Brody's Human Pharmacology: With STUDENT CONSULT

Chapter 20 Antihypertensive Drugs

MAJOR DRUG CLASSES

Diuretics

Renin-angiotensin inhibitors

Adrenergic receptor antagonists

Centrally acting sympatholytics

2 receptor agonists)

Ca++ channel blockers

Direct vasodilators

Therapeutic Overview

Hypertension is the most prominent risk factor contributing to the prevalence of cardiovascular disease. For every 20 mm Hg increase in systolic blood pressure or 10 mm Hg increase in diastolic blood pressure, the risk of death from ischemic heart disease and stroke doubles. The incidence of hypertension, particularly elevated systolic blood pressure, increases with age, and approximately half of all people aged 60 to 69 years old and three quarters of those more than 70 years old have elevated blood pressure. The importance of hypertension as a public health problem will increase as the population ages, and preventing hypertension will be a major public health challenge for this century.

Although these statistics are daunting, prevention of hypertension and the associated reduction in cardiovascular disease has been remarkably successful over the last 30 years, and age-adjusted death rates from stroke and coronary heart disease have declined approximately 50% since 1972. However, it is also estimated that in the United States, approximately 30% of hypertensive adults are unaware of their condition, more than 40% are not being treated, and more than 60% of patients who are receiving treatment are not being adequately controlled.

Hypertension is defined as an elevation of arterial blood pressure above an arbitrarily defined normal value. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7) classifies hypertension based on both systolic and diastolic blood pressures. Most candidates for antihypertensive drug therapy have a systolic blood pressure above 140 mm Hg, a diastolic pressure above 90 mm Hg, or both. The presence of other risk factors (e.g., smoking, hyperlipidemia, target-organ damage) is also an important determinant in the decision to treat patients with drugs.

A small number (<10%) of people have hypertension traceable to specific causes, such as renal disease or endocrine tumors. However, most patients are simply at the

Abbreviations

ACE

Angiotensin-converting enzyme

ARB

Angiotensin receptor blocker

AV

Atrioventricular

CNS

Central nervous system

CO

Cardiac output

Epi

Epinephrine

NE

Norepinephrine

TPR

Total peripheral resistance

upper end of the normal distribution of blood pressure values for their population group. This most common form of hypertension, with no readily identifiable cause, is called essential hypertension. It is usually first diagnosed in middle-aged people but can also be found in children and young adults. Because of its prevalence, it is the disease most often treated with antihypertensive drugs.

Unless its onset is rapid and severe, hypertension does not produce noticeable symptoms. The purpose of treating hypertension is to prevent or reduce the severity of diseases, such as atherosclerosis, coronary artery disease, aortic aneurysm, congestive heart failure, stroke, diabetes, and renal and retinal disease. In this regard many clinical trials have shown that antihypertensive drug therapy reduces the morbidity and mortality associated with these disorders.

Therapy of hypertension involves both pharmacological and nonpharmacological interventions. The therapeutic goal is to reduce blood pressure to below 140/90 mm Hg. This can often be accomplished by targeting a reduction in systolic blood pressure to below 140 mm Hg, which is usually accompanied by a reduction in diastolic pressure below 90 mm Hg. For initial treatment, monotherapy with a single drug is advisable. If necessary, drug dose should be gradually increased toward the upper range of its therapeutic effectiveness or until side effects become limiting. Although monotherapy increases patient compliance, nearly two thirds of patients will require more than one drug to control their blood pressure. If two or more drugs are used, each should be selected to target distinct physiological mechanisms.

Adoption of healthy lifestyles may lower blood pressure as much as some drugs. It may also prevent the onset or progression of hypertension. Patients differ in their sensitivity to these techniques. For example, maintenance of normal body weight and increased physical activity lowers blood pressure in most sedentary and overweight hypertensive individuals, whereas Na+ restriction lowers

Therapeutic Overview

Hypertension is defined as:

Systolic pressure >140 mm Hg and/or diastolic pressure >90 mm Hg

Hypertension is a major risk factor for:

Atherosclerosis

Coronary artery disease

Congestive heart failure

Diabetes

Insulin resistance

Stroke

Renal disease

Retinal disease

Hypertension therapy

Nonpharmacological

Weight reduction, dietary (reduce salt and saturated fat, increase fruits and vegetables, use low-fat dairy products), exercise, smoking cessation, decrease excessive (>30 mL/day) alcohol intake

Pharmacological

Diuretics, renin-angiotensin inhibitors, sympatholytics, Ca++ channel blockers, direct vasodilators

blood pressure mainly in hypertensive people categorized as “salt-sensitive.” The major advantage of nonpharmacological therapies is relative safety, as compared with drug therapy. Their principal limitation is the lack of compliance by most people. For most hypertensive patients control of hypertension requires drug treatment to achieve an adequate, sustained blood pressure reduction. Nevertheless, lifestyle modification plays a valuable and important role in management.

The disorders for which hypertension represents a major risk factor and the treatments for hypertension are presented in the Therapeutic Overview Box.

Mechanisms of Action

Blood Pressure Regulation

Systemic blood pressure is regulated redundantly by several physiological control systems to ensure optimal tissue perfusion throughout the body. When blood pressure decreases by any means, including antihypertensive drug therapy, one or more of these regulatory mechanisms are activated to compensate for decreases in arterial blood pressure (Fig. 20-1).

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FIGURE 20–1 Physiological compensatory mechanisms that counteract a decrease in blood pressure.

The Sympathetic Nervous System

A decrease in blood pressure activates the baroreceptor reflex (Chapter 19), producing increased sympathetic activity, leading to:

• Increased force and rate of cardiac contraction and enhanced cardiac filling, which combine to elevate cardiac output (CO).

• Constriction of most blood vessels, increasing total peripheral resistance (TPR) and venous return of blood to the heart.

• Release of renin from the kidney.

• Renal retention of salt and H2O, mediated by sympathetic nerves innervating renal blood vessels and tubules.

Renin-Angiotensin-Aldosterone System

A decrease in arterial pressure produces a decrease in renal perfusion pressure and baroreflex-mediated sympathetic activation of renal β1 adrenergic receptors, inducing the release of renin from the juxtaglomerular cells of the kidney into the blood. Renin cleaves the decapeptide angiotensin I from a circulating glycoprotein, angiotensinogen, which is synthesized mainly in liver. Angiotensin I is converted to the octapeptide angiotensin II by angiotensin-converting enzyme (ACE) present in endothelial cell membranes, especially in the lung. Angiotensin II constricts blood vessels, enhances sympathetic nervous system activity, and causes renal Na+ and H2O retention by direct intrarenal actions and by stimulating the adrenal cortex to release aldosterone (see Fig. 20-1).

Role of Vasopressin

A decrease in arterial pressure causes a baroreflex-mediated release of vasopressin (antidiuretic hormone) from the neurohypophysis of the pituitary gland, which acts on the renal collecting duct to enhance H2O retention by the kidney.

Fluid Retention by the Kidney

A decrease in arterial pressure causes the kidney to excrete less Na+ and H2O. This results, in part, from the direct intrarenal hydraulic effect of reduced renal perfusion pressure and, in part, from the mechanisms discussed. The resultant expansion of extracellular fluid and plasma volume tends to increase CO and arterial pressure, which can reduce the blood pressure-lowering action of many antihypertensive drugs.

The most effective and best-tolerated antihypertensive drug regimens impair the operation of one or more of these physiological mechanisms. In addition, drug therapy for hypertension must usually be continued for the lifetime of the patient.

Diuretics

Diuretics cause Na+ excretion and reduce fluid volume by inhibiting electrolyte transport in the renal tubules. The diuretics can be classified into three broad categories related to their sites and mechanisms of action (see Chapter 21). Thiazide diuretics inhibit the Na+/Cl cotransporter principally in the distal convoluted tubules and produce a relatively sustained diuresis, natriuresis, and kaliuresis. These diuretics are most effective in patients with adequate renal function.

Loop diuretics inhibit electrolyte transport in the ascending limb of the loop of Henle. They are useful in patients with compromised renal function and in those resistant to the actions of thiazides. Loop diuretics produce a pronounced, although shorter, diuresis than do the thiazides. Both thiazide and loop diuretics can cause K+ depletion. With chronic administration, this effect is more pronounced with the longer-acting thiazides.

K+-sparing diuretics inhibit Na+ reabsorption in the collecting duct. Thiazide and loop diuretic-induced hypokalemia can often be alleviated by including one of the K+-sparing diuretics in the drug regimen. The K+-sparing diuretics, although producing relatively less diuresis and natriuresis than the thiazide or loop diuretics, can counteract their hypokalemic properties.

Renin-Angiotensin Inhibitors

As discussed, renin catalyzes the cleavage of angiotensinogen to angiotensin I. In 2007, the first direct-acting renin inhibitor was approved for the treatment of hypertension by the U.S. Food and Drug Administration. This agent, aliskiren, binds renin in the plasma with high affinity to prevent the first and rate-limiting step of the renin-angiotensin-aldosterone system, leading to reduced levels of both angiotensin I and II.

The active component of the renin-angiotensin system, angiotensin II, is generated by enzymatic conversion of the decapeptide angiotensin I to angiotensin II, a reaction catalyzed by ACE (or kininase II), which is widely distributed in the body, with highest activity in the endothelium of the pulmonary vasculature. ACE inhibitors such as captopril, enalapril, and lisinopril reversibly inhibit this enzyme and reduce blood pressure by inhibiting angiotensin II formation.

The angiotensin receptor blockers (ARBs) such as losartan and valsartan reversibly bind the AT1 subtype of angiotensin II receptors in blood vessels and other tissues to reduce the physiological effects of angiotensin II. The ARBs have antihypertensive actions similar to those of the ACE inhibitors.

Drugs Affecting the Sympathetic Nervous System

Adrenergic Receptor Antagonists

There is wide diversity in the pharmacological profile of adrenergic β receptor antagonists (see Chapter 11). Some of these compounds, such as propranolol and pindolol, are nonselective and antagonize both β1 and β2 receptors, whereas others, like atenolol, are selective for the β1 receptor subtype. In addition, some β receptor blockers such as pindolol have modest intrinsic sympathomimetic activity, while others including labetalol and carvedilol are competitive antagonists at α1, β1, and β2 adrenergic receptors. Despite these differences, all β receptor blockers used for the treatment of hypertension share the common characteristic of competitively antagonizing the effects of norepinephrine (NE) and epinephrine (Epi) on β1 adrenergic receptors in the heart and renin-secreting cells of the kidney. Furthermore, clinically useful α1 adrenergic receptor antagonists lower blood pressure by blocking α1 receptors on vascular smooth muscle.

Centrally Acting Sympatholytics

Sympatholytics with actions in the central nervous system (CNS) decrease blood pressure by reducing the firing rate of sympathetic nerves, principally by activation of α2 adrenergic receptors. Drugs in this class include α-methyldopa, clonidine, guanfacine, and guanabenz.

The antihypertensive effects of the prodrug α-methyldopa are attributed to its conversion in the brain by l-aromatic amino acid decarboxylase and dopamine-β-hydroxylase to α-methyl-NE, which is a preferential agonist at α2 adrenergic receptors (see Chapter 11Fig. 11-12). Clonidine, guanfacine, and guanabenz, which readily enter the brain after systemic administration, are selective agonists at central α2 receptors (see Chapter 11). In addition, because these drugs are taken orally for the treatment of hypertension, activation of presynaptic α2 adrenergic receptors on peripheral sympathetic nerve terminals may inhibit the release of NE and potentially contribute to their antihypertensive action.

The central site(s) where α2 receptor agonists act to lower blood pressure have not been completely identified and characterized but may include the nucleus of the solitary tract and the C1 neurons of the rostral ventrolateral medulla (see Chapter 19).

Peripheral Sympatholytics

Sympatholytics with a peripheral action lower blood pressure by interfering with the synthesis, storage, and release of NE from sympathetic nerve terminals. α-Methylparatyrosine (metyrosine) inhibits the enzyme tyrosine hydroxylase, which is rate-limiting for the synthesis of catecholamines. Guanethidine and guanadrel are charged molecules that serve as substrates for the NE transporter and the vesicular amine transporter and are thus taken up into peripheral noradrenergic nerve terminals and concentrated in synaptic vesicles. These drugs displace NE from synaptic vesicles into the nerve terminal cytoplasm, where it is degraded by monoamine oxidase. Thus the amount of vesicular NE that can be released by depolarization is reduced. When used chronically, these drugs lead to a long-term depletion of NE from synaptic vesicles in peripheral sympathetic nerves.

Reserpine is a plant alkaloid that was the first drug to be used widely for the treatment of mild to moderate hypertension. Reserpine is lipophilic and binds almost irreversibly to the vesicular amine transporter in both peripheral and CNS catecholaminergic and serotonergic nerves. This action prevents accumulation of monoamines into protective synaptic vesicles, and catecholamine and indoleamine neurotransmitters are degraded by intraneuronal monoamine oxidase, resulting in long-term depletion of NE from peripheral sympathetic nerves, accompanied by some reduction in monoaminergic neurotransmitters in the brain.

Calcium Channel Blockers

The primary action of these drugs is to inhibit the inward movement of Ca++ through L-type voltage-dependent Ca++ channels. Based on their electrophysiological and pharmacological properties, the voltage-dependent Ca++ channels can be divided into different types. The best characterized are the L-type (long-lasting, large channels), T-type (transient, tiny channels), and N-type (present in neuronal tissue and distinct from the other two in terms of kinetics or inhibitor sensitivity). Only the L-type Ca++ channels, which are enriched in cardiac and vascular muscle, are affected by Ca++ channel blockers, which accounts for the generally low toxicity of these drugs.

The primary modulator of these channels is membrane potential. Under resting conditions the membrane potential is -30 to -100 mV, depending on cell type, and channels are closed. Free intracellular Ca++ (0.1 µM) is more than 10,000 times lower than extracellular Ca++ (1 to 1.5 mM), a gradient that provides an enormous driving force for Ca++ to enter the cell. This gradient is maintained by a membrane largely impermeable to Ca++ that contains active-transport systems that pump Ca++ out of the cell. When the membrane depolarizes, the channels open, and Ca++ enters the cell. This is followed by relatively slow inactivation of the channels in which they are impermeable to Ca++. They must transition from the inactivated state to the resting conformation before they can open again.

Ca++ channel-blocking drugs bind with high affinity only when the channel is in the inactivated state. Because the channel can transition to the inactivated state only after opening, and channel opening depends on membrane depolarization, drug binding is said to be “use-dependent.” In addition to use dependence, binding of Ca++ channel blockers is also frequency-dependent. In part, because these drugs are lipid soluble, they dissociate relatively rapidly from their binding sites on the channel. If the time between sequential membrane depolarizations is relatively long, most drugs will dissociate from the channel between depolarizations, resulting in little inhibition of Ca++ flux. However, if the frequency is rapid, the channels will cycle more frequently, drug will bind to or remain bound to the channel, and blockade of the channel will persist. Therefore inhibition of Ca++ channels will be directly proportional to depolarization rate, that is, it will be frequency-dependent. Verapamil exhibits much more frequency dependence than nifedipine. The frequency dependence of diltiazem is intermediate.

Voltage-dependent Ca++ channels play important roles in the excitation-contraction-relaxation cycle (see Chapter 22 and Chapter 24). Under resting conditions, when intracellular Ca++ is low, regulatory proteins prevent actin and myosin filaments from interacting with each other, and muscle is relaxed. When intracellular Ca++ concentrations increase by influx or release from internal stores, Ca++ occupies binding sites on Ca++-binding regulatory proteins, such as troponin C (in cardiac and skeletal muscle) and calmodulin (in vascular smooth muscle). These proteins then interact with other proteins and enzymes (e.g., troponin I in cardiac and skeletal muscle and myosin light-chain kinase in smooth muscle), facilitating cross-bridge formation between actin and myosin, which underlies contraction. When Ca++ channels inactivate, Ca++ is pumped out of the cell, activation of contractile proteins is reversed, actin dissociates from myosin, and the muscle relaxes.

Direct Vasodilators

The direct-acting vasodilators are among the most powerful drugs used to lower blood pressure and include hydralazine, minoxidil, diazoxide, nitroprusside, and fenoldopam. As indicated in Chapter 24, several purported mechanisms have been proposed to mediate the ability of hydralazine to dilate arterioles, whereas minoxidil and pinacidil bind to ATP-sensitive K+ channels, causing them to open. This allows K+ to partially equilibrate along its concentration gradient, which shifts the membrane potential toward the K+ hyperpolarizing reversal potential. The net effect is to reduce the probability of arterial smooth muscle depolarization and resultant contraction. Diazoxide produces arteriolar vasodilation and decreases peripheral vascular resistance through an action that may also involve K+ channels. Nitroprusside rapidly decomposes to release nitric oxide that activates guanylyl cyclase, which increases intracellular cGMP concentrations, particularly in veins (see Chapter 24). Fenoldopam is an agonist at D1 dopamine receptors with an action on renal arterioles, and trimethaphan has its vasodilatory effect by blocking autonomic ganglia.

The direct-acting vasodilators may produce marked compensatory reactions (see Fig. 20-1), including fluid retention and reflex-mediated increases in renin release, heart rate, and contractility. Because of their pronounced antihypertensive action and potential for producing these and other side effects (see Chapter 24), the direct-acting vasodilators are usually reserved for the treatment of hypertension that is severe or refractory to other drugs.

Pharmacokinetics

Pharmacokinetic parameters for ACE inhibitors, ARBs, and Ca++ channel blockers are summarized in Table 20-1. Pharmacokinetic parameters for the β receptor blocking drugs and sympatholytics are discussed in Chapter 11, for diuretics in Chapter 21, and for direct-acting vasodilators in Chapter 24.

TABLE 20–1 Selected Pharmacokinetic Parameters

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The renin inhibitor aliskiren is an orally active nonpeptide with poor absorption (approximately 2.5% bioavailability). Peak plasma levels are reached within 1 to 3 hours, and approximately 25% of the absorbed dose is excreted unchanged in the urine. The remainder is excreted unchanged in the feces with minimal metabolism.

ACE inhibitors are given orally and have a rapid onset of action (minutes for captopril and hours for the prodrug enalapril). These drugs are subject to both metabolism and renal excretion, and several in this class require biotransformation to an active compound for activity.

The ARBs are typically greater than 90% bound to plasma proteins. Although there are some differences in plasma t1/2 and selectivity for the AT1 receptor, these drugs have similar effectiveness as antihypertensive agents.

The Ca++ channel blocker verapamil is well absorbed from the gastrointestinal tract, although bioavailability is low because of extensive first-pass metabolism by the liver. Norverapamil, an active metabolite, has a potency approximately 20% to 30% of that of verapamil. Metabolites are excreted in the urine, with an elimination t1/2 of approximately 5 hours, which is much longer in patients with hepatic disease.

Absorption of nifedipine is essentially complete. Because of first-pass metabolism by the liver, only 60% to 70% of administered drug reaches the systemic circulation. Nifedipine is metabolized in the liver to inactive metabolites, which are excreted in urine. The elimination t1/2 is approximately 2 hours but is longer in patients with compromised hepatic function.

Diltiazem is well absorbed and also subject to first-pass hepatic metabolism, with low bioavailability. Desacetyl diltiazem is an active metabolite with an activity approximately 25% to 50% of the parent compound. The elimination t1/2 of diltiazem is 3.5 hours and longer in patients with liver disease.

Of the direct-acting vasodilator drugs used for the emergency reduction of hypertension, both nitroprusside and fenoldopam are administered by continuous intravenous infusion. Nitroprusside achieves full effects in seconds, and recovery takes place within a few minutes of terminating the infusion. Fenoldopam produces steady-state plasma levels proportionate to its rate of infusion, with an elimination t1/2 of approximately 5 minutes. Diazoxide is usually given in repeated low-dose intravenous injections, with the desired reduction in blood pressure occurring 1 to 5 minutes after dosing. The duration of effect varies from hours to a day. Trimethaphan must be administered by continuous intravenous infusion; a full response occurs in seconds and is greater when the patient is upright. It takes 10 to 60 minutes for blood pressure to recover after trimethaphan infusion.

Relationship of Mechanisms of Action to Clinical Response

The seven classes of antihypertensives produce different physiological responses (Table 20-2) and have proven to be of clinical benefit, either alone or in combination, for several indications (Table 20-3). The choice of therapy for a patient with essential hypertension depends on the initial blood pressure of the individual, as well as age, race, family history of cardiovascular disease, and other risk factors such as smoking, obesity, and sedentary lifestyle. Most important is the presence of other conditions, such as kidney disease, ischemic heart disease, heart failure, previous myocardial infarction or stroke, or diabetes. Each of these must be given due consideration to determine an appropriate treatment plan.

TABLE 20–2 Physiological Responses to Antihypertensive Drugs

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TABLE 20–3 Compelling Indications for Use of Individual Drug Classes Rights were not granted to include this table in electronic media. Please refer to the printed book.

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Indications for which specific classes of antihypertensive drugs have proven clinical benefit. These drugs may be used alone or in combination with a thiazide diuretic. BB, β receptor blocker; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CCB, Ca++ channel blocker; Aldo ANT, aldosterone antagonist (see Chapter 23).

Modified from Chobanian AV, Bakris GL, Black HR, et al. Hypertension 2003; 42:1206-1252.

In general, more than 50% of patients require more than one drug to control their hypertension (Fig. 20-2). If two or more drugs are used, each should target a different physiological mechanism (Fig. 20-3). For example, it would be more beneficial to combine a diuretic with a vasodilator than to use two drugs that both reduce smooth muscle contraction. In most instances a diuretic should be included in any regimen using two or more antihypertensive drugs.

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FIGURE 20–2 Treatment of hypertension. Treatment goal is to reduce systolic blood pressure to less than 140 mm Hg and diastolic blood pressure to less than 90 mm Hg. In patients with diabetes or renal disease, the goal is to decrease blood pressure to less than 130/80 mm Hg. ACEI, Angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BB, β receptor blocker; CCB, Ca++ channel blocker.

Adapted from Chobanian AV, Bakris GL, Black HR, et al. Hypertension 2003; 42:1206-1252.

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FIGURE 20–3 Summary of sites and mechanisms by which antihypertensive drugs reduce blood pressure. CO, Cardiac output; TPR, total peripheral resistance.

Diuretics

A large-scale clinical trial (ALLHAT) comparing a thiazide diuretic with a Ca++ channel blocker and an ACE inhibitor found that these latter two drugs were no more effective than the diuretic in lowering blood pressure and reducing adverse cardiovascular events. The diuretics are well tolerated and less costly than many other drugs, and are particularly effective for treating hypertension in African-Americans. These findings are consistent with many previous clinical trials demonstrating the effectiveness of thiazide diuretics in reducing hypertension and associated cardiovascular sequelae. Based upon these results, thiazide diuretics are recommended as initial therapy for treatment of uncomplicated hypertension.

Initial administration of a diuretic produces a pronounced increase in urinary H2O and electrolyte excretion and a reduction in extracellular and plasma fluid volume. Reduced plasma volume decreases CO, which lowers arterial pressure. After several days, urinary excretion returns to normal, but blood pressure remains reduced. Plasma volume and CO return to, or nearly to, pretreatment values, and TPR declines. The net result of these changes is a long-term lowering of arterial blood pressure.

Although the renal targets of the diuretics are well known (see Chapter 21), the precise mechanism(s) responsible for their antihypertensive action are not as well understood. The decline in TPR may initially involve autoregulatory vascular adjustments in response to decreased perfusion, but this would not be expected to remain operative after CO is normalized. Other possible mechanisms include a decreased vascular reactivity to NE and other endogenous pressor substances, and a decreased “structural” vascular resistance caused by the removal of Na+ and H2O from the blood vessel wall. These changes could result directly from the actions of diuretic drugs or indirectly from the generalized loss of Na+ and H2O. The latter seems probable, because diuretics fail to lower blood pressure in patients who do not exhibit salt and H2O loss (i.e., nephrectomized patients on hemodialysis). However, the antihypertensive actions of diuretics do not parallel their efficacy in causing fluid loss, except in patients with renal insufficiency.

Finally, some diuretics relax vascular smooth muscle directly but usually only at doses well above the effective diuretic range. An exception is indapamide, which is a vasodilator at normal therapeutic doses, an action likely responsible for a major portion of its antihypertensive effect.

Renin-Angiotensin Inhibitors

The renin inhibitor aliskiren produces a modest decrease in blood pressure in patients with mild to moderate hypertension when used as monotherapy. It has additive effects with both the thiazide diuretics and the ARBs for combination therapy. However, studies to date have not supported improved clinical outcomes as have been observed with both ACE inhibitors and the ARBs.

ACE inhibitors are particularly effective antihypertensive drugs in patients with elevated plasma renin activity and presumably increased circulating levels of angiotensin II. However, ACE inhibitors also lower blood pressure in hypertensive individuals with normal or even low plasma renin activity. This may be due to ACE inhibition, reduced angiotensin II formation, or activation of AT1 receptors at local tissue sites.

In vascular smooth muscle, there is some evidence that inhibition of vascular ACE activity correlates temporally with the hypotensive response to ACE inhibitors. In the kidney, angiotensin II can be produced locally by intrarenal renin and may exert an antinatriuretic and antidiuretic effect. Inhibition of intrarenal angiotensin II formation by ACE inhibitors could lower blood pressure by promoting salt and H2O excretion in a manner similar to that of diuretics. A third potential site is angiotensin II formed in brain. In experimental animals CNS administration of angiotensin II increases sympathetic nervous system activity and blood pressure. ACE inhibitors could decrease blood pressure in hypertensive individuals by reducing sympathetic nervous system activity in a manner similar to that of the centrally acting sympatholytics. ACE inhibitors are particularly useful for treating hypertension associated with other risk factors such as heart failure, postmyocardial infarction, diabetes, kidney disease, and stroke (see Table 20-3).

ARBs inhibit angiotensin II binding to AT1 receptors and reduce its physiological effects. The antihypertensive action of angiotensin receptor blockers is therefore similar to that of the ACE inhibitors, although they may produce fewer side effects.

Drugs Affecting the Sympathetic Nervous System

Many mechanisms have been proposed to account for the antihypertensive action of the β receptor blockers, but none by itself can account for the blood pressure-lowering action of these drugs. Acute and chronic decreases in CO are observed in most studies assessing β receptor antagonists in hypertensive patients. A long-term decrease in CO, which may be accompanied by a transient increase in TPR, appears to be responsible for lowering arterial pressure acutely. In some studies, however, CO was reported to return to normal over a period of days to weeks, whereas TPR declined over the same time period. The decrease in TPR may result from a long-term autoregulatory response to decreased tissue blood flow or to other effects of the drugs. Although an initial decrease in CO is characteristic of most β receptor blockers, this is not always the case. The β receptor antagonists with partial agonist activity modestly stimulate β receptors (intrinsic sympathomimetic activity), do not appreciably reduce CO, and lower blood pressure primarily by reducing TPR. This may be due, in part, to partial activation of vascular vasodilatory β2 receptors or blockade of presynaptic β receptors that reduce NE release.

In addition to these hemodynamic mechanisms, inhibition of sympathetically evoked renin release contributes significantly to the antihypertensive efficacy of the β receptor blockers in patients with elevated plasma renin activity. However, pretreatment plasma renin activity is not a good predictor of the clinical response to β receptor blockade. There is also evidence in humans that β receptor antagonists have a CNS-mediated sympathoinhibitory effect, and studies in animals have shown that administration of β receptor blockers into the CNS lowers blood pressure at doses that are ineffective when given peripherally. However, some β receptor blockers, such as sotalol, do not readily penetrate into the brain after oral administration but still retain antihypertensive efficacy.

In addition to their use as primary antihypertensive drugs, β receptor antagonists are often used in combination with other antihypertensive agents, particularly direct vasodilators and α1 adrenergic receptor antagonists. As blood pressure is reduced, the baroreceptor reflexes become activated and increase sympathetic nerve discharge. Catecholamines can then activate β adrenergic receptors in the heart and kidney to increase cardiac function (tachycardia and contractility) and renin release, respectively. Because these sympathetic effects can offset the blood pressure-lowering action of some drugs and increase cardiac work, which increases the potential to produce angina, β receptor blockers are valuable adjuncts to ameliorate these effects.

Peripherally acting α1 receptor antagonists such as prazosin lower blood pressure primarily by reducing TPR. Because of the propensity toward fluid retention, diuretics are often given in conjunction with the α1 receptor blockers when used for treatment of hypertension.

The centrally acting sympatholytics reduce sympathetic nerve discharge. They lower blood pressure mainly by reducing TPR with an additional contribution from reduced CO. Baroreceptor reflexes are relatively well maintained. Sympatholytic drugs with actions primarily on peripheral sympathetic nerve terminals reduce TPR and CO consistent with their effects on sympathetic nerves. They produce more marked fluid retention and impairment of baroreceptor reflexes than do the centrally acting drugs.

Calcium Channel Blockers

All excitable tissues contain voltage-dependent Ca++ channels and high-affinity, reversible, and stereospecific binding sites for Ca++ channel blockers. However, Ca++ channel blockers do not affect every tissue equally. Some tissues (atrioventricular [AV] node) rely primarily on exogenous Ca++ and are more sensitive to these drugs than other tissues (skeletal muscle) that require little or no external Ca++ for function. Moreover, because the resting membrane potential differs in various tissues, the effects of these drugs may also vary. The resting potential of vascular smooth muscle is less hyperpolarized (-30 to -40 mV) than heart muscle (-70 to -90 mV). This may contribute to the vascular selectivity of many Ca++ channel-blocking drugs.

Verapamil was the first selective Ca++ channel inhibitor available for treatment of cardiovascular disorders, including hypertension. Like the dihydropyridines, it relaxes both coronary and peripheral arterioles. However, it has significantly more potent negative inotropic effects than the dihydropyridines or diltiazem. Verapamil can also depress AV nodal rate and conduction, and for this reason it can be used for the treatment of supraventricular tachycardia (see Chapter 22). It is also effective for the treatment of angina pectoris and hypertension. The reflex increase in adrenergic tone caused by a sudden decrease in blood pressure mitigates but does not overcome its strong direct negative inotropic and chronotropic effects. Because of its cardiodepressant effects, verapamil is generally contraindicated for the treatment of increased peripheral resistance associated with heart failure.

Like all Ca++ channel blockers, diltiazem increases coronary blood flow and decreases blood pressure. Similar to verapamil, it inhibits AV nodal conduction, although to a lesser degree than verapamil. Diltiazem is effective in reducing hypertension and has fewer negative inotropic and chronotropic effects than do β receptor blockers.

Dihydropyridines such as nifedipine are relatively selective arteriolar dilators. These drugs reduce peripheral resistance, arterial pressure, and afterload on the heart. These effects are larger in hypertensive than in normotensive individuals. However, if the drug has a relatively sudden onset of action, the decrease in blood pressure can produce reflex sympathoexcitation, tachycardia, and augmented cardiac contractility. These effects may be counteracted by the cardiodepressant action of some Ca++ channel blockers such as verapamil, but usually not by dihydropyridines, at doses typically used for treatment of hypertension. Nevertheless, because of the potential to exacerbate cardiac disease, slow-release, sustained-action formulations of dihydropyridine-type drugs are preferred for chronic therapeutic applications, such as the treatment of hypertension.

In contrast to verapamil and diltiazem, the dihydropyridines have no significant effect on AV nodal conduction in vivo. The efficacy of the dihydropyridines for the treatment of mild to moderate hypertension is similar to that of the β receptor blockers and diuretics. Although dihydropyridines are effective antihypertensive drugs when used alone, their use in combination with low doses of β receptor blockers can be particularly effective in some hypertensive patients, because reflex increases in heart rate and plasma renin activity can be attenuated by the β receptor blocker. However, β receptor antagonists should not be used in combination with Ca++ channel blockers such as verapamil, or high doses of dihydropyridines, in patients with limited cardiac reserve because of the potential to produce deleterious cardiac depression.

Nicardipine, isradipine, and felodipine are dihydropyridine Ca++ channel blockers similar to nifedipine. At lower doses they increase coronary blood flow in patients with coronary artery disease without causing myocardial depression. They also decrease systemic vascular resistance and have a potent antihypertensive effect. At higher doses they can produce negative inotropy and exacerbate heart failure in patients with left ventricular dysfunction. They have little or no effect on cardiac conduction and have been approved for treatment of hypertension alone or in combination with thiazide diuretics or β receptor blockers.

Felodipine, unlike some other Ca++ channel blockers, has minimal effect on cardiac function. It has a relatively long duration of action and in an extended-release formulation is appropriate for treatment of hypertension with a once-daily dose. A reflex increase in heart rate frequently occurs during the first week of therapy with many Ca++ channel blockers, but this effect subsides over time and can be inhibited by β receptor antagonists. Amlodipine has a long plasma t1/2 and is an effective antihypertensive drug with once-daily dosing.

Direct Vasodilators

The orally active direct vasodilators, hydralazine and minoxidil, lower blood pressure by directly and preferentially relaxing arterial smooth muscle. Their selectivity for arterioles is greater than that of the Ca++ channel blockers (see Chapter 24).

Under some clinical circumstances, blood pressure must be reduced rapidly for a relatively short period of time (Box 20-1). Although several of the antihypertensive agents discussed can be administered parenterally for this purpose, the direct-acting vasodilators nitroprusside and diazoxide and the short-acting ganglionic blocker trimethaphan are used exclusively to rapidly reduce blood pressure. Diazoxide is used only for short-term treatment of severe hypertension because of its hyperglycemic properties.

BOX 20–1 Conditions Requiring Rapid Blood Pressure Reduction

Malignant hypertension

Pheochromocytoma

Hypertensive encephalopathy

Refractory hypertension of pregnancy

Acute left ventricular failure

Aortic dissection

Coronary insufficiency

Intracranial hemorrhage

Pharmacovigilance: Side Effects, Clinical Problems, and Toxicity

Adverse reactions and side effects associated with the use of the antihypertensive agents are summarized in the Clinical Problems Box.

Diuretics

Lower doses of diuretics are used to treat hypertension than to treat edema. Larger doses do not produce greater blood pressure reduction, but they significantly increase the incidence and severity of side effects, particularly decreased plasma K+ and increased uric acid concentrations. There is some concern that diuretic-induced hypokalemia may increase the incidence of sudden cardiac death. Diuretics may also impair glucose tolerance and increase serum lipid concentrations. Monitoring serum K+, using relatively low doses of thiazide diuretics and including a K+-sparing diuretic or adding K+ supplements in the drug regimen, should all be considered when thiazide or loop diuretics are used. In addition, K+ depletion can be reduced when ACE inhibitors or ARBs are used in combination with diuretics. Additional details on the side effects of diuretics are presented in Chapter 21.

Renin-Angiotensin Inhibitors

African-American patients often have normal or subnormal plasma renin activity and thus respond less predictably or require higher doses of ACE inhibitors than do caucasians. However, combining ACE inhibitors and diuretics lowers blood pressure in most patients and also reduces the incidence of diuretic-induced hypokalemia. ACE inhibitors have a low incidence of side effects and are generally well tolerated. The most common side effect is a persistent dry cough, which occurs in 10% to 30% of patients. A much less common side effect is angioedema, or swelling of some mucous membranes, which can be life-threatening if it occurs in the airways. The mechanism by which the ACE inhibitors precipitate cough and angioedema is attributed to the accumulation of the irritant and pro-inflammatory peptides bradykinin and substance P, which are normally degraded by ACE, also known as kininase II. The incidence of these side effects is much lower with the renin inhibitor aliskiren and with the ARBs, because these agents do not increases levels of these peptides.

Both ACE inhibitors and ARBs can produce hyperkalemia, particularly in patients with impaired renal function, or if used with K+-sparing diuretics or nonsteroidal anti-inflammatory drugs; hyperkalemia is uncommon with aliskiren. Glomerular filtration in some patients with renal artery stenosis may be dependent on the angiotensin-mediated constriction of the efferent glomerular arterioles. Inhibition of angiotensin function in these patients may precipitate renal failure.

In addition, angiotensin may play a role in tissue growth and differentiation during development. There is evidence of an increased risk of congenital malformations when ACE inhibitors are used during the first trimester of pregnancy. Thus drugs that interfere with the actions of either renin or angiotensin are contraindicated for use during pregnancy or in women who are breast-feeding.

Drugs Affecting the Sympathetic Nervous System

Side effects of β receptor blocker therapy are discussed in Chapter 11. It is preferable to use selective β1 receptor antagonists in patients with asthma or diabetes, but any β receptor antagonist should be used with some caution. Because β1 receptor blockade impairs sympathetic stimulation of the heart, β receptor blockers can impair exercise tolerance. Abrupt cessation of β receptor antagonists has been associated with tachycardia, angina pectoris, and (rarely) myocardial infarction.

Centrally acting sympatholytics are notable for causing less orthostatic hypotension than many other antihypertensives. They also do not impair renal function and thus are suitable for patients with renal insufficiency. The preferred drug for treatment of hypertension during pregnancy is α-methyldopa (see Chapter 11). A special problem associated with clonidine and other centrally acting α2 receptor agonists is a dramatic sympathetic hypertensive response that occurs in some patients after abrupt withdrawal of therapy. For this reason termination of these drugs should be done gradually, and clonidine-like drugs should be used cautiously, or not at all, in potentially noncompliant patients.

Drugs that deplete peripheral sympathetic nerve terminals of NE are not used as commonly as other classes due primarily to side effects related to widespread sympathetic impairment including orthostatic hypotension, sexual dysfunction, and gastrointestinal disturbance. Reserpine, although once widely used, may precipitate clinical depression in susceptible patients because of its CNS actions. However, some of these drugs may be useful for the therapy of catecholamine-secreting tumors or excessive sympathoexcitation.

Of the peripherally acting drugs, doxazosin, prazosin, or other α1 receptor antagonists have been used to treat mild to moderate hypertension, usually in conjunction with a diuretic. However, compared with thiazide diuretics, antihypertensive therapy with α1 receptor blockers increases the risk of adverse cardiovascular events in individuals older than 55 years of age (ALLHAT) and is not the preferred therapy for use in this patient population.

Calcium Channel Blockers

Most side effects of Ca++ channel blockers result from excessive vasodilation and cardiodepression or excessive reflex sympathoexcitation. Short-acting formulations of Ca++ channel blockers may increase mortality risk in patients with heart disease. Extended-release formulations, or drugs with long half-lives, are preferred for treatment of hypertension in all patients. Generally, side effects such as dizziness, headache, and flushing diminish or disappear with time or when the drug dose is decreased. Although true withdrawal symptoms are not observed with these drugs, sudden withdrawal of large doses of Ca++channel blockers can produce peripheral and coronary vasoconstriction and precipitate angina.

Direct Vasodilators

Because of the marked lowering of blood pressure produced by these drugs, fluid retention and reflex tachycardia are common. These compensatory reactions may be so pronounced that they mask part of the antihypertensive action of the direct vasodilators. For this reason a diuretic and a β receptor blocker are usually given with a vasodilator to offset these compensatory responses. Other side effects of the vasodilator drugs are discussed in Chapter 24.

The side effects of drugs used for hypertensive emergencies can be significant. The usual side effects of diazoxide are fluid retention, tachycardia, and hyperglycemia. Nitroprusside reacts with blood and tissue to release cyanide ions, which are converted to thiocyanate by the liver. Other side effects of nitroprusside are discussed in Chapter 24. Side effects of trimethaphan are those expected of ganglionic blockade and include mydriasis, cycloplegia, constipation, and urinary retention (see Chapter 10). Tachyphylaxis occurs a day or two after the hypotensive action of trimethaphan develops.

OTHER CONSIDERATIONS

Although the goal of antihypertensive therapy is to reduce end-organ damage associated with chronically elevated blood pressure, the effects of therapy on other cardiovascular risk factors must also be considered. End-organ damage is not related exclusively to blood pressure. If an antihypertensive drug effectively lowers blood pressure but increases the influence of other risk factors for cardiovascular disease, the benefit of therapy may be reduced. In some studies thiazide diuretics did not decrease the incidence of coronary artery disease, despite their ability to significantly reduce blood pressure. This may be related to the modest elevation of low-density lipoprotein and total triglycerides produced by K+-losing diuretics, although the causative link or potential clinical significance of this finding has not been established. Other risk factors that can be affected by antihypertensive drugs include alterations in plasma glucose, K+, and uric acid concentrations. In particular, insulin resistance is now recognized to be prevalent in patients with hypertension. Elevated insulin is a risk factor for coronary artery disease. Thus it is noteworthy that thiazide diuretics and β receptor blockers increase, ACE inhibitors and prazosin decrease, and Ca++ channel blockers have no effect on insulin resistance. Because of wide interpatient variability in risk factors and disease, therapeutic generalizations are difficult, and antihypertensive drug therapy must be tailored to each patient.

CLINICAL PROBLEMS

Thiazide Diuretics

K+ and Mg++ loss

Increase in cholesterol concentrations

Dysrhythmias

Renin-angiotensin Inhibitors

Hyperkalemia (ACE inhibitors and ARBs)

Dry cough (primarily ACE inhibitors)

Angioedema (primarily ACE inhibitors)

Teratogenesis

β Receptor Blockers

Use with caution in patients with bronchial asthma

Abrupt withdrawal may precipitate cardiac problems

α-Methyldopa

Positive direct Coombs’ test result (usually but not always false)

Accumulates in patients with impaired renal function

Clonidine

Sudden withdrawal of drug produces rebound hypertension

CNS side effects

Ca++ Channel Blockers

Cardiodepression

Hypotension

Headache

Peripheral edema

Direct Vasodilators

Headache

Palpitations

Tachycardia

Fluid retention

Hydralazine

Lupus-like syndrome

TRADE NAMES

(In addition to generic and fixed-combination preparations, the following trade-named materials are some of the important compounds available in the United States.*)

Renin Inhibitor

Aliskiren (Tekturna)

Angiotensin-converting Enzyme Inhibitors

Benazepril (Lotensin)

Captopril (Capoten)

Enalapril (Vasotec)

Fosinopril (Monopril)

Lisinopril (Prinivil, Zestril)

Moexipril (Univasc)

Perindopril (Aceon)

Quinapril (Accupril)

Ramipril (Altace)

Trandolapril (Mavik)

Ca++ channel Blockers

Amlodipine (Norvasc)

Diltiazem (Cardizem)

Felodipine (Plendil)

Isradipine (DynaCirc)

Nicardipine (Cardene)

Nisoldipine (Sular)

Nifedipine (Procardia, Adalat)

Verapamil (Calan, Isoptin)

Dopamine D1 Agonist Vasodilator

Fenoldopam (Corlopam)

Combination Products

Diuretic combinations

Amiloride and hydrochlorothiazide (Moduretic)

Spironolactone and hydrochlorothiazide (Aldactazide)

Triamterene and hydrochlorothiazide (Dyazide, Maxzide)

β receptor blockers and diuretics

Atenolol and chlorthalidone (Tenoretic)

Bisoprolol and hydrochlorothiazide (Ziac)

Metoprolol and hydrochlorothiazide (Lopressor HCT)

Nadolol and bendroflumethazide (Corzide)

Propranolol and hydrochlorothiazide (Inderide)

Timolol and hydrochlorothiazide (Timolide)

Angiotensin-converting enzyme inhibitors and diuretics

Benazepril and hydrochlorothiazide (Lotensin)

Captopril and hydrochlorothiazide (Capozide)

Enalapril and hydrochlorothiazide (Vaseretic)

Lisinopril and hydrochlorothiazide (Prinzide, Zestoretic)

Moexipril and hydrochlorothiazide (Uniretic)

Angiotensin receptor blockers and diuretics

Losartan and hydrochlorothiazide (Hyzaar)

Valsartan and hydrochlorothiazide (Diovan)

Ca++ channel blockers and angiotensin-converting enzyme inhibitors

Amlodipine and benazepril (Lotrel)

Diltiazem and enalapril (Teczem)

Felodipine and enalapril (Lexxel)

Verapamil and trandolapril (Tarka)

Ca++ channel blockers and angiotensin receptor blockers

Amlodipine and valsartan (Exforge)

Amlodipine and olmesartan (Azor)

* With the exception of the combination products listed, the trade-named materials available for diuretics are presented in Chapter 21, β receptor blockers and sympatholytics in Chapter 11, angiotensin receptor blockers and aldosterone antagonists in Chapter 23, and vasodilators in Chapter 24

New Horizons

Several new approaches to the pharmacological therapy of hypertension may be available in the United States in the near future. As indicated, aliskiren, the first direct renin inhibitor, was introduced in 2007, and additional agents aimed at blocking the synthesis of angiotensin I are in development. Drugs that increase the open time of K+ channels in vascular smooth muscle are also being developed, as are agents that decrease the metabolism of endogenous vasodilator substances, such as atrial natriuretic peptide. Newer therapies may focus on enhancing or interfering with the actions of the mediators released from endothelial cells such as nitric oxide, eicosanoids, and endothelin; these exert tonic control over vascular smooth muscle contraction. Indeed, ambrisentan, a selective antagonist at the endothelin type A receptor, has recently been approved for the treatment of pulmonary arterial hypertension. Finally, discovery of drugs such as rilmenidine and moxonidine, which decrease sympathetic nervous system activity, presumably by activating imidazoline receptors in the brainstem, may have fewer side effects than currently available centrally acting sympatholytics.

FURTHER READING

ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic. The antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT).JAMA. 2002;288:2981-2997.

Anonymous. Drugs for hypertension. Treat Guidel Med Lett. 2005;3:39-48.

Chobanian et al. 2003 Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Hypertension. 2003;42:1206-1252.

Kaplan NM. Kaplan’s clinical hypertension, 8. New York: Lippincott Williams & Wilkins, 2002.

SELF-ASSESSMENT QUESTIONS

1. Which type of antihypertensive drug, when given alone, often produces marked reflex tachycardia and renin release?

A. β-Adrenergic receptor blockers

B. Direct-acting vasodilators

C. Drugs that deplete sympathetic nerve terminals of NE

D. Centrally acting sympatholytics

2. Sedation is a side effect of which of the following drugs used for the treatment of hypertension?

A. Nifedipine

B. Clonidine

C. Hydralazine

D. Losartan

E. Prazosin

3. Compared with thiazide diuretics, which antihypertensive increases the risk of adverse cardiovascular events in individuals older than 55 years of age?

A. Prazosin

B. Labetalol

C. Lisinopril

D. Losartan

E. Amlodipine

4. Which class of agents is recommended by the JNC-7 for the initial pharmacotherapy of uncomplicated hypertension?

A. α1 Adrenergic receptor blocking agents

B. Angiotensin converting enzyme inhibitors

C. Angiotensin receptor blockers

D. Loop diuretics

E. Thiazides

5. Although a patient’s blood pressure is being treated very successfully with enalapril, he has developed a dry, hacking cough. Which of the following is recommend as the best alternative drug for this person?

A. Hydrochlorothiazide

B. Losartan

C. Diltiazem

D. Prazosin

E. Propranolol