Basic and Clinical Pharmacology, 14th Edition, Antihypertensive Agents PDF

SECTION III CARDIOVASCULAR-RENAL DRUGS 11 C H A P T E R Antihypertensive Agents Neal L...

SECTION III CARDIOVASCULAR-RENAL DRUGS 11 C H A P T E R Antihypertensive Agents Neal L. Benowitz, MD C ASE STUDY A 35-year-old man presents with a blood pressure of examination is remarkable only for moderate obesity. Total 150/95 mm Hg. He has been generally healthy, is sedentary, cholesterol is 220, and high-density lipoprotein (HDL) drinks several cocktails per day, and does not smoke cholesterol level is 40 mg/dL. Fasting glucose is 105 mg/dL. cigarettes. He has a family history of hypertension, and his Chest X-ray is normal. Electrocardiogram shows left ven- father died of a myocardial infarction at age 55. Physical tricular enlargement. How would you treat this patient? Hypertension is the most common cardiovascular disease. In a accurate prediction of efficacy and toxicity. The rational use of National Health and Nutrition Examination Survey (NHANES) these agents, alone or in combination, can lower blood pressure carried out in 2011 to 2012, hypertension was found in 29% with minimal risk of serious toxicity in most patients. of American adults and 65% of adults age 65 years or older. The prevalence varies with age, race, education, and many other variables. According to some studies, 60–80% of both men and HYPERTENSION & REGULATION OF women will develop hypertension by age 80. Sustained arterial BLOOD PRESSURE hypertension damages blood vessels in kidney, heart, and brain and leads to an increased incidence of renal failure, coronary Diagnosis disease, heart failure, stroke, and dementia. Effective pharma- The diagnosis of hypertension is based on repeated, reproducible cologic lowering of blood pressure has been shown to prevent measurements of elevated blood pressure (Table 11–1). The diagno- damage to blood vessels and to substantially reduce morbidity and sis serves primarily as a prediction of consequences for the patient; it mortality rates. However, NHANES found that, unfortunately, seldom includes a statement about the cause of hypertension. only one-half of Americans with hypertension had adequate blood Epidemiologic studies indicate that the risks of damage to pressure control. Many effective drugs are available. Knowledge kidney, heart, and brain are directly related to the extent of of their antihypertensive mechanisms and sites of action allows blood pressure elevation. Even mild hypertension (blood pressure 173 174    SECTION III Cardiovascular-Renal Drugs TABLE 11–1 Classification of hypertension on the potassium or calcium intake) as contributing to the development basis of blood pressure. of hypertension. Increase in blood pressure with aging does not occur in populations with low daily sodium intake. Patients with Systolic/Diastolic Pressure labile hypertension appear more likely than normal controls to (mm Hg) Category have blood pressure elevations after salt loading. < 120/80 Normal The heritability of essential hypertension is estimated to be 120–139/80–89 Prehypertension about 30%. Mutations in several genes have been linked to vari- ≥ 140/90 Hypertension ous rare causes of hypertension. Functional variations of the genes for angiotensinogen, angiotensin-converting enzyme (ACE), the 140–159/90–99 Stage 1 angiotensin II receptor, the β2 adrenoceptor, α adducin (a cyto- ≥ 160/100 Stage 2 skeletal protein), and others appear to contribute to some cases of From the Joint National Committee on prevention, detection, evaluation, and treatment essential hypertension. of high blood pressure. JAMA 2003;289:2560. Normal Regulation of Blood Pressure 140/90 mm Hg) increases the risk of eventual end-organ damage. According to the hydraulic equation, arterial blood pressure (BP) Starting at 115/75 mm Hg, cardiovascular disease risk doubles is directly proportionate to the product of the blood flow (cardiac with each increment of 20/10 mm Hg throughout the blood pres- output, CO) and the resistance to passage of blood through sure range. Both systolic hypertension and diastolic hypertension precapillary arterioles (peripheral vascular resistance, PVR): are associated with end-organ damage; so-called isolated systolic BP = CO × PVR hypertension is not benign. The risks—and therefore the urgency of instituting therapy—increase in proportion to the magnitude Physiologically, in both normal and hypertensive individuals, of blood pressure elevation. The risk of end-organ damage at any blood pressure is maintained by moment-to-moment regula- level of blood pressure or age is greater in African Americans and tion of cardiac output and peripheral vascular resistance, exerted relatively less in premenopausal women than in men. Other posi- at three anatomic sites (Figure 11–1): arterioles, postcapillary tive risk factors include smoking; metabolic syndrome, including venules (capacitance vessels), and heart. A fourth anatomic control obesity, dyslipidemia, and diabetes; manifestations of end-organ site, the kidney, contributes to maintenance of blood pressure by damage at the time of diagnosis; and a family history of cardio- regulating the volume of intravascular fluid. Baroreflexes, medi- vascular disease. ated by autonomic nerves, act in combination with humoral It should be noted that the diagnosis of hypertension depends mechanisms, including the renin-angiotensin-aldosterone sys- on measurement of blood pressure and not on symptoms reported tem, to coordinate function at these four control sites and to by the patient. In fact, hypertension is usually asymptomatic until maintain normal blood pressure. Finally, local release of vasoac- overt end-organ damage is imminent or has already occurred. tive substances from vascular endothelium may also be involved in the regulation of vascular resistance. For example, endothelin-1 Etiology of Hypertension A specific cause of hypertension can be established in only 10–15% 2. Capacitance of patients. Patients in whom no specific cause of hypertension can Venules 3. Pump output be found are said to have essential or primary hypertension. Patients Heart with a specific etiology are said to have secondary hypertension. It is important to consider specific causes in each case, however, because some of them are amenable to definitive surgical treatment: renal CNS– artery constriction, coarctation of the aorta, pheochromocytoma, Sympathetic nerves Cushing’s disease, and primary aldosteronism. 4. Volume In most cases, elevated blood pressure is associated with an Kidneys overall increase in resistance to flow of blood through arterioles, 1. Resistance Arterioles whereas cardiac output is usually normal. Meticulous investiga- tion of autonomic nervous system function, baroreceptor reflexes, the renin-angiotensin-aldosterone system, and the kidney has Renin failed to identify a single abnormality as the cause of increased peripheral vascular resistance in essential hypertension. It appears, Aldosterone Angiotensin therefore, that elevated blood pressure is usually caused by a combination of several (multifactorial) abnormalities. Epidemio- logic evidence points to genetic factors, psychological stress, and environmental and dietary factors (increased salt and decreased FIGURE 11–1 Anatomic sites of blood pressure control.  CHAPTER 11 Antihypertensive Agents    175 (see Chapter 17) constricts and nitric oxide (see Chapter 19) B. Renal Response to Decreased Blood Pressure dilates blood vessels. By controlling blood volume, the kidney is primarily responsible Blood pressure in a hypertensive patient is controlled by the for long-term blood pressure control. A reduction in renal perfu- same mechanisms that are operative in normotensive subjects. sion pressure causes intrarenal redistribution of blood flow and Regulation of blood pressure in hypertensive patients differs from increased reabsorption of salt and water. In addition, decreased healthy patients in that the baroreceptors and the renal blood pressure in renal arterioles as well as sympathetic neural activ- volume-pressure control systems appear to be “set” at a higher ity (via β adrenoceptors) stimulates production of renin, which level of blood pressure. All antihypertensive drugs act by interfer- increases production of angiotensin II (see Figure 11–1 and ing with these normal mechanisms, which are reviewed below. Chapter 17). Angiotensin II causes (1) direct constriction of resistance vessels and (2) stimulation of aldosterone synthesis in A. Postural Baroreflex the adrenal cortex, which increases renal sodium absorption and Baroreflexes are responsible for rapid, moment-to-moment adjust- intravascular blood volume. Vasopressin released from the pos- ments in blood pressure, such as in transition from a reclining to terior pituitary gland also plays a role in maintenance of blood an upright posture (Figure 11–2). Central sympathetic neurons pressure through its ability to regulate water reabsorption by the arising from the vasomotor area of the medulla are tonically kidney (see Chapters 15 and 17). active. Carotid baroreceptors are stimulated by the stretch of the vessel walls brought about by the internal pressure (arterial blood pressure). Baroreceptor activation inhibits central sympathetic BASIC PHARMACOLOGY OF discharge. Conversely, reduction in stretch results in a reduction in baroreceptor activity. Thus, in the case of a transition to upright ANTIHYPERTENSIVE AGENTS posture, baroreceptors sense the reduction in arterial pressure All antihypertensive agents act at one or more of the four ana- that results from pooling of blood in the veins below the level tomic control sites depicted in Figure 11–1 and produce their of the heart as reduced wall stretch, and sympathetic discharge effects by interfering with normal mechanisms of blood pressure is disinhibited. The reflex increase in sympathetic outflow acts regulation. A useful classification of these agents categorizes through nerve endings to increase peripheral vascular resistance them according to the principal regulatory site or mechanism on (constriction of arterioles) and cardiac output (direct stimula- which they act (Figure 11–3). Because of their common mecha- tion of the heart and constriction of capacitance vessels, which nisms of action, drugs within each category tend to produce increases venous return to the heart), thereby restoring normal a similar spectrum of toxicities. The categories include the blood pressure. The same baroreflex acts in response to any event following: that lowers arterial pressure, including a primary reduction in peripheral vascular resistance (eg, caused by a vasodilating agent) 1. Diuretics, which lower blood pressure by depleting the body of or a reduction in intravascular volume (eg, due to hemorrhage or sodium and reducing blood volume and perhaps by other to loss of salt and water via the kidney). mechanisms. IC 2. Nucleus of the tractus solitarius Brain- CP Sensory fiber stem 1. Baroreceptor in carotid sinus Inhibitory interneurons X XI XII Arterial blood pressure Vessel wall 3. Vasomotor center Motor fibers 5 6 Spinal cord 4. Autonomic 5. Sympathetic ganglion nerve ending 6. α or β receptor FIGURE 11–2 Baroreceptor reflex arc. CP, cerebellar peduncle; IC, inferior colliculus. 176    SECTION III Cardiovascular-Renal Drugs Vasomotor center Methyldopa Clonidine Guanabenz Guanfacine Sympathetic nerve terminals Guanethidine Guanadrel Reserpine Sympathetic ganglia β-Receptors of heart Trimethaphan Propranolol and other β-blockers Angiotensin α-Receptors of vessels Vascular smooth muscle receptors of vessels Prazosin and Hydralazine Verapamil and other Losartan and other α1 blockers Minoxidil calcium channel other angiotensin Nitroprusside blockers receptor blockers Diazoxide Fenoldopam β-Receptors of juxtaglomerular Kidney tubules cells that release renin Thiazides, etc Propranolol and other β blockers Angiotensin- converting enzyme Renin Angiotensin II Angiotensin I Angiotensinogen Aliskiren Captopril and other ACE inhibitors FIGURE 11–3 Sites of action of the major classes of antihypertensive drugs. 2. Sympathoplegic agents, which lower blood pressure by reduc- increased efficacy and, in some cases, decreased toxicity. (See Box: ing peripheral vascular resistance, inhibiting cardiac function, Resistant Hypertension & Polypharmacy.) and increasing venous pooling in capacitance vessels. (The lat- ter two effects reduce cardiac output.) These agents are further subdivided according to their putative sites of action in the DRUGS THAT ALTER SODIUM & sympathetic reflex arc (see below). WATER BALANCE 3. Direct vasodilators, which reduce pressure by relaxing vascular smooth muscle, thus dilating resistance vessels and—to varying Dietary sodium restriction has been known for many years to degrees—increasing capacitance as well. decrease blood pressure in hypertensive patients. With the advent of diuretics, sodium restriction was thought to be less important. 4. Agents that block production or action of angiotensin and However, there is now general agreement that dietary control of thereby reduce peripheral vascular resistance and (potentially) blood pressure is a relatively nontoxic therapeutic measure and blood volume. may even be preventive. Even modest dietary sodium restriction The fact that these drug groups act by different mechanisms lowers blood pressure (though to varying extents) in many hyper- permits the combination of drugs from two or more groups with tensive persons.  CHAPTER 11 Antihypertensive Agents    177 Resistant Hypertension & Polypharmacy Monotherapy of hypertension (treatment with a single drug) is inhibitors report a maximal lowering of blood pressure of less desirable because compliance is likely to be better and the cost than 10 mm Hg. In patients with more severe hypertension is lower, and because in some cases adverse effects are fewer. (pressure > 160/100 mm Hg), this is inadequate to prevent all However, most patients with hypertension require two or more the sequelae of hypertension, but ACE inhibitors have important drugs acting by different mechanisms (polypharmacy). Accord- long-term benefits in preventing or reducing renal disease in ing to some estimates, up to 40% of patients may respond inad- diabetic persons and in reduction of heart failure. Finally, the equately even to two agents and are considered to have “resistant toxicity of some effective drugs prevents their use at maximally hypertension.” Some of these patients have treatable secondary effective doses. hypertension that has been missed, but most do not, and three In practice, when hypertension does not respond adequately or more drugs are required. to a regimen of one drug, a second drug from a different class One rationale for polypharmacy in hypertension is that most with a different mechanism of action and different pattern of drugs evoke compensatory regulatory mechanisms for main- toxicity is added. If the response is still inadequate and com- taining blood pressure (see Figures 6–7 and 11–1), which may pliance is known to be good, a third drug should be added. If markedly limit their effect. For example, vasodilators such as three drugs (usually including a diuretic) are inadequate, other hydralazine cause a significant decrease in peripheral vascular causes of resistant hypertension such as excessive dietary resistance, but evoke a strong compensatory tachycardia and sodium intake, use of nonsteroidal anti-inflammatory or stimu- salt and water retention (Figure 11–4) that are capable of almost lant drugs, or the presence of secondary hypertension should be completely reversing their effect. The addition of a β blocker considered. In some instances, an additional drug may be neces- prevents the tachycardia; addition of a diuretic (eg, hydrochloro- sary, and mineralocorticoid antagonists, such as spironolactone, thiazide) prevents the salt and water retention. In effect, all three have been found to be particularly useful. Occasionally patients drugs increase the sensitivity of the cardiovascular system to each are resistant to four or more drugs, and nonpharmacologic other’s actions. approaches have been considered. Two promising treatments A second reason is that some drugs have only modest maxi- that are still under investigation, particularly for patients with mum efficacy but reduction of long-term morbidity mandates advanced kidney disease, are renal denervation and carotid their use. Many studies of angiotensin-converting enzyme (ACE) barostimulation. Mechanisms of Action & Hemodynamic Use of Diuretics Effects of Diuretics The sites of action within the kidney and the pharmacokinetics Diuretics lower blood pressure primarily by depleting body sodium of various diuretic drugs are discussed in Chapter 15. Thiazide stores. Initially, diuretics reduce blood pressure by reducing blood diuretics are appropriate for most patients with mild or moder- volume and cardiac output; peripheral vascular resistance may ate hypertension and normal renal and cardiac function. While increase. After 6–8 weeks, cardiac output returns toward normal all thiazides lower blood pressure, the use of chlorthalidone in while peripheral vascular resistance declines. Sodium is believed to preference to others is supported by evidence of improved 24-hour contribute to vascular resistance by increasing vessel stiffness and blood pressure control and reduced cardiovascular events in large neural reactivity, possibly related to altered sodium-calcium exchange clinical trials. Chlorthalidone is likely to be more effective than with a resultant increase in intracellular calcium. These effects are hydrochlorothiazide because it has a longer duration of action. reversed by diuretics or dietary sodium restriction. More powerful diuretics (eg, those acting on the loop of Henle) Diuretics are effective in lowering blood pressure by 10–15 mm Hg such as furosemide are necessary in severe hypertension, when in most patients, and diuretics alone often provide adequate treat- multiple drugs with sodium-retaining properties are used; ment for mild or moderate essential hypertension. In more severe in renal insufficiency, when glomerular filtration rate is less hypertension, diuretics are used in combination with sympathople- than 30–40 mL/min; and in cardiac failure or cirrhosis, in which gic and vasodilator drugs to control the tendency toward sodium sodium retention is marked. retention caused by these agents. Vascular responsiveness—ie, Potassium-sparing diuretics are useful both to avoid excessive the ability to either constrict or dilate—is diminished by sympa- potassium depletion and to enhance the natriuretic effects of thoplegic and vasodilator drugs, so that the vasculature behaves other diuretics. Aldosterone receptor antagonists in particular also like an inflexible tube. As a consequence, blood pressure becomes have a favorable effect on cardiac function in people with heart exquisitely sensitive to blood volume. Thus, in severe hyperten- failure. sion, when multiple drugs are used, blood pressure may be well Some pharmacokinetic characteristics and the initial and controlled when blood volume is 95% of normal but much too usual maintenance dosages of diuretics are listed in Table 11–2. high when blood volume is 105% of normal. Although thiazide diuretics are more natriuretic at higher doses 178    SECTION III Cardiovascular-Renal Drugs Vasodilator drugs Decreased systemic vascular resistance Decreased 1 Decreased Increased renal arterial sympathetic sodium pressure nervous system excretion outflow 2 Increased renin 1 release 2 2 Increased Increased Increased Decreased Increased Increased systemic heart cardiac venous aldosterone angiotensin II vascular rate contractility capacitance resistance Sodium retention, Increased Increased increased plasma arterial cardiac volume pressure output FIGURE 11–4 Compensatory responses to vasodilators; basis for combination therapy with β blockers and diuretics. 1 Effect blocked by diuretics. 2 Effect blocked by β blockers. (up to 100–200 mg of hydrochlorothiazide), when used as a single receptor blockers; spironolactone (a steroid) is associated with agent, lower doses (25–50 mg) exert as much antihypertensive gynecomastia. effect as do higher doses. In contrast to thiazides, the blood pres- sure response to loop diuretics continues to increase at doses many times greater than the usual therapeutic dose. DRUGS THAT ALTER SYMPATHETIC NERVOUS SYSTEM FUNCTION Toxicity of Diuretics In many patients, hypertension is initiated and sustained at least In the treatment of hypertension, the most common adverse effect in part by sympathetic neural activation. In patients with moder- of diuretics (except for potassium-sparing diuretics) is potassium ate to severe hypertension, most effective drug regimens include depletion. Although mild degrees of hypokalemia are tolerated an agent that inhibits function of the sympathetic nervous well by many patients, hypokalemia may be hazardous in persons system. Drugs in this group are classified according to the site taking digitalis, those who have chronic arrhythmias, or those at which they impair the sympathetic reflex arc (Figure 11–2). with acute myocardial infarction or left ventricular dysfunction. This neuroanatomic classification explains prominent differ- Potassium loss is coupled to reabsorption of sodium, and restric- ences in cardiovascular effects of drugs and allows the clinician tion of dietary sodium intake therefore minimizes potassium loss. to predict interactions of these drugs with one another and with Diuretics may also cause magnesium depletion, impair glucose other drugs. tolerance, and increase serum lipid concentrations. Diuretics The subclasses of sympathoplegic drugs exhibit different pat- increase uric acid concentrations and may precipitate gout. The terns of potential toxicity. Drugs that lower blood pressure by use of low doses minimizes these adverse metabolic effects without actions on the central nervous system tend to cause sedation and impairing the antihypertensive action. Potassium-sparing diuret- mental depression and may produce disturbances of sleep, including ics may produce hyperkalemia, particularly in patients with renal nightmares. Drugs that act by inhibiting transmission through auto- insufficiency and those taking ACE inhibitors or angiotensin nomic ganglia (ganglion blockers) produce toxicity from inhibition  CHAPTER 11 Antihypertensive Agents    179 TABLE 11–2 Pharmacokinetic characteristics and dosage of selected oral antihypertensive drugs. Bioavailability Suggested Initial Usual Maintenance Reduction of Dosage Required Drug Half-life (h) (percent) Dose Dose Range in Moderate Renal Insufficiency1 Amlodipine 35 65 2.5 mg/d 5–10 mg/d No Atenolol 6 60 50 mg/d 50–100 mg/d Yes 2 Benazepril 0.6 35 5–10 mg/d 20–40 mg/d Yes Captopril 2.2 65 50–75 mg/d 75–150 mg/d Yes Chlorthalidone 40–60 65 25 mg/d 25–50 mg/d No Clonidine 8–12 95 0.2 mg/d 0.2–1.2 mg/d Yes Diltiazem 3.5 40 120–140 mg/d 240–360 mg/d No Hydralazine 1.5–3 25 40 mg/d 40–200 mg/d No Hydrochlorothiazide 12 70 25 mg/d 25–50 mg/d No Lisinopril 12 25 10 mg/d 10–80 mg/d Yes Losartan 1–23 36 50 mg/d 25–100 mg/d No Methyldopa 2 25 1 g/d 1–2 g/d No Metoprolol 3–7 40 50–100 mg/d 200–400 mg/d No Minoxidil 4 90 5–10 mg/d 40 mg/d No 4 Nebivolol 12 Nd 5 mg/d 10–40 mg/d No Nifedipine 2 50 30 mg/d 30–60 mg/d No Prazosin 3–4 70 3 mg/d 10–30 mg/d No Propranolol 3–5 25 80 mg/d 80–480 mg/d No Reserpine 24–48 50 0.25 mg/d 0.25 mg/d No Verapamil 4–6 22 180 mg/d 240–480 mg/d No 1 Creatinine clearance ≥ 30 mL/min. Many of these drugs do require dosage adjustment if creatinine clearance falls below 30 mL/min. 2 The active metabolite of benazepril has a half-life of 10 hours. 3 The active metabolite of losartan has a half-life of 3–4 hours. 4 Nd, not determined. of parasympathetic regulation, in addition to profound sympathetic Mechanisms & Sites of Action blockade and are no longer used. Drugs that act chiefly by reducing These agents reduce sympathetic outflow from vasomotor centers release of norepinephrine from sympathetic nerve endings cause in the brain stem but allow these centers to retain or even increase effects that are similar to those of surgical sympathectomy, includ- their sensitivity to baroreceptor control. Accordingly, the anti- ing inhibition of ejaculation, and hypotension that is increased by hypertensive and toxic actions of these drugs are generally less upright posture and after exercise. Drugs that block postsynaptic dependent on posture than are the effects of drugs that act directly adrenoceptors produce a more selective spectrum of effects depend- on peripheral sympathetic neurons. ing on the class of receptor to which they bind. Methyldopa (l-α-methyl-3,4-dihydroxyphenylalanine) is an Finally, one should note that all of the agents that lower blood analog of l-dopa and is converted to α-methyldopamine and pressure by altering sympathetic function can elicit compensatory α-methylnorepinephrine; this pathway directly parallels the synthe- effects through mechanisms that are not dependent on adrenergic sis of norepinephrine from dopa illustrated in Figure 6–5. Alpha- nerves. Thus, the antihypertensive effect of any of these agents methylnorepinephrine is stored in adrenergic nerve vesicles, where it used alone may be limited by retention of sodium by the kidney stoichiometrically replaces norepinephrine, and is released by nerve and expansion of blood volume. For this reason, sympathoplegic stimulation to interact with postsynaptic adrenoceptors. However, antihypertensive drugs are most effective when used concomitantly this replacement of norepinephrine by a false transmitter in periph- with a diuretic. eral neurons is not responsible for methyldopa’s antihypertensive effect, because the α-methylnorepinephrine released is an effective CENTRALLY ACTING agonist at the α adrenoceptors that mediate peripheral sympathetic SYMPATHOPLEGIC DRUGS constriction of arterioles and venules. In fact, methyldopa’s anti- hypertensive action appears to be due to stimulation of central α Centrally acting sympathoplegic drugs were once widely used in adrenoceptors by α-methylnorepinephrine or α-methyldopamine. the treatment of hypertension. With the exception of clonidine, The antihypertensive action of clonidine, a 2-imidazoline deriv- these drugs are rarely used today. ative, was discovered in the course of testing the drug for use as a 180    SECTION III Cardiovascular-Renal Drugs nasal decongestant. After intravenous injection, clonidine produces Pharmacokinetics & Dosage a brief rise in blood pressure followed by more prolonged hypoten- Pharmacokinetic characteristics of methyldopa are listed in sion. The pressor response is due to direct stimulation of α adreno- Table 11–2. Methyldopa enters the brain via an aromatic amino ceptors in arterioles. The drug is classified as a partial agonist at α acid transporter. The usual oral dose of methyldopa produces its receptors because it also inhibits pressor effects of other α agonists. maximal antihypertensive effect in 4–6 hours, and the effect can Considerable evidence indicates that the hypotensive effect persist for up to 24 hours. Because the effect depends on accu- of clonidine is exerted at α adrenoceptors in the medulla of the mulation and storage of a metabolite (α-methylnorepinephrine) brain. In animals, the hypotensive effect of clonidine is prevented in the vesicles of nerve endings, the action persists after the by central administration of α antagonists. Clonidine reduces parent drug has disappeared from the circulation. sympathetic and increases parasympathetic tone, resulting in blood pressure lowering and bradycardia. The reduction in pres- sure is accompanied by a decrease in circulating catecholamine Toxicity levels. These observations suggest that clonidine sensitizes brain The most common undesirable effect of methyldopa is sedation, stem vasomotor centers to inhibition by baroreflexes. particularly at the onset of treatment. With long-term therapy, Thus, studies of clonidine and methyldopa suggest that patients may complain of persistent mental lassitude and impaired normal regulation of blood pressure involves central adrenergic mental concentration. Nightmares, mental depression, vertigo, neurons that modulate baroreceptor reflexes. Clonidine and and extrapyramidal signs may occur but are relatively infrequent. α-methylnorepinephrine bind more tightly to α2 than to α1 adre- Lactation, associated with increased prolactin secretion, can occur noceptors. As noted in Chapter 6, α2 receptors are located on pre- both in men and in women treated with methyldopa. This toxicity synaptic adrenergic neurons as well as some postsynaptic sites. It is probably mediated by inhibition of dopaminergic mechanisms is possible that clonidine and α-methylnorepinephrine act in the in the hypothalamus. brain to reduce norepinephrine release onto relevant receptor sites. Other important adverse effects of methyldopa are develop- Alternatively, these drugs may act on postsynaptic α2 adrenocep- ment of a positive Coombs test (occurring in 10–20% of patients tors to inhibit activity of appropriate neurons. Finally, clonidine undergoing therapy for longer than 12 months), which sometimes also binds to a nonadrenoceptor site, the imidazoline receptor, makes cross-matching blood for transfusion difficult and rarely is which may also mediate antihypertensive effects. associated with hemolytic anemia, as well as hepatitis and drug Methyldopa and clonidine produce slightly different hemody- fever. Discontinuation of the drug usually results in prompt rever- namic effects: clonidine lowers heart rate and cardiac output more sal of these abnormalities. than does methyldopa. This difference suggests that these two drugs do not have identical sites of action. They may act primar- ily on different populations of neurons in the vasomotor centers CLONIDINE of the brain stem. Guanabenz and guanfacine are centrally active antihyper- Blood pressure lowering by clonidine results from reduction tensive drugs that share the central α-adrenoceptor-stimulating of cardiac output due to decreased heart rate and relaxation of effects of clonidine. They do not appear to offer any advantages capacitance vessels, as well as a reduction in peripheral vascular over clonidine and are rarely used. resistance. METHYLDOPA CI N Methyldopa was widely used in the past but is now used primar- NH ily for hypertension during pregnancy. It lowers blood pressure N chiefly by reducing peripheral vascular resistance, with a variable CI reduction in heart rate and cardiac output. Clonidine Most cardiovascular reflexes remain intact after administration of methyldopa, and blood pressure reduction is not markedly dependent Reduction in arterial blood pressure by clonidine is accompa- on posture. Postural (orthostatic) hypotension sometimes occurs, nied by decreased renal vascular resistance and maintenance of particularly in volume-depleted patients. One potential advantage renal blood flow. As with methyldopa, clonidine reduces blood of methyldopa is that it causes reduction in renal vascular resistance. pressure in the supine position and only rarely causes postural hypotension. Pressor effects of clonidine are not observed after OH ingestion of therapeutic doses of clonidine, but severe hyperten- HO C O sion can complicate a massive overdose. HO CH2 C NH2 Pharmacokinetics & Dosage CH3 α-Methyldopa Typical pharmacokinetic characteristics are listed in Table 11–2. (α-methyl group in color) Clonidine is lipid-soluble and rapidly enters the brain from  CHAPTER 11 Antihypertensive Agents    181 the circulation. Because of its relatively short half-life and the ADRENERGIC NEURON-BLOCKING fact that its antihypertensive effect is directly related to blood concentration, oral clonidine must be given twice a day (or as a AGENTS patch, below) to maintain smooth blood pressure control. How- These drugs lower blood pressure by preventing normal physi- ever, as is not the case with methyldopa, the dose-response curve ologic release of norepinephrine from postganglionic sympathetic of clonidine is such that increasing doses are more effective (but neurons. also more toxic). A transdermal preparation of clonidine that reduces blood pressure for 7 days after a single application is also available. This Guanethidine preparation appears to produce less sedation than clonidine tablets Guanethidine is no longer available in the USA but may be but may be associated with local skin reactions. used elsewhere. In high enough doses, guanethidine can produce profound sympathoplegia. Guanethidine can thus produce all of Toxicity the toxicities expected from “pharmacologic sympathectomy,” including marked postural hypotension, diarrhea, and impaired Dry mouth and sedation are common. Both effects are centrally ejaculation. Because of these adverse effects, guanethidine is now mediated and dose-dependent and coincide temporally with the rarely used. drug’s antihypertensive effect. Guanethidine is too polar to enter the central nervous system. Clonidine should not be given to patients who are at risk for As a result, this drug has none of the central effects seen with many mental depression and should be withdrawn if depression occurs of the other antihypertensive agents described in this chapter. during therapy. Concomitant treatment with tricyclic antidepres- Guanadrel is a guanethidine-like drug that is no longer used in sants may block the antihypertensive effect of clonidine. The the USA. Bethanidine and debrisoquin, antihypertensive agents interaction is believed to be due to α-adrenoceptor-blocking not available for clinical use in the USA, are similar. actions of the tricyclics. Withdrawal of clonidine after protracted use, particularly with A. Mechanism and Sites of Action high dosages (more than 1 mg/d), can result in life-threatening hypertensive crisis mediated by increased sympathetic nervous Guanethidine inhibits the release of norepinephrine from activity. Patients exhibit nervousness, tachycardia, headache, and sympathetic nerve endings (see Figure 6–4). This effect is prob- sweating after omitting one or two doses of the drug. Because of ably responsible for most of the sympathoplegia that occurs in the risk of severe hypertensive crisis when clonidine is suddenly patients. Guanethidine is transported across the sympathetic nerve withdrawn, all patients who take clonidine should be warned of membrane by the same mechanism that transports norepinephrine this possibility. If the drug must be stopped, it should be done itself (NET, uptake 1), and uptake is essential for the drug’s action. gradually while other antihypertensive agents are being substi- Once guanethidine has entered the nerve, it is concentrated in tuted. Treatment of the hypertensive crisis consists of reinstitution transmitter vesicles, where it replaces norepinephrine and causes of clonidine therapy or administration of α- and β-adrenoceptor- a gradual depletion of norepinephrine stores in the nerve ending. blocking agents. 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) GANGLION-BLOCKING AGENTS block its effects. Historically, drugs that block activation of postganglionic auto- nomic neurons by acetylcholine were among the first agents used B. Pharmacokinetics and Dosage in the treatment of hypertension. Most such drugs are no longer Because of guanethidine’s long half-life (5 days), the onset of available clinically because of intolerable toxicities related to their sympathoplegia is gradual (maximal effect in 1–2 weeks), and primary action (see below). sympathoplegia persists for a comparable period after cessation of Ganglion blockers competitively block nicotinic cholinocep- therapy. The dose should not ordinarily be increased at intervals tors on postganglionic neurons in both sympathetic and parasym- shorter than 2 weeks. pathetic ganglia. In addition, these drugs may directly block the nicotinic acetylcholine channel, in the same fashion as neuromus- C. Toxicity cular nicotinic blockers. Therapeutic use of guanethidine is often associated with symp- The adverse effects of ganglion blockers are direct extensions tomatic postural hypotension and hypotension following exercise, of their pharmacologic effects. These effects include both sympa- particularly when the drug is given in high doses. Guanethidine- thoplegia (excessive orthostatic hypotension and sexual dysfunc- induced sympathoplegia in men may be associated with delayed tion) and parasympathoplegia (constipation, urinary retention, or retrograde ejaculation (into the bladder). Guanethidine com- precipitation of glaucoma, blurred vision, dry mouth, etc). These monly causes diarrhea, which results from increased gastrointesti- severe toxicities are the major reason for the abandonment of nal motility due to parasympathetic predominance in controlling ganglion blockers for the therapy of hypertension. the activity of intestinal smooth muscle. 182    SECTION III Cardiovascular-Renal Drugs Interactions with other drugs may complicate guanethidine ADRENOCEPTOR ANTAGONISTS therapy. Sympathomimetic agents, at doses available in over-the- counter cold preparations, can produce hypertension in patients The detailed pharmacology of α- and β-adrenoceptor blockers is taking guanethidine. Similarly, guanethidine can produce hyper- presented in Chapter 10. tensive crisis by releasing catecholamines in patients with pheo- chromocytoma. When tricyclic antidepressants are administered BETA-ADRENOCEPTOR-BLOCKING to patients taking guanethidine, the drug’s antihypertensive effect is attenuated, and severe hypertension may follow. AGENTS Of the large number of β blockers tested, most have been shown Reserpine to be effective in lowering blood pressure. The pharmacologic Reserpine, an alkaloid extracted from the roots of an Indian plant, properties of several of these agents differ in ways that may confer Rauwolfia serpentina, was one of the first effective drugs used on a therapeutic benefits in certain clinical situations. large scale in the treatment of hypertension. At present, it is rarely used owing to its adverse effects. Propranolol Propranolol was the first β blocker shown to be effective in hyper- A. Mechanism and Sites of Action tension and ischemic heart disease. Propranolol has now been Reserpine blocks the ability of aminergic transmitter vesicles to largely replaced by cardioselective β blockers such as metoprolol take up and store biogenic amines, probably by interfering with the and atenolol. All β-adrenoceptor-blocking agents are useful for vesicular membrane-associated transporter (VMAT, see Figure 6–4). lowering blood pressure in mild to moderate hypertension. In severe This effect occurs throughout the body, resulting in depletion of nor- hypertension, β blockers are especially useful in preventing the epinephrine, dopamine, and serotonin in both central and periph- reflex tachycardia that often results from treatment with direct vaso- eral neurons. Chromaffin granules of the adrenal medulla are also dilators. Beta blockers have been shown to reduce mortality after a depleted of catecholamines, although to a lesser extent than are the myocardial infarction and some also reduce mortality in patients vesicles of neurons. Reserpine’s effects on adrenergic vesicles appear with heart failure; they are particularly advantageous for treating irreversible; trace amounts of the drug remain bound to vesicular hypertension in patients with these conditions (see Chapter 13). membranes for many days. Depletion of peripheral amines probably accounts for much A. Mechanism and Sites of Action of the beneficial antihypertensive effect of reserpine, but a central Propranolol’s efficacy in treating hypertension as well as most of component cannot be ruled out. Reserpine readily enters the its toxic effects result from nonselective β blockade. Propranolol brain, and depletion of cerebral amine stores causes sedation, decreases blood pressure primarily as a result of a decrease in mental depression, and parkinsonism symptoms. cardiac output. Other β blockers may decrease cardiac output or At lower doses used for treatment of mild hypertension, reser- decrease peripheral vascular resistance to various degrees, depend- pine lowers blood pressure by a combination of decreased cardiac ing on cardioselectivity and partial agonist activities. output and decreased peripheral vascular resistance. Propranolol inhibits the stimulation of renin production by catecholamines (mediated by β1 receptors). It is likely that propran- B. Pharmacokinetics and Dosage olol’s effect is due in part to depression of the renin-angiotensin- See Table 11–2. aldosterone system. Although most effective in patients with high plasma renin activity, propranolol also reduces blood pressure in C. Toxicity hypertensive patients with normal or even low renin activity. Beta blockers might also act on peripheral presynaptic β adrenoceptors At the low doses usually administered, reserpine produces little to reduce sympathetic vasoconstrictor nerve activity. postural hypotension. Most of the unwanted effects of reserpine In mild to moderate hypertension, propranolol produces a result from actions on the brain or gastrointestinal tract. significant reduction in blood pressure without prominent pos- High doses of reserpine characteristically produce sedation, tural hypotension. lassitude, nightmares, and severe mental depression; occasionally, these occur even in patients receiving low doses (0.25 mg/d). B. Pharmacokinetics and Dosage Much less frequently, ordinary low doses of reserpine produce See Table 11–2. Resting bradycardia and a reduction in the heart extrapyramidal effects resembling Parkinson’s disease, probably as rate during exercise are indicators of propranolol’s β-blocking a result of dopamine depletion in the corpus striatum. Although effect, and changes in these parameters may be used as guides for these central effects are uncommon, it should be stressed that they regulating dosage. Propranolol can be administered twice daily, may occur at any time, even after months of uneventful treatment. and slow-release once-daily preparations are available. Patients with a history of mental depression should not receive reserpine, and the drug should be stopped if depression appears. C. Toxicity Reserpine rather often produces mild diarrhea and gastrointes- The principal toxicities of propranolol result from blockade tinal cramps and increases gastric acid secretion. The drug should of cardiac, vascular, or bronchial β receptors and are described not be given to patients with a history of peptic ulcer. in more detail in Chapter 10. The most important of these  CHAPTER 11 Antihypertensive Agents    183 predictable extensions of the β1-blocking action occur in patients Labetalol, Carvedilol, & Nebivolol with bradycardia or cardiac conduction disease, and those of the These drugs have both β-blocking and vasodilating effects. Labet- β2-blocking action occur in patients with asthma, peripheral alol is formulated as a racemic mixture of four isomers (it has vascular insufficiency, and diabetes. two centers of asymmetry). Two of these isomers—the (S,S)- and When β blockers are discontinued after prolonged regular (R,S)-isomers—are relatively inactive, a third (S,R)- is a potent use, some patients experience a withdrawal syndrome, mani- α blocker, and the last (R,R)- is a potent β blocker. Labetalol fested by nervousness, tachycardia, increased intensity of angina, has a 3:1 ratio of β:α antagonism after oral dosing. Blood pres- and increase of blood pressure. Myocardial infarction has been sure is lowered by reduction of systemic vascular resistance (via reported in a few patients. Although the incidence of these com- α blockade) without significant alteration in heart rate or cardiac plications is probably low, β blockers should not be discontinued output. Because of its combined α- and β-blocking activity, abruptly. The withdrawal syndrome may involve upregulation or labetalol is useful in treating the hypertension of pheochromocy- supersensitivity of β adrenoceptors. toma and hypertensive emergencies. Oral daily doses of labetalol range from 200 to 2400 mg/d. Labetalol is given as repeated Metoprolol & Atenolol intravenous bolus injections of 20–80 mg to treat hypertensive Metoprolol and atenolol, which are cardioselective, are the most emergencies. widely used β blockers in the treatment of hypertension. Meto- Carvedilol, like labetalol, is administered as a racemic mixture. prolol is approximately equipotent to propranolol in inhibiting The S(-) isomer is a nonselective β-adrenoceptor blocker, but stimulation of β1 adrenoceptors such as those in the heart but 50- both S(-) and R(+) isomers have approximately equal α-blocking to 100-fold less potent than propranolol in blocking β2 receptors. potency. The isomers are stereoselectively metabolized in the Relative cardioselectivity is advantageous in treating hypertensive liver, which means that their elimination half-lives may differ. patients who also suffer from asthma, diabetes, or peripheral The average half-life is 7–10 hours. The usual starting dosage vascular disease. Although cardioselectivity is not complete, of carvedilol for ordinary hypertension is 6.25 mg twice daily. metoprolol causes less bronchial constriction than propranolol at Carvedilol reduces mortality in patients with heart failure and is doses that produce equal inhibition of β1-adrenoceptor responses. therefore particularly useful in patients with both heart failure and Metoprolol is extensively metabolized by CYP2D6 with high hypertension. first-pass metabolism. The drug has a relatively short half-life of Nebivolol is a β1-selective blocker with vasodilating properties 4–6 hours, but the extended-release preparation can be dosed once that are not mediated by α blockade. d-Nebivolol has highly selec- daily (Table 11–2). Sustained-release metoprolol is effective in tive β1-blocking effects, while the l-isomer causes vasodilation; reducing mortality from heart failure and is particularly useful in the drug is marketed as a racemic mixture. The vasodilating effect patients with hypertension and heart failure. may be due to an increase in endothelial release of nitric oxide via Atenolol is not extensively metabolized and is excreted primar- induction of endothelial nitric oxide synthase. The hemodynamic ily in the urine with a half-life of 6 hours; it is usually dosed once effects of nebivolol therefore differ from those of pure β block- daily. Atenolol is reported to be less effective than metoprolol in ers in that peripheral vascular resistance is acutely lowered (by preventing the complications of hypertension. A possible reason nebivolol) as opposed to increased acutely (by the older agents). for this difference is that once-daily dosing does not maintain ade- Nebivolol is extensively metabolized and has active metabolites. quate blood levels of atenolol. The usual dosage is 50–100 mg/d. The half-life is 10–12 hours, but the drug can be given once daily. Patients with reduced renal function should receive lower doses. 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 Nadolol, Carteolol, Betaxolol, & Bisoprolol of other antihypertensive agents, but several studies report fewer Nadolol and carteolol, nonselective β-receptor antagonists, are not adverse effects. appreciably metabolized and are excreted to a considerable extent in the urine. Betaxolol and bisoprolol are β1-selective blockers Esmolol that are primarily metabolized in the liver but have long half- Esmolol is a β1-selective blocker that is rapidly metabolized lives. Because of these relatively long half-lives, these drugs can be via hydrolysis by red blood cell esterases. It has a short half-life administered once daily. Nadolol is usually begun at a dosage of (9–10 minutes) and is administered by intravenous infusion. 40 mg/d, carteolol at 2.5 mg/d, betaxolol at 10 mg/d, and bisoprolol Esmolol is generally administered as a loading dose (0.5–1 mg/kg), at 5 mg/d. Increases in dosage to obtain a satisfactory therapeutic followed by a constant infusion. The infusion is typically started at effect should take place no more often than every 4 or 5 days. 50–150 mcg/kg/min, and the dose increased every 5 minutes, up Patients with reduced renal function should receive correspond- to 300 mcg/kg/min, as needed to achieve the desired therapeutic ingly reduced doses of nadolol and carteolol. effect. Esmolol is used for management of intraoperative and post- operative hypertension, and sometimes for hypertensive emergen- Pindolol, Acebutolol, & Penbutolol cies, particularly when hypertension is associated with tachycardia Pindolol, acebutolol, and penbutolol are partial agonists, ie, β or when there is concern about toxicity such as aggravation of blockers with some intrinsic sympathomimetic activity. They lower severe heart failure, in which case a drug with a short duration of blood pressure but are rarely used in hypertension. action that can be discontinued quickly is advantageous. 184    SECTION III Cardiovascular-Renal Drugs PRAZOSIN & OTHER ALPHA1 BLOCKERS β blocker to treat the clonidine withdrawal syndrome, described previously). Their pharmacology is described in Chapter 10. Mechanism & Sites of Action Prazosin, terazosin, and doxazosin produce most of their antihy- VASODILATORS pertensive effects by selectively blocking α1 receptors in arterioles and venules. These agents produce less reflex tachycardia when Mechanism & Sites of Action lowering blood pressure than do nonselective α antagonists such This class of drugs includes the oral vasodilators, hydralazine as phentolamine. Alpha1-receptor selectivity allows norepineph- and minoxidil, which are used for long-term outpatient therapy rine to exert unopposed negative feedback (mediated by presyn- of hypertension; the parenteral vasodilators, nitroprusside and aptic α2 receptors) on its own release (see Chapter 6); in contrast, fenoldopam, which are used to treat hypertensive emergencies; the phentolamine blocks both presynaptic and postsynaptic α recep- calcium channel blockers, which are used in both circumstances; tors, with the result that reflex activation of sympathetic neurons and the nitrates, which are used mainly in ischemic heart disease by phentolamine’s effects produces greater release of transmitter but sometimes also in hypertensive emergencies (Table 11–3). onto β receptors and correspondingly greater cardioacceleration. Chapter 12 contains additional discussion of vasodilators. All the Alpha blockers reduce arterial pressure by dilating both resistance vasodilators that are useful in hypertension relax smooth muscle of and capacitance vessels. As expected, blood pressure is reduced more arterioles, thereby decreasing systemic vascular resistance. Sodium in the upright than in the supine position. Retention of salt and nitroprusside and the nitrates also relax veins. Decreased arterial resis- water occurs when these drugs are administered without a diuretic. tance and decreased mean arterial blood pressure elicit compensatory The drugs are more effective when used in combination with other responses, mediated by baroreceptors and the sympathetic nervous agents, such as a β blocker and a diuretic, than when used alone. system (Figure 11–4), as well as renin, angiotensin, and aldosterone. Owing to their beneficial effects in men with prostatic hyperplasia Because sympathetic reflexes are intact, vasodilator therapy does not and bladder obstruction symptoms, these drugs are used primarily in cause orthostatic hypotension or sexual dysfunction. men with concurrent hypertension and benign prostatic hyperplasia. Vasodilators work best in combination with other antihy- pertensive drugs that oppose the compensatory cardiovascular Pharmacokinetics & Dosage responses. (See Box: Resistant Hypertension & Polypharmacy.) Pharmacokinetic characteristics of prazosin are listed in Table 11–2. Terazosin is also extensively metabolized but undergoes very little HYDRALAZINE first-pass metabolism and has a half-life of 12 hours. Doxazosin has an intermediate bioavailability and a half-life of 22 hours. Hydralazine, a hydrazine derivative, dilates arterioles but not Terazosin can often be given once daily, with doses of veins. It has been available for many years, although it was initially 5–20 mg/d. Doxazosin is usually given once daily starting at thought not to be particularly effective because tachyphylaxis to its 1 mg/d and progressing to 4 mg/d or more as needed. Although antihypertensive effects developed rapidly. The benefits of combi- long-term treatment with these α blockers causes relatively nation therapy are now recognized, and hydralazine may be used little postural hypotension, a precipitous drop in standing blood more effectively, particularly in severe hypertension. The combi- pressure develops in some patients shortly after the first dose nation of hydralazine with nitrates is effective in heart failure and is absorbed. For this reason, the first dose should be small and should be considered in patients with both hypertension and heart should be administered at bedtime. Although the mechanism of failure, especially in African-American patients. this first-dose phenomenon is not clear, it occurs more commonly in patients who are salt- and volume-depleted. Pharmacokinetics & Dosage Aside from the first-dose phenomenon, the reported toxici- Hydralazine is well absorbed and rapidly metabolized by the ties of the α1 blockers are relatively infrequent and mild. These liver during the first pass, so that bioavailability is low (averaging include dizziness, palpitations, headache, and lassitude. Some 25%) and variable among individuals. It is metabolized in part by patients develop a positive test for antinuclear factor in serum acetylation at a rate that appears to be bimodally distributed in the 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 TABLE 11–3 Mechanisms of action of vasodilators. not been shown to confer any benefit on clinical outcomes. Mechanism Examples Release of nitric oxide from drug Nitroprusside, hydralazine, OTHER ALPHA-ADRENOCEPTOR- or endothelium nitrates,1 histamine, acetylcholine BLOCKING AGENTS Reduction of calcium influx Verapamil, diltiazem, nifedipine1 Hyperpolarization of cell Minoxidil, diazoxide The nonselective agents, phentolamine and phenoxybenzamine, membranes through opening of potassium channels are useful in diagnosis and treatment of pheochromocytoma and in other clinical situations associated with exaggerated release Activation of dopamine receptors Fenoldopam of catecholamines (eg, phentolamine may be combined with a 1 See Chapter 12.  CHAPTER 11 Antihypertensive Agents    185 population (see Chapter 4). As a consequence, rapid acetylators Pharmacokinetics & Dosage have greater first-pass metabolism, lower blood levels, and less Pharmacokinetic parameters of minoxidil are listed in Table 11–2. antihypertensive benefit from a given dose than do slow acety- Even more than with hydralazine, the use of minoxidil is associated lators. The half-life of hydralazine ranges from 1.5 to 3 hours, with reflex sympathetic stimulation and sodium and fluid reten- but vascular effects persist longer than do blood concentrations, tion. Minoxidil must be used in combination with a β blocker possibly due to avid binding to vascular tissue. and a loop diuretic. N Toxicity N Tachycardia, palpitations, angina, and edema are observed when N NH2 doses of co-administered β blockers and diuretics are inadequate. H Headache, sweating, and hypertrichosis (the latter particularly Hydralazine bothersome in women) are relatively common. Minoxidil illus- trates how one person’s toxicity may become another person’s Usual dosage ranges from 40 to 200 mg/d. The higher dosage therapy. Topical minoxidil (as Rogaine) is used as a stimulant to was selected as the dose at which there is a small possibility of hair growth for correction of baldness. developing the lupus erythematosus-like syndrome described in the next section. However, higher dosages result in greater vaso- dilation and may be used if necessary. Dosing two or three times SODIUM NITROPRUSSIDE daily provides smooth control of blood pressure. Sodium nitroprusside is a powerful parenterally administered Toxicity vasodilator that is used in treating hypertensive emergencies as well as severe heart failure. Nitroprusside dilates both arterial and The most common adverse effects of hydralazine are headache, venous vessels, resulting in reduced peripheral vascular resistance nausea, anorexia, palpitations, sweating, and flushing. In patients and venous return. The action occurs as a result of activation with ischemic heart disease, reflex tachycardia and sympathetic of guanylyl cyclase, either via release of nitric oxide or by direct stimulation may provoke angina or ischemic arrhythmias. With stimulation of the enzyme. The result is increased intracellular dosages of 400 mg/d or more, there is a 10–20% incidence— cGMP, which relaxes vascular smooth muscle (see Figure 12–2). chiefly in persons who slowly acetylate the drug—of a syndrome In the absence of heart failure, blood pressure decreases, owing characterized by arthralgia, myalgia, skin rashes, and fever that to decreased vascular resistance, whereas cardiac output does not resembles lupus erythematosus. The syndrome is not associated change or decreases slightly. In patients with heart failure and low with renal damage and is reversed by discontinuance of hydrala- cardiac output, output often increases owing to afterload reduction. zine. Peripheral neuropathy and drug fever are other serious but uncommon adverse effects. + NO MINOXIDIL CN– CN– Minoxidil is a very efficacious orally active vasodilator. The effect results from the opening of potassium channels in smooth muscle Fe 2+ membranes by minoxidil sulfate, the active metabolite. Increased potassium permeability stabilizes the membrane at its resting CN– CN– potential and makes contraction less likely. Like hydralazine, min- oxidil dilates arterioles but not veins. Because of its greater poten- CN– tial antihypertensive effect, minoxidil should replace hydralazine Nitroprusside 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 O Nitroprusside is a complex of iron, cyanide groups, and a nitroso H2N N NH2 moiety. It is rapidly metabolized by uptake into red blood cells with release of nitric oxide and cyanide. Cyanide in turn is metab- olized by the mitochondrial enzyme rhodanese, in the presence of N a sulfur donor, to the less toxic thiocyanate. Thiocyanate is dis- N tributed 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 Minoxidil solution is sensitive to light and must therefore be made up fresh 186    SECTION III Cardiovascular-Renal Drugs before each administration and covered with opaque foil. Infusion well characterized. The remainder is excreted unchanged. Its half- solutions should be changed after several hours. Dosage typically life is approximately 24 hours, but the relationship between blood begins at 0.5 mcg/kg/min and may be increased up to 10 mcg/kg/ concentration and hypotensive action is not well established. The min as necessary to control blood pressure. Higher rates of infu- blood pressure-lowering effect after a rapid injection is established sion, if continued for more than an hour, may result in toxicity. within 5 minutes and lasts for 4–12 hours. Because of its efficacy and rapid onset of effect, nitroprusside When diazoxide was first marketed for use in hypertension, a should be administered by infusion pump and arterial blood dose of 300 mg by rapid injection was recommended. It appears, pressure continuously monitored via intra-arterial recording. however, that excessive hypotension can be avoided by beginning with smaller doses (50–150 mg). If necessary, doses of 150 mg Toxicity may be repeated every 5–15 minutes until blood pressure is low- ered satisfactorily. Alternatively, diazoxide may be administered Other than excessive blood pressure lowering, the most serious by intravenous infusion at rates of 15–30 mg/min. Because of toxicity is related to accumulation of cyanide; metabolic acidosis, reduced protein binding, smaller doses should be administered arrhythmias, excessive hypotension, and death have resulted. In a to persons with chronic renal failure. The hypotensive effects of few cases, toxicity after relatively low doses of nitroprusside sug- diazoxide are also greater when patients are pretreated with gested a defect in cyanide metabolism. Administration of sodium β blockers to prevent the reflex tachycardia and associated increase thiosulfate as a sulfur donor facilitates metabolism of cyanide. in cardiac output. Hydroxocobalamin combines with cyanide to form the nontoxic cyanocobalamin. Both have been advocated for prophylaxis or treatment of cyanide poisoning during nitroprusside infusion. Toxicity Thiocyanate may accumulate over the course of prolonged admin- The most significant toxicity from parenteral diazoxide has been istration, usually several days or more, particularly in patients with excessive hypotension, resulting from the original recommenda- renal insufficiency who do not excrete thiocyanate at a normal tion to use a fixed dose of 300 mg in all patients. Such hypoten- rate. Thiocyanate toxicity is manifested as weakness, disorienta- sion has resulted in stroke and myocardial infarction. The reflex tion, psychosis, muscle spasms, and convulsions, and the diagnosis sympathetic response can provoke angina, electrocardiographic is confirmed by finding serum concentrations greater than 10 mg/ evidence of ischemia, and cardiac failure in patients with ischemic dL. Rarely, delayed hypothyroidism occurs, owing to thiocyanate heart disease, and diazoxide should be avoided in this situation. inhibition of iodide uptake by the thyroid. Methemoglobinemia Occasionally, hyperglycemia complicates diazoxide use, particu- during infusion of nitroprusside has also been reported. larly in persons with renal insufficiency. In contrast to the structurally related thiazide diuretics, diazox- ide causes renal salt and water retention. However, because the DIAZOXIDE drug is used for short periods only, this is rarely a problem. 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 FENOLDOPAM was formerly used parenterally to treat hypertensive emergencies. Fenoldopam is a peripheral arteriolar dilator used for hypertensive Injection of diazoxide results in a rapid fall in systemic vascular emergencies and postoperative hypertension. It acts primarily as an resistance and mean arterial blood pressure. At present, it is used agonist of dopamine D1 receptors, resulting in dilation of periph- orally in the USA for the treatment of hypoglycemia in hyperinsu- eral arteries and natriuresis. The commercial product is a racemic linism. Diazoxide inhibits insulin release from the pancreas (prob- mixture with the (R)-isomer mediating the pharmacologic activity. ably by opening potassium channels in the beta cell membrane) Fenoldopam is rapidly metabolized, primarily by conjugation. and is used to treat hypoglycemia secondary to insulinoma. Its half-life is 10 minutes. The drug is administered by continu- N ous intravenous infusion. Fenoldopam is initiated at a low dosage CH3 (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 NH CI S desired blood pressure reduction is achieved. O2 As with other direct vasodilators, the major toxicities are reflex Diazoxide tachycardia, headache, and flushing. Fenoldopam also increases intra- ocular pressure and should be avoided in patients with glaucoma. Pharmacokinetics & Dosage Oral dosage for hypoglycemia is 3–8 mg/kg/day in 3 divided CALCIUM CHANNEL BLOCKERS doses, with a maximum of 15 mg/kg/day. Diazoxide is similar chemically to the thiazide diuretics but has no diuretic activity. In addition to their antianginal (see Chapter 12) and antiarrhyth- It is bound extensively to serum albumin and to vascular tissue. mic effects (see Chapter 14), calcium channel blockers also reduce Diazoxide is partially metabolized; its metabolic pathways are not peripheral resistance and blood pressure. The mechanism of action  CHAPTER 11 Antihypertensive Agents    187 in hypertension (and, in part, in angina) is inhibition of calcium Angiotensin II has vasoconstrictor and sodium-retaining activity. influx into arterial smooth muscle cells. Angiotensin II and III both stimulate aldosterone release. Angio- Verapamil, diltiazem, and the dihydropyridine family (amlo- tensin may contribute to maintaining high vascular resistance in dipine, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, hypertensive states associated with high plasma renin activity, such and nitrendipine [withdrawn in the USA]) are all equally effective as renal arterial stenosis, some types of intrinsic renal disease, and in lowering blood pressure, and many formulations are currently malignant hypertension, as well as in essential hypertension after approved for this use in the USA. Clevidipine is a newer member of treatment with sodium restriction, diuretics, or vasodilators. How- this group that is formulated for intravenous use only. ever, even in low-renin hypertensive states, these drugs can lower Hemodynamic differences among calcium channel blockers blood pressure (see below). may influence the choice of a particular agent. Nifedipine and the A parallel system for angiotensin generation exists in several other dihydropyridine agents are more selective as vasodilators and other tissues (eg, heart) and may be responsible for trophic changes have less cardiac depressant effect than verapamil and diltiazem. such as cardiac hypertrophy. The converting enzyme involved in Reflex sympathetic activation with slight tachycardia maintains or tissue angiotensin II synthesis is also inhibited by ACE inhibitors. increases cardiac output in most patients given dihydropyridines. Three classes of drugs act specifically on the renin-angiotensin Verapamil has the greatest depressant effect on the heart and may system: ACE inhibitors; the competitive inhibitors of angiotensin decrease heart rate and cardiac output. Diltiazem has intermedi- at its receptors, including losartan and other nonpeptide antagonists; ate actions. The pharmacology and toxicity of these drugs are and aliskiren, an orally active renin antagonist (see Chapter 17). A discussed in more detail in Chapter 12. Doses of calcium channel fourth group of drugs, the aldosterone receptor inhibitors (eg, blockers used in treating hypertension are similar to those used in spironolactone, eplerenone), is discussed with the diuretics. In treating angina. Some epidemiologic studies reported an increased addition, β blockers, as noted earlier, can reduce renin secretion. risk of myocardial infarction or mortality in patients receiving short-acting nifedipine for hypertension. It is therefore recom- mended that short-acting oral dihydropyridines not be used for ANGIOTENSIN-CONVERTING ENZYME hypertension. Sustained-release calcium blockers or calcium block- (ACE) INHIBITORS ers with long half-lives provide smoother blood pressure control and are more appropriate for treatment of chronic hypertension. Captopril and other drugs in this class inhibit the converting Intravenous nicardipine and clevidipine are available for the treat- enzyme peptidyl dipeptidase that hydrolyzes angiotensin I to ment of hypertension when oral therapy is not feasible; parenteral angiotensin II and (under the name plasma kininase) inactivates verapamil and diltiazem can also be used for the same indication. bradykinin, a potent vasodilator that works at least in part by Nicardipine is typically infused at rates of 2–15 mg/h. Clevidipine stimulating release of nitric oxide and prostacyclin. The hypoten- is infused starting at 1–2 mg/h and progressing to 4–6 mg/h. It has sive activity of captopril results both from an inhibitory action a rapid onset of action and has been used in acute hypertension on the renin-angiotensin system and a stimulating action on occurring during surgery. Oral short-acting nifedipine has been the kallikrein-kinin system (Figure 11–5). The latter mechanism used in emergency management of severe hypertension. has been demonstrated by showing that a bradykinin receptor antagonist, icatibant (see Chapter 17), blunts the blood pressure- lowering effect of captopril. INHIBITORS OF ANGIOTENSIN Enalapril is an oral prodrug that is converted by hydrolysis to a converting enzyme inhibitor, enalaprilat, with effects similar to Renin, angiotensin, and aldosterone play important roles in those of captopril. Enalaprilat itself is available only for intravenous some people with essential hypertension. Approximately 20% use, primarily for hypertensive emergencies. Lisinopril is a lysine of patients with essential hypertension have inappropriately low derivative of enalaprilat. Benazepril, fosinopril, moexipril, per- and 20% have inappropriately high plasma renin activity. Blood indopril, quinapril, ramipril, and trandolapril are other long- pressure of patients with high-renin hypertension responds well to acting members of the class. All are prodrugs, like enalapril, and are drugs that interfere with the system, supporting a role