Antihypertensive Agents and the Drug Therapy of Hypertension

Arterial pressure is the product of cardiac output and peripheral vascular resistance. Drugs lower pressure by actions on either the peripheral resistance or the cardiac output or both. The cardiac output may be reduced by drugs that either inhibit myocardial contractility or decrease ventricular filling pressure. Many of the antihypertensive drugs that affect adrenergic receptors, the renin-angiotensin system, Ca²⁺channels, and Na⁺ and water balance are also discussed in Chapters 9: Agents Acting at the Neuromuscular Junction and Autonomic Ganglia, 10: Catecholamines, Sympathomimetic Drugs, and Adrenergic Receptor Antagonists, 29: Diuretics, 31: Renin and Angiotensin, 32: Drugs Used for the Treatment of Myocardial Ischemia, and 34: Pharmacological Treatment of Heart Failure. The pharmacology of antihypertensive agents that are not discussed elsewhere is presented here; in addition, the properties of all of the major drugs that are particularly relevant to their use in hypertension are reviewed, and an overview of the therapy of hypertension is provided.

Hypertension is the most common cardiovascular disease. As many as 43 million adults in the United States have systolic and/or diastolic blood pressure above 140/90.

Elevated arterial pressure causes pathological changes in the vasculature and hypertrophy of the left ventricle. As a consequence, hypertension is the principal cause of stroke, leads to disease of the coronary arteries with myocardial infarction and sudden cardiac death, and is a major contributor to cardiac failure, renal insufficiency, and dissecting aneurysm of the aorta.

Hypertension is defined conventionally as blood pressure 140/90; this serves to characterize a group of patients who carry a risk of hypertension-related cardiovascular disease that is high enough to merit medical attention. However, from the standpoint of health promotion, it should be noted that the risk of both fatal and nonfatal cardiovascular disease in adults is lowest with systolic blood pressures of less than 120 mm Hg and diastolic of less than 80 mm Hg; these risks increase progressively with higher levels of both systolic and diastolic blood pressure. Although many of the clinical trials classify the severity of hypertension by diastolic pressure, progressive elevations of systolic pressure are similarly predictive of adverse cardiovascular events; at every level of diastolic pressure, risks are greater with higher levels of systolic blood pressure. Indeed, in elderly patients, systolic blood pressure predicts outcome better than diastolic blood pressure.

At very severe levels of hypertension (systolic 210 and/or diastolic 120), a subset of patients develops fulminant arteriolopathy 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 malignant hypertension, which is associated with rapidly progressive microvascular occlusive disease in the kidney (with renal failure), brain (hypertensive encephalopathy), retina (hemorrhages, exudates, and discedema), and other organs. The severe endothelial disruption can lead to microangiopathic hemolytic anemia. Untreated malignant hypertension is rapidly fatal and requires in-hospital management on an emergency basis.

The presence of certain target organ changes confers on a patient a worse prognosis than that for a patient with the same level of blood pressure lacking these findings. Thus, retinal hemorrhages, exudates, and discedema indicate a far worse short-term prognosis for a given level of blood pressure. Left ventricular hypertrophy defined by electrocardiogram, or more accurately 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 and by elevated low-density lipoprotein; the coexistence of hypertension with these risk factors increases cardiovascular morbidity and mortality to an extent that is supraadditive.

Robust evidence from multiple controlled trials indicates that pharmacological treatment of patients with diastolic pressures of 95 mm Hg or greater will reduce morbidity, disability, and mortality from cardiovascular disease. Effective antihypertensive therapy will almost completely prevent the hemorrhagic strokes, cardiac failure, and renal insufficiency due to hypertension. There is a marked reduction in total strokes. Moreover, several recent clinical trials suggest that reduction of diastolic blood pressure to 85 mm Hg confers a greater therapeutic benefit than reduction to 90 mm Hg, particularly in patients with diabetes (Hansson et al., 1998).

The usual approach to patients with diastolic blood pressure in the range of 85 to 94 mm Hg is to use nonpharmacological therapy as an initial strategy. Because blood pressures in this range predict a clear increase in cardiovascular risk, the recommendations for nonpharmacological therapy should be accompanied by careful observation; in addition to the value of regular follow-up visits to maintain surveillance of blood pressure, they also afford an opportunity to assist and support patients in their efforts to achieve the changes in lifestyle required for effective nonpharmacological reduction in blood pressure.

Antihypertensive drugs can be classified according to their sites or mechanisms of action (see Table 331). As arterial pressure is the product of cardiac output and peripheral vascular resistance, it can be lowered by actions of drugs on either the peripheral resistance or the cardiac output, or both. Drugs may reduce the cardiac output by either inhibiting myocardial contractility or decreasing ventricular filling pressure. Reduction in ventricular filling pressure may be achieved by actions on the venous tone or on blood volume via renal effects. Drugs can reduce peripheral resistance by acting on smooth muscle to cause relaxation of resistance vessels or by interfering with the activity of systems that produce constriction of resistance vessels (e.g., the sympathetic nervous system).

The hemodynamic consequences of long-term treatment with antihypertensive agents are presented in Table 332, which also provides a framework for potential complementary effects of concurrent therapy with two or more drugs. The simultaneous use of drugs with similar mechanisms of action and hemodynamic effects often produces little additional benefit. However, concurrent use of drugs from different classes is a strategy for achieving effective control of blood pressure while minimizing dose-related adverse effects.

One of the earliest strategies for the management of hypertension was to alter Na⁺ balance by restriction of salt in the diet. Pharmacological alteration of Na⁺ balance became practical in the 1950s with the development of the orally active thiazide diuretics (see Chapter 29: Diuretics). These and related diuretic agents have antihypertensive effects when used alone, and they enhance the efficacy of virtually all other antihypertensive drugs.

The exact mechanism for reduction of arterial blood pressure by diuretics is not certain. Initially, the drugs decrease extracellular volume and cardiac output. However, the hypotensive effect is maintained during long-term therapy because of reduced vascular resistance; cardiac output returns to pretreatment values and extracellular volume remains somewhat reduced. Because of the persistent reduction in vascular resistance, some investigators have postulated that the diuretics have a direct effect on vascular smooth muscle that is independent of their saluretic effect. However, substantial data indicate that this is not the case. Thus, anephric patients and nephrectomized animals do not show a reduction in blood pressure when given diuretics (Bennett et al., 1977); a high salt intake or an infusion of saline (but not dextran) to counteract the net negative Na⁺ balance produced by diuretics reverses the antihypertensive effect; during effective therapy, plasma volume remains about 5% below pretreatment values and the plasma renin activity remains elevated, confirming a persistent reduction in body Na⁺ (Shah et al., 1978); diuretics do not relax vascular smooth muscle in vitro; and the hemodynamic effects of the diuretics to reduce vascular resistance are reproduced by restriction of salt (Freis, 1983).

Potential mechanisms for reduction of vascular resistance by a persistent, albeit small, reduction in body Na⁺ include a decrease in interstitial fluid volume; a fall in smooth muscle Na⁺ concentration that may secondarily reduce the intracellular Ca²⁺ concentration, such that the cells are more resistant to contractile stimuli; and a change in the affinity and response of cell surface receptors to vasoconstrictor hormones (Insel and Motulsky, 1984).

Benzothiadiazines and Related Compounds

Benzothiadiazines ('thiazides') and related diuretics make up the most frequently used class of antihypertensive agents in the United States. Following the discovery of chlorothiazide, the first benzothiadiazine, a number of oral diuretics were developed that have an aryl-sulfonamide structure and block the Na⁺-Cl symporter. Some of these are not benzothiadiazines, but because they have structural features and molecular functions that are similar to the original benzothiadiazine compounds, they have been designated as members of the 'thiazide class' of diuretics. For example, chlorthalidone, one of the nonbenzothiadiazines in the thiazide class of diuretics, is widely used in the treatment of hypertension. Because the thiazide class of drugs has the same pharmacological effects, they are generally interchangeable with appropriate adjustment of dosage (see Chapter 29: Diuretics).

Regimen for Administration of the Thiazide-Class Diuretics in Hypertension

When a thiazide-class diuretic is utilized as the sole antihypertensive drug (monotherapy), it should be administered in a low dose. Further, there is mounting evidence that the administration of these diuretics in the long-term treatment of hypertension should be in conjunction with a K⁺-sparing agent.

Antihypertensive effects can be achieved in many patients with as little as 12.5 mg of chlorthalidone (HYGROTON) or hydrochlorothiazide (HYDRODIURIL) daily. This should be the initial dose in most elderly patients who do not require urgent reduction of pressure. 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, abundant evidence indicates that doses higher than this are not required for monotherapy of hypertension and probably are not as safe.

A large study comparing 25 and 50 mg hydrochlorothiazide daily in an elderly population did not show a greater decrease in blood pressure with the larger dose (MRC Working Party, 1987). In the randomized, controlled trials of antihypertensive therapy in the elderly (SHEP Cooperative Research Group, 1991; Dahlf et al., 1991; MRC Working Party, 1992) that demonstrate the best outcomes in cardiovascular morbidity and mortality, 25 mg of hydrochlorothiazide or chlorthalidone was the maximum dose given; if greater reduction of blood pressure than achieved with this dose was required, treatment with a second drug was initiated. 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 greater than 25 mg daily. This finding supports the hypothesis engendered by a retrospective analysis of the Multiple Risk Factor Intervention Trial (Multiple Risk Factor Intervention Trial Research Group, 1982), suggesting that increased cardiovascular mortality is associated with higher diuretic doses. Further, the drug-specific metabolic effects of the thiazide-class diuretics, as well as the side effects perceived by patients, are to some degree dose-dependent, providing additional reasons not to administer more than the 25-mg dose of hydrochlorothiazide/chlorthalidone required to achieve nearly maximum blood pressure reduction. Taken together, clinical studies to date 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.

When used in the treatment of hypertension, thiazide-class diuretics usually should be administered in conjunction with a K⁺-sparing agent. Attenuation of the kaliuretic effect of the thiazide-class diuretics can be achieved by drugs that block the Na⁺ channels in the late distal tubule and collecting duct (amiloride and triamterene), or by inhibition of aldosterone action (spironolactone). Oral K⁺ supplementation in the usual doses is not as effective as these K⁺-sparing agents. At this time, the data from clinical trials most strongly support the use of amiloride in combination with a thiazide-class diuretic. In the two large clinical trials that demonstrate the best results in terms of cardiovascular morbidity and mortality (Dahlf et al., 1991; MRC Working Party, 1992), amiloride was the drug employed together with hydrochlorothiazide, used in a ratio of 1 mg amiloride/10 mg hydrochlorothiazide.

Angiotensin converting enzyme inhibitors and angiotensin receptor antagonists will attenuate diuretic-induced loss of potassium to some degree, and this is a consideration if a second drug is required to achieve further blood pressure reduction beyond that attained with the diuretic alone. Because the diuretic and hypotensive effects of these drugs are greatly enhanced when they are given in combination, care should be taken to initiate combination therapy with low doses of each of these drugs. Administration of angiotensin converting enzyme inhibitors or angiotensin receptor antagonists together with other K⁺-sparing agents or with K⁺ supplements requires caution; combination of K⁺-sparing agents with each other or with K⁺ supplementation can cause serious hyperkalemia in occasional patients.

In contrast with the limitation on dose of thiazide-class diuretics used as monotherapy, the treatment of severe hypertension that is unresponsive to three or more drugs may require larger doses of the thiazide-class diuretics. Indeed, hypertensive patients may become refractory to drugs that block the sympathetic nervous system or to vasodilator drugs, because these drugs engender a state in which the blood pressure is very volume-dependent. Therefore, it is appropriate to consider the use of thiazide-class diuretics in doses of 50 mg of daily hydrochlorothiazide equivalent when treatment with appropriate combinations and doses of three or more drugs fails to yield adequate control of the blood pressure. Dietary Na⁺ restriction is a valuable adjunct to the management of such refractory patients and will minimize the dose of diuretic that is required. This can be achieved by a modest restriction of Na⁺ intake to 2 g daily. A more strict Na⁺ restriction is not feasible for most patients. Since the degree of K⁺ loss relates to the amount of Na⁺ delivered to the distal tubule, such restriction of Na⁺ can minimize the development of hypokalemia and alkalosis. The effectiveness of the thiazide class of drugs as diuretic or antihypertensive agents is progressively diminished when the glomerular filtration rate falls below 30 ml/min. One exception is metolazone, which retains efficacy in patients with this degree of renal insufficiency.

Most patients will respond to the thiazide class of diuretics with a reduction in blood pressure within 2 to 4 weeks, although a minority will not achieve maximum reduction in arterial pressure for up to 12 weeks on a given dose. Therefore, doses should not be increased more often than every 2 to 4 weeks. Although the blood pressure of patients who have suppressed plasma renin activity is almost uniformly sensitive to diuretics in the thiazide class, most other patients also respond. There is no way to predict the antihypertensive response from the duration or severity of the hypertension in a given patient, although diuretics are unlikely to be effective as a sole therapy in patients with severe hypertension. Since the effect of the thiazide class of diuretics is additive with that of other antihypertensive drugs, combination regimens that include these diuretics are common and rational. Diuretics also have the advantage of minimizing the retention of salt and water that is commonly caused by vasodilators and some sympatholytic drugs.

Adverse Effects and Precautions

The adverse effects of diuretics are discussed in Chapter 29: Diuretics. Some of these are effects that determine whether patients can tolerate and comply with diuretic treatment. Sexual impotence is the most common troublesome side 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. Muscle cramps also are related to diuretic therapy in a dose-dependent manner. Other effects of the thiazide-class diuretics are laboratory observations that are of concern primarily because they are putative surrogate markers for adverse drug effects on morbidity and mortality.

Surrogate markers are factors that, in epidemiological studies, have been found to correlate with disease outcomes and therefore are used in investigations of drug therapy as a surrogate of the actual effect of a drug on disease outcome. Thus, reduction in systolic blood pressure is an example of a surrogate marker for the reduction of stroke by antihypertensive therapy that has been extensively validated (SHEP Cooperative Research Group, 1991). In contrast, the epidemiological evidence linking frequent ventricular ectopic depolarizations to sudden cardiac death had suggested that these ventricular arrhythmias might be surrogate markers for a beneficial effect of antiarrhythmic drugs on sudden cardiac death. However, reduction of ventricular ectopic depolarizations and nonsustained ventricular tachycardia by the antiarrhythmic drugs encainide and flecainide was associated with an increase in sudden cardiac death, demonstrating the fallibility of using surrogate markers to predict the outcome of a specific pharmacological intervention (CAST Investigators, 1989). Accordingly, the effect of drugs on surrogate markers cannot be considered as convincing evidence; rather, surrogate markers form the basis for hypotheses that require testing with controlled clinical trials. Until such trials are carried out, however, the effect of drugs on surrogate markers that predict adverse outcomes do cause concern and influence decisions regarding dose.

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 over a wide range of doses and is variable among individuals, such that a subset of patients may become substantially K⁺-depleted on diuretic drugs. Even small doses given chronically, however, lead to some K⁺ depletion.

There are two types of ventricular arrhythmia 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. Such drug-induced polymorphic ventricular tachycardia is an arrhythmia initiated by abnormal ventricular repolarization, and it is markedly enhanced by drugs that produce K⁺ depletion, which elicits abnormal repolarization (see Chapter 35: Antiarrhythmic Drugs). Accordingly, thiazide diuretics should not be given together with drugs that can cause polymorphic ventricular tachycardia.

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; Yano et al., 1989). A case-control study of hypertensive patients has found 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 has demonstrated a significantly greater occurrence of sudden cardiac death in patients treated with 50 mg of hydrochlorothiazide daily in comparison with the -adrenergic antagonist metoprolol (MRC Working Party, 1992). Controlled clinical trials comparing the effect of diuretics with other antihypertensive drugs on cardiovascular mortality are now under way and should further illuminate this question. In the meantime, the available data on sudden cardiac death support the limitation of diuretic dose as monotherapy to 25 mg of hydrochlorothiazide daily (or equivalent) and the use of an adjunctive K⁺-sparing agent.

The thiazide class of diuretics elevates the levels of low-density lipoprotein (LDL) and increases the ratio of LDL/high-density lipoprotein (HDL). A linkage between increased LDL and increased coronary heart disease has been demonstrated in epidemiological studies and in investigations of lipid-lowering drugs, justifying, the consideration that LDL is a surrogate marker for coronary heart disease morbidity and mortality. Whether the increase in the LDL/HDL ratio caused by diuretics is in fact predictive of increased coronary heart disease in patients on diuretics is not presently known, and until adequate morbidity and mortality trials comparing antihypertensive drugs are completed, the effect of the thiazide-class diuretics on plasma lipids can be a basis for concern but not for definitive recommendations regarding the choice of these drugs relative to other antihypertensive agents.

In epidemiological studies, left ventricular hypertrophy is a powerful predictor of an increase in cardiac death in hypertensive patients. The thiazide-class diuretics are less effective in reducing left ventricular hypertrophy than are other antihypertensive drugs such as the angiotensin converting enzyme inhibitors (Dahlf et al., 1992).

The thiazide-class diuretics increase glycosylated hemoglobin in patients with diabetes mellitus (Gall et al., 1992). This finding, taken together with evidence that angiotensin converting enzyme inhibitors delay the deterioration of renal function in diabetic patients, suggests that thiazide-class diuretics are not the first drugs of choice in the monotherapy of hypertensive patients with diabetes mellitus.

All of the thiazide-like drugs cross the placenta, but they have not been found 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. Since the thiazides appear in breast milk, they should be avoided by nursing mothers.

The Choice of a Thiazide-Type Diuretic as the Initial Drug in the Treatment of Hypertension

Few issues in hypertension are more controversial than whether or not patients should be placed on a diuretic as the initial or only drug for the treatment of hypertension (Joint National Committee, 1997; Tobian et al., 1994). A definitive answer to this question awaits the completion of a large clinical trial (the ALLHAT trial) conducted by the National Institutes of Health comparing a thiazide-class diuretic with other antihypertensive drugs as the initial or only therapeutic agents. In the interim, decisions will be made based on interpretations of the available data. There are several general types of data, from which interpretations have been inferred, but none provides convincing evidence.

One set of data is the group of metabolic effects of the thiazide-class of diuretics discussed above: the increase in LDL, depletion of K⁺, impairment of diabetes control, and a reduction of left ventricular hypertrophy that is less than achieved with other drugs. The case-control study demonstrating a dose-dependent linkage of these diuretics to sudden cardiac death strengthens the inference that K⁺ depletion is not benign (Siscovick et al., 1994).

Another type of data is that obtained from the clinical trials that have established the benefit of antihypertensive therapy. In controlled clinical trials conducted before 1991 in predominantly middle-aged patients, the beneficial effect of antihypertensive therapy on coronary heart disease and cardiac death was found to be less than the effect on stroke. Long-term prospective observational studies predict that a decrease of 5 to 6 mm Hg in diastolic pressure should lead to a 35% to 40% reduction in stroke; indeed, an overview of 14 randomized trials of pharmacological therapy (Collins et al., 1990) reveals that the prevalence of fatal plus nonfatal stroke is lowered by 42% (p<0.0002) as a consequence of that change in diastolic pressure. Whereas the observational studies predict a 20% to 25% reduction in fatal plus nonfatal coronary heart disease with a difference of 5 to 6 mm Hg in diastolic pressure, reduction of pressure to this degree with antihypertensive treatment lowered total coronary heart disease by only 14% (p<0.01). Fatal stroke was lowered by 45% (p<0.0001), whereas fatal coronary heart disease was reduced by only 11% (not significant) during antihypertensive treatment. The failure of antihypertensive therapy to yield the expected reduction in coronary heart disease, and particularly coronary heart disease mortality, has led to considerable speculation, including the possibility that the diuretic drugs that were the primary agents used in these trials may impose adverse effects on coronary heart disease, including sudden cardiac death. These disappointing results in terms of coronary heart disease were obtained in trials on mostly middle-aged patients that predominantly employed hydrochlorothiazide or chlorthalidone in doses up to 50 mg without a K⁺-sparing agent.

Subsequent to this meta-analysis of the 14 controlled trials, 2 trials in elderly patients that used a low dose of hydrochlorothiazide (25 mg daily) together with the K⁺-sparing agent amiloride demonstrated more favorable trends in reducing coronary mortality, lowering it by 50% (Dahlf et al., 1991) and 40% (MRC Working Party, 1992). In the latter study, the reduction in stroke and coronary events was significant on diuretic therapy, whereas no significant reductions in these endpoints were seen in a comparison group randomized to the -adrenergic blocker atenolol.

The following approach to selection of a diuretic as the initial drug is derived from the data above. In elderly patients (age 65 or greater), selection of a thiazide-class diuretic as the initial drug is rational if it is given in doses in the range of 12.5 to 25 mg of hydrochlorothiazide (or equivalent) daily and together with a K⁺-sparing agent. This is based on the high level of efficacy in the clinical trials with such regimens, the relatively low profile of side effects, and the fact that elderly patients are likely to have a good response to diuretic therapy.

In patients under age 65, a greater individualization of choice of the initial antihypertensive drug seems warranted. The earlier clinical trials (conducted in this age group with high doses of the thiazide-class drug given without K⁺-sparing agents) provide neither reassurance regarding the thiazide-class diuretics nor rejection of them. Individualization of initial drug choice can consider several factors. In diabetic patients, angiotensin converting enzyme inhibitors attenuate the decline in renal function, making these drugs preferable to diuretics, which may impair glucose tolerance in diabetes. Other drugs, particularly the angiotensin converting enzyme inhibitors, are more effective than diuretics in reducing left ventricular mass in patients with left ventricular hypertrophy. Caucasian race, age less than 65, and a high or normal renin status at baseline predict an antihypertensive response to an angiotensin converting enzyme inhibitor or a -adrenergic receptor antagonist that is superior to that with a diuretic.

Other Diuretic Antihypertensive Agents

The thiazide-type diuretics are more effective antihypertensive agents than are the loop diuretics, such as furosemide and bumetanide, in patients who have normal renal function (Ram et al., 1981). This differential effect is most likely related to the short duration of action of loop diuretics, such that a single daily dose does not cause a significant net loss of Na⁺ for an entire 24-hour period. The spectacular efficacy of the loop diuretics in producing a rapid and profound natriuresis is a potential detriment for the treatment of hypertension. When a loop diuretic is given twice daily, the acute diuresis can be excessive and lead to more side effects than occur with a slower-acting, milder thiazide diuretic. The loop diuretics produce hypercalciuria, rather than the hypocalciuria associated with the thiazides. However, other metabolic consequences of the thiazides are shared with the loop diuretics, including hypokalemia, hyperuricemia, glucose intolerance, and potentially adverse effects on plasma concentrations of lipids. Loop diuretics may be particularly useful in patients with azotemia and in patients with severe edema associated with a vasodilator such as minoxidil.

Although spironolactone in doses up to 100 mg per day is equivalent to hydrochlorothiazide in its hypotensive effect (Jeunemaitre et al., 1988), higher doses produce an unacceptable incidence of side effects (Schrijver and Weinberger, 1979). Spironolactone may be particularly useful for individuals with clinically significant hyperuricemia, hypokalemia, or glucose intolerance, and it is the agent of choice for management of primary aldosteronism. In contrast to thiazide diuretics, spironolactone does not affect plasma concentrations of Ca²⁺ or glucose. The effects of spironolactone on plasma lipids have not been studied extensively, but data indicate that the changes in triglycerides, LDL cholesterol, and total cholesterol are less than those seen with the thiazides. However, spironolactone may decrease the concentration of HDL cholesterol (Falch and Schreiner, 1983). The other K⁺-sparing diuretics, triamterene and amiloride, are used primarily to reduce the kaliuresis and potentiate the hypotensive effect of a thiazide (DeCarvalho et al., 1980; Multicenter Diuretic Cooperative Study Group, 1981). These agents should be used cautiously with frequent measurements of K⁺ concentrations in plasma in patients predisposed to hyperkalemia. Patients taking spironolactone, amiloride, or triamterene should be cautioned regarding the possibility that concurrent use of K⁺-containing 'salt substitutes' could produce hyperkalemia. Renal insufficiency is a relative contraindication to the use of K⁺-sparing diuretics.

Diuretic-Associated Drug Interactions

Since the antihypertensive effects of diuretics are frequently additive with those of other antihypertensive agents, a diuretic commonly is used in combination with other drugs. As discussed above, the concurrent administration of diuretics with quinidine and other drugs that cause polymorphic ventricular tachycardia greatly increases the risk of this drug-induced arrhythmia. The K⁺- and Mg²⁺-depleting effects of the thiazide-like and loop diuretics also can potentiate arrhythmias that arise from digitalis toxicity. Corticosteroids can amplify the hypokalemia produced by the diuretics. All diuretics can decrease the clearance of Li⁺, resulting in increased plasma concentrations of Li⁺ and potential toxicity (Amdisen, 1982). Nonsteroidal antiinflammatory drugs (see Chapter 27: Analgesic-Antipyretic and Antiinflammatory Agents and Drugs Employed in the Treatment of Gout) that inhibit the synthesis of prostaglandins reduce the antihypertensive effects of diuretics. It is not known if this interaction is due to Na⁺ retention resulting from blockade of the natriuretic effect of the diuretic by the antiinflammatory agent or is related to inhibition of vascular synthesis of prostaglandins (Webster, 1985). Based on recent studies, it would appear that the effects of selective COX-2 inhibitors on renal prostaglandin synthesis and function are similar to those of the nonselective nonsteroidal antiinflammatory drugs. Nonsteroidal antiinflammatory drugs, -adrenergic receptor antagonists, and angiotensin converting enzyme inhibitors reduce plasma concentrations of aldosterone and can potentiate the hyperkalemic effects of a K⁺-sparing diuretic.

Hydralazine

Hydralazine APRESOLINE) was one of the first orally active antihypertensive drugs to be marketed in the United States; however, the drug initially was used infrequently because of tachycardia and tachyphylaxis. With a better understanding of the compensatory cardiovascular responses that accompany use of arteriolar vasodilators, hydralazine was combined with sympatholytic agents and diuretics with greater therapeutic success. Numerous phthalazines have been synthesized in the hope of producing vasoactive agents, but only those with hydrazine moieties in the 1 or 4 position of the ring have vasodilatory activity (Reece, 1981). None of the analogs has any advantage over hydralazine. Hydralazine (1-hydrazinophthalazine) has the following structural formula:

Locus and Mechanism of Action

Hydralazine causes direct relaxation of arteriolar smooth muscle. The molecular mechanism of this effect is not known. It is not a dilator of capacitance vessels (e.g., the epicardial coronary arteries) and does not relax venous smooth muscle. Hydralazine-induced vasodilation is associated with powerful stimulation of the sympathetic nervous system, which results in increased heart rate and contractility, increased plasma renin activity, and fluid retention; all of these effects counteract the antihypertensive effect of hydralazine. Although most of the sympathetic activity is due to a baroreceptor-mediated reflex, hydralazine may stimulate the release of norepinephrine from sympathetic nerve terminals and augment myocardial contractility directly (Azuma et al., 1987).

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 equally in the supine and upright positions. Although hydralazine lowers pulmonary vascular resistance, the greater increase in cardiac output can cause mild pulmonary hypertension. It is difficult to predict which patients will respond in this manner, but the increase in cardiac output can be attenuated by the use of -adrenergic receptor blocking agents.

Absorption, Metabolism, and Excretion

Hydralazine is N-acetylated in the bowel and/or the liver. The rate of acetylation is genetically determined; about half of the people in the United States acetylate rapidly and half do so slowly. Since the acetylated compound is inactive, the dose necessary to produce a systemic effect is larger in fast acetylators. Hydralazine is well absorbed through the gastrointestinal tract, but the systemic bioavailability is low (16% in fast acetylators and 35% in slow acetylators). The half-life of hydralazine is 1 hour, and the systemic clearance of the drug is about 50 ml/kg per minute. Since the systemic clearance exceeds hepatic blood flow, extrahepatic metabolism must occur. Indeed, hydralazine rapidly combines with circulating -keto acids to form hydrazones, and the major metabolite recovered from the plasma is hydralazine pyruvic acid hydrazone. This metabolite has a longer half-life than hydralazine, but it does not appear to be very active (Reece et al., 1985). 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 to 120 minutes of ingestion. Although its half-life 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 side effects occur after the use of hydralazine. The first, which are extensions of the pharmacological effects of the drug, include headache, nausea, flushing, hypotension, palpitation, tachycardia, dizziness, and angina pectoris. Myocardial ischemia occurs because of the increased oxygen demand imposed by the baroreflex-induced stimulation of the sympathetic nervous system and also because hydralazine does not dilate the epicardial coronary arteries; thus, the arteriolar dilation it produces may cause a 'steal' of blood flow away from the ischemic region. Following parenteral administration to patients with coronary artery disease, the myocardial ischemia may be sufficiently severe and protracted to cause frank myocardial infarction. For this reason, parenteral administration of hydralazine is contraindicated in hypertensive patients with coronary artery disease and inadvisable for most hypertensive patients over 40 years old. In addition, if the drug is used alone, there may be salt retention with development of high-output congestive heart failure. These symptoms were common during the early clinical use of hydralazine; because tachyphylaxis developed, the daily dose of the drug was frequently increased to 400 to 1000 mg. When combined with a -adrenergic receptor blocker and a diuretic, hydralazine is better tolerated, although side effects such as headache are still commonly described and may necessitate discontinuation of the drug.

The second type of side 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, but hydralazine has been shown to inhibit methylation of DNA and induce self-reactivity in T cells (Cornacchia et al., 1988).

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 (Perry, 1973). In one study, after three years of treatment with hydralazine, drug-induced lupus occurred in 10.4% of patients who received 200 mg daily, 5.4% 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, since 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 up to 200 mg per day.

Therapeutic Uses

Hydralazine generally is not used as the sole drug for the long-term treatment of hypertension because of the development of tachyphylaxis secondary to an increase in cardiac output and fluid retention. In addition, the drug should be used with the greatest of caution in elderly patients and in hypertensive patients with coronary artery disease because of the possibility of precipitation of myocardial ischemia. The usual oral dosage of hydralazine is 25 to 100 mg twice daily. 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 per day to minimize drug-induced lupus syndrome. Slow acetylators show a better response to this dosage than do fast acetylators because of the greater bioavailability of the drug.

Hydralazine has been used widely to treat hypertension that occurs during pregnancy. However, the drug should be used cautiously during early pregnancy, since hydralazine can combine with DNA and cause a positive Ames test (Williams et al., 1980). Parenteral administration of hydralazine has been used for the treatment of hypertensive emergencies in pregnancy, but is not recommended for the treatment of hypertensive emergencies in patients in the age range for coronary artery disease. The drug is contraindicated for the short-term production of hypotension in patients with dissecting aortic aneurysm or in those with symptomatic ischemic heart disease.

Minoxidil

The discovery in 1965 of the hypotensive action of minoxidil (LONITEN) was a significant advance in the treatment of hypertension, since the drug has proven to be efficacious in patients with the most severe and drug-resistant forms of hypertension. The chemical structure of minoxidil is as follows:

Locus and Mechanism of Action

Minoxidil is not active in vitro but must be metabolized by hepatic sulfotransferase to the active molecule, minoxidil N-O sulfate (McCall et al., 1983); the formation of this active metabolite is a minor pathway in the metabolic disposition of minoxidil. Minoxidil sulfate relaxes vascular smooth muscle in isolated systems where the parent drug is inactive. Minoxidil sulfate activates the ATP-modulated potassium channel. By opening potassium channels in smooth muscle and thereby permitting potassium efflux, it causes hyperpolarization and relaxation of smooth muscle (Leblanc et al., 1989).

Pharmacological Effects

Minoxidil produces arteriolar vasodilation with essentially no effect on the capacitance vessels; the drug resembles hydralazine and diazoxide in this regard. Minoxidil increases blood flow to skin, skeletal muscle, the gastrointestinal tract, and the heart more than to the CNS. The disproportionate increase in blood flow to the heart may have a metabolic basis, in that administration of minoxidil is associated with a reflex increase in myocardial contractility and in cardiac output. The cardiac output can increase markedly, as much as three- to fourfold. The principal determinant of the elevation in cardiac output is the action of minoxidil on peripheral vascular resistance to enhance venous return to the heart; by inference from studies with other drugs, the increased venous return probably results from enhancement of flow in the regional vascular beds with a fast time constant for venous return to the heart (Ogilvie, 1985). The adrenergically mediated increase in myocardial contractility contributes to the increased cardiac output, but is not the predominant causal factor.

The effects of minoxidil on the kidney are complex. Minoxidil is a renal vasodilator, but systemic hypotension produced by the drug occasionally can decrease renal blood flow. However, in the majority of patients who take minoxidil for the treatment of hypertension, renal function improves, 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.

Absorption, Metabolism, and Excretion

Minoxidil is well absorbed from the gastrointestinal 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. Only about 20% of the absorbed drug is excreted unchanged in the urine, and the main route of elimination is by hepatic metabolism. 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 human beings. Minoxidil has a half-life in plasma of 3 to 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 are predictable and can be 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 -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. This is especially true if the patient has any degree of renal dysfunction.

The cardiac consequences of the baroreceptor-mediated activation of the sympathetic nervous system during minoxidil therapy are similar to those seen with hydralazine; there is an increase in heart rate, myocardial contractility, and myocardial oxygen 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 -adrenergic blocker. The adrenergically induced increase in renin secretion also can be ameliorated by a -adrenergic receptor antagonist or an angiotensin converting enzyme inhibitor, with enhancement of the 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 failure 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. Effusion usually clears when the drug is discontinued, but it will recur if treatment with minoxidil is resumed (Reichgott, 1981).

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 potassium 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.

Hypertrichosis occurs in all patients who receive minoxidil for an extended period and is probably a consequence of potassium channel activation. Growth of hair occurs on the face, back, arms, and legs and is particularly offensive to women. Frequent shaving or depilatory agents can be used to manage this problem. Topical minoxidil (ROGAINE) is now marketed for the treatment of male-pattern baldness. The topical use of minoxidil can cause measurable cardiovascular effects in some individuals (Leenen et al., 1988).

Other side effects of the drug are rare and include rashes, StevensJohnson syndrome, glucose intolerance, serosanguinous bullae, formation of antinuclear antibodies, and thrombocytopenia.

Therapeutic Uses

Minoxidil is best reserved for the treatment of severe hypertension that responds poorly to other antihypertensive medications (Campese, 1981). It has been used successfully in the treatment of hypertension in both adults and children. Minoxidil should never be used alone; it must be given concurrently with a diuretic to avoid fluid retention and with a sympatholytic drug (usually a receptor antagonist) to control reflex cardiovascular effects. The drug usually is administered either once or twice a day, but some patients may require more frequent dosage for adequate control of blood pressure. The initial daily dose of minoxidil may be as little as 1.25 mg, which can be increased gradually to 40 mg in one or two daily doses.

Sodium Nitroprusside

Although sodium nitroprusside has been known since 1850 and its hypotensive effect in human beings was described in 1929, its safety and usefulness for the short-term control of severe hypertension were not demonstrated until the mid-1950s. Several investigators subsequently demonstrated that sodium nitroprusside also was effective in improving cardiac function in patients with left ventricular failure (see Chapter 34: Pharmacological Treatment of Heart Failure). The structural formula of sodium nitroprusside is as follows:

Locus and Mechanism of Action

Nitroprusside is a nitrovasodilator. It is metabolized by blood vessels to its active metabolite, nitric oxide. Nitric oxide activates guanylyl cyclase, leading to the formation of cyclic GMP and vasodilation (Murad, 1986). The metabolic activation of nitroprusside is catalyzed by a different nitric oxidegenerating system than that for nitroglycerin, probably accounting for the difference in the potency of these drugs at different vascular sites and the fact that tolerance develops to nitroglycerin but not to nitroprusside (Kowaluk et al., 1992).

Pharmacological Effects

Nitroprusside dilates both arterioles and venules, and the hemodynamic response to its administration results from a combination of venous pooling and reduced arterial impedance. Because of its effect on venules, the hypotensive effect of sodium nitroprusside is greater when the patient is upright. In subjects with normal left ventricular function, venous pooling affects cardiac output more than does the reduction of afterload; cardiac output thus tends to fall. In contrast, in patients with severely impaired left ventricular function and diastolic ventricular distention, the reduction of arterial impedance is the predominant effect, leading to a rise in cardiac output (see Chapter 34: Pharmacological Treatment of Heart Failure).

Sodium nitroprusside is a nonselective vasodilator, and regional distribution of blood flow is little affected by the drug. In general, renal blood flow and glomerular filtration are maintained, and plasma renin activity increases. Unlike minoxidil, hydralazine, diazoxide, and other arteriolar vasodilators, sodium nitroprusside usually causes only a modest increase in heart rate and an overall reduction in myocardial demand for oxygen.

Absorption, Metabolism, and Excretion

Sodium nitroprusside is an unstable molecule that decomposes under strongly alkaline conditions and when exposed to light. The drug must be 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 nitric oxide (Bates et al., 1991; Ivankovich et al., 1978). Cyanide is further metabolized by liver rhodanase to thiocyanate, which is eliminated almost entirely in the urine. The mean elimination half-time for thiocyanate is 3 days in patients with normal renal function, and it can be much longer in patients with renal insufficiency.

Toxicity and Precautions

The short-term side 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 can occur usually if sodium nitroprusside is infused at a rate greater than 5 g/kg per minute, but such toxicity can occur in some patients receiving doses about 2 g/kg per minute. 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 to 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. Rebound hypertension may occur after abrupt cessation of short-term nitroprusside infusions (Packer et al., 1979); this may be caused by persistently elevated concentrations of renin in the plasma.

Therapeutic Uses

Sodium nitroprusside is used primarily to treat hypertensive emergencies, but the drug can be used in many situations when short-term reduction of cardiac preload and/or afterload is desired. Thus, nitroprusside has been used to lower blood pressure during acute aortic dissection, to increase cardiac output in congestive heart failure (see Chapter 34: Pharmacological Treatment of Heart Failure), and to decrease myocardial oxygen demand after acute myocardial infarction. In addition, nitroprusside is the drug most often used to induce controlled hypotension during anesthesia in order to reduce bleeding in surgical procedures. In the treatment of acute aortic dissection, it is important to administer a -adrenergic receptor antagonist with nitroprusside, since reduction of blood pressure with nitroprusside alone can increase the rate of rise in pressure in the aorta as a result of increased myocardial contractility, thereby enhancing propagation of the dissection.

Sodium nitroprusside is available in vials that contain 50 mg. The contents of the vial should be dissolved in 2 to 3 ml of 5% dextrose in water. Addition of this solution to 250 to 1000 ml of 5% dextrose in water produces a concentration of 50 to 200 g/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 to 1.5 g/kg per minute. Higher rates of infusion are necessary to produce controlled hypotension in normotensive patients under surgical anesthesia. Infusion of nitroprusside at rates exceeding 5 g/kg per minute over a prolonged period can cause cyanide and/or thiocyanate poisoning. Patients who are receiving other antihypertensive medications usually require less nitroprusside to lower blood pressure. If infusion rates of 10 g/kg per minute do not produce adequate reduction of blood pressure within 10 minutes, the rate of administration of nitroprusside should be reduced to minimize potential toxicity.

Diazoxide

Diazoxide HYPERSTAT IV) is used in the treatment of hypertensive emergencies. Sodium nitroprusside is the drug of choice for this indication, but diazoxide maintains a place in the treatment of hypertensive emergencies in situations in which accurate infusion pumps are not available and/or close monitoring of blood pressure is not feasible. The drug is a benzothiadiazine derivative, like the thiazide diuretics, but it does not cause diuresis, apparently because it lacks a sulfonamido group. Its structural formula is as follows:

Mechanism of Action and Pharmacological Effects

Diazoxide hyperpolarizes arterial smooth muscle cells by activating ATP-sensitive K⁺ channels; this causes relaxation of the vascular smooth muscle (Standen et al., 1989). The effect of the drug in vivo is exclusively arteriolar, with negligible effect on capacitance vessels. This produces substantial reflex activation of the sympathetic nervous system. Cardiac output may double from stimulation of heart rate and myocardial contractility. The avid retention of salt and water is probably a result of stimulation of renal sympathetic nerves and changes in intrarenal hemodynamics, as with other arteriolar vasodilators. Diazoxide increases coronary blood flow, and cerebral and renal blood flows are maintained by autoregulation. Renin secretion is enhanced, and the combination of an increased cardiac output, salt and water retention, and elevated concentrations of angiotensin II counteract the antihypertensive effects of diazoxide.

Absorption, Metabolism, and Excretion

Although well absorbed orally, diazoxide is administered only intravenously for the treatment of severe hypertension. Approximately 20% to 50% of the drug is eliminated as such by the kidney, and the rest is metabolized in the liver to the 3-hydroxymethyl and 3-carboxy derivatives (Pruitt et al., 1974). Although the plasma half-life of diazoxide is 20 to 60 hours, the duration of the hypotensive response to the drug is variable and can be as short as 4 hours or as long as 20 hours; the development of a brisk rise in renin secretion may antagonize the early hypotensive effect of diazoxide.

The main indication for the use of diazoxide is for the treatment of hypertensive emergencies. Injection of an intravenous bolus lowers blood pressure within 30 seconds, and a maximum effect is achieved within 3 to 5 minutes. Although initial recommendations were to administer a 300-mg bolus of diazoxide, excessive hypotension with resultant cerebral and cardiovascular damage has resulted from this practice. Hypotension can be minimized by the administration of a 'minibolus' of 50 to 150 mg at intervals of 5 to 15 minutes until the desired blood pressure is achieved (Wilson and Vidt, 1978). Diazoxide also can be given by slow intravenous infusion at a rate of 15 to 30 mg per minute (Garrett and Kaplan, 1982). Prior administration of a -adrenergic receptor antagonist will enhance the hypotensive effect of the drug. Diazoxide should not be used to treat hypertension associated with aortic coarctation, arteriovenous shunts, or aortic dissection. Similarly, risks outweigh benefits in its use for acute pulmonary edema and ischemic heart disease.

Adverse Effects and Precautions

The most common side effects caused by diazoxide are myocardial ischemia, salt and water retention, and hyperglycemia. Myocardial ischemia may be precipitated or aggravated by diazoxide, and it results from the reflex adrenergic stimulation of the heart and from increased flow to nonischemic regions that 'steal' blood flow from the regions supplied by stenotic vessels. Retention of fluid can be avoided by restriction of salt and water. The routine use of diuretic agents with diazoxide is not recommended because patients with malignant hypertension are frequently volume-depleted. Hyperglycemia results from diazoxide's capacity to inhibit the secretion of insulin from pancreatic cells. This effect also appears to result from stimulation of ATP-sensitive K⁺ channels (Znkler et al., 1988). The drug does not alter the response to administration of insulin. Thus, hyperglycemia is mainly a problem in non-insulin-dependent diabetic patients who are being treated with oral hypoglycemic agents. Severe hyperglycemia with hyperosmolar, nonketotic coma has been described. Cerebral ischemia may be caused by excessive hypotension. Diazoxide relaxes uterine smooth muscle and may arrest labor when used to treat the hypertensive crisis of eclampsia. Rare side effects include gastrointestinal disturbances, flushing, local pain and inflammation after extravasation, altered ability to taste and smell, excessive salivation, and dyspnea.

Ca²⁺-channel blocking agents are an important group of drugs for the treatment of hypertension. The general pharmacology of these drugs is presented in Chapter 32: Drugs Used for the Treatment of Myocardial Ischemia; their use in heart failure is discussed in Chapter 34: Pharmacological Treatment of Heart Failure; and their use in cardiac arrhythmia is covered in Chapter 35: Antiarrhythmic Drugs. The logic behind their use in hypertension comes from the understanding that fixed hypertension is the result of increased peripheral vascular resistance. Since contraction of vascular smooth muscle is dependent on the free intracellular concentration of Ca²⁺, inhibition of transmembrane movement of Ca²⁺ should decrease the total amount of Ca²⁺ that reaches intracellular sites. Indeed, all of the Ca²⁺-channel blockers lower blood pressure by relaxing arteriolar smooth muscle and decreasing peripheral vascular resistance (Lehmann et al., 1983). As a consequence of a decrease in peripheral vascular resistance, the Ca²⁺-channel blockers evoke a baroreceptor-mediated sympathetic discharge. In the case of the dihydropyridines, mild to moderate tachycardia ensues from the adrenergic stimulation of the sinoatrial node, whereas tachycardia is minimal to absent with verapamil and diltiazem because of the direct negative chronotropic effect of these two drugs. The increased adrenergic stimulation of the heart serves to counter the negative inotropic effect of Ca²⁺-channel blockers such as verapamil, diltiazem, and nifedipine; the importance of this compensatory support of myocardial contractility should be considered in decisions regarding possible concurrent use of -adrenergic receptor antagonists, particularly in patients who may be prone to hypertensive cardiac failure. The adrenergic reflex response to Ca²⁺-channel blockers also acts to attenuate the hypotensive effect of these drugs; thus, when the reflex vasoconstriction is diminished, as in the elderly or during treatment with -adrenergic receptor antagonists, the hypotensive effect of the Ca²⁺-channel blockers is increased, sometimes excessively.

In considering the cardiovascular effects of the Ca²⁺-channel blockers, it is essential to evaluate both the hemodynamic effects in the normal heart and the interaction of these drugs with cardiac disease, given that both cardiac failure and coronary artery diseases are important consequences of hypertension and that left ventricular hypertrophy is a harbinger for sudden cardiac death in hypertensive patients. As a consequence of the peripheral vasodilation, Ca²⁺-channel blockers may increase venous return, which will result in an increased cardiac output except in the case of those that exert substantial negative inotropic effects (e.g., verapamil and diltiazem). The increased venous return is not as great as with minoxidil or hydralazine, but is a consideration in the management of patients with diastolic dysfunction due to hypertensive cardiomyopathy who are at risk of left ventricular failure. The Ca²⁺-channel blockers do not improve the diastolic function of the ventricle. Although earlier noninvasive studies had demonstrated that peak filling rates of the left ventricle of hypertensive patients were shortened by Ca²⁺-channel blockers, direct hemodynamic evaluation of ventricular function has demonstrated that verapamil causes an increase in left ventricular end-diastolic pressure, an undesirable hemodynamic consequence that occurs in conjunction with, and probably as a contributor to, the acceleration of peak filling rate (Nishimura et al., 1993).

In addition to these findings that Ca²⁺-channel blockers do not improve and have the potential for worsening the hemodynamics in diastolic dysfunction, the long-term effects of the Ca²⁺-channel blockers on left ventricular hypertrophy, a major contributor to diastolic dysfunction, should be considered. An overview of all trials evaluating the effects of antihypertensive agents on left ventricular mass concludes that, although Ca²⁺-channel blockers do reduce left ventricular mass and do so more effectively than diuretics, they are less effective than angiotensin converting enzyme inhibitors and methyldopa (Dalhf et al., 1993). Based on the sum of this evidence, Ca²⁺-channel blockers probably are not the first choice as the initial drug in the treatment of patients whose hypertension is accompanied by left ventricular hypertrophy nor as the predominant drug in a combination for their treatment.

All Ca²⁺-channel blockers are equally effective when used alone for the treatment of mild to moderate hypertension; and in comparative trials, Ca²⁺-channel blockers are as effective in lowering blood pressure as -adrenergic receptor antagonists or diuretics (Doyle, 1983; Inouye et al., 1984).

The presence of ischemic heart disease in conjunction with hypertension raises a special set of concerns regarding some of the Ca²⁺-channel blockers. Dihydropyridine Ca²⁺-channel blockers do not improve survival in patients following myocardial infarction. Neither verapamil nor diltiazem improves mortality in the entire group of postinfarction patients. Data suggesting that diltiazem may exert a favorable effect on mortality in the subset of patients who exhibit no abnormality in systolic ventricular function does not form a strong basis for its use in such patients because of the post hoc selection of this group for analysis (Multicenter Diltiazem Postinfarction Trial Research Group, 1988). This is in contrast to the clear benefit to the survival of patients after myocardial infarction that is conferred by treatment with -adrenergic receptor antagonists and angiotensin converting enzyme inhibitors. Accordingly, the Ca²⁺-channel blockers are not the initial or even the second drugs to be used in the treatment of the hypertension in patients who have had a myocardial infarction.

In diabetic patients with hypertension, the available evidence favors an angiotensin converting enzyme inhibitor as the initial antihypertensive drug (Estacio et al., 1998), following which it is appropriate to consider adding a Ca²⁺-channel blocker if a second drug is required.

The profile of adverse reactions to the Ca²⁺-channel blockers varies among the drugs in this class, but only a small fraction of patients discontinue these drugs because of perceived adverse reactions. The dihydropyridines cause the highest incidence of vascular side effects. Approximately 10% of patients receiving the standard formulation of nifedipine (immediate-release capsules) develop headache, flushing, dizziness, and peripheral edema. Dizziness and flushing are much less of a problem with the sustained-release formulations and with the dihydropyridines having a long half-life and relatively constant concentrations of drug in plasma. The edema usually is not the result of fluid retention; it most likely results from increased hydrostatic pressure in the lower extremities owing to precapillary dilation and reflex postcapillary constriction. Contraction of the lower esophageal sphincter is inhibited by the Ca²⁺-channel blockers. Accordingly, all Ca²⁺-channel blockers can cause gastroesophageal reflux. Constipation is a common side effect of verapamil, but it occurs less frequently with other Ca²⁺-channel blockers. Inhibition of sinoatrial node function by diltiazem and verapamil can lead to bradycardia and even sinoatrial node arrest, particularly in patients with sinoatrial node dysfunction; this effect is exaggerated by concurrent use of -adrenergic receptor antagonists.

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. Short-acting, parenterally administered agents should be used in the setting of hypertensive emergency. Nifedipine is a suboptimal choice for treatment of hypertensive pulmonary edema; nitroprusside produces a greater reduction in left ventricular end-diastolic pressure than do equihypotensive doses of nifedipine (Aroney et al., 1991), and the magnitude of nitroprusside's pharmacological effect can be regulated more effectively. 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.

Ca²⁺-channel blockers are versatile drugs with proven efficacy in all types of patients (Kiowski et al., 1985). They seem to be especially efficacious in low-renin hypertension. Compared with other classes of antihypertensive agents, there is 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. Long-acting dihydropyridine Ca²⁺-channel blockers have been found to reduce cardiovascular mortality in older patients (Staessen et al., 1997). The efficacy of Ca²⁺-channel blockers is enhanced by the concomitant use of an angiotensin converting enzyme inhibitor, methyldopa, or -adrenergic receptor antagonists. When -adrenergic receptor antagonists are administered concurrently, the preferred Ca²⁺-channel blocker would be one from the group that is relatively vasoselective (e.g., amlodipine, isradipine, nicardipine). Diuretics also may enhance the efficacy of Ca²⁺-channel blockers, but the data have not been consistent.

Significant drugdrug interactions may be encountered when Ca²⁺-channel blockers are used to treat hypertension. Verapamil blocks the drug transporter, P-glycoprotein. Both the renal and hepatic disposition of digoxin occur 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 1: Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, and Elimination) (Pedersen et al., 1981). When used with quinidine, Ca²⁺-channel blockers may cause excessive hypotension, particularly in patients with idiopathic hypertrophic subaortic stenosis.

Ca²⁺-channel blockers should not be used in patients with SA or AV nodal abnormalities or in patients with overt congestive heart failure. These drugs usually are safe, however, in hypertensive patients with asthma, hyperlipidemia, diabetes mellitus, and renal dysfunction. Unlike -adrenergic receptor antagonists, Ca²⁺-channel blockers do not alter exercise tolerance; nor do they alter plasma concentrations of lipids, uric acid, or electrolytes.

Angiotensin II is an important regulator of cardiovascular function (see Chapter 31: Renin and Angiotensin). The ability to reduce levels of angiotensin II with orally effective inhibitors of angiotensin converting enzyme (ACE) represents an important advance in the treatment of hypertension. Captopril (CAPOTEN) was the first such agent to be developed for the treatment of hypertension. Since then, enalapril (VASOTEC), lisinopril (PRINIVIL), quinapril (ACCUPRIL), ramipril (ALTACE), benazepril (LOTENSIN), moexipril (UNIVASC), fosinopril (MONOPRIL), trandolapril (MAVIK), and perindopril (ACEON) also have become available. These drugs have proven to be very useful for the treatment of hypertension because of their efficacy and their very favorable profile of side effects, which enhances compliance.

The angiotensin converting enzyme inhibitors appear to confer a special advantage in the treatment of patients with diabetes, slowing the development of diabetic glomerulopathy. They also have been shown to be effective in slowing the progression of other forms of chronic renal disease, such as glomerulosclerosis, and many of these patients also have hypertension. An angiotensin converting enzyme inhibitor is probably the preferred initial agent in the treatment of hypertensive patients with left ventricular hypertrophy. Patients with hypertension and ischemic heart disease are candidates for treatment with angiotensin converting enzyme inhibitors; this includes treatment in the immediate postmyocardial infarction period which has been shown to lead to improved ventricular function and reduced morbidity and mortality (see also Chapter 34: Pharmacological Treatment of Heart Failure).

The endocrine consequences of inhibiting the biosynthesis of angiotensin II are of importance in a number of facets of hypertension treatment. Because angiotensin converting enzyme inhibitors blunt the normal aldosterone response to Na⁺ loss, the normal role of aldosterone to oppose diuretic-induced natriuresis is diminished. Thus, angiotensin converting enzyme inhibitors enhance the efficacy of diuretic drugs. This means that even very small doses of diuretics may substantially improve the antihypertensive efficacy of angiotensin converting enzyme inhibitors; and on the other end of the spectrum, the use of high doses of diuretics together with angiotensin converting enzyme inhibitors may lead to excessive reduction in blood pressure and to Na⁺ loss in some patients.

The attenuation of aldosterone production by the angiotensin converting enzyme inhibitors also influences K⁺ homeostasis. There is only a very small and clinically unimportant rise in serum K⁺ when angiotensin converting inhibitors are used alone in patients with normal renal function. However, substantial retention of K⁺ can occur in some patients with renal insufficiency. Furthermore, the potential for developing hyperkalemia should be considered when angiotensin converting enzyme inhibitors are used with other drugs that can cause K⁺ retention; these include the K⁺-sparing diuretics (amiloride, triamterene, spironolactone), nonsteroidal antiinflammatory drugs, K⁺ supplements, and -adrenergic receptor antagonists.

There are several cautions in the use of angiotensin converting enzyme inhibitors in patients with hypertension. Angioedema is an infrequent but serious and potentially fatal adverse effect of all of the angiotensin converting enzyme inhibitors. Thus, patients starting treatment with these drugs should be explicitly warned to discontinue their use with the advent of any signs of angioedema. The angiotensin converting enzyme inhibitors should not be used during pregnancy, a fact that should be communicated to patients of childbearing age.

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

Converting enzyme inhibitors lower the blood pressure to some extent in most patients with hypertension. Following the initial dose of a converting enzyme inhibitor, there may be a considerable fall in blood pressure in some patients; this response to the initial dose is a function of pretreatment plasma renin activity. The potential for a large initial drop in blood pressure is the reason for using a low dose for initiating therapy. On continuing treatment, there usually is a progressive fall in blood pressure that in most patients does not reach a maximum for about one week. The level of blood pressure seen during chronic treatment is not strongly correlated with the level of pretreatment plasma renin activity. Young and middle-aged Caucasian patients have a higher probability of responding to the angiotensin converting enzyme inhibitors. Elderly African-American patients as a group are more resistant to the hypotensive effect of these drugs, but concurrent use of a diuretic in low doses overcomes this relative resistance. These drugs are discussed in detail in Chapter 31: Renin and Angiotensin.

The importance of angiotensin II in regulating cardiovascular function has led to the development of nonpeptide antagonists of the angiotensin II receptor for clinical use. Losartan (COZAAR), candesartan (ATACAND), irbesartan (AVAPRO), valsartan (DIOVAN), telmisartan (MICARDIS), and eprosartan (TEVETEN) have been approved for the treatment of hypertension. By preventing effects of angiotensin II, these agents relax smooth muscle and thereby promote vasodilation, increase renal salt and water excretion, reduce plasma volume, and decrease cellular hypertrophy. Angiotensin IIreceptor antagonists also theoretically overcome some of the disadvantages of ACE inhibitors, which not only prevent conversion of angiotensin I to angiotensin II but also prevent ACE-mediated degradation of bradykinin and substance P. Cough, an adverse effect of ACE inhibitors, has not been associated with angiotensin IIreceptor antagonists. Angioedema occurs rarely.

Two distinct subtypes of angiotensin II receptors have been cloned, designated as type 1 (AT₁) and type 2 (AT₂). The AT₁ angiotensin II receptor subtype is located predominantly in vascular and myocardial tissue and also in brain, kidney, and adrenal glomerulosa cells, which secrete aldosterone (see Chapter 31: Renin and Angiotensin). The AT₂ subtype of angiotensin II receptor is found in the adrenal medulla, kidney, and in the CNS, and may play a role in vascular development (Horiuchi et al., 1999). Because the AT₁ receptor mediates feedback inhibition of renin release, renin and angiotensin II concentrations are increased during AT₁-receptor antagonism. The clinical consequences of increased angiotensin II effects on an uninhibited AT₂ receptor are unknown; however, emerging data suggest that the AT₂ receptor may elicit antigrowth and antiproliferative responses.

Adverse Effects and Precautions

The adverse effects of AT₁-receptor antagonists may be considered in the context of those known to be associated with the ACE inhibitors. ACE inhibitors cause problems of two major types, those related to a diminished level of angiotensin II and those due to molecular actions independent of abrogating the function of angiotensin II.

Adverse effects of ACE inhibitors that result from inhibiting angiotensin II-related functions (see above) occur also 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 angiotensin II, 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 is essential. Hyperkalemia will occur only 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.

In contrast with ACE inhibitors, the AT₁-receptor antagonists do not cause cough. Angioedema has been reported, but it is not clear whether or not the rate of angioedema in patients taking the AT₁-receptor antagonists is any higher than that in the general population. Hepatic dysfunction has been reported with the AT₁-receptor antagonists.

AT₁-receptor antagonists should not be administered during the second or third trimester of pregnancy and should be discontinued as soon as pregnancy is detected. Although it is not yet known whether or not AT₁-receptor antagonists are secreted in human breast milk, significant amounts are detected in the milk of animals; consequently, AT₁-receptor antagonists should not be administered to patients who are breast-feeding.

Therapeutic Uses

When given in adequate doses, the AT₁-receptor antagonists appear to be as effective as ACE inhibitors in the treatment of hypertension. As with ACE inhibitors, these drugs may be less effective in African-American and low-renin patients.

The full effect of AT₁-receptor antagonists on blood pressure typically is not observed until 3 to 6 weeks after the initiation of therapy. If blood pressure is not controlled by an AT₁-receptor antagonist alone, a low dose of a hydrochlorothiazide or other diuretic may be added. In several randomized, double-blind studies of patients with mild to severe hypertension, the addition of hydrochlorothiazide to an AT₁-receptor antagonist produced significant additional reductions in blood pressure in patients who demonstrated an insufficient response to hydrochlorothiazide alone. A smaller initial dosage is preferred for patients who have already received diuretics and therefore have an intravascular volume depletion, and for other patients whose blood pressure is highly dependent on angiotensin II.

Ongoing clinical trials should shed light on the relative efficacy of ACE inhibitors and AT₁-receptor antagonists in patients with diabetic nephropathy, coronary artery disease, and left ventricular dysfunction (Pitt et al., 1999a). Given the different mechanisms by which they act, there is no assurance that the effects of ACE inhibitors and antagonists of the AT₁ receptor will be equivalent.

Nonpharmacological approaches to the reduction of blood pressure generally are advisable as the initial approach to treatment of patients with diastolic blood pressures in the range of 90 to 95 mm Hg. Further, these approaches will augment the effectiveness of pharmacological therapy in patients with higher levels of blood pressure. Also, for patients with diastolic blood pressures in the range of 85 to 90 mm Hg, the epidemiological data on cardiovascular risks support the institution of nonpharmacological therapy. To maintain compliance with a therapeutic regimen, the intervention should not lessen the quality of life. All drugs have side effects. If minor alterations of normal activity or diet can reduce blood pressure to a satisfactory level, the complications of drug therapy can be avoided. In addition, nonpharmacological methods to lower blood pressure allow the patient to participate actively in the management of his or her disease. Reduction of weight, restriction of salt, and moderation in the use of alcohol may reduce blood pressure and improve the efficacy of drug treatment. In addition, regular isotonic exercise also lowers blood pressure in hypertensive patients.

Smoking per se does not cause hypertension. However, smokers do have a higher incidence of malignant hypertension (Isles et al., 1979), and smoking is a major risk factor for coronary heart disease. Hypertensive patients have an exceptionally great incentive to stop smoking. Consumption of caffeine can raise blood pressure and elevate plasma concentrations of norepinephrine, but long-term consumption of caffeine causes tolerance to these effects and has not been associated with the development of hypertension. An increased intake of Ca²⁺ has been reported by some investigators to lower blood pressure. The mechanism of this effect is not understood, but suppression of the secretion of parathyroid hormone apparently is involved. However, supplemental Ca²⁺ does not lower blood pressure when populations of hypertensive subjects are studied. Although it is possible that there are some hypertensive patients who have a hypotensive response to Ca²⁺, there is no easy way to identify such individuals. Supplemental use of Ca²⁺ for this purpose cannot be recommended at the present time (Kaplan, 1988).

Reduction of Body Weight

Obesity and hypertension are closely associated, and the degree of obesity is positively correlated with the incidence of hypertension. Obese hypertensives may lower their blood pressure by losing weight regardless of a change in salt consumption (Maxwell et al., 1984). The mechanism by which obesity causes hypertension is unclear, but increased secretion of insulin in obesity could result in insulin-mediated enhancement of renal tubular reabsorption of Na⁺ and an expansion of extracellular volume. Obesity also is associated with increased activity of the sympathetic nervous system; this is reversed by weight loss. Maintenance of weight loss is difficult for many. A combination of aerobic physical exercise and dietary counseling may enhance compliance.

Sodium Restriction

Severe restriction of salt will lower the blood pressure in most hospitalized hypertensive patients; this treatment method was advocated prior to the development of effective antihypertensive drugs (Kempner, 1948). However, severe salt restriction is not practical from a standpoint of compliance. Several studies have shown that moderate restriction of salt intake to approximately 5 g per day (2 g Na⁺) will, on average, lower blood pressure by 12 mm Hg systolic and 6 mm Hg diastolic. The higher the initial blood pressure, the greater the response. In addition, subjects over 40 years of age are more responsive to the hypotensive effect of moderate restriction of salt (Grobbee and Hofman, 1986). Even though not all hypertensive patients respond to restriction of salt, this intervention is benign and can easily be advised as an initial approach in all patients with mild hypertension. An additional benefit of salt restriction is improved responsiveness to some antihypertensive drugs.

Alcohol Restriction

Consumption of alcohol can raise blood pressure, but it is unclear how much alcohol must be consumed to observe this effect (MacMahon et al., 1984). Heavy consumption of alcohol increases the risk of cerebrovascular accidents but not coronary heart disease (Kagan et al., 1985). In fact, small amounts of ethanol have been found to protect against the development of coronary artery disease. The mechanism by which alcohol raises blood pressure is unknown, but it may involve increased transport of Ca²⁺ into vascular smooth muscle cells. Excessive intake of alcohol also may result in poor compliance with antihypertensive regimens. All hypertensive patients should be advised to restrict consumption of ethanol to no more than 30 ml per day.

Physical Exercise

Increased physical activity lowers rates of cardiovascular disease in men (Paffenbarger et al., 1986). It is not known if this beneficial effect is secondary to an antihypertensive response to exercise. Lack of physical activity is associated with a higher incidence of hypertension (Blair et al., 1984). Although consistent changes in blood pressure are not always observed, meticulously controlled studies have demonstrated that regular isotonic exercise reduces both systolic and diastolic blood pressures by approximately 10 mm Hg (Nelson et al., 1986). The mechanism by which exercise can lower blood pressure is not clear, but several hemodynamic and humoral changes have been documented. Regular isotonic exercise reduces blood volume and plasma catecholamines and elevates plasma concentrations of atrial natriuretic factor. The beneficial effect of exercise can occur in subjects who demonstrate no change in body weight or salt intake during the training period.

Relaxation and Biofeedback Therapy

The fact that long-term stressful stimuli can cause sustained hypertension in animals has given credence to the possibility that relaxation therapy will lower blood pressure in some hypertensive patients. A few studies have generated positive results but, in general, relaxation therapy has inconsistent and modest effects on blood pressure (Jacob et al., 1986). In addition, the long-term efficacy of such treatment has been difficult to demonstrate, presumably in part because patients must be highly motivated to respond to relaxation and biofeedback therapy. Only those few patients with mild hypertension who wish to use this method should be encouraged to try, and these patients should be closely followed and receive pharmacological treatment if necessary.

Potassium Therapy

There is a positive correlation between total body Na⁺ and blood pressure and a negative correlation between total body K⁺ and blood pressure in hypertensive patients (Lever et al., 1981). In addition, dietary intake, plasma concentrations, and urinary excretion of K⁺ are reduced in various populations of hypertensive subjects. Increased intake of K⁺ might reduce blood pressure by increasing excretion of Na⁺, suppressing renin secretion, causing arteriolar dilation (possibly by stimulating Na⁺, K⁺-ATPase activity and decreasing intracellular concentrations of Ca²⁺), and impairing responsiveness to endogenous vasoconstrictors. In hypertensive rats, supplementation with K⁺ decreases blood pressure and reduces the incidence of stroke, irrespective of blood pressure (Tobian, 1986). In mildly hypertensive patients, oral K⁺ supplements of 48 mmol per day reduce both systolic and diastolic blood pressure (Siani et al., 1987). Supplementation with K⁺ also may protect against ventricular ectopy and stroke (Khaw and Barrett-Connor, 1987). Based on all of these data, it seems prudent to use a high-K⁺ diet in conjunction with moderate restriction of Na⁺ in the nonpharmacological treatment of hypertension. However, a high-K⁺ diet should not be recommended for patients on angiotensin converting enzyme inhibitors.

The most anticipated development in antihypertensive therapy is the new knowledge expected from clinical trials comparing the effectiveness of drugs on the important endpoints of morbidity and mortality. One clinical trial addressing these endpoints has been launched by the National Heart, Lung, and Blood Institute (Davis et al., 1996). It is the Antihypertensive and Lipid Lowering treatment to prevent Heart Attack Trial (ALLHAT) and is comparing the outcomes of treatment with a thiazide-class diuretic (chlorthalidone), an angiotensin converting enzyme inhibitor (lisinopril), a Ca²⁺-channel blocker (amlodipine), and an -adrenergic receptor antagonist (doxazosin). This trial is evaluating the effects of these drugs in patients over the age of 55 who are at high risk for vascular occlusive events. Concurrently, the benefit of a cholesterol-lowering drug, pravastatin, is being assessed in the same population. The Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study is comparing the AT₁-receptor antagonist losartan and -adrenergic receptor blocker atenolol on cardiovascular mortality and morbidity in patients, aged 55 to 88 years, with hypertension and left ventricular hypertrophy (Dahlf et al., 1998). The African-American Study of Kidney Disease (AASK) will determine the efficacy of two different levels of blood pressure control and three different antihypertensive regimens on the progression of renal disease in African Americans with hypertensive nephropathy (Wright et al., 1996).

A growing recognition of the contribution of the renin-angiotensin-aldosterone system (RAAS) to the development and progression of hypertensive end-organ damage promises to bring a number of studies examining new strategies for interrupting the RAAS. For example, studies comparing the efficacy of ACE inhibition, AT₁-receptor antagonism, and the combination of ACE inhibition and AT₁-receptor antagonism are ongoing. The finding that the addition of an aldosterone antagonist decreases mortality in patients with congestive heart failure treated with an ACE inhibitor (Pitt et al., 1999b) has sparked a renewed interest in aldosterone antagonists in the treatment of hypertension. These studies, if they are successful, could profoundly influence the approach to treating hypertension.

For further discussion of hypertension, see Chapter 230 in Harrison's Principles of Internal Medicine, 16th ed., McGraw-Hill, New York, 2005.