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).

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:

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

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.

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 t_1/2 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.

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.