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

SECTION III CARDIOVASCULAR-RENAL DRUGS 11 C H A P T E R Antihypertensive Agents Neal L. Benowitz, MD CASE STUDY A 35-year-old man presents with a blood pressure of 150/95 remarkable only for moderate obesity. Total cholesterol is mm Hg. He has been generally healthy, is sedentary, drinks 220, and high-density lipoprotein (HDL) cholesterol level is several cocktails per day, and does not smoke cigarettes. He 40 mg/dL. Fasting glucose is 105 mg/dL. Chest x-ray is nor- has a family history of hypertension, and his father died of a mal. Electrocardiogram shows left ventricular enlargement. myocardial infarction at age 55. Physical examination is How would you treat this patient? Hypertension is the most common cardiovascular disease. In a in combination, can lower blood pressure with minimal risk of survey carried out in 2007/2008, hypertension was found in 29% serious toxicity in most patients. of American adults. The prevalence varies with age, race, educa- tion, and many other variables. According to some studies, 60–80% of both men and women will develop hypertension by age 80. Sustained arterial hypertension damages blood vessels in HYPERTENSION & REGULATION OF kidney, heart, and brain and leads to an increased incidence of BLOOD PRESSURE renal failure, coronary disease, heart failure, stroke, and dementia. Effective pharmacologic lowering of blood pressure has been Diagnosis shown to prevent damage to blood vessels and to substantially The diagnosis of hypertension is based on repeated, reproducible reduce morbidity and mortality rates. Unfortunately, several sur- measurements of elevated blood pressure (Table 11–1). The diagno- veys indicate that only one third to one half of Americans with sis serves primarily as a prediction of consequences for the patient; hypertension have adequate blood pressure control. Many effec- it seldom includes a statement about the cause of hypertension. tive drugs are available. Knowledge of their antihypertensive Epidemiologic studies indicate that the risks of damage to mechanisms and sites of action allows accurate prediction of effi- kidney, heart, and brain are directly related to the extent of blood cacy and toxicity. As a result, rational use of these agents, alone or pressure elevation. Even mild hypertension (blood pressure 169 170 SECTION III Cardiovascular-Renal Drugs TABLE 11–1 Classification of hypertension on the contributing to the development of hypertension. Increase in blood basis of blood pressure. pressure with aging does not occur in populations with low daily sodium intake. Patients with labile hypertension appear more likely Systolic/Diastolic Pressure than normal controls to have blood pressure elevations after salt (mm Hg) Category loading. < 120/80 Normal The heritability of essential hypertension is estimated to be 120–135/80–89 Prehypertension about 30%. Mutations in several genes have been linked to various ≥ 140/90 Hypertension rare causes of hypertension. Functional variations of the genes for 140–159/90–99 Stage 1 angiotensinogen, angiotensin-converting enzyme (ACE), the β2 adrenoceptor, and α adducin (a cytoskeletal protein) appear to ≥ 160/100 Stage 2 contribute to some cases of essential hypertension. From the Joint National Committee on prevention, detection, evaluation, and treat- ment of high blood pressure. JAMA 2003;289:2560. Normal Regulation of Blood Pressure According to the hydraulic equation, arterial blood pressure (BP) 140/90 mm Hg) increases the risk of eventual end-organ damage. is directly proportionate to the product of the blood flow (cardiac Starting at 115/75 mm Hg, cardiovascular disease risk doubles output, CO) and the resistance to passage of blood through pre- with each increment of 20/10 mm Hg throughout the blood pres- capillary arterioles (peripheral vascular resistance, PVR): sure range. Both systolic hypertension and diastolic hypertension 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 of Physiologically, in both normal and hypertensive individuals, blood pressure elevation. The risk of end-organ damage at any blood pressure is maintained by moment-to-moment regulation level of blood pressure or age is greater in African Americans and of cardiac output and peripheral vascular resistance, exerted at relatively less in premenopausal women than in men. Other posi- three anatomic sites (Figure 11–1): arterioles, postcapillary venules tive risk factors include smoking; metabolic syndrome, including (capacitance vessels), and heart. A fourth anatomic control site, obesity, dyslipidemia, and diabetes; manifestations of end-organ the kidney, contributes to maintenance of blood pressure by regu- damage at the time of diagnosis; and a family history of cardiovas- lating the volume of intravascular fluid. Baroreflexes, mediated by cular disease. autonomic nerves, act in combination with humoral mechanisms, It should be noted that the diagnosis of hypertension depends including the renin-angiotensin-aldosterone system, to coordinate on measurement of blood pressure and not on symptoms reported function at these four control sites and to maintain normal blood by the patient. In fact, hypertension is usually asymptomatic until pressure. Finally, local release of vasoactive substances from vascu- overt end-organ damage is imminent or has already occurred. lar endothelium may also be involved in the regulation of vascular Etiology of Hypertension A specific cause of hypertension can be established in only 10–15% of patients. Patients in whom no specific cause of hyper- tension can be found are said to have essential or primary hyper- 2. Capacitance tension. Patients with a specific etiology are said to have secondary Venules 3. Pump output hypertension. It is important to consider specific causes in each Heart case, however, because some of them are amenable to definitive surgical treatment: renal artery constriction, coarctation of the aorta, pheochromocytoma, Cushing’s disease, and primary CNS– aldosteronism. Sympathetic nerves In most cases, elevated blood pressure is associated with an over- all increase in resistance to flow of blood through arterioles, whereas 4. Volume Kidneys cardiac output is usually normal. Meticulous investigation of auto- 1. Resistance nomic nervous system function, baroreceptor reflexes, the renin- Arterioles angiotensin-aldosterone system, and the kidney has failed to identify a single abnormality as the cause of increased peripheral vascular Renin resistance in essential hypertension. It appears, therefore, that ele- vated blood pressure is usually caused by a combination of several (multifactorial) abnormalities. Epidemiologic evidence points to Aldosterone Angiotensin genetic factors, psychological stress, and environmental and dietary factors (increased salt and decreased potassium or calcium intake) as FIGURE 11–1 Anatomic sites of blood pressure control.  CHAPTER 11 Antihypertensive Agents 171 resistance. For example, endothelin-1 (see Chapter 17) constricts B. Renal Response to Decreased Blood Pressure and nitric oxide (see Chapter 19) 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 activity volume-pressure control systems appear to be “set” at a higher (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 resis- tance vessels and (2) stimulation of aldosterone synthesis in the A. Postural Baroreflex adrenal cortex, which increases renal sodium absorption and intra- Baroreflexes are responsible for rapid, moment-to-moment adjust- vascular blood volume. Vasopressin released from the posterior ments in blood pressure, such as in transition from a reclining to pituitary gland also plays a role in maintenance of blood pressure an upright posture (Figure 11–2). Central sympathetic neurons through its ability to regulate water reabsorption by the kidney arising from the vasomotor area of the medulla are tonically active. (see Chapters 15 and 17). Carotid baroreceptors are stimulated by the stretch of the vessel walls brought about by the internal pressure (arterial blood pres- sure). Baroreceptor activation inhibits central sympathetic dis- charge. Conversely, reduction in stretch results in a reduction in BASIC PHARMACOLOGY OF baroreceptor activity. Thus, in the case of a transition to upright ANTIHYPERTENSIVE AGENTS posture, baroreceptors sense the reduction in arterial pressure that results from pooling of blood in the veins below the level of the All antihypertensive agents act at one or more of the four ana- heart as reduced wall stretch, and sympathetic discharge is disin- tomic control sites depicted in Figure 11–1 and produce their hibited. The reflex increase in sympathetic outflow acts through effects by interfering with normal mechanisms of blood pressure nerve endings to increase peripheral vascular resistance (constric- regulation. A useful classification of these agents categorizes them tion of arterioles) and cardiac output (direct stimulation of the according to the principal regulatory site or mechanism on which heart and constriction of capacitance vessels, which increases they act (Figure 11–3). Because of their common mechanisms of venous return to the heart), thereby restoring normal blood pres- action, drugs within each category tend to produce a similar spec- sure. The same baroreflex acts in response to any event that lowers trum of toxicities. The categories include the following: arterial pressure, including a primary reduction in peripheral vas- cular resistance (eg, caused by a vasodilating agent) or a reduction 1. Diuretics, which lower blood pressure by depleting the body in intravascular volume (eg, due to hemorrhage or to loss of salt of sodium and reducing blood volume and perhaps by other 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 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. 172 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). 3. Direct vasodilators, which reduce pressure by relaxing vascu- WATER BALANCE lar smooth muscle, thus dilating resistance vessels and—to Dietary sodium restriction has been known for many years to decrease varying degrees—increasing capacitance as well. blood pressure in hypertensive patients. With the advent of diuretics, 4. Agents that block production or action of angiotensin and sodium restriction was thought to be less important. However, there thereby reduce peripheral vascular resistance and (potentially) is now general agreement that dietary control of blood pressure is a blood volume. relatively nontoxic therapeutic measure and may even be preventive. The fact that these drug groups act by different mechanisms Even modest dietary sodium restriction lowers blood pressure (though permits the combination of drugs from two or more groups with to varying extents) in many hypertensive persons.  CHAPTER 11 Antihypertensive Agents 173 Resistant Hypertension & Polypharmacy Monotherapy of hypertension (treatment with a single drug) is their use. Many studies of angiotensin-converting enzyme (ACE) desirable because compliance is likely to be better and cost is inhibitors report a maximal lowering of blood pressure of less lower, and because in some cases adverse effects are fewer. than 10 mm Hg. In patients with stage 2 hypertension (pressure However, most patients with hypertension require two or more > 160/100 mm Hg), this is inadequate to prevent all the sequelae drugs, preferably acting by different mechanisms (polyphar- of hypertension, but ACE inhibitors have important long-term macy). According to some estimates, up to 40% of patients may benefits in preventing or reducing renal disease in diabetic per- respond inadequately even to two agents and are considered to sons, and reduction of heart failure. have “resistant hypertension.” Some of these patients have treat- Finally, the toxicity of some effective drugs prevents their able secondary hypertension that has been missed, but most do use at maximally effective dosage. The widespread indiscrimi- not and three or more drugs are required. nate use of β blockers has been criticized because several large One rationale for polypharmacy in hypertension is that most clinical trials indicate that some members of the group, eg, drugs evoke compensatory regulatory mechanisms for maintain- metoprolol and carvedilol, have a greater benefit than others, ing blood pressure (see Figures 6–7 and 11–1), which may mark- eg, atenolol. However, all β blockers appear to have similar ben- edly limit their effect. For example, vasodilators such as efits in reducing mortality after myocardial infarction, so these hydralazine cause a significant decrease in peripheral vascular drugs are particularly indicated in patients with an infarct and resistance, but evoke a strong compensatory tachycardia and hypertension. salt and water retention (Figure 11–4) that is capable of almost In practice, when hypertension does not respond adequately completely reversing their effect. The addition of a β blocker to a regimen of one drug, a second drug from a different class prevents the tachycardia; addition of a diuretic (eg, hydrochloro- with a different mechanism of action and different pattern of thiazide) prevents the salt and water retention. In effect, all three toxicity is added. If the response is still inadequate and compli- drugs increase the sensitivity of the cardiovascular system to ance is known to be good, a third drug should be added. If three each other’s actions. drugs (usually including a diuretic) are inadequate, dietary A second reason is that some drugs have only modest maxi- sodium restriction and an additional drug may be necessary. mum efficacy but reduction of long-term morbidity mandates Mechanisms of Action & Hemodynamic when blood volume is 95% of normal but much too high when blood volume is 105% of normal. Effects of Diuretics Diuretics lower blood pressure primarily by depleting body sodium stores. Initially, diuretics reduce blood pressure by reducing blood Use of Diuretics volume and cardiac output; peripheral vascular resistance may The sites of action within the kidney and the pharmacokinetics of increase. After 6–8 weeks, cardiac output returns toward normal various diuretic drugs are discussed in Chapter 15. Thiazide while peripheral vascular resistance declines. Sodium is believed to diuretics are appropriate for most patients with mild or moderate contribute to vascular resistance by increasing vessel stiffness and hypertension and normal renal and cardiac function. More power- neural reactivity, possibly related to altered sodium-calcium ful diuretics (eg, those acting on the loop of Henle) such as furo- exchange with a resultant increase in intracellular calcium. These semide are necessary in severe hypertension, when multiple drugs effects are reversed by diuretics or sodium restriction. with sodium-retaining properties are used; in renal insufficiency, Diuretics are effective in lowering blood pressure by 10–15 mm Hg when glomerular filtration rate is less than 30 or 40 mL/min; and in most patients, and diuretics alone often provide adequate treat- in cardiac failure or cirrhosis, in which sodium retention is ment for mild or moderate essential hypertension. In more severe marked. hypertension, diuretics are used in combination with sympathople- Potassium-sparing diuretics are useful both to avoid excessive gic and vasodilator drugs to control the tendency toward sodium potassium depletion and to enhance the natriuretic effects of retention caused by these agents. Vascular responsiveness—ie, the other diuretics. Aldosterone receptor antagonists in particular ability to either constrict or dilate—is diminished by sympathople- also have a favorable effect on cardiac function in people with gic and vasodilator drugs, so that the vasculature behaves like an heart failure. inflexible tube. As a consequence, blood pressure becomes exqui- Some pharmacokinetic characteristics and the initial and usual sitely sensitive to blood volume. Thus, in severe hypertension, when maintenance dosages of hydrochlorothiazide are listed in Table multiple drugs are used, blood pressure may be well controlled 11–2. Although thiazide diuretics are more natriuretic at higher 174 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. doses (up to 100–200 mg of hydrochlorothiazide), when used hyperkalemia, particularly in patients with renal insufficiency and as a single agent, lower doses (25–50 mg) exert as much anti- those taking ACE inhibitors or angiotensin receptor blockers; hypertensive effect as do higher doses. In contrast to thiazides, spironolactone (a steroid) is associated with gynecomastia. the blood pressure 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 In the treatment of hypertension, the most common adverse effect part by sympathetic neural activation. In patients with moderate to of diuretics (except for potassium-sparing diuretics) is potassium severe hypertension, most effective drug regimens include an depletion. Although mild degrees of hypokalemia are tolerated well agent that inhibits function of the sympathetic nervous system. by many patients, hypokalemia may be hazardous in persons taking Drugs in this group are classified according to the site at which digitalis, those who have chronic arrhythmias, or those with acute they impair the sympathetic reflex arc (Figure 11–2). This neuro- myocardial infarction or left ventricular dysfunction. Potassium anatomic classification explains prominent differences in cardiovas- loss is coupled to reabsorption of sodium, and restriction of dietary cular effects of drugs and allows the clinician to predict interactions sodium intake therefore minimizes potassium loss. Diuretics may of these drugs with one another and with other drugs. also cause magnesium depletion, impair glucose tolerance, and The subclasses of sympathoplegic drugs exhibit different pat- increase serum lipid concentrations. Diuretics increase uric acid terns of potential toxicity. Drugs that lower blood pressure by concentrations and may precipitate gout. The use of low doses actions on the central nervous system tend to cause sedation and minimizes these adverse metabolic effects without impairing the mental depression and may produce disturbances of sleep, includ- antihypertensive action. Potassium-sparing diuretics may produce ing nightmares. Drugs that act by inhibiting transmission through  CHAPTER 11 Antihypertensive Agents 175 TABLE 11–2 Pharmacokinetic characteristics and dosage of selected oral antihypertensive drugs. Bioavailability Suggested Usual Maintenance Reduction of Dosage Required in Drug Half-life (h) (percent) Initial Dose Dose Range 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 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 Guanethidine 120 3–50 10 mg/d 25–50 mg/d Possible 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 3 Losartan 1–2 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. autonomic ganglia (ganglion blockers) produce toxicity from CENTRALLY ACTING inhibition of parasympathetic regulation, in addition to profound sympathetic blockade and are no longer used. Drugs that act SYMPATHOPLEGIC DRUGS chiefly by reducing release of norepinephrine from sympathetic Centrally acting sympathoplegic drugs were once widely used in nerve endings cause effects that are similar to those of surgical the treatment of hypertension. With the exception of clonidine, sympathectomy, including inhibition of ejaculation, and hypoten- these drugs are rarely used today. sion 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 Mechanisms & Sites of Action they bind. Although not discussed in this chapter, it should be These agents reduce sympathetic outflow from vasomotor centers noted that renal sympathetic denervation is effective in lowering in the brainstem but allow these centers to retain or even increase blood pressure in patients with hypertension resistant to antihyper- their sensitivity to baroreceptor control. Accordingly, the antihy- tensive drugs. pertensive and toxic actions of these drugs are generally less depen- Finally, one should note that all of the agents that lower blood dent on posture than are the effects of drugs that act directly on pressure by altering sympathetic function can elicit compensatory peripheral sympathetic neurons. effects through mechanisms that are not dependent on adrenergic Methyldopa (L-α-methyl-3,4-dihydroxyphenylalanine) is an nerves. Thus, the antihypertensive effect of any of these agents analog of L-dopa and is converted to α-methyldopamine and used alone may be limited by retention of sodium by the kidney α-methylnorepinephrine; this pathway directly parallels the synthesis and expansion of blood volume. For this reason, sympathoplegic of norepinephrine from dopa illustrated in Figure 6–5. Alpha- antihypertensive drugs are most effective when used concomi- methylnorepinephrine is stored in adrenergic nerve vesicles, where it tantly with a diuretic. stoichiometrically replaces norepinephrine, and is released by nerve 176 SECTION III Cardiovascular-Renal Drugs stimulation to interact with postsynaptic adrenoceptors. However, dependent on posture. Postural (orthostatic) hypotension some- this replacement of norepinephrine by a false transmitter in periph- times occurs, particularly in volume-depleted patients. One eral neurons is not responsible for methyldopa’s antihypertensive potential advantage of methyldopa is that it causes reduction in effect, because the α-methylnorepinephrine released is an effective renal vascular resistance. agonist at the α adrenoceptors that mediate peripheral sympathetic OH constriction of arterioles and venules. In fact, methyldopa’s antihy- HO pertensive action appears to be due to stimulation of central α adre- C O noceptors by α-methylnorepinephrine or α-methyldopamine. HO CH2 C NH2 The antihypertensive action of clonidine, a 2-imidazoline derivative, was discovered in the course of testing the drug for use CH3 as a nasal decongestant. α-Methyldopa (α-methyl group in color) 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 Pharmacokinetics & Dosage because it also inhibits pressor effects of other α agonists. Pharmacokinetic characteristics of methyldopa are listed in Considerable evidence indicates that the hypotensive effect of Table 11–2. Methyldopa enters the brain via an aromatic amino clonidine is exerted at α adrenoceptors in the medulla of the acid transporter. The usual oral dose of methyldopa produces its brain. In animals, the hypotensive effect of clonidine is prevented maximal antihypertensive effect in 4–6 hours, and the effect can by central administration of α antagonists. Clonidine reduces persist for up to 24 hours. Because the effect depends on accumu- sympathetic and increases parasympathetic tone, resulting in lation and storage of a metabolite (α-methylnorepinephrine) in blood pressure lowering and bradycardia. The reduction in pres- the vesicles of nerve endings, the action persists after the parent sure is accompanied by a decrease in circulating catecholamine drug has disappeared from the circulation. levels. These observations suggest that clonidine sensitizes brain- stem vasomotor centers to inhibition by baroreflexes. Toxicity Thus, studies of clonidine and methyldopa suggest that nor- mal regulation of blood pressure involves central adrenergic The most common undesirable effect of methyldopa is sedation, neurons that modulate baroreceptor reflexes. Clonidine and α- particularly at the onset of treatment. With long-term therapy, methylnorepinephrine bind more tightly to α2 than to α1 adreno- patients may complain of persistent mental lassitude and impaired ceptors. As noted in Chapter 6, α2 receptors are located on mental concentration. Nightmares, mental depression, vertigo, presynaptic adrenergic neurons as well as some postsynaptic sites. and extrapyramidal signs may occur but are relatively infrequent. It is possible that clonidine and α-methylnorepinephrine act in Lactation, associated with increased prolactin secretion, can occur the brain to reduce norepinephrine release onto relevant receptor both in men and in women treated with methyldopa. This toxicity sites. Alternatively, these drugs may act on postsynaptic α2 adre- is probably mediated by inhibition of dopaminergic mechanisms noceptors to inhibit activity of appropriate neurons. Finally, cloni- in the hypothalamus. dine also binds to a nonadrenoceptor site, the imidazoline Other important adverse effects of methyldopa are develop- receptor, which may also mediate antihypertensive effects. ment of a positive Coombs test (occurring in 10–20% of patients Methyldopa and clonidine produce slightly different hemody- undergoing therapy for longer than 12 months), which sometimes namic effects: clonidine lowers heart rate and cardiac output more than makes cross-matching blood for transfusion difficult and rarely is does methyldopa. This difference suggests that these two drugs do not associated with hemolytic anemia, as well as hepatitis and drug have identical sites of action. They may act primarily on different fever. Discontinuation of the drug usually results in prompt rever- populations of neurons in the vasomotor centers of the brainstem. sal of these abnormalities. Guanabenz and guanfacine are centrally active antihyperten- sive drugs that share the central α-adrenoceptor–stimulating effects of clonidine. They do not appear to offer any advantages CLONIDINE over clonidine and are rarely used. Blood pressure lowering by clonidine results from reduction of cardiac output due to decreased heart rate and relaxation of capaci- tance vessels, as well as a reduction in peripheral vascular resistance. METHYLDOPA CI Methyldopa was widely used in the past but is now used primarily N for hypertension during pregnancy. It lowers blood pressure NH chiefly by reducing peripheral vascular resistance, with a variable N reduction in heart rate and cardiac output. CI Most cardiovascular reflexes remain intact after administration of methyldopa, and blood pressure reduction is not markedly Clonidine  CHAPTER 11 Antihypertensive Agents 177 Reduction in arterial blood pressure by clonidine is accompa- ganglia. In addition, these drugs may directly block the nicotinic nied by decreased renal vascular resistance and maintenance of acetylcholine channel, in the same fashion as neuromuscular nico- renal blood flow. As with methyldopa, clonidine reduces blood tinic blockers (see Figure 27–6). pressure in the supine position and only rarely causes postural The adverse effects of ganglion blockers are direct extensions of hypotension. Pressor effects of clonidine are not observed after their pharmacologic effects. These effects include both sym- ingestion of therapeutic doses of clonidine, but severe hyperten- pathoplegia (excessive orthostatic hypotension and sexual dys- sion can complicate a massive overdose. function) and parasympathoplegia (constipation, urinary retention, precipitation of glaucoma, blurred vision, dry mouth, etc). These Pharmacokinetics & Dosage severe toxicities are the major reason for the abandonment of ganglion blockers for the therapy of hypertension. 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 ADRENERGIC NEURON-BLOCKING its antihypertensive effect is directly related to blood concentration, AGENTS oral clonidine must be given twice a day (or as a patch, below) to maintain smooth blood pressure control. However, as is not the These drugs lower blood pressure by preventing normal physio- case with methyldopa, the dose-response curve of clonidine is such logic release of norepinephrine from postganglionic sympathetic that increasing doses are more effective (but also more toxic). neurons. 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 but is often associated with local skin reactions. In high enough doses, guanethidine can produce profound sym- pathoplegia. The resulting high maximal efficacy of this agent made it the mainstay of outpatient therapy of severe hypertension for many Toxicity years. For the same reason, guanethidine can produce all of the tox- Dry mouth and sedation are common. Both effects are centrally icities expected from “pharmacologic sympathectomy,” including mediated and dose-dependent and coincide temporally with the marked postural hypotension, diarrhea, and impaired ejaculation. drug’s antihypertensive effect. Because of these adverse effects, guanethidine is now rarely used. Clonidine should not be given to patients who are at risk for Guanethidine is too polar to enter the central nervous system. mental depression and should be withdrawn if depression occurs As a result, this drug has none of the central effects seen with many during therapy. Concomitant treatment with tricyclic antidepres- of the other antihypertensive agents described in this chapter. sants may block the antihypertensive effect of clonidine. The Guanadrel is a guanethidine-like drug that is available in the interaction is believed to be due to α-adrenoceptor–blocking USA. Bethanidine and debrisoquin, antihypertensive agents not actions of the tricyclics. available for clinical use in the USA, are similar. Withdrawal of clonidine after protracted use, particularly with high dosages (more than 1 mg/d), can result in life-threatening A. Mechanism and Sites of Action hypertensive crisis mediated by increased sympathetic nervous Guanethidine inhibits the release of norepinephrine from sympa- activity. Patients exhibit nervousness, tachycardia, headache, and thetic nerve endings (see Figure 6–4). This effect is probably sweating after omitting one or two doses of the drug. Because of responsible for most of the sympathoplegia that occurs in patients. the risk of severe hypertensive crisis when clonidine is suddenly Guanethidine is transported across the sympathetic nerve mem- withdrawn, all patients who take clonidine should be warned of brane by the same mechanism that transports norepinephrine the 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. Because it of clonidine therapy or administration of α- and β-adrenoceptor– replaces norepinephrine, the drug causes a gradual depletion of blocking agents. norepinephrine stores in the nerve ending. Because neuronal uptake is necessary for the hypotensive activ- GANGLION-BLOCKING AGENTS ity of guanethidine, drugs that block the catecholamine uptake process or displace amines from the nerve terminal (see Chapter 6) Historically, drugs that block activation of postganglionic auto- block its effects. These include cocaine, amphetamine, tricyclic nomic neurons by acetylcholine were among the first agents used antidepressants, phenothiazines, and phenoxybenzamine. in the treatment of hypertension. Most such drugs are no longer available clinically because of intolerable toxicities related to their B. Pharmacokinetics and Dosage primary action (see below). Because of guanethidine’s long half-life (5 days), the onset of sym- Ganglion blockers competitively block nicotinic cholinoceptors pathoplegia is gradual (maximal effect in 1–2 weeks), and sym- on postganglionic neurons in both sympathetic and parasympathetic pathoplegia persists for a comparable period after cessation of 178 SECTION III Cardiovascular-Renal Drugs therapy. The dose should not ordinarily be increased at intervals High doses of reserpine characteristically produce sedation, shorter than 2 weeks. lassitude, nightmares, and severe mental depression; occasionally, these occur even in patients receiving low doses (0.25 mg/d). C. Toxicity Much less frequently, ordinary low doses of reserpine produce Therapeutic use of guanethidine is often associated with symp- extrapyramidal effects resembling Parkinson’s disease, probably as tomatic postural hypotension and hypotension following exercise, a result of dopamine depletion in the corpus striatum. Although particularly when the drug is given in high doses. Guanethidine- these central effects are uncommon, it should be stressed that induced sympathoplegia in men may be associated with delayed or they may occur at any time, even after months of uneventful retrograde ejaculation (into the bladder). Guanethidine com- treatment. Patients with a history of mental depression should monly causes diarrhea, which results from increased gastrointesti- not receive reserpine, and the drug should be stopped if depres- nal motility due to parasympathetic predominance in controlling sion appears. the activity of intestinal smooth muscle. Reserpine rather often produces mild diarrhea and gastrointes- Interactions with other drugs may complicate guanethidine tinal cramps and increases gastric acid secretion. The drug should therapy. Sympathomimetic agents, at doses available in over-the- not be given to patients with a history of peptic ulcer. counter cold preparations, can produce hypertension in patients taking guanethidine. Similarly, guanethidine can produce hyper- tensive crisis by releasing catecholamines in patients with pheo- ADRENOCEPTOR ANTAGONISTS chromocytoma. When tricyclic antidepressants are administered The detailed pharmacology of α- and β-adrenoceptor blockers is to patients taking guanethidine, the drug’s antihypertensive effect presented in Chapter 10. is attenuated, and severe hypertension may follow. Reserpine BETA-ADRENOCEPTOR–BLOCKING Reserpine, an alkaloid extracted from the roots of an Indian plant, AGENTS Rauwolfia serpentina, was one of the first effective drugs used on a Of the large number of β blockers tested, most have been shown large scale in the treatment of hypertension. At present, it is rarely to be effective in lowering blood pressure. The pharmacologic used owing to its adverse effects. properties of several of these agents differ in ways that may confer therapeutic benefits in certain clinical situations. 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 Propranolol vesicular membrane-associated transporter (VMAT, see Figure 6–4). Propranolol was the first β blocker shown to be effective in hyper- This effect occurs throughout the body, resulting in depletion of tension and ischemic heart disease. Propranolol has now been norepinephrine, dopamine, and serotonin in both central and largely replaced by cardioselective β blockers such as metoprolol peripheral neurons. Chromaffin granules of the adrenal medulla and atenolol. All β-adrenoceptor–blocking agents are useful for are also depleted of catecholamines, although to a lesser extent lowering blood pressure in mild to moderate hypertension. In than are the vesicles of neurons. Reserpine’s effects on adrenergic severe hypertension, β blockers are especially useful in preventing vesicles appear irreversible; trace amounts of the drug remain the reflex tachycardia that often results from treatment with direct bound to vesicular membranes for many days. vasodilators. Beta blockers have been shown to reduce mortality Depletion of peripheral amines probably accounts for much of after a myocardial infarction and some also reduce mortality in the beneficial antihypertensive effect of reserpine, but a central patients with heart failure; they are particularly advantageous for component cannot be ruled out. Reserpine readily enters the treating hypertension in patients with these conditions (see brain, and depletion of cerebral amine stores causes sedation, Chapter 13). mental depression, and parkinsonism symptoms. At lower doses used for treatment of mild hypertension, reser- A. Mechanism and Sites of Action pine lowers blood pressure by a combination of decreased cardiac Propranolol’s efficacy in treating hypertension as well as most of output and decreased peripheral vascular resistance. its toxic effects result from nonselective β blockade. Propranolol decreases blood pressure primarily as a result of a decrease in car- B. Pharmacokinetics and Dosage diac output. Other β blockers may decrease cardiac output or See Table 11–2. decrease peripheral vascular resistance to various degrees, depend- ing on cardioselectivity and partial agonist activities. C. Toxicity Propranolol inhibits the stimulation of renin production by At the low doses usually administered, reserpine produces little catecholamines (mediated by β1 receptors). It is likely that propra- postural hypotension. Most of the unwanted effects of reserpine nolol’s effect is due in part to depression of the renin-angiotensin- result from actions on the brain or gastrointestinal tract. aldosterone system. Although most effective in patients with high  CHAPTER 11 Antihypertensive Agents 179 plasma renin activity, propranolol also reduces blood pressure in Nadolol, Carteolol, Betaxolol, & Bisoprolol hypertensive patients with normal or even low renin activity. Beta Nadolol and carteolol, nonselective β-receptor antagonists, are not blockers might also act on peripheral presynaptic β adrenoceptors appreciably metabolized and are excreted to a considerable extent to reduce sympathetic vasoconstrictor nerve activity. in the urine. Betaxolol and bisoprolol are β1-selective blockers that In mild to moderate hypertension, propranolol produces a are primarily metabolized in the liver but have long half-lives. significant reduction in blood pressure without prominent pos- Because of these relatively long half-lives, these drugs can be tural hypotension. 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 biso- B. Pharmacokinetics and Dosage prolol at 5 mg/d. Increases in dosage to obtain a satisfactory See Table 11–2. Resting bradycardia and a reduction in the heart therapeutic effect should take place no more often than every 4 or rate during exercise are indicators of propranolol’s β-blocking 5 days. Patients with reduced renal function should receive corre- effect, and changes in these parameters may be used as guides for spondingly reduced doses of nadolol and carteolol. regulating dosage. Propranolol can be administered twice daily, and slow-release preparations are available. Pindolol, Acebutolol, & Penbutolol C. Toxicity Pindolol, acebutolol, and penbutolol are partial agonists, ie, β The principal toxicities of propranolol result from blockade of blockers with some intrinsic sympathomimetic activity. They cardiac, vascular, or bronchial β receptors and are described in lower blood pressure by decreasing vascular resistance and appear more detail in Chapter 10. The most important of these predict- to depress cardiac output or heart rate less than other β blockers, able extensions of the β-blocking action occur in patients with perhaps because of significantly greater agonist than antagonist bradycardia or cardiac conduction disease, asthma, peripheral effects at β2 receptors. This may be particularly beneficial for vascular insufficiency, and diabetes. patients with bradyarrhythmias or peripheral vascular disease. When propranolol is discontinued after prolonged regular use, Daily doses of pindolol start at 10 mg; of acebutolol, at 400 mg; some patients experience a withdrawal syndrome, manifested by and of penbutolol, at 20 mg. nervousness, tachycardia, increased intensity of angina, and increase of blood pressure. Myocardial infarction has been Labetalol, Carvedilol, & Nebivolol reported in a few patients. Although the incidence of these com- These drugs have both β-blocking and vasodilating effects. plications is probably low, propranolol should not be discontinued Labetalol is formulated as a racemic mixture of four isomers (it abruptly. The withdrawal syndrome may involve up-regulation or has two centers of asymmetry). Two of these isomers—the (S,S)- supersensitivity of β adrenoceptors. 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. Metoprolol & Atenolol Labetalol has a 3:1 ratio of β:α antagonism after oral dosing. Metoprolol and atenolol, which are cardioselective, are the most Blood pressure is lowered by reduction of systemic vascular resis- widely used β blockers in the treatment of hypertension. tance (via α blockade) without significant alteration in heart rate Metoprolol is approximately equipotent to propranolol in inhibit- or cardiac output. Because of its combined α- and β-blocking ing stimulation of β1 adrenoceptors such as those in the heart but activity, labetalol is useful in treating the hypertension of pheo- 50- to 100-fold less potent than propranolol in blocking β2 receptors. chromocytoma and hypertensive emergencies. Oral daily doses of Relative cardioselectivity may be advantageous in treating hyper- labetalol range from 200 to 2400 mg/d. Labetalol is given as tensive patients who also suffer from asthma, diabetes, or periph- repeated intravenous bolus injections of 20–80 mg to treat hyper- eral vascular disease. Although cardioselectivity is not complete, tensive emergencies. metoprolol causes less bronchial constriction than propranolol at Carvedilol, like labetalol, is administered as a racemic mixture. doses that produce equal inhibition of β1-adrenoceptor responses. The S(–) isomer is a nonselective β-adrenoceptor blocker, but both Metoprolol is extensively metabolized by CYP2D6 with high first- S(–) and R(+) isomers have approximately equal α-blocking pass metabolism. The drug has a relatively short half-life of 4–6 potency. The isomers are stereoselectively metabolized in the liver, hours, but the extended-release preparation can be dosed once which means that their elimination half-lives may differ. The aver- daily (Table 11–2). Sustained-release metoprolol is effective in age half-life is 7–10 hours. The usual starting dosage of carvedilol reducing mortality from heart failure and is particularly useful in for ordinary hypertension is 6.25 mg twice daily. Carvedilol reduces patients with hypertension and heart failure. mortality in patients with heart failure and is therefore particularly Atenolol is not extensively metabolized and is excreted primarily useful in patients with both heart failure and hypertension. in the urine with a half-life of 6 hours; it is usually dosed once daily. Nebivolol is a β1-selective blocker with vasodilating properties Recent studies have found atenolol less effective than metoprolol in that are not mediated by α blockade. D-Nebivolol has highly selec- preventing the complications of hypertension. A possible reason for tive β1 blocking effects, while the L-isomer causes vasodilation; the this difference is that once-daily dosing does not maintain adequate drug is marketed as a racemic mixture. The vasodilating effect may blood levels of atenolol. The usual dosage is 50–100 mg/d. Patients be due to an increase in endothelial release of nitric oxide via with reduced renal function should receive lower doses. induction of endothelial nitric oxide synthase. The hemodynamic 180 SECTION III Cardiovascular-Renal Drugs effects of nebivolol therefore differ from those of pure β blockers first-pass metabolism and has a half-life of 12 hours. Doxazosin has in that peripheral vascular resistance is acutely lowered (by nebi- an intermediate bioavailability and a half-life of 22 hours. volol) as opposed to increased acutely (by the older agents). Terazosin can often be given once daily, with doses of 5–20 Nebivolol is extensively metabolized and has active metabolites. mg/d. Doxazosin is usually given once daily starting at 1 mg/d and The half-life is 10–12 hours, but the drug can be given once daily. progressing to 4 mg/d or more as needed. Although long-term Dosing is generally started at 5 mg/d, with dose escalation as high treatment with these α blockers causes relatively little postural as 40 mg, if necessary. The efficacy of nebivolol is similar to that hypotension, a precipitous drop in standing blood pressure devel- of other antihypertensive agents, but several studies report fewer ops in some patients shortly after the first dose is absorbed. For adverse effects. this reason, the first dose should be small and should be adminis- tered at bedtime. Although the mechanism of this first-dose phe- nomenon is not clear, it occurs more commonly in patients who Esmolol are salt- and volume-depleted. Esmolol is a β1-selective blocker that is rapidly metabolized via Aside from the first-dose phenomenon, the reported toxicities hydrolysis by red blood cell esterases. It has a short half-life of the α1 blockers are relatively infrequent and mild. These (9–10 minutes) and is administered by constant intravenous include dizziness, palpitations, headache, and lassitude. Some infusion. Esmolol is generally administered as a loading dose patients develop a positive test for antinuclear factor in serum (0.5–1 mg/kg), followed by a constant infusion. The infusion is while on prazosin therapy, but this has not been associated with typically started at 50–150 mcg/kg/min, and the dose increased rheumatic symptoms. The α1 blockers do not adversely and may every 5 minutes, up to 300 mcg/kg/min, as needed to achieve the even beneficially affect plasma lipid profiles, but this action has desired therapeutic effect. Esmolol is used for management of not been shown to confer any benefit on clinical outcomes. intraoperative and postoperative hypertension, and sometimes for hypertensive emergencies, particularly when hypertension is asso- ciated with tachycardia. OTHER ALPHA-ADRENOCEPTOR– BLOCKING AGENTS The nonselective agents, phentolamine and phenoxybenzamine, PRAZOSIN & OTHER ALPHA1 BLOCKERS are useful in diagnosis and treatment of pheochromocytoma and in other clinical situations associated with exaggerated release of Mechanism & Sites of Action catecholamines (eg, phentolamine may be combined with propra- Prazosin, terazosin, and doxazosin produce most of their antihy- nolol to treat the clonidine withdrawal syndrome, described previ- pertensive effects by selectively blocking α1 receptors in arterioles ously). Their pharmacology is described in Chapter 10. and venules. These agents produce less reflex tachycardia when lowering blood pressure than do nonselective α antagonists such as phentolamine. Alpha1-receptor selectivity allows norepineph- rine to exert unopposed negative feedback (mediated by presynap- VASODILATORS tic α2 receptors) on its own release (see Chapter 6); in contrast, Mechanism & Sites of Action phentolamine blocks both presynaptic and postsynaptic α receptors, This class of drugs includes the oral vasodilators, hydralazine and with the result that reflex activation of sympathetic neurons by minoxidil, which are used for long-term outpatient therapy of phentolamine’s effects produces greater release of transmitter onto hypertension; the parenteral vasodilators, nitroprusside, diazoxide, β receptors and correspondingly greater cardioacceleration. and fenoldopam, which are used to treat hypertensive emergencies; Alpha blockers reduce arterial pressure by dilating both resis- the calcium channel blockers, which are used in both circumstances; tance and capacitance vessels. As expected, blood pressure is and the nitrates, which are used mainly in angina (Table 11–3). reduced more in the upright than in the supine position. Retention Chapter 12 contains additional discussion of vasodilators. All of salt and water occurs when these drugs are administered with- the vasodilators that are useful in hypertension relax smooth out a diuretic. The drugs are more effective when used in combi- muscle of arterioles, thereby decreasing systemic vascular resis- nation with other agents, such as a β blocker and a diuretic, than tance. Sodium nitroprusside and the nitrates also relax veins. when used alone. Owing to their beneficial effects in men with Decreased arterial resistance and decreased mean arterial blood prostatic hyperplasia and bladder obstruction symptoms, these pressure elicit compensatory responses, mediated by baroreceptors drugs are used primarily in men with concurrent hypertension and and the sympathetic nervous system (Figure 11–4), as well as benign prostatic hyperplasia. renin, angiotensin, and aldosterone. Because sympathetic reflexes are intact, vasodilator therapy does not cause orthostatic hypoten- sion or sexual dysfunction. Pharmacokinetics & Dosage Vasodilators work best in combination with other antihyper- Pharmacokinetic characteristics of prazosin are listed in Table 11–2. tensive drugs that oppose the compensatory cardiovascular Terazosin is also extensively metabolized but undergoes very little responses. (See Box: Resistant Hypertension & Polypharmacy.)  CHAPTER 11 Antihypertensive Agents 181 TABLE 11–3 Mechanisms of action of vasodilators. Toxicity Mechanism Examples The most common adverse effects of hydralazine are headache, nau- sea, anorexia, palpitations, sweating, and flushing. In patients with Release of nitric oxide from drug or Nitroprusside, hydralazine, ischemic heart disease, reflex tachycardia and sympathetic stimula- 1 endothelium nitrates, histamine, acetylcholine tion may provoke angina or ischemic arrhythmias. With dosages of 400 mg/d or more, there is a 10–20% incidence—chiefly in persons Reduction of calcium influx Verapamil, diltiazem, nifedipine who slowly acetylate the drug—of a syndrome characterized by arth- ralgia, myalgia, skin rashes, and fever that resembles lupus erythema- Hyperpolarization of smooth Minoxidil, diazoxide muscle membrane through tosus. The syndrome is not associated with renal damage and is opening of potassium channels reversed by discontinuance of hydralazine. Peripheral neuropathy Activation of dopamine receptors Fenoldopam and drug fever are other serious but uncommon adverse effects. 1 See Chapter 12. MINOXIDIL Minoxidil is a very efficacious orally active vasodilator. The HYDRALAZINE effect results from the opening of potassium channels in smooth muscle membranes by minoxidil sulfate, the active metabolite. Hydralazine, a hydrazine derivative, dilates arterioles but not Increased potassium permeability stabilizes the membrane at its veins. It has been available for many years, although it was initially resting potential and makes contraction less likely. Like hydrala- thought not to be particularly effective because tachyphylaxis to its zine, minoxidil dilates arterioles but not veins. Because of its antihypertensive effects developed rapidly. The benefits of combi- greater potential antihypertensive effect, minoxidil should nation therapy are now recognized, and hydralazine may be used replace hydralazine when maximal doses of the latter are not more effectively, particularly in severe hypertension. The combi- effective or in patients with renal failure and severe hyperten- nation of hydralazine with nitrates is effective in heart failure and sion, who do not respond well to hydralazine. should be considered in patients with both hypertension and heart failure, especially in African-American patients. O H2N N NH2 Pharmacokinetics & Dosage N Hydralazine is well absorbed and rapidly metabolized by the liver during the first pass, so that bioavailability is low (averaging 25%) N and variable among individuals. It is metabolized in part by acety- lation 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 Minoxidil antihypertensive benefit from a given dose than do slow acetyla- tors. The half-life of hydralazine ranges from 1.5 to 3 hours, but vascular effects persist longer than do blood concentrations, pos- Pharmacokinetics & Dosage sibly due to avid binding to vascular tissue. Pharmacokinetic parameters of minoxidil are listed in Table 11–2. Even more than with hydralazine, the use of minoxidil is associ- N ated with reflex sympathetic stimulation and sodium and fluid N retention. Minoxidil must be used in combination with a β blocker and a loop diuretic. N NH2 H Hydralazine Toxicity Tachycardia, palpitations, angina, and edema are observed when Usual dosage ranges from 40 mg/d to 200 mg/d. The higher doses of β blockers and diuretics are inadequate. Headache, sweat- dosage was selected as the dose at which there is a small possibility ing, and hypertrichosis, which is particularly bothersome in of developing the lupus erythematosus-like syndrome described in women, are relatively common. Minoxidil illustrates how one the next section. However, higher dosages result in greater vasodi- person’s toxicity may become another person’s therapy. Topical lation and may be used if necessary. Dosing two or three times minoxidil (as Rogaine) is used as a stimulant to hair growth for daily provides smooth control of blood pressure. correction of baldness. 182 SECTION III Cardiovascular-Renal Drugs SODIUM NITROPRUSSIDE a defect in cyanide metabolism. Administration of sodium thiosul- fate as a sulfur donor facilitates metabolism of cyanide. Sodium nitroprusside is a powerful parenterally administered Hydroxocobalamin combines with cyanide to form the nontoxic vasodilator that is used in treating hypertensive emergencies as cyanocobalamin. Both have been advocated for prophylaxis or well as severe heart failure. Nitroprusside dilates both arterial and treatment of cyanide poisoning during nitroprusside infusion. venous vessels, resulting in reduced peripheral vascular resistance Thiocyanate may accumulate over the course of prolonged admin- and venous return. The action occurs as a result of activation of istration, usually several days or more, particularly in patients with guanylyl cyclase, either via release of nitric oxide or by direct renal insufficiency who do not excrete thiocyanate at a normal stimulation of the enzyme. The result is increased intracellular rate. Thiocyanate toxicity is manifested as weakness, disorienta- cGMP, which relaxes vascular smooth muscle (Figure 12–2). tion, psychosis, muscle spasms, and convulsions, and the diagnosis In the absence of heart failure, blood pressure decreases, owing to is confirmed by finding serum concentrations greater than 10 mg/dL. decreased vascular resistance, whereas cardiac output does not change Rarely, delayed hypothyroidism occurs, owing to thiocyanate inhi- or decreases slightly. In patients with heart failure and low cardiac bition of iodide uptake by the thyroid. Methemoglobinemia dur- output, output often increases owing to afterload reduction. ing infusion of nitroprusside has also been reported. + NO DIAZOXIDE CN– CN – Diazoxide is an effective and relatively long-acting parenterally Fe 2+ administered arteriolar dilator that is occasionally used to treat hypertensive emergencies. Diminishing usage suggests that it may CN – CN – be withdrawn. Injection of diazoxide results in a rapid fall in sys- temic vascular resistance and mean arterial blood pressure. Studies CN– of its mechanism suggest that it prevents vascular smooth muscle contraction by opening potassium channels and stabilizing the Nitroprusside membrane potential at the resting level. N CH3 Pharmacokinetics & Dosage NH CI Nitroprusside is a complex of iron, cyanide groups, and a nitroso S O2 moiety. It is rapidly metabolized by uptake into red blood cells Diazoxide with liberation of cyanide. Cyanide in turn is metabolized by the mitochondrial enzyme rhodanase, in the presence of a sulfur donor, to the less toxic thiocyanate. Thiocyanate is distributed in extracellular fluid and slowly eliminated by the kidney. Pharmacokinetics & Dosage Nitroprusside rapidly lowers blood pressure, and its effects disappear within 1–10 minutes after discontinuation. The drug Diazoxide is similar chemically to the thiazide diuretics but has no is given by intravenous infusion. Sodium nitroprusside in aque- diuretic activity. It is bound extensively to serum albumin and to ous solution is sensitive to light and must therefore be made up vascular tissue. Diazoxide is partially metabolized; its metabolic fresh before each administration and covered with opaque foil. pathways are not well characterized. The remainder is excreted Infusion solutions should be changed after several hours. unchanged. Its half-life is approximately 24 hours, but the relation- Dosage typically begins at 0.5 mcg/kg/min and may be ship between blood concentration and hypotensive action is not increased up to 10 mcg/kg/min as necessary to control blood well established. The blood pressure-lowering effect after a rapid pressure. Higher rates of infusion, if continued for more than injection is established within 5 minutes and lasts for 4–12 hours. an hour, may result in toxicity. Because of its efficacy and rapid When diazoxide was first marketed, a dose of 300 mg by rapid onset of effect, nitroprusside should be administered by infu- injection was recommended. It appears, however, that excessive sion pump and arterial blood pressure continuously monitored hypotension can be avoided by beginning with smaller doses via intra-arterial recording. (50–150 mg). If necessary, doses of 150 mg may be repeated every 5 to 15 minutes until blood pressure is lowered satisfactorily. Nearly all patients respond to a maximum of three or four doses. Toxicity Alternatively, diazoxide may be administered by intravenous infu- Other than excessive blood pressure lowering, the most serious sion at rates of 15–30 mg/min. Because of reduced protein bind- toxicity is related to accumulation of cyanide; metabolic acidosis, ing, hypotension occurs after smaller doses in persons with arrhythmias, excessive hypotension, and death have resulted. In a chronic renal failure, and smaller doses should be administered to few cases, toxicity after relatively low doses of nitroprusside suggested these patients. The hypotensive effects of diazoxide are also greater  CHAPTER 11 Antihypertensive Agents 183 when patients are pretreated with β blockers to prevent the reflex other dihydropyridine agents are more selective as vasodilators and tachycardia and associated increase in cardiac output. have less cardiac depressant effect than verapamil and diltiazem. Reflex sympathetic activation with slight tachycardia maintains or Toxicity increases cardiac output in most patients given dihydropyridines. Verapamil has the greatest depressant effect on the heart and may The most significant toxicity from diazoxide has been excessive decrease heart rate and cardiac output. Diltiazem has intermediate hypotension, resulting from the recommendation to use a fixed actions. The pharmacology and toxicity of these drugs is discussed dose of 300 mg in all patients. Such hypotension has resulted in in more detail in Chapter 12. Doses of calcium channel blockers stroke and myocardial infarction. The reflex sympathetic response used in treating hypertension are similar to those used in treating can provoke angina, electrocardiographic evidence of ischemia, angina. Some epidemiologic studies reported an increased risk of and cardiac failure in patients with ischemic heart disease, and myocardial infarction or mortality in patients receiving short-act- diazoxide should be avoided in this situation. ing nifedipine for hypertension. It is therefore recommended that Diazoxide inhibits insulin release from the pancreas (probably short-acting oral dihydropyridines not be used for hypertension. by opening potassium channels in the beta cell membrane) and is Sustained-release calcium blockers or calcium blockers with long used to treat hypoglycemia secondary to insulinoma. Occasionally, half-lives provide smoother blood pressure control and are more hyperglycemia complicates diazoxide use, particularly in persons appropriate for treatment of chronic hypertension. Intravenous with renal insufficiency. nicardipine and clevidipine are available for the treatment of In contrast to the structurally related thiazide diuretics, diazox- hypertension when oral therapy is not feasible; parenteral vera- ide causes renal salt and water retention. However, because the pamil and diltiazem can also be used for the same indication. drug is used for short periods only, this is rarely a problem. 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 FENOLDOPAM has a rapid onset of action and has been used in acute hyperten- sion occurring during surgery. Oral short-acting nifedipine has Fenoldopam is a peripheral arteriolar dilator used for hypertensive been used in emergency management of severe hypertension. 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 pharmaco- INHIBITORS OF ANGIOTENSIN logic activity. Fenoldopam is rapidly metabolized, primarily by conjugation. Renin, angiotensin, and aldosterone play important roles in at least Its half-life is 10 minutes. The drug is administered by continuous some people with essential hypertension. Approximately 20% of intravenous infusion. Fenoldopam is initiated at a low dosage patients with essential hypertension have inappropriately low and (0.1 mcg/kg/min), and the dose is then titrated upward every 15 20% have inappropriately high plasma renin activity. Blood pres- or 20 minutes to a maximum dose of 1.6 mcg/kg/min or until the sure of patients with high-renin hypertension responds well to desired blood pressure reduction is achieved. drugs that interfere with the system, supporting a role for excess As with other direct vasodilators, the major toxicities are renin and angiotensin in this population. reflex tachycardia, headache, and flushing. Fenoldopam also increases intraocular pressure and should be avoided in patients Mechanism & Sites of Action with glaucoma. Renin release from the kidney cortex is stimulated by reduced renal arterial pressure, sympathetic neural stimulation, and CALCIUM CHANNEL BLOCKERS reduced sodium delivery or increased sodium concentration at the distal renal tubule (see Chapter 17). Renin acts upon angio- In addition to their antianginal (see Chapter 12) and antiarrhyth- tensinogen to split off the inactive precursor decapeptide angio- mic effects (see Chapter 14), calcium channel blockers also reduce tensin I. Angiotensin I is then converted, primarily by endothelial peripheral resistance and blood pressure. The mechanism of action ACE, to the arterial vasoconstrictor octapeptide angiotensin II in hypertension (and, in part, in angina) is inhibition of calcium (Figure 11–5), which is in turn converted in the adrenal gland to influx into arterial smooth muscle cells. angiotensin III. Angiotensin II has vasoconstrictor and sodium- Verapamil, diltiazem, and the dihydropyridine family (amlo- retaining activity. Angiotensin II and III both stimulate aldoster- dipine, felodipine, isradipine, nicardipine, nifedipine, and one release. Angiotensin may contribute to maintaining high nisoldipine) are all equally effective in lowering blood pressure, vascular resistance in hypertensive states associated with high and many formulations are currently approved for this use in the plasma renin activity, such as renal arterial stenosis, some types of USA. Clevidipine is a newer member of this group that is formu- intrinsic renal disease, and malignant hypertension, as well as in lated for intravenous use only. essential hypertension after treatment with sodium restriction, Hemodynamic differences among calcium channel blockers diuretics, or vasodilators. However, even in low-renin hypertensive may influence the choice of a particular agent. Nifedipine and the states, these drugs can lower blood pressure (see below). 184 SECTION III Cardiovascular-Renal Drugs Angiotensinogen Kininogen Renin Kallikrein – Aliskiren Increased prostaglandin Angiotensin I Bradykinin synthesis Angiotensin-converting enzyme (kininase II) – Angiotensin II Inactive ACE metabolites inhibitors ARBs – –