). Taking the drug with a high-fat meal may substantially decrease plasma concentrations. Aliskiren has an elimination t_1/2 of at least 24 hours. Elimination of the drug may be primarily through hepatobiliary excretion with limited metabolism via CYP3A4.

Toxicity and Precautions. Aliskiren is generally well tolerated. Diarrhea may occur, especially at higher than recommended doses. The incidence of cough may be higher than for placebo but substantially less than found with ACE inhibitors. Aliskiren has been associated with several cases of angioedema in clinical trials (Frampton and Curran, 2007). Drugs acting on the RAS may damage the fetus and should not be used in pregnant women.

Therapeutic Uses. Aliskiren is effective as monotherapy in treating patients with hypertension with dose-dependent increasing efficacy at 150-300 mg/day (top recommended dose). The drug's action appears to persist for 24 hours as assessed with ambulatory blood pressure monitoring. The combination of aliskiren with hydrochlorothiazide has a greater lowering effect on blood pressure than either drug alone (Baldwin and Plosker, 2009). Aliskiren formulated in combination with hydrochlorothiazine (tekturna hct) or with valsartan (valturna) is available in the U.S. 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. Overall, aliskiren appears to be an effective antihypertensive drug that is well tolerated. Long-term outcome studies—including assessments of target organ damage in the heart, brain, and kidneys—will be important in establishing the role of this relatively new drug in the therapy of hypertension.

Locus and Mechanism of Action. Hydralazine directly relaxes arteriolar smooth muscle. The molecular mechanisms mediating this action are not clear but may ultimately involve a fall in intracellular calcium concentrations. While a variety of changes in cellular signaling pathways are influenced by hydralazine, precise molecular targets that explain its capacity to dilate arteries remain uncertain. There is evidence suggesting that hydralazine inhibits IP₃-induced release of Ca²⁺ from intracellular storage sites in arteries, leading to diminished contraction (Ellershaw and Gurney, 2001). There is also evidence that hydralazine promotes arterial dilation by opening high conductance Ca²⁺-activated K⁺ channels (Bang et al., 1998). Hydralazine induces transient expression of hypoxia-inducible factor (HIF-1) and downstream targets of HIF in vascular smooth muscle cells (Knowles et al., 2004). However, the relationship between these pharmacological effects and the clinical consequence of use of hydralazine are unclear. In addition, hydralazine has been found to induce DNA demethylation (Arce et al., 2006).

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, increased plasma renin activity, and fluid retention; all of these effects tend to counteract the antihypertensive effect of hydralazine.

Pharmacological Effects. Most of the effects of hydralazine are confined to the cardiovascular system. 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 gastrointestinal 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. The t_1/2 of hydralazine is 1 hour, and 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. Because the systemic clearance exceeds hepatic blood flow, extrahepatic metabolism must occur. Indeed, hydralazine rapidly combines with circulating α-keto acids to form hydrazones, and the major metabolite recovered from the plasma is hydralazine pyruvic acid hydrazone. This metabolite has a longer t_1/2 than hydralazine, but it does not appear to be very active. Although the rate of acetylation is an important determinant of the bioavailability of hydralazine, it does not play a role in the systemic elimination of the drug, probably because the hepatic clearance is so high that systemic elimination is principally a function of hepatic blood flow.

The peak concentration of hydralazine in plasma and the peak hypotensive effect of the drug occur within 30-120 minutes of ingestion. Although its t_1/2 in plasma is about an hour, the duration of the hypotensive effect of hydralazine can last as long as 12 hours. There is no clear explanation for this discrepancy.

Toxicity and Precautions. Two types of adverse effects occur after the use of hydralazine. The first, which are extensions of the pharmacological 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, although adverse effects such as headache are still commonly described and may necessitate discontinuation of the drug.

The second type of adverse effect is caused by immunological reactions, of which the drug-induced lupus syndrome is the most common. Administration of 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, although it has been suggested that the drug's capacity to promote DNA demethylation may be involved (Arce et al., 2006).

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. In one study, after 3 years of treatment with hydralazine, drug-induced lupus occurred in 10% of patients who received 200 mg daily, 5% who received 100 mg daily, and none who received 50 mg daily (Cameron and Ramsay, 1984). The incidence is four times higher in women than in men, and the syndrome is seen more commonly in Caucasians than in African-Americans. The rate of conversion to a positive antinuclear antibody test is faster in slow acetylators than in rapid acetylators, suggesting that the native drug or a nonacetylated metabolite is responsible. However, because the majority of patients with positive antinuclear antibody tests do not develop the drug-induced lupus syndrome, hydralazine need not be discontinued unless clinical features of the syndrome appear. These features are similar to those of other drug-induced lupus syndromes and consist mainly of arthralgia, arthritis, and fever. Pleuritis and pericarditis may be present, and pericardial effusion can occasionally cause cardiac tamponade. 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. Hydralazine is no longer a first-line drug in the treatment of hypertension on account of its relatively unfavorable adverse-effect profile. 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 severe hypertension, can be part of evidence-based therapy in 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. Off-label twice-daily administration is as effective as administration four times a day for control of blood pressure, regardless of acetylator phenotype. The maximum recommended dose of hydralazine is 200 mg/day to minimize the risk of drug-induced lupus syndrome.

The effects of minoxidil on the kidney are complex. 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 (Mitchell et al., 1980). Minoxidil is a very potent stimulator of renin secretion; this effect is mediated by a combination of renal sympathetic stimulation and activation of the intrinsic renal mechanisms for regulation of renin release.

Discovery of K⁺_ATP channels in a variety of cell types and in mitochondria is prompting consideration of K⁺_ATP channel modulators as therapeutic agents in myriad cardiovascular diseases (Pollesello and Mebazaa, 2004) and may provide explanations for some of the effects of minoxidil noted in the previous section. Various K⁺_ATP channels possess different regulatory sulfonylurea receptor subunits and thus exhibit tissue-specific responses. Recent studies suggest that certain actions of K⁺_ATP channel openers can be influenced by hypercholesterolemia and by concurrent administration of sulfonylurea hypoglycemic agents (Miura and Miki, 2003).

Absorption, Metabolism, and Excretion. Minoxidil is well absorbed from the GI tract. Although peak concentrations of minoxidil in blood occur 1 hour 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. The major metabolite of minoxidil is the glucuronide conjugate at the N-oxide position in the pyrimidine ring. This metabolite is less active than minoxidil, but it persists longer in the body. The extent of biotransformation of minoxidil to its active metabolite, minoxidil N-O sulfate, has not been evaluated in humans. Minoxidil has a plasma t_1/2 of 3-4 hours, but its duration of action is 24 hours or occasionally even longer. It has been proposed that persistence of minoxidil in vascular smooth muscle is responsible for this discrepancy. However, without knowledge of the pharmacokinetic properties of the active metabolite, an explanation for the prolonged duration of action cannot be given.

Adverse Effects and Precautions. The adverse effects of minoxidil can be severe and are divided into three 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. Retention of salt and water in patients taking minoxidil may be profound, requiring large doses of loop diuretics to prevent edema formation.

The cardiac consequences of the baroreceptor-mediated activation of the sympathetic nervous system during minoxidil therapy are similar to those seen with hydralazine; there is an increase in heart rate, myocardial contractility, and myocardial O₂ consumption. 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, with enhancement of blood pressure control.

The increased cardiac output evoked by 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 probably is a major contributor to the increased pulmonary artery pressure seen with minoxidil (and hydralazine) therapy in hypertensive patients and is compounded by the retention of salt and water caused by minoxidil. 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. These drugs 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 (Chi et al., 1990). The effect of minoxidil on the refractory period and ischemic ventricular fibrillation has not been investigated; whether or not such findings enhance the risk of ventricular fibrillation in human myocardial ischemia is unknown.

Absorption, Metabolism, and Excretion. Sodium nitroprusside is an unstable molecule that decomposes under strongly alkaline conditions or when exposed to light. The drug must be protected from light and given by continuous intravenous infusion to be effective. Its onset of action is within 30 seconds; the peak hypotensive effect occurs within 2 minutes, and when the infusion of the drug is stopped, the effect disappears within 3 minutes.

The metabolism of nitroprusside by smooth muscle is initiated by its reduction, which is followed by the release of cyanide and then NO (Bates et al., 1991). Cyanide is further metabolized by liver rhodanase to form thiocyanate, which is eliminated almost entirely in the urine. The mean elimination t_1/2 for thiocyanate is 3 days in patients with normal renal function, and it can be much longer in patients with renal insufficiency.

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. The majority of hypertensive patients respond to an infusion of 0.25-1.5 μg/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 minutes, 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, with hypotension and the consequences thereof. Close monitoring of blood pressure and the use of a continuous variable-rate infusion pump will prevent an excessive hemodynamic response to the drug in the majority of cases.

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 limiting factor in the metabolism of cyanide appears to be the availability of sulfur-containing substrates in the body (mainly thiosulfate). The concomitant administration of sodium thiosulfate can prevent accumulation of cyanide in patients who are receiving higher-than-usual doses of sodium nitroprusside; the efficacy of the drug is unchanged (Schulz, 1984). The risk of thiocyanate toxicity increases when sodium nitroprusside is infused for more than 24-48 hours, 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.

Diazoxide. Diazoxide was used in the treatment of hypertensive emergencies but fell out of favor at least in part due to the risk of marked falls in blood pressure when large bolus doses of the drug were used. Other drugs are now preferred for parenteral administration in the control of hypertension. Diazoxide also is administered orally (proglycem) to treat patients with various forms of hypoglycemia (see Chapter 43).