All antihypertensive agents act at one or more of the four anatomic control sites depicted in Figure 11–1 and produce their effects by interfering with normal mechanisms of blood pressure regulation. A useful classification of these agents categorizes them according to the principal regulatory site or mechanism on which they act (Figure 11–3). Because of their common mechanisms of action, drugs within each category tend to produce a similar spectrum of toxicities. The categories include the following:
Sites of action of the major classes of antihypertensive drugs.
Diuretics, which lower blood pressure by depleting the body of sodium and reducing blood volume and perhaps by other mechanisms.
Sympathoplegic agents, which lower blood pressure by reducing peripheral vascular resistance, inhibiting cardiac function, and increasing venous pooling in capacitance vessels. (The latter two effects reduce cardiac output.) These agents are further subdivided according to their putative sites of action in the sympathetic reflex arc (see below).
Direct vasodilators, which reduce pressure by relaxing vascular smooth muscle, thus dilating resistance vessels and—to varying degrees—increasing capacitance as well.
Agents that block production or action of angiotensin and thereby reduce peripheral vascular resistance and (potentially) blood volume.
The fact that these drug groups act by different mechanisms permits the combination of drugs from two or more groups with increased efficacy and, in some cases, decreased toxicity. (See Box: Resistant Hypertension & Polypharmacy.)
Resistant Hypertension & Polypharmacy
Monotherapy of hypertension (treatment with a single drug) is desirable because compliance is likely to be better and the cost is lower, and because in some cases adverse effects are fewer. However, most patients with hypertension require two or more drugs acting by different mechanisms (polypharmacy). According to some estimates, up to 40% of patients may respond inadequately even to two agents and are considered to have “resistant hypertension.” Some of these patients have treatable secondary hypertension that has been missed, but most do not, and three or more drugs are required.
One rationale for polypharmacy in hypertension is that most drugs evoke compensatory regulatory mechanisms for maintaining blood pressure (see Figures 6–7 and 11–1), which may markedly limit their effect. For example, vasodilators such as hydralazine cause a significant decrease in peripheral vascular resistance, but evoke a strong compensatory tachycardia and salt and water retention (Figure 11–4) that are capable of almost completely reversing their effect. The addition of a β blocker prevents the tachycardia; addition of a diuretic (eg, hydrochlorothiazide) prevents the salt and water retention. In effect, all three drugs increase the sensitivity of the cardiovascular system to each other’s actions.
A second reason is that some drugs have only modest maximum efficacy but reduction of long-term morbidity mandates their use. Many studies of angiotensin-converting enzyme (ACE) inhibitors report a maximal lowering of blood pressure of less than 10 mm Hg. In patients with more severe hypertension (pressure > 160/100 mm Hg), this is inadequate to prevent all the sequelae of hypertension, but ACE inhibitors have important long-term benefits in preventing or reducing renal disease in diabetic persons and in reduction of heart failure. Finally, the toxicity of some effective drugs prevents their use at maximally effective doses.
In practice, when hypertension does not respond adequately to a regimen of one drug, a second drug from a different class with a different mechanism of action and different pattern of toxicity is added. If the response is still inadequate and compliance is known to be good, a third drug should be added. If three drugs (usually including a diuretic) are inadequate, other causes of resistant hypertension such as excessive dietary sodium intake, use of nonsteroidal anti-inflammatory or stimulant drugs, or the presence of secondary hypertension should be considered. In some instances, an additional drug may be necessary, and mineralocorticoid antagonists, such as spironolactone, have been found to be particularly useful. Occasionally patients are resistant to four or more drugs, and nonpharmacologic approaches have been considered. Two promising treatments that are still under investigation, particularly for patients with advanced kidney disease, are renal denervation and carotid barostimulation.
DRUGS THAT ALTER SODIUM & WATER BALANCE
Dietary sodium restriction has been known for many years to decrease blood pressure in hypertensive patients. With the advent of diuretics, sodium restriction was thought to be less important. However, there is now general agreement that dietary control of blood pressure is a relatively nontoxic therapeutic measure and may even be preventive. Even modest dietary sodium restriction lowers blood pressure (though to varying extents) in many hypertensive persons.
Compensatory responses to vasodilators; basis for combination therapy with β blockers and diuretics.
Effect blocked by diuretics.
Effect blocked by β blockers.
Mechanisms of Action & Hemodynamic Effects of Diuretics
Diuretics lower blood pressure primarily by depleting body sodium stores. Initially, diuretics reduce blood pressure by reducing blood volume and cardiac output; peripheral vascular resistance may increase. After 6–8 weeks, cardiac output returns toward normal while peripheral vascular resistance declines. Sodium is believed to contribute to vascular resistance by increasing vessel stiffness and neural reactivity, possibly related to altered sodium-calcium exchange with a resultant increase in intracellular calcium. These effects are reversed by diuretics or dietary sodium restriction.
Diuretics are effective in lowering blood pressure by 10–15 mm Hg in most patients, and diuretics alone often provide adequate treatment for mild or moderate essential hypertension. In more severe hypertension, diuretics are used in combination with sympathoplegic and vasodilator drugs to control the tendency toward sodium retention caused by these agents. Vascular responsiveness—ie, the ability to either constrict or dilate—is diminished by sympathoplegic and vasodilator drugs, so that the vasculature behaves like an inflexible tube. As a consequence, blood pressure becomes exquisitely sensitive to blood volume. Thus, in severe hypertension, when multiple drugs are used, blood pressure may be well controlled when blood volume is 95% of normal but much too high when blood volume is 105% of normal.
The sites of action within the kidney and the pharmacokinetics of various diuretic drugs are discussed in Chapter 15. Thiazide diuretics are appropriate for most patients with mild or moderate hypertension and normal renal and cardiac function. While all thiazides lower blood pressure, the use of chlorthalidone in preference to others is supported by evidence of improved 24-hour blood pressure control and reduced cardiovascular events in large clinical trials. Chlorthalidone is likely to be more effective than hydrochlorothiazide because it has a longer duration of action. More powerful diuretics (eg, those acting on the loop of Henle) such as furosemide are necessary in severe hypertension, when multiple drugs with sodium-retaining properties are used; in renal insufficiency, when glomerular filtration rate is less than 30–40 mL/min; and in cardiac failure or cirrhosis, in which sodium retention is marked.
Potassium-sparing diuretics are useful both to avoid excessive potassium depletion and to enhance the natriuretic effects of other diuretics. Aldosterone receptor antagonists in particular also have a favorable effect on cardiac function in people with heart failure.
Some pharmacokinetic characteristics and the initial and usual maintenance dosages of diuretics are listed in Table 11–2. Although thiazide diuretics are more natriuretic at higher doses (up to 100–200 mg of hydrochlorothiazide), when used as a single agent, lower doses (25–50 mg) exert as much antihypertensive effect as do higher doses. In contrast to thiazides, the blood pressure response to loop diuretics continues to increase at doses many times greater than the usual therapeutic dose.
TABLE 11–2Pharmacokinetic characteristics and dosage of selected oral antihypertensive drugs. ||Download (.pdf) TABLE 11–2 Pharmacokinetic characteristics and dosage of selected oral antihypertensive drugs.
In the treatment of hypertension, the most common adverse effect of diuretics (except for potassium-sparing diuretics) is potassium depletion. Although mild degrees of hypokalemia are tolerated well by many patients, hypokalemia may be hazardous in persons taking digitalis, those who have chronic arrhythmias, or those with acute myocardial infarction or left ventricular dysfunction. Potassium loss is coupled to reabsorption of sodium, and restriction of dietary sodium intake therefore minimizes potassium loss. Diuretics may also cause magnesium depletion, impair glucose tolerance, and increase serum lipid concentrations. Diuretics increase uric acid concentrations and may precipitate gout. The use of low doses minimizes these adverse metabolic effects without impairing the antihypertensive action. Potassium-sparing diuretics may produce hyperkalemia, particularly in patients with renal insufficiency and those taking ACE inhibitors or angiotensin receptor blockers; spironolactone (a steroid) is associated with gynecomastia.
DRUGS THAT ALTER SYMPATHETIC NERVOUS SYSTEM FUNCTION
In many patients, hypertension is initiated and sustained at least in part by sympathetic neural activation. In patients with moderate to severe hypertension, most effective drug regimens include an agent that inhibits function of the sympathetic nervous system. Drugs in this group are classified according to the site at which they impair the sympathetic reflex arc (Figure 11–2). This neuroanatomic classification explains prominent differences in cardiovascular effects of drugs and allows the clinician to predict interactions of these drugs with one another and with other drugs.
The subclasses of sympathoplegic drugs exhibit different patterns of potential toxicity. Drugs that lower blood pressure by actions on the central nervous system tend to cause sedation and mental depression and may produce disturbances of sleep, including nightmares. Drugs that act by inhibiting transmission through autonomic ganglia (ganglion blockers) produce toxicity from inhibition of parasympathetic regulation, in addition to profound sympathetic blockade and are no longer used. Drugs that act chiefly by reducing release of norepinephrine from sympathetic nerve endings cause effects that are similar to those of surgical sympathectomy, including inhibition of ejaculation, and hypotension that is increased by upright posture and after exercise. Drugs that block postsynaptic adrenoceptors produce a more selective spectrum of effects depending on the class of receptor to which they bind.
Finally, one should note that all of the agents that lower blood pressure by altering sympathetic function can elicit compensatory effects through mechanisms that are not dependent on adrenergic nerves. Thus, the antihypertensive effect of any of these agents used alone may be limited by retention of sodium by the kidney and expansion of blood volume. For this reason, sympathoplegic antihypertensive drugs are most effective when used concomitantly with a diuretic.
CENTRALLY ACTING SYMPATHOPLEGIC DRUGS
Centrally acting sympathoplegic drugs were once widely used in the treatment of hypertension. With the exception of clonidine, these drugs are rarely used today.
Mechanisms & Sites of Action
These agents reduce sympathetic outflow from vasomotor centers in the brain stem but allow these centers to retain or even increase their sensitivity to baroreceptor control. Accordingly, the antihypertensive and toxic actions of these drugs are generally less dependent on posture than are the effects of drugs that act directly on peripheral sympathetic neurons.
Methyldopa (L-α-methyl-3,4-dihydroxyphenylalanine) is an analog of L-dopa and is converted to α-methyldopamine and α-methylnorepinephrine; this pathway directly parallels the synthesis of norepinephrine from dopa illustrated in Figure 6–5. Alpha-methylnorepinephrine is stored in adrenergic nerve vesicles, where it stoichiometrically replaces norepinephrine, and is released by nerve stimulation to interact with postsynaptic adrenoceptors. However, this replacement of norepinephrine by a false transmitter in peripheral neurons is not responsible for methyldopa’s antihypertensive effect, because the α-methylnorepinephrine released is an effective agonist at the α adrenoceptors that mediate peripheral sympathetic constriction of arterioles and venules. In fact, methyldopa’s antihypertensive action appears to be due to stimulation of central α adrenoceptors by α-methylnorepinephrine or α-methyldopamine.
The antihypertensive action of clonidine, a 2-imidazoline derivative, was discovered in the course of testing the drug for use as a nasal decongestant. After intravenous injection, clonidine produces a brief rise in blood pressure followed by more prolonged hypotension. The pressor response is due to direct stimulation of α adrenoceptors in arterioles. The drug is classified as a partial agonist at α receptors because it also inhibits pressor effects of other α agonists.
Considerable evidence indicates that the hypotensive effect of clonidine is exerted at α adrenoceptors in the medulla of the brain. In animals, the hypotensive effect of clonidine is prevented by central administration of α antagonists. Clonidine reduces sympathetic and increases parasympathetic tone, resulting in blood pressure lowering and bradycardia. The reduction in pressure is accompanied by a decrease in circulating catecholamine levels. These observations suggest that clonidine sensitizes brain stem vasomotor centers to inhibition by baroreflexes.
Thus, studies of clonidine and methyldopa suggest that normal regulation of blood pressure involves central adrenergic neurons that modulate baroreceptor reflexes. Clonidine and α-methylnorepinephrine bind more tightly to α2 than to α1 adrenoceptors. As noted in Chapter 6, α2 receptors are located on presynaptic adrenergic neurons as well as some postsynaptic sites. It is possible that clonidine and α-methylnorepinephrine act in the brain to reduce norepinephrine release onto relevant receptor sites. Alternatively, these drugs may act on postsynaptic α2 adrenoceptors to inhibit activity of appropriate neurons. Finally, clonidine also binds to a nonadrenoceptor site, the imidazoline receptor, which may also mediate antihypertensive effects.
Methyldopa and clonidine produce slightly different hemodynamic effects: clonidine lowers heart rate and cardiac output more than does methyldopa. This difference suggests that these two drugs do not have identical sites of action. They may act primarily on different populations of neurons in the vasomotor centers of the brain stem.
Guanabenz and guanfacine are centrally active antihypertensive drugs that share the central α-adrenoceptor-stimulating effects of clonidine. They do not appear to offer any advantages over clonidine and are rarely used.
Methyldopa was widely used in the past but is now used primarily for hypertension during pregnancy. It lowers blood pressure chiefly by reducing peripheral vascular resistance, with a variable reduction in heart rate and cardiac output.
Most cardiovascular reflexes remain intact after administration of methyldopa, and blood pressure reduction is not markedly dependent on posture. Postural (orthostatic) hypotension sometimes occurs, particularly in volume-depleted patients. One potential advantage of methyldopa is that it causes reduction in renal vascular resistance.
Pharmacokinetics & Dosage
Pharmacokinetic characteristics of methyldopa are listed in Table 11–2. Methyldopa enters the brain via an aromatic amino acid transporter. The usual oral dose of methyldopa produces its maximal antihypertensive effect in 4–6 hours, and the effect can persist for up to 24 hours. Because the effect depends on accumulation and storage of a metabolite (α-methylnorepinephrine) in the vesicles of nerve endings, the action persists after the parent drug has disappeared from the circulation.
The most common undesirable effect of methyldopa is sedation, particularly at the onset of treatment. With long-term therapy, patients may complain of persistent mental lassitude and impaired mental concentration. Nightmares, mental depression, vertigo, and extrapyramidal signs may occur but are relatively infrequent. Lactation, associated with increased prolactin secretion, can occur both in men and in women treated with methyldopa. This toxicity is probably mediated by inhibition of dopaminergic mechanisms in the hypothalamus.
Other important adverse effects of methyldopa are development of a positive Coombs test (occurring in 10–20% of patients undergoing therapy for longer than 12 months), which sometimes makes cross-matching blood for transfusion difficult and rarely is associated with hemolytic anemia, as well as hepatitis and drug fever. Discontinuation of the drug usually results in prompt reversal of these abnormalities.
Blood pressure lowering by clonidine results from reduction of cardiac output due to decreased heart rate and relaxation of capacitance vessels, as well as a reduction in peripheral vascular resistance.
Reduction in arterial blood pressure by clonidine is accompanied by decreased renal vascular resistance and maintenance of renal blood flow. As with methyldopa, clonidine reduces blood pressure in the supine position and only rarely causes postural hypotension. Pressor effects of clonidine are not observed after ingestion of therapeutic doses of clonidine, but severe hypertension can complicate a massive overdose.
Pharmacokinetics & Dosage
Typical pharmacokinetic characteristics are listed in Table 11–2. Clonidine is lipid-soluble and rapidly enters the brain from the circulation. Because of its relatively short half-life and the fact that its antihypertensive effect is directly related to blood concentration, oral clonidine must be given twice a day (or as a patch, below) to maintain smooth blood pressure control. However, as is not the case with methyldopa, the dose-response curve of clonidine is such that increasing doses are more effective (but also more toxic).
A transdermal preparation of clonidine that reduces blood pressure for 7 days after a single application is also available. This preparation appears to produce less sedation than clonidine tablets but may be associated with local skin reactions.
Dry mouth and sedation are common. Both effects are centrally mediated and dose-dependent and coincide temporally with the drug’s antihypertensive effect.
Clonidine should not be given to patients who are at risk for mental depression and should be withdrawn if depression occurs during therapy. Concomitant treatment with tricyclic antidepressants may block the antihypertensive effect of clonidine. The interaction is believed to be due to α-adrenoceptor-blocking actions of the tricyclics.
Withdrawal of clonidine after protracted use, particularly with high dosages (more than 1 mg/d), can result in life-threatening hypertensive crisis mediated by increased sympathetic nervous activity. Patients exhibit nervousness, tachycardia, headache, and sweating after omitting one or two doses of the drug. Because of the risk of severe hypertensive crisis when clonidine is suddenly withdrawn, all patients who take clonidine should be warned of this possibility. If the drug must be stopped, it should be done gradually while other antihypertensive agents are being substituted. Treatment of the hypertensive crisis consists of reinstitution of clonidine therapy or administration of α- and β-adrenoceptor-blocking agents.
Historically, drugs that block activation of postganglionic autonomic neurons by acetylcholine were among the first agents used in the treatment of hypertension. Most such drugs are no longer available clinically because of intolerable toxicities related to their primary action (see below).
Ganglion blockers competitively block nicotinic cholinoceptors on postganglionic neurons in both sympathetic and parasympathetic ganglia. In addition, these drugs may directly block the nicotinic acetylcholine channel, in the same fashion as neuromuscular nicotinic blockers.
The adverse effects of ganglion blockers are direct extensions of their pharmacologic effects. These effects include both sympathoplegia (excessive orthostatic hypotension and sexual dysfunction) and parasympathoplegia (constipation, urinary retention, precipitation of glaucoma, blurred vision, dry mouth, etc). These severe toxicities are the major reason for the abandonment of ganglion blockers for the therapy of hypertension.
ADRENERGIC NEURON-BLOCKING AGENTS
These drugs lower blood pressure by preventing normal physiologic release of norepinephrine from postganglionic sympathetic neurons.
Guanethidine is no longer available in the USA but may be used elsewhere. In high enough doses, guanethidine can produce profound sympathoplegia. Guanethidine can thus produce all of the toxicities expected from “pharmacologic sympathectomy,” including marked postural hypotension, diarrhea, and impaired ejaculation. Because of these adverse effects, guanethidine is now rarely used.
Guanethidine is too polar to enter the central nervous system. As a result, this drug has none of the central effects seen with many of the other antihypertensive agents described in this chapter.
Guanadrel is a guanethidine-like drug that is no longer used in the USA. Bethanidine and debrisoquin, antihypertensive agents not available for clinical use in the USA, are similar.
A. Mechanism and Sites of Action
Guanethidine inhibits the release of norepinephrine from sympathetic nerve endings (see Figure 6–4). This effect is probably responsible for most of the sympathoplegia that occurs in patients. Guanethidine is transported across the sympathetic nerve membrane by the same mechanism that transports norepinephrine itself (NET, uptake 1), and uptake is essential for the drug’s action. Once guanethidine has entered the nerve, it is concentrated in transmitter vesicles, where it replaces norepinephrine and causes a gradual depletion of norepinephrine stores in the nerve ending.
Because neuronal uptake is necessary for the hypotensive activity of guanethidine, drugs that block the catecholamine uptake process or displace amines from the nerve terminal (cocaine, amphetamine, tricyclic antidepressants, phenothiazines, and phenoxybenzamine) block its effects.
B. Pharmacokinetics and Dosage
Because of guanethidine’s long half-life (5 days), the onset of sympathoplegia is gradual (maximal effect in 1–2 weeks), and sympathoplegia persists for a comparable period after cessation of therapy. The dose should not ordinarily be increased at intervals shorter than 2 weeks.
Therapeutic use of guanethidine is often associated with symptomatic postural hypotension and hypotension following exercise, particularly when the drug is given in high doses. Guanethidine-induced sympathoplegia in men may be associated with delayed or retrograde ejaculation (into the bladder). Guanethidine commonly causes diarrhea, which results from increased gastrointestinal motility due to parasympathetic predominance in controlling the activity of intestinal smooth muscle.
Interactions with other drugs may complicate guanethidine therapy. Sympathomimetic agents, at doses available in over-the-counter cold preparations, can produce hypertension in patients taking guanethidine. Similarly, guanethidine can produce hypertensive crisis by releasing catecholamines in patients with pheochromocytoma. When tricyclic antidepressants are administered to patients taking guanethidine, the drug’s antihypertensive effect is attenuated, and severe hypertension may follow.
Reserpine, an alkaloid extracted from the roots of an Indian plant, Rauwolfia serpentina, was one of the first effective drugs used on a large scale in the treatment of hypertension. At present, it is rarely used owing to its adverse effects.
A. Mechanism and Sites of Action
Reserpine blocks the ability of aminergic transmitter vesicles to take up and store biogenic amines, probably by interfering with the vesicular membrane-associated transporter (VMAT, see Figure 6–4). This effect occurs throughout the body, resulting in depletion of norepinephrine, dopamine, and serotonin in both central and peripheral neurons. Chromaffin granules of the adrenal medulla are also depleted of catecholamines, although to a lesser extent than are the vesicles of neurons. Reserpine’s effects on adrenergic vesicles appear irreversible; trace amounts of the drug remain bound to vesicular membranes for many days.
Depletion of peripheral amines probably accounts for much of the beneficial antihypertensive effect of reserpine, but a central component cannot be ruled out. Reserpine readily enters the brain, and depletion of cerebral amine stores causes sedation, mental depression, and parkinsonism symptoms.
At lower doses used for treatment of mild hypertension, reserpine lowers blood pressure by a combination of decreased cardiac output and decreased peripheral vascular resistance.
B. Pharmacokinetics and Dosage
At the low doses usually administered, reserpine produces little postural hypotension. Most of the unwanted effects of reserpine result from actions on the brain or gastrointestinal tract.
High doses of reserpine characteristically produce sedation, lassitude, nightmares, and severe mental depression; occasionally, these occur even in patients receiving low doses (0.25 mg/d). Much less frequently, ordinary low doses of reserpine produce extrapyramidal effects resembling Parkinson’s disease, probably as a result of dopamine depletion in the corpus striatum. Although these central effects are uncommon, it should be stressed that they may occur at any time, even after months of uneventful treatment. Patients with a history of mental depression should not receive reserpine, and the drug should be stopped if depression appears.
Reserpine rather often produces mild diarrhea and gastrointestinal cramps and increases gastric acid secretion. The drug should not be given to patients with a history of peptic ulcer.
The detailed pharmacology of α- and β-adrenoceptor blockers is presented in Chapter 10.
Of the large number of β blockers tested, most have been shown to be effective in lowering blood pressure. The pharmacologic properties of several of these agents differ in ways that may confer therapeutic benefits in certain clinical situations.
Propranolol was the first β blocker shown to be effective in hypertension and ischemic heart disease. Propranolol has now been largely replaced by cardioselective β blockers such as metoprolol and atenolol. All β-adrenoceptor-blocking agents are useful for lowering blood pressure in mild to moderate hypertension. In severe hypertension, β blockers are especially useful in preventing the reflex tachycardia that often results from treatment with direct vasodilators. Beta blockers have been shown to reduce mortality after a myocardial infarction and some also reduce mortality in patients with heart failure; they are particularly advantageous for treating hypertension in patients with these conditions (see Chapter 13).
A. Mechanism and Sites of Action
Propranolol’s efficacy in treating hypertension as well as most of its toxic effects result from nonselective β blockade. Propranolol decreases blood pressure primarily as a result of a decrease in cardiac output. Other β blockers may decrease cardiac output or decrease peripheral vascular resistance to various degrees, depending on cardioselectivity and partial agonist activities.
Propranolol inhibits the stimulation of renin production by catecholamines (mediated by β1 receptors). It is likely that propranolol’s effect is due in part to depression of the renin-angiotensin-aldosterone system. Although most effective in patients with high plasma renin activity, propranolol also reduces blood pressure in hypertensive patients with normal or even low renin activity. Beta blockers might also act on peripheral presynaptic β adrenoceptors to reduce sympathetic vasoconstrictor nerve activity.
In mild to moderate hypertension, propranolol produces a significant reduction in blood pressure without prominent postural hypotension.
B. Pharmacokinetics and Dosage
See Table 11–2. Resting bradycardia and a reduction in the heart rate during exercise are indicators of propranolol’s β-blocking effect, and changes in these parameters may be used as guides for regulating dosage. Propranolol can be administered twice daily, and slow-release once-daily preparations are available.
The principal toxicities of propranolol result from blockade of cardiac, vascular, or bronchial β receptors and are described in more detail in Chapter 10. The most important of these predictable extensions of the β1-blocking action occur in patients with bradycardia or cardiac conduction disease, and those of the β2-blocking action occur in patients with asthma, peripheral vascular insufficiency, and diabetes.
When β blockers are discontinued after prolonged regular use, some patients experience a withdrawal syndrome, manifested by nervousness, tachycardia, increased intensity of angina, and increase of blood pressure. Myocardial infarction has been reported in a few patients. Although the incidence of these complications is probably low, β blockers should not be discontinued abruptly. The withdrawal syndrome may involve upregulation or supersensitivity of β adrenoceptors.
Metoprolol and atenolol, which are cardioselective, are the most widely used β blockers in the treatment of hypertension. Metoprolol is approximately equipotent to propranolol in inhibiting stimulation of β1 adrenoceptors such as those in the heart but 50- to 100-fold less potent than propranolol in blocking β2 receptors. Relative cardioselectivity is advantageous in treating hypertensive patients who also suffer from asthma, diabetes, or peripheral vascular disease. Although cardioselectivity is not complete, metoprolol causes less bronchial constriction than propranolol at doses that produce equal inhibition of β1-adrenoceptor responses. Metoprolol is extensively metabolized by CYP2D6 with high first-pass metabolism. The drug has a relatively short half-life of 4–6 hours, but the extended-release preparation can be dosed once daily (Table 11–2). Sustained-release metoprolol is effective in reducing mortality from heart failure and is particularly useful in patients with hypertension and heart failure.
Atenolol is not extensively metabolized and is excreted primarily in the urine with a half-life of 6 hours; it is usually dosed once daily. Atenolol is reported to be less effective than metoprolol in preventing the complications of hypertension. A possible reason for this difference is that once-daily dosing does not maintain adequate blood levels of atenolol. The usual dosage is 50–100 mg/d. Patients with reduced renal function should receive lower doses.
Nadolol and carteolol, nonselective β-receptor antagonists, are not appreciably metabolized and are excreted to a considerable extent in the urine. Betaxolol and bisoprolol are β1-selective blockers that are primarily metabolized in the liver but have long half-lives. Because of these relatively long half-lives, these drugs can be administered once daily. Nadolol is usually begun at a dosage of 40 mg/d, carteolol at 2.5 mg/d, betaxolol at 10 mg/d, and bisoprolol at 5 mg/d. Increases in dosage to obtain a satisfactory therapeutic effect should take place no more often than every 4 or 5 days. Patients with reduced renal function should receive correspondingly reduced doses of nadolol and carteolol.
Pindolol, acebutolol, and penbutolol are partial agonists, ie, β blockers with some intrinsic sympathomimetic activity. They lower blood pressure but are rarely used in hypertension.
These drugs have both β-blocking and vasodilating effects. Labetalol is formulated as a racemic mixture of four isomers (it has two centers of asymmetry). Two of these isomers—the (S,S)- and (R,S)-isomers—are relatively inactive, a third (S,R)- is a potent α blocker, and the last (R,R)- is a potent β blocker. Labetalol has a 3:1 ratio of β:α antagonism after oral dosing. Blood pressure is lowered by reduction of systemic vascular resistance (via α blockade) without significant alteration in heart rate or cardiac output. Because of its combined α- and β-blocking activity, labetalol is useful in treating the hypertension of pheochromocytoma and hypertensive emergencies. Oral daily doses of labetalol range from 200 to 2400 mg/d. Labetalol is given as repeated intravenous bolus injections of 20–80 mg to treat hypertensive emergencies.
Carvedilol, like labetalol, is administered as a racemic mixture. The S(-) isomer is a nonselective β-adrenoceptor blocker, but both S(-) and R(+) isomers have approximately equal α-blocking potency. The isomers are stereoselectively metabolized in the liver, which means that their elimination half-lives may differ. The average half-life is 7–10 hours. The usual starting dosage of carvedilol for ordinary hypertension is 6.25 mg twice daily. Carvedilol reduces mortality in patients with heart failure and is therefore particularly useful in patients with both heart failure and hypertension.
Nebivolol is a β1-selective blocker with vasodilating properties that are not mediated by α blockade. D-Nebivolol has highly selective β1-blocking effects, while the L-isomer causes vasodilation; the drug is marketed as a racemic mixture. The vasodilating effect may be due to an increase in endothelial release of nitric oxide via induction of endothelial nitric oxide synthase. The hemodynamic effects of nebivolol therefore differ from those of pure β blockers in that peripheral vascular resistance is acutely lowered (by nebivolol) as opposed to increased acutely (by the older agents). Nebivolol is extensively metabolized and has active metabolites. The half-life is 10–12 hours, but the drug can be given once daily. Dosing is generally started at 5 mg/d, with dose escalation as high as 40 mg/d, if necessary. The efficacy of nebivolol is similar to that of other antihypertensive agents, but several studies report fewer adverse effects.
Esmolol is a β1-selective blocker that is rapidly metabolized via hydrolysis by red blood cell esterases. It has a short half-life (9–10 minutes) and is administered by intravenous infusion. Esmolol is generally administered as a loading dose (0.5–1 mg/kg), followed by a constant infusion. The infusion is typically started at 50–150 mcg/kg/min, and the dose increased every 5 minutes, up to 300 mcg/kg/min, as needed to achieve the desired therapeutic effect. Esmolol is used for management of intraoperative and postoperative hypertension, and sometimes for hypertensive emergencies, particularly when hypertension is associated with tachycardia or when there is concern about toxicity such as aggravation of severe heart failure, in which case a drug with a short duration of action that can be discontinued quickly is advantageous.
PRAZOSIN & OTHER ALPHA1 BLOCKERS
Mechanism & Sites of Action
Prazosin, terazosin, and doxazosin produce most of their antihypertensive effects by selectively blocking α1 receptors in arterioles and venules. These agents produce less reflex tachycardia when lowering blood pressure than do nonselective α antagonists such as phentolamine. Alpha1-receptor selectivity allows norepinephrine to exert unopposed negative feedback (mediated by presynaptic α2 receptors) on its own release (see Chapter 6); in contrast, phentolamine blocks both presynaptic and postsynaptic α receptors, with the result that reflex activation of sympathetic neurons by phentolamine’s effects produces greater release of transmitter onto β receptors and correspondingly greater cardioacceleration.
Alpha blockers reduce arterial pressure by dilating both resistance and capacitance vessels. As expected, blood pressure is reduced more in the upright than in the supine position. Retention of salt and water occurs when these drugs are administered without a diuretic. The drugs are more effective when used in combination with other agents, such as a β blocker and a diuretic, than when used alone. Owing to their beneficial effects in men with prostatic hyperplasia and bladder obstruction symptoms, these drugs are used primarily in men with concurrent hypertension and benign prostatic hyperplasia.
Pharmacokinetics & Dosage
Pharmacokinetic characteristics of prazosin are listed in Table 11–2. Terazosin is also extensively metabolized but undergoes very little first-pass metabolism and has a half-life of 12 hours. Doxazosin has an intermediate bioavailability and a half-life of 22 hours.
Terazosin can often be given once daily, with doses of 5–20 mg/d. Doxazosin is usually given once daily starting at 1 mg/d and progressing to 4 mg/d or more as needed. Although long-term treatment with these α blockers causes relatively little postural hypotension, a precipitous drop in standing blood pressure develops in some patients shortly after the first dose is absorbed. For this reason, the first dose should be small and should be administered at bedtime. Although the mechanism of this first-dose phenomenon is not clear, it occurs more commonly in patients who are salt- and volume-depleted.
Aside from the first-dose phenomenon, the reported toxicities of the α1 blockers are relatively infrequent and mild. These include dizziness, palpitations, headache, and lassitude. Some patients develop a positive test for antinuclear factor in serum while on prazosin therapy, but this has not been associated with rheumatic symptoms. The α1 blockers do not adversely and may even beneficially affect plasma lipid profiles, but this action has not been shown to confer any benefit on clinical outcomes.
OTHER ALPHA-ADRENOCEPTOR-BLOCKING AGENTS
The nonselective agents, phentolamine and phenoxybenzamine, are useful in diagnosis and treatment of pheochromocytoma and in other clinical situations associated with exaggerated release of catecholamines (eg, phentolamine may be combined with a β blocker to treat the clonidine withdrawal syndrome, described previously). Their pharmacology is described in Chapter 10.
Mechanism & Sites of Action
This class of drugs includes the oral vasodilators, hydralazine and minoxidil, which are used for long-term outpatient therapy of hypertension; the parenteral vasodilators, nitroprusside and fenoldopam, which are used to treat hypertensive emergencies; the calcium channel blockers, which are used in both circumstances; and the nitrates, which are used mainly in ischemic heart disease but sometimes also in hypertensive emergencies (Table 11–3).
TABLE 11–3Mechanisms of action of vasodilators.
Chapter 12 contains additional discussion of vasodilators. All the vasodilators that are useful in hypertension relax smooth muscle of arterioles, thereby decreasing systemic vascular resistance. Sodium nitroprusside and the nitrates also relax veins. Decreased arterial resistance and decreased mean arterial blood pressure elicit compensatory responses, mediated by baroreceptors and the sympathetic nervous system (Figure 11–4), as well as renin, angiotensin, and aldosterone. Because sympathetic reflexes are intact, vasodilator therapy does not cause orthostatic hypotension or sexual dysfunction.
Vasodilators work best in combination with other antihypertensive drugs that oppose the compensatory cardiovascular responses. (See Box: Resistant Hypertension & Polypharmacy.)
Hydralazine, a hydrazine derivative, dilates arterioles but not veins. It has been available for many years, although it was initially thought not to be particularly effective because tachyphylaxis to its antihypertensive effects developed rapidly. The benefits of combination therapy are now recognized, and hydralazine may be used more effectively, particularly in severe hypertension. The combination of hydralazine with nitrates is effective in heart failure and should be considered in patients with both hypertension and heart failure, especially in African-American patients.
Pharmacokinetics & Dosage
Hydralazine is well absorbed and rapidly metabolized by the liver during the first pass, so that bioavailability is low (averaging 25%) and variable among individuals. It is metabolized in part by acetylation at a rate that appears to be bimodally distributed in the population (see Chapter 4). As a consequence, rapid acetylators have greater first-pass metabolism, lower blood levels, and less antihypertensive benefit from a given dose than do slow acetylators. The half-life of hydralazine ranges from 1.5 to 3 hours, but vascular effects persist longer than do blood concentrations, possibly due to avid binding to vascular tissue.
Usual dosage ranges from 40 to 200 mg/d. The higher dosage was selected as the dose at which there is a small possibility of developing the lupus erythematosus-like syndrome described in the next section. However, higher dosages result in greater vasodilation and may be used if necessary. Dosing two or three times daily provides smooth control of blood pressure.
The most common adverse effects of hydralazine are headache, nausea, anorexia, palpitations, sweating, and flushing. In patients with ischemic heart disease, reflex tachycardia and sympathetic stimulation may provoke angina or ischemic arrhythmias. With dosages of 400 mg/d or more, there is a 10–20% incidence—chiefly in persons who slowly acetylate the drug—of a syndrome characterized by arthralgia, myalgia, skin rashes, and fever that resembles lupus erythematosus. The syndrome is not associated with renal damage and is reversed by discontinuance of hydralazine. Peripheral neuropathy and drug fever are other serious but uncommon adverse effects.
Minoxidil is a very efficacious orally active vasodilator. The effect results from the opening of potassium channels in smooth muscle membranes by minoxidil sulfate, the active metabolite. Increased potassium permeability stabilizes the membrane at its resting potential and makes contraction less likely. Like hydralazine, minoxidil dilates arterioles but not veins. Because of its greater potential antihypertensive effect, minoxidil should replace hydralazine when maximal doses of the latter are not effective or in patients with renal failure and severe hypertension, who do not respond well to hydralazine.
Pharmacokinetics & Dosage
Pharmacokinetic parameters of minoxidil are listed in Table 11–2. Even more than with hydralazine, the use of minoxidil is associated with reflex sympathetic stimulation and sodium and fluid retention. Minoxidil must be used in combination with a β blocker and a loop diuretic.
Tachycardia, palpitations, angina, and edema are observed when doses of co-administered β blockers and diuretics are inadequate. Headache, sweating, and hypertrichosis (the latter particularly bothersome in women) are relatively common. Minoxidil illustrates how one person’s toxicity may become another person’s therapy. Topical minoxidil (as Rogaine) is used as a stimulant to hair growth for correction of baldness.
Sodium nitroprusside is a powerful parenterally administered vasodilator that is used in treating hypertensive emergencies as well as severe heart failure. Nitroprusside dilates both arterial and venous vessels, resulting in reduced peripheral vascular resistance and venous return. The action occurs as a result of activation of guanylyl cyclase, either via release of nitric oxide or by direct stimulation of the enzyme. The result is increased intracellular cGMP, which relaxes vascular smooth muscle (see Figure 12–2).
In the absence of heart failure, blood pressure decreases, owing to decreased vascular resistance, whereas cardiac output does not change or decreases slightly. In patients with heart failure and low cardiac output, output often increases owing to afterload reduction.
Pharmacokinetics & Dosage
Nitroprusside is a complex of iron, cyanide groups, and a nitroso moiety. It is rapidly metabolized by uptake into red blood cells with release of nitric oxide and cyanide. Cyanide in turn is metabolized by the mitochondrial enzyme rhodanese, in the presence of a sulfur donor, to the less toxic thiocyanate. Thiocyanate is distributed in extracellular fluid and slowly eliminated by the kidney.
Nitroprusside rapidly lowers blood pressure, and its effects disappear within 1–10 minutes after discontinuation. The drug is given by intravenous infusion. Sodium nitroprusside in aqueous solution is sensitive to light and must therefore be made up fresh before each administration and covered with opaque foil. Infusion solutions should be changed after several hours. Dosage typically begins at 0.5 mcg/kg/min and may be increased up to 10 mcg/kg/min as necessary to control blood pressure. Higher rates of infusion, if continued for more than an hour, may result in toxicity. Because of its efficacy and rapid onset of effect, nitroprusside should be administered by infusion pump and arterial blood pressure continuously monitored via intra-arterial recording.
Other than excessive blood pressure lowering, the most serious toxicity is related to accumulation of cyanide; metabolic acidosis, arrhythmias, excessive hypotension, and death have resulted. In a few cases, toxicity after relatively low doses of nitroprusside suggested a defect in cyanide metabolism. Administration of sodium thiosulfate as a sulfur donor facilitates metabolism of cyanide. Hydroxocobalamin combines with cyanide to form the nontoxic cyanocobalamin. Both have been advocated for prophylaxis or treatment of cyanide poisoning during nitroprusside infusion. Thiocyanate may accumulate over the course of prolonged administration, usually several days or more, particularly in patients with renal insufficiency who do not excrete thiocyanate at a normal rate. Thiocyanate toxicity is manifested as weakness, disorientation, psychosis, muscle spasms, and convulsions, and the diagnosis is confirmed by finding serum concentrations greater than 10 mg/dL. Rarely, delayed hypothyroidism occurs, owing to thiocyanate inhibition of iodide uptake by the thyroid. Methemoglobinemia during infusion of nitroprusside has also been reported.
Diazoxide is an effective and relatively long-acting potassium channel opener that causes hyperpolarization in smooth muscle and pancreatic β cells. Because of its arteriolar dilating property, it was formerly used parenterally to treat hypertensive emergencies. Injection of diazoxide results in a rapid fall in systemic vascular resistance and mean arterial blood pressure. At present, it is used orally in the USA for the treatment of hypoglycemia in hyperinsulinism. Diazoxide inhibits insulin release from the pancreas (probably by opening potassium channels in the beta cell membrane) and is used to treat hypoglycemia secondary to insulinoma.
Pharmacokinetics & Dosage
Oral dosage for hypoglycemia is 3–8 mg/kg/day in 3 divided doses, with a maximum of 15 mg/kg/day. Diazoxide is similar chemically to the thiazide diuretics but has no diuretic activity. It is bound extensively to serum albumin and to vascular tissue. Diazoxide is partially metabolized; its metabolic pathways are not well characterized. The remainder is excreted unchanged. Its half-life is approximately 24 hours, but the relationship between blood concentration and hypotensive action is not well established. The blood pressure-lowering effect after a rapid injection is established within 5 minutes and lasts for 4–12 hours.
When diazoxide was first marketed for use in hypertension, a dose of 300 mg by rapid injection was recommended. It appears, however, that excessive hypotension can be avoided by beginning with smaller doses (50–150 mg). If necessary, doses of 150 mg may be repeated every 5–15 minutes until blood pressure is lowered satisfactorily. Alternatively, diazoxide may be administered by intravenous infusion at rates of 15–30 mg/min. Because of reduced protein binding, smaller doses should be administered to persons with chronic renal failure. The hypotensive effects of diazoxide are also greater when patients are pretreated with β blockers to prevent the reflex tachycardia and associated increase in cardiac output.
The most significant toxicity from parenteral diazoxide has been excessive hypotension, resulting from the original recommendation to use a fixed dose of 300 mg in all patients. Such hypotension has resulted in stroke and myocardial infarction. The reflex sympathetic response can provoke angina, electrocardiographic evidence of ischemia, and cardiac failure in patients with ischemic heart disease, and diazoxide should be avoided in this situation. Occasionally, hyperglycemia complicates diazoxide use, particularly in persons with renal insufficiency.
In contrast to the structurally related thiazide diuretics, diazoxide causes renal salt and water retention. However, because the drug is used for short periods only, this is rarely a problem.
Fenoldopam is a peripheral arteriolar dilator used for hypertensive emergencies and postoperative hypertension. It acts primarily as an agonist of dopamine D1 receptors, resulting in dilation of peripheral arteries and natriuresis. The commercial product is a racemic mixture with the (R)-isomer mediating the pharmacologic activity.
Fenoldopam is rapidly metabolized, primarily by conjugation. Its half-life is 10 minutes. The drug is administered by continuous intravenous infusion. Fenoldopam is initiated at a low dosage (0.1 mcg/kg/min), and the dose is then titrated upward every 15 or 20 minutes to a maximum dose of 1.6 mcg/kg/min or until the desired blood pressure reduction is achieved.
As with other direct vasodilators, the major toxicities are reflex tachycardia, headache, and flushing. Fenoldopam also increases intraocular pressure and should be avoided in patients with glaucoma.
In addition to their antianginal (see Chapter 12) and antiarrhythmic effects (see Chapter 14), calcium channel blockers also reduce peripheral resistance and blood pressure. The mechanism of action in hypertension (and, in part, in angina) is inhibition of calcium influx into arterial smooth muscle cells.
Verapamil, diltiazem, and the dihydropyridine family (amlodipine, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, and nitrendipine [withdrawn in the USA]) are all equally effective in lowering blood pressure, and many formulations are currently approved for this use in the USA. Clevidipine is a newer member of this group that is formulated for intravenous use only.
Hemodynamic differences among calcium channel blockers may influence the choice of a particular agent. Nifedipine and the other dihydropyridine agents are more selective as vasodilators and have less cardiac depressant effect than verapamil and diltiazem. Reflex sympathetic activation with slight tachycardia maintains or increases cardiac output in most patients given dihydropyridines. Verapamil has the greatest depressant effect on the heart and may decrease heart rate and cardiac output. Diltiazem has intermediate actions. The pharmacology and toxicity of these drugs are discussed in more detail in Chapter 12. Doses of calcium channel blockers used in treating hypertension are similar to those used in treating angina. Some epidemiologic studies reported an increased risk of myocardial infarction or mortality in patients receiving short-acting nifedipine for hypertension. It is therefore recommended that short-acting oral dihydropyridines not be used for hypertension. Sustained-release calcium blockers or calcium blockers with long half-lives provide smoother blood pressure control and are more appropriate for treatment of chronic hypertension. Intravenous nicardipine and clevidipine are available for the treatment of hypertension when oral therapy is not feasible; parenteral verapamil and diltiazem can also be used for the same indication. Nicardipine is typically infused at rates of 2–15 mg/h. Clevidipine is infused starting at 1–2 mg/h and progressing to 4–6 mg/h. It has a rapid onset of action and has been used in acute hypertension occurring during surgery. Oral short-acting nifedipine has been used in emergency management of severe hypertension.