Adrenergic Receptor Antagonists

Adrenergic Receptor Antagonists Competitive antagonists of adrenergic receptors, or blockers, have received enormous clinical attention because of their efficacy in the treatment of hypertension, ischemic heart disease, congestive heart failure, and certain arrhythmias. History Ahlquist's hypothesis that the effects of catecholamines were mediated by activation of distinct and receptors provided the initial impetus for the synthesis and pharmacological evaluation of receptor antagonists (Chapter 8). The first such selective agent was dichloroisoproterenol, a partial agonist. Sir James Black and his colleagues initiated a program in the late 1950s to develop additional blockers, with the resulting synthesis and characterization of propranolol. Overview Propranolol is a competitive receptor antagonist and remains the prototype to which other antagonists are compared. antagonists can be distinguished by the following properties: relative affinity for 1 and 2 receptors, intrinsic sympathomimetic activity, blockade of receptors, differences in lipid solubility, capacity to induce vasodilation, and pharmacokinetic parameters. Some of these distinguishing characteristics have clinical significance and help guide the appropriate choice of a receptor antagonist for an individual patient. Propranolol has equal affinity for 1 and 2 adrenergic receptors; thus, it is a non-selective adrenergic receptor antagonist. Agents such as metoprolol, atenolol, acebutolol, bisoprolol, and esmolol have somewhat greater affinity for 1 than for 2 receptors; these are examples of 1-selective antagonists, even though the selectivity is not absolute. Propranolol is a pure antagonist, and it has no capacity to activate receptors. Several blockers (e.g., pindolol and acebutolol) activate receptors partially in the absence of catecholamines; however, the intrinsic activities of these drugs are less than that of a full agonist such as isoproterenol. These partial agonists are said to have intrinsic sympathomimetic activity. Substantial sympathomimetic activity would be counterproductive to the response desired from a antagonist; however, slight residual activity may, e.g., prevent profound bradycardia or negative inotropy in a resting heart. The potential clinical advantage of this property, however, is unclear and may be disadvantageous in the context of secondary prevention of myocardial infarction (described under Therapeutic Uses). In addition, other receptor antagonists have been found to have the property of inverse agonism (Chapter 3). These drugs can decrease basal activity of receptor signaling by shifting the equilibrium of spontaneously active receptors toward the inactive state (Chidiac et al., 1994). Several receptor antagonists also have local anesthetic or membrane-stabilizing activity, similar to lidocaine, that is independent of blockade. Such drugs include propranolol, acebutolol, and carvedilol. Pindolol, metoprolol, betaxolol, and labetalol have slight membrane-stabilizing effects. Although most receptor antagonists do not block adrenergic receptors, labetalol, carvedilol, and bucindolol are examples of agents that block both 1 and adrenergic receptors. In addition to carvedilol, labetalol, and bucindolol, many other receptor antagonists have vasodilating properties due to various mechanisms discussed below. These include celiprolol, nebivolol, nipradilol, carteolol, betaxolol, bopindolol, and bevantolol (Toda, 2003). Pharmacological Properties As in the case of receptor blocking agents, the pharmacological properties of receptor antagonists can be explained largely from knowledge of the responses elicited by the receptors in the various tissues and the activity of the sympathetic nerves that innervate these tissues (Table 8–1). For example, receptor blockade has relatively little effect on the normal heart of an individual at rest, but has profound effects when sympathetic control of the heart is dominant, as during exercise or stress. In this chapter, adrenergic receptor antagonists are classified as non–subtype-selective ("first generation"), 1-selective ("second generation"), and non–subtype or subtype-selective with additional cardiovascular actions ("third generation"). These latter drugs have additional cardiovascular properties (especially vasodilation) that seem unrelated to blockade. Table 12–3 summarizes important pharmacological and pharmacokinetic properties of receptor an Metabolic Effects Receptor antagonists modify the metabolism of carbohydrates and lipids. Catecholamines promote glycogenolysis and mobilize glucose in response to hypoglycemia. Non-selective blockers may delay recovery from hypoglycemia in type 1 (insulin-dependent) diabetes mellitus, but infrequently in type 2 diabetes mellitus. In addition to blocking glycogenolysis, receptor antagonists can interfere with the counter-regulatory effects of catecholamines secreted during hypoglycemia by blunting the perception of symptoms such as tremor, tachycardia, and nervousness. Thus, adrenergic receptor antagonists should be used with great caution in patients with labile diabetes and frequent hypoglycemic reactions. If such a drug is indicated, a 1-selective antagonist is preferred, since these drugs are less likely to delay recovery from hypoglycemia (DiBari et al., 2003). The receptors mediate activation of hormone-sensitive lipase in fat cells, leading to release of free fatty acids into the circulation (Chapter 8). This increased flux of fatty acids is an important source of energy for exercising muscle. Receptor antagonists can attenuate the release of free fatty acids from adipose tissue. Non-selective receptor antagonists consistently reduce HDL cholesterol, increase LDL cholesterol, and increase triglycerides. In contrast, 1-selective antagonists, including celiprolol, carteolol, nebivolol, carvedilol, and bevantolol, reportedly improve the serum lipid profile of dyslipidemic patients. While drugs such as propranolol and atenolol increase triglycerides, plasma triglycerides are reduced with chronic celiprolol, carvedilol, and carteolol (Toda, 2003). In contrast to classical blockers, which decrease insulin sensitivity, the vasodilating receptor antagonists (e.g., celiprolol, nipradilol, carteolol, carvedilol, and dilevalol) increase insulin sensitivity in patients with insulin resistance. Together with their cardioprotective effects, improvement in insulin sensitivity from vasodilating receptor antagonists may partially counterbalance the hazard from worsened lipid abnormalities associated with diabetes. If blockers are to be used, 1-selective or vasodilating receptor antagonists are preferred. In addition, it may be necessary to use receptor antagonists in conjunction with other drugs, (e.g., HMGCoA reductase inhibitors) to ameliorate adverse metabolic effects (Dunne et al., 2001). Receptor agonists decrease the plasma concentration of K+ by promoting the uptake of the ion, predominantly into skeletal muscle. At rest, an infusion of epinephrine causes a decrease in the plasma concentration of K+. The marked increase in the concentration of epinephrine that occurs with stress (such as myocardial infarction) may cause hypokalemia, which could predispose to cardiac arrhythmias. The hypokalemic effect of epinephrine is blocked by an experimental antagonist, ICI 118551, which has a high affinity for 2 and 3 receptors. Exercise causes an increase in the efflux of K+ from skeletal muscle. Catecholamines tend to buffer the rise in K+ by increasing its influx into muscle. Blockers negate this buffering effect. Other Effects Receptor antagonists block catecholamine-induced tremor. They also block inhibition of mast-cell degranulation by catecholamines. Adverse Effects and Precautions The most common adverse effects of receptor antagonists arise as pharmacological consequences of blockade of receptors; serious adverse effects unrelated to receptor blockade are rare. Non-Selective Adrenergic Receptor Antagonists Propranolol In view of the extensive experience with propranolol (INDERAL, others), it is a useful prototype (Table 12–5). Propranolol interacts with 1 and 2 receptors with equal affinity, lacks intrinsic sympathomimetic activity, and does not block receptors Nadolol Nadolol (CORGARD, others) is a long-acting antagonist with equal affinity for 1 and 2 receptors. It is devoid of both membrane-stabilizing and intrinsic sympathomimetic activity. A distinguishing characteristic of nadolol is its relatively long t1/2. It can be used to treat hypertension and angina pectoris. Unlabeled uses have included migraine prophylaxis, parkinsonian tremors, and variceal bleeding in portal hypertension. Absorption, Fate, and Excretion Nadolol is very soluble in water and is incompletely absorbed from the gut; its bioavailability is ~35%. Interindividual variability is less than with propranolol. The low lipid solubility of nadolol may result in lower concentrations of the drug in the brain as compared with more lipid-soluble receptor antagonists. Although it frequently has been suggested that the incidence of CNS adverse effects is lower with hydrophilic receptor antagonists, data from controlled trials to support this contention are limited. Nadolol is not extensively metabolized and is largely excreted intact in the urine. The t1/2 of the drug in plasma is ~20 hours; consequently, it generally is administered once daily. Nadolol may accumulate in patients with renal failure, and dosage should be reduced in such individuals. Timolol Timolol (BLOCADREN, others) is a potent, non-selective receptor antagonist. It has no intrinsic sympathomimetic or membrane-stabilizing activity. It is used for hypertension, congestive heart failure, acute MI, andmigraine prophylaxis. In ophthalmology, timolol has been used in the treatment of open-angle glaucoma and intraocular hypertension. Its mechanism of action in treating open angle glaucoma is not precisely known; but the drug appears to reduce aqueous humour production through blockade of receptors on the ciliary epithelium. Absorption, Fate, and Excretion Timolol is well absorbed from the GI tract. It is metabolized extensively by CYP2D6 in the liver and undergoes first-pass metabolism. Only a small amount of unchanged drug appears in the urine. The t1/2 in plasma is ~4 hours. Interestingly, the ocular formulation of timolol (TIMOPTIC, others), used for the treatment of glaucoma, may be extensively absorbed systemically (Chapter 64); adverse effects can occur in susceptible patients, such as those with asthma or congestive heart failure. The systemic administration of cimetidine with topical ocular timolol increases the degree of blockade, resulting in a reduction of resting heart rate, intraocular pressure, and exercise tolerance (Ishii et al., 2000). For ophthalmic use timolol is available combined with other medications (e.g., with dorzolamide or travoprost). Timolol also provide benefits to patients with coronary heart disease: in the acute post MI period, timolol produced a 39% reduction in mortality in the Norwegian Multicenter Study. Pindolol Pindolol (VISKEN, others) is a non-selective receptor antagonist with intrinsic sympathomimetic activity. It has low membrane-stabilizing activity and low lipid solubility. It is used to treat angina pectoris and hypertension. Although only limited data are available, blockers with slight partial agonist activity may produce smaller reductions in resting heart rate and blood pressure. Hence, such drugs may be preferred as antihypertensive agents in individuals with diminished cardiac reserve or a propensity for bradycardia. Nonetheless, the clinical significance of partial agonism has not been substantially demonstrated in controlled trials but may be of importance in individual patients. Agents such as pindolol block exercise-induced increases in heart rate and cardiac output. Absorption, Fate, and Excretion Pindolol is almost completely absorbed after oral administration and has moderately high bioavailability. These properties tend to minimize interindividual variation in the plasma concentrations of the drug that are achieved after its oral administration. Approximately 50% of pindolol ultimately is metabolized in the liver. The principal metabolites are hydroxylated derivatives that subsequently are conjugated with either glucuronide or sulfate before renal excretion. The remainder of the drug is excreted unchanged in the urine. The plasma t1/2 of pindolol is ~4 hours; clearance is reduced in patients with renal failure. 1 Selective Adrenergic Receptor Antagonists Metoprolol Metoprolol (LOPRESSOR, others) is a 1-selective receptor antagonist that is devoid of intrinsic sympathomimetic activity and membrane-stabilizing activity. Absorption, Fate, and Excretion Metoprolol is almost completely absorbed after oral administration, but bioavailability is relatively low (~40%) because of first-pass metabolism. Plasma concentrations of the drug vary widely (up to 17-fold), perhaps because of genetically determined differences in the rate of metabolism. Metoprolol is extensively metabolized in the liver, with CYP2D6 the major enzyme involved, and only 10% of the administered drug is recovered unchanged in the urine. The t1/2 of metoprolol is 3-4 hours, but can increase to 7-8 hours in CYP2D6 poor metabolizers. It recently has been reported that CYP2D6 poor metabolizers have a 5-fold higher risk for developing adverse effects during metoprolol treatment than patients who are not poor metabolizers (Wuttke et al., 2002). An extended-release formulation (TOPROL XL) is available for once-daily administration. Therapeutic Uses Metoprolol has been used to treat essential hypertension, angina pectoris, tachycardia, heart failure, vasovagal syncope, and as secondary prevention after myocardial infarction, an adjunct in treatment of hyperthyroidism, and for migraine prophylaxis. For the treatment of hypertension, the usual initial dose is 100 mg/day. The drug sometimes is effective when given once daily, although it frequently is used in two divided doses. Dosage may be increased at weekly intervals until optimal reduction of blood pressure is achieved. If the drug is taken only once daily, it is important to confirm that blood pressure is controlled for the entire 24-hour period. Metoprolol generally is used in two divided doses for the treatment of stable angina. For the initial treatment of patients with acute myocardial infarction, an intravenous formulation of metoprolol tartrate is available. Oral dosing is initiated as soon as the clinical situation permits. Metoprolol generally is contraindicated for the treatment of acute myocardial infarction in patients with heart rates of < 45 beats per minute, heart block greater than first-degree (PR interval 0.24 second), systolic blood pressure <100 mm Hg, or moderate to severe heart failure. Metoprolol also has been proven to be effective in chronic heart failure. Its use is associated with a striking reduction in all-cause mortality and hospitalization for worsening heart failure and a modest reduction in all-cause hospitalization (MERIT-HF Study Group, 1999; Prakash and Markham, 2000). Atenolol Atenolol (TENORMIN, others) is a 1-selective antagonist that is devoid of intrinsic sympathomimetic and membrane stabilizing activity. Atenolol is very hydrophilic and appears to penetrate the CNS only to a limited extent. Its t1/2 is somewhat longer than that of metoprolol. Absorption, Fate, and Excretion Atenolol is incompletely absorbed (~50%), but most of the absorbed dose reaches the systemic circulation. There is relatively little interindividual variation in the plasma concentrations of atenolol; peak concentrations in different patients vary over only a 4-fold range. The drug is excreted largely unchanged in the urine, and the elimination t1/2 is 5-8 hours. The drug accumulates in patients with renal failure, and dosage should be adjusted for patients whose creatinine clearance is < 35 mL/min. Therapeutic Uses Atenol can be used to treat hypertension, coronary heart disease, arrhythmias, and angina pectoris, and to treat or reduce the risk of heart complications following myocardial infarction. It is also used to treat Graves disease until anti-thyroid medication can take effect. The initial dose of atenolol for the treatment of hypertension usually is 50 mg/day, given once daily. If an adequate therapeutic response is not evident within several weeks, the daily dose may be increased to 100 mg; higher doses are unlikely to provide any greater antihypertensive effect. Atenolol has been shown to be efficacious, in combination with a diuretic, in elderly patients with isolated systolic hypertension. Atenolol causes fewer CNS side effects (depression, nightmares) than most blockers and few bronchospatic reactions due to its pharmacological and pharmacokinetic profile (Varon, 2008). Esmolol Esmolol (BREVIBLOC, others) is a 1-selective antagonist with a rapid onset and a very short duration of action. It has little if any intrinsic sympathomimetic activity and lacks membrane-stabilizing actions. Esmolol is administered intravenously and is used when blockade of short duration is desired or in critically ill patients in whom adverse effects of bradycardia, heart failure, or hypotension may necessitate rapid withdrawal of the drug. It is a class II anti-arrhythmic agent (Chapter 29). Absorption, Fate, and Excretion Esmolol is given by slow IV injection and has a t1/2 of ~8 minutes and an apparent volume of distribution of ~2 L/kg. The drug contains an ester linkage, and it is hydrolyzed rapidly by esterases in erythrocytes. The t1/2 of the carboxylic acid metabolite of esmolol is far longer (4 hours), and it accumulates during prolonged infusion of esmolol. However, this metabolite has very low potency as a receptor antagonist (1/500 of the potency of esmolol); it is excreted in the urine. Esmolol is commonly used in patients during surgery to prevent or treat tachycardia and in the treatment of supraventricular tachycardia. The onset and cessation of receptor blockade with esmolol are rapid; peak hemodynamic effects occur within 6-10 minutes of administration of a loading dose, and there is substantial attenuation of blockade within 20 minutes of stopping an infusion. Esmolol may have striking hypotensive effects in normal subjects, although the mechanism of this effect is unclear. Because esmolol is used in urgent settings where immediate onset of blockade is warranted, a partial loading dose typically is administered, followed by a continuous infusion of the drug. If an adequate therapeutic effect is not observed within 5 minutes, the same loading dose is repeated, followed by a maintenance infusion at a higher rate. This process, including progressively greater infusion rates, may need to be repeated until the desired end point (e.g., lowered heart rate or blood pressure) is approached. Esmolol is particularly useful in severe postoperative hypertension and is a suitable agent in situations where cardiac output, heart rate, and blood pressure are increased. The American Heart Association/American College of Cardiology guidelines recommend against using esmolol in patients already on blocker therapy, bradycardiac patients, and decompensated heart failure patients, as the drug may compromise their myocardial function (Varon, 2008). Bisoprolol Bisoprolol (ZEBETA) is a highly selective 1 receptor antagonist that does not have intrinsic sympathomimetic or membrane-stabilizing activity (McGavin and Keating, 2002). It has a higher degree of 1-selective activity than atenolol, metoprolol, or betaxolol but less than nebivolol. It is approved for the treatment of hypertension and has been investigated in randomized, double-blind multicenter trials in combination with ACE inhibitors and diuretics in patients with moderate to severe chronic heart failure (Simon et al., 2003). All-case mortality was significantly lower with bisoprolol than placebo. Bisoprolol generally is well tolerated; side effects include dizziness, bradycardia, hypotension, and fatigue. Bisoprolol is well absorbed following oral administration, with bioavailability of ~90%. It is eliminated by renal excretion (50%) and liver metabolism to pharmacologically inactive metabolites (50%). Bisoprolol has a plasma t1/2 of 11-17 hours. Bisoprolol can be considered a standard treatment option when selecting a blocker for use in combination with ACE inhibitors and diuretics in patients with stable, moderate to severe chronic heart failure and in treating hypertension (McGavin and Keating, 2002; Simon et al., 2003). It has also been used to treat arrhythmias and ischemic heart disease. Bisoprolol was associated with a 34% mortality benefit in the Cardiac Insufficiency Bisoprolol Study-II (CIBIS-II). tagonists. Adrenergic Receptor Antagonists Many types of drugs interfere with the function of the sympathetic nervous system and thus have profound effects on the physiology of sympathetically innervated organs. Several of these drugs are important in clinical medicine, particularly for the treatment of cardiovascular diseases. The remainder of this chapter focuses on the pharmacology of adrenergic receptor antagonists, drugs that inhibit the interaction of NE, epinephrine, and other sympathomimetic drugs with and receptors (Figure 12–5). Almost all of these agents are competitive antagonists; an important exception is phenoxybenzamine, an irreversible antagonist that binds covalently to receptors. There are important structural differences among the various types of adrenergic receptors (Chapter 8). Since compounds have been developed that have different affinities for the various receptors, it is possible to interfere selectively with responses that result from stimulation of the sympathetic nervous system. For example, selective antagonists of 1 receptors block most actions of epinephrine and NE on the heart, while having less effect on 2 receptors in bronchial smooth muscle and no effect on responses mediated by 1 or 2 receptors. Detailed knowledge of the autonomic nervous system and the sites of action of drugs that act on adrenergic receptors is essential for understanding the pharmacological properties and therapeutic uses of this important class of drugs. Additional background material is presented in Chapter 8. Agents that block DA receptors are considered in Chapter 13. Figure 12–5. Classification of adrenergic receptor antagonists. Drugs marked by an asterisk (*) also block 1 receptors.

Adrenergic Receptor Antagonists The adrenergic receptors mediate many of the important actions of endogenous catecholamines. Responses of particular clinical relevance include 1 receptor–mediated contraction of arterial, venous and visceral smooth muscle. The 2 receptors are involved in suppressing sympathetic output, increasing vagal tone, facilitating platelet aggregation, inhibiting the release of NE and ACh from nerve endings, and regulating metabolic effects. These effects include suppression of insulin secretion and inhibition of lipolysis. The 2 receptors also mediate contraction of some arteries and veins. receptor antagonists have a wide spectrum of pharmacological specificities and are chemically heterogeneous. Some of these drugs have markedly different affinities for 1 and 2 receptors. For example, prazosin is much more potent in blocking 1 than 2 receptors (i.e., 1 selective), whereas yohimbine is 2 selective; phentolamine has similar affinities for both of these receptor subtypes. More recently, agents that discriminate among the various subtypes of a particular receptor have become available; e.g., tamsulosin has higher potency at 1A than at 1B receptors. Figure 12–6 shows the structural formulas of many of these agents. Prior editions of this textbook contain information about the chemistry of receptor antagonists. Figure 12–6. Structural formulas of some adrenergic receptor antagonists. Some of the most important effects of receptor antagonists observed clinically are on the cardiovascular system. Actions in both the CNS and the periphery are involved; the outcome depends on the cardiovascular status of the patient at the time of drug administration and the relative selectivity of the agent for 1 and 2 receptors. Catecholamines increase the output of glucose from the liver; in humans this effect is mediated predominantly by receptors, although receptors may contribute. Receptor antagonists therefore may reduce glucose release. Receptors of the 2A subtype facilitate platelet aggregation; the effect of blockade of platelet 2 receptors in vivo is not clear. Activation of 2 receptors in the pancreatic islets suppresses insulin secretion; conversely, blockade of pancreatic 2 receptors may facilitate insulin release (Chapter 43). 1 Receptor Antagonists General Pharmacological Properties Blockade of 1 adrenergic receptors inhibits vasoconstriction induced by endogenous catecholamines; vasodilation may occur in both arteriolar resistance vessels and veins. The result is a fall in blood pressure due to decreased peripheral resistance. The magnitude of such effects depends on the activity of the sympathetic nervous system at the time the antagonist is administered, and thus is less in supine than in upright subjects and is particularly marked if there is hypovolemia. For most receptor antagonists, the fall in blood pressure is opposed by baroreceptor reflexes that cause increases in heart rate and cardiac output, as well as fluid retention. These reflexes are exaggerated if the antagonist also blocks 2 receptors on peripheral sympathetic nerve endings, leading to enhanced release of NE and increased stimulation of postsynaptic 1 receptors in the heart and on juxtaglomerular cells (Chapter 8) (Starke et al., 1989). Although stimulation of 1 receptors in the heart may cause an increased force of contraction, the importance of blockade at this site in humans is uncertain. Blockade of 1 receptors also inhibits vasoconstriction and the increase in blood pressure produced by the administration of a sympathomimetic amine. The pattern of effects depends on the adrenergic agonist that is administered: pressor responses to phenylephrine can be completely suppressed; those to NE are only incompletely blocked because of residual stimulation of cardiac 1 receptors; and pressor responses to epinephrine may be transformed to vasodepressor effects because of residual stimulation of 2 receptors in the vasculature with resultant vasodilation. Blockade of 1 receptors can alleviate some of the symptoms of benign prostatic hyperplasia (BPH). The symptoms of BPH include a resistance to urine outflow. This results from mechanical pressure on the urethra due to an increase in smooth muscle mass and an adrenergic receptor mediated increase in smooth muscle tone in the prostate and neck of the bladder. Antagonism of 1 receptors permits relaxation of the smooth muscle and decreases the resistance to the outflow of urine. The prostate and lower urinary tract tissues exhibit a high proportion of 1A receptors (Michel and Vrydag, 2006). Available Agents Prazosin and Related Drugs Due in part to its greater 1 receptor selectivity, this class of receptor antagonists exhibits greater clinical utility and has largely replaced the non-selective haloalkylamine (e.g., phenoxybenzamine) and imidazoline (e.g., phentolamine) receptor antagonists. Prazosin is the prototypical 1-selective antagonist. The affinity of prazosin for 1 adrenergic receptors is ~1000-fold greater than that for 2 adrenergic receptors. Prazosin has similar potencies at 1A, 1B, and 1D subtypes. Interestingly, the drug also is a relatively potent inhibitor of cyclic nucleotide phosphodiesterases, and it originally was synthesized for this purpose. The pharmacological properties of prazosin have been characterized extensively. Prazosin and the related receptor antagonists, doxazosin and tamsulosin, frequently are used for the treatment of hypertension (Chapter 27). Pharmacological Properties The major effects of prazosin result from its blockade of 1 receptors in arterioles and veins. This leads to a fall in peripheral vascular resistance and in venous return to the heart. Unlike other vasodilating drugs, administration of prazosin usually does not increase heart rate. Since prazosin has little or no 2 receptor–blocking effect at concentrations achieved clinically, it probably does not promote the release of NE from sympathetic nerve endings in the heart. In addition, prazosin decreases cardiac preload and thus has little tendency to increase cardiac output and rate, in contrast to vasodilators such as hydralazine that have minimal dilatory effects on veins. Although the combination of reduced preload and selective 1 receptor blockade might be sufficient to account for the relative absence of reflex tachycardia, prazosin also may act in the CNS to suppress sympathetic outflow. Prazosin appears to depress baroreflex function in hypertensive patients. Prazosin and related drugs in this class tend to have favorable effects on serum lipids in humans, decreasing low-density lipoproteins (LDL) and triglycerides while increasing concentrations of high-density lipoproteins (HDL). Prazosin and related drugs may have effects on cell growth unrelated to antagonism of 1 receptors (Hu et al., 1998). Prazosin (MINIPRESS, others) is well absorbed after oral administration, and bioavailability is ~ 50-70%. Peak concentrations of prazosin in plasma generally are reached 1-3 hours after an oral dose. The drug is tightly bound to plasma proteins (primarily 1-acid glycoprotein), and only 5% of the drug is free in the circulation; diseases that modify the concentration of this protein (e.g., inflammatory processes) may change the free fraction. Prazosin is extensively metabolized in the liver, and little unchanged drug is excreted by the kidneys. The plasma t1/2 is ~3 hours (may be prolonged to 6-8 hours in congestive heart failure). The duration of action of the drug typically is 7-10 hours in the treatment of hypertension. The initial dose should be 1 mg, usually given at bedtime so that the patient will remain recumbent for at least several hours to reduce the risk of syncopal reactions that may follow the first dose of prazosin. Therapy is begun with 1 mg given two or three times daily, and the dose is titrated upward depending on the blood pressure. A maximal effect generally is observed with a total daily dose of 20 mg in patients with hypertension. In the off-label treatment of benign prostatic hyperplasia (BPH), doses from 1-5 mg twice daily typically are used. Terazosin Terazosin (HYTRIN, others) is a close structural analog of prazosin. It is less potent than prazosin but retains high specificity for 1 receptors; terazosin does not discriminate among 1A, 1B, and 1D receptors. The major distinction between the two drugs is in their pharmacokinetic properties. Terazosin is more soluble in water than is prazosin, and its bioavailability is high (>90%). The t1/2 of elimination of terazosin is ~12 hours, and its duration of action usually extends beyond 18 hours. Consequently, the drug may be taken once daily to treat hypertension and BPH in most patients. Terazosin has been found more effective than finasteride in treatment of BPH (Lepor et al., 1996). An interesting aspect of the action of terazosin and doxazosin in the treatment of lower urinary tract problems in men with BPH is the induction of apoptosis in prostate smooth muscle cells. This apoptosis may lessen the symptoms associated with chronic BPH by limiting cell proliferation. The apoptotic effect of terazosin and doxazosin appears to be related to the quinazoline moiety rather than 1 receptor antagonism; tamsulosin, a non-quinazoline 1 receptor antagonist, does not produce apoptosis (Kyprianou, 2003). Only ~10% of terazosin is excreted unchanged in the urine. An initial first dose of 1 mg is recommended. Doses are slowly titrated upward depending on the therapeutic response. Doses of 10 mg/day may be required for maximal effect in BPH. Doxazosin Doxazosin (CARDURA, others) is another structural analog of prazosin and a highly selective antagonist at 1 receptors. It is non-selective among 1 receptor subtypes, and differs from prazosin in its pharmacokinetic profile. The t1/2 of doxazosin is ~20 hours, and its duration of action may extend to 36 hours. The bioavailability and extent of metabolism of doxazosin and prazosin are similar. Most doxazosin metabolites are eliminated in the feces. The hemodynamic effects of doxazosin appear to be similar to those of prazosin. As in the cases of prazosin and terazosin, doxazosin should be given initially as a 1-mg dose in the treatment of hypertension or BPH. Doxazosin also may have beneficial actions in the long-term management of BPH related to apoptosis that are independent of 1 receptor antagonism. Doxazosin is typically administered once daily. An extended-release formulation marketed for BPH is not recommended for the treatment of hypertension. Alfuzosin Alfuzosin (UROXATRAL) is a quinazoline-based 1 receptor antagonist with similar affinity at all of the 1 receptor subtypes. It has been used extensively in treating BPH; it is not approved for treatment of hypertension. Its bioavailability is ~64%; it has a t1/2 of 3-5 hours. Alfuzosin is a substrate of CYP3A4 and the concomitant administration of CPY3A4 inhibitors (e.g., ketoconazole, clarithromycin, itraconazole, ritonavir) is contraindicated. Alfuzosin should be avoided in patients at risk for prolonged QT syndrome. The recommended dosage is one 10-mg extended-release tablet daily to be taken after the same meal each day. Tamsulosin Tamsulosin (FLOMAX), a benzenesulfonamide, is an 1 receptor antagonist with some selectivity for 1A (and 1D) subtypes compared to the 1B subtype (Kenny et al., 1996). This selectivity may favor blockade of 1A receptors in prostate. Tamsulosin is efficacious in the treatment of BPH with little effect on blood pressure (Beduschi et al., 1998); tamsulosin is not approved for the treatment of hypertension. Tamsulosin is well absorbed and has a t1/2 of 5-10 hours. It is extensively metabolized by CYPs. Tamsulosin may be administered at a 0.4-mg starting dose; a dose of 0.8 mg ultimately will be more efficacious in some patients. Abnormal ejaculation is an adverse effect of tamsulosin, experienced by ~18% of patients receiving the higher dose. Silodosin Silidosin (RAPAFLO) also exhibits selectivity for the 1A, over the 1B adrenergic receptor. The drug is metabolized by several pathways; the main metabolite is a glucuronide formed by UGT2B7; co-administration with inhibitors of this enzyme (e.g., probenecid, valproic acid, fluconazole) increases systemic exposure to silodosin. The drug is approved for the treatment of BPH and is reported, as is tamsulosin, to have lesser effects on blood pressure than the non-1 subtype selective antagonists. Nevertheless, dizziness and orthostatic hypotension can occur. The chief side effect of silodosin is retrograde ejaculation (in 28% of those treated). Silodosin is available as 4-mg and 8-mg capsules. Adverse Effects A major potential adverse effect of prazosin and its congeners is the first-dose effect; marked postural hypotension and syncope sometimes are seen 30-90 minutes after an initial dose of prazosin and 2-6 hours after an initial dose of doxazosin. Syncopal episodes also have occurred with a rapid increase in dosage or with the addition of a second antihypertensive drug to the regimen of a patient who already is taking a large dose of prazosin. The mechanisms responsible for such exaggerated hypotensive responses or for the development of tolerance to these effects are not clear. An action in the CNS to reduce sympathetic outflow may contribute (described earlier). The risk of the first-dose phenomenon is minimized by limiting the initial dose (e.g., 1 mg at bedtime), by increasing the dosage slowly, and by introducing additional antihypertensive drugs cautiously. Since orthostatic hypotension may be a problem during long-term treatment with prazosin or its congeners, it is essential to check standing as well as recumbent blood pressure. Nonspecific adverse effects such as headache, dizziness, and asthenia rarely limit treatment with prazosin. The nonspecific complaint of dizziness generally is not due to orthostatic hypotension. Although not extensively documented, the adverse effects of the structural analogs of prazosin appear to be similar to those of the parent compound. For tamsulosin, at a dose of 0.4 mg daily, effects on blood pressure are not expected, although impaired ejaculation may occur. Therapeutic Uses Hypertension Prazosin and its congeners have been used successfully in the treatment of essential hypertension (Chapter 28). Considerable interest has also focused on the tendency of these drugs to improve rather than worsen lipid profiles and glucose-insulin metabolism in patients with hypertension who are at risk for atherosclerotic disease (Grimm, 1991). Catecholamines are also powerful stimulators of vascular smooth muscle hypertrophy, acting by 1 receptors. To what extent these effects of 1 antagonists have clinical significance in diminishing the risk of atherosclerosis is not known. Congestive Heart Failure receptor antagonists have been used in the treatment of congestive heart failure, as have other vasodilating drugs. The short-term effects of prazosin in these patients are due to dilation of both arteries and veins, resulting in a reduction of preload and afterload, which increases cardiac output and reduces pulmonary congestion. In contrast to results obtained with inhibitors of angiotensin-converting enzyme or a combination of hydralazine and an organic nitrate, prazosin has not been found to prolong life in patients with congestive heart failure.

₂ Adrenergic Receptor Antagonists

The ₂ receptors have an important role in regulation of the activity of the sympathetic nervous system, both peripherally and centrally. As mentioned earlier, activation of presynaptic ₂ receptors inhibits the release of NE and other co-transmitters from peripheral sympathetic nerve endings. Activation of ₂ receptors in the pontomedullary region of the CNS inhibits sympathetic nervous system activity and leads to a fall in blood pressure; these receptors are a site of action for drugs such as clonidine. Blockade of ₂ receptors with selective antagonists such as yohimbine thus can increase sympathetic outflow and potentiate the release of NE from nerve endings, leading to activation of ₁ and ₁ receptors in the heart and peripheral vasculature with a consequent rise in blood pressure. Antagonists that also block ₁ receptors give rise to similar effects on sympathetic outflow and release of NE, but the net increase in blood pressure is prevented by inhibition of vasoconstriction.

Although certain vascular beds contain ₂ receptors that promote contraction of smooth muscle, it is thought that these receptors are preferentially stimulated by circulating catecholamines, whereas ₁ receptors are activated by NE released from sympathetic nerve fibers. In other vascular beds, ₂ receptors reportedly promote vasodilation by stimulating the release of NO from endothelial cells. The physiological role of vascular ₂ receptors in the regulation of blood flow within various vascular beds is uncertain. The ₂ receptors contribute to smooth muscle contraction in the human saphenous vein, whereas ₁ receptors are more prominent in dorsal hand veins. The effects of ₂ receptor antagonists on the cardiovascular system are dominated by actions in the CNS and on sympathetic nerve endings.

Yohimbine

Yohimbine (YOCON, APHRODYNE) is a competitive antagonist that is selective for ₂ receptors. The compound is an indolealkylamine alkaloid and is found in the bark of the tree Pausinystalia yohimbe and in Rauwolfia root; its structure resembles that of reserpine. Yohimbine readily enters the CNS, where it acts to increase blood pressure and heart rate; it also enhances motor activity and produces tremors. These actions are opposite to those of clonidine, an ₂ agonist. Yohimbine also antagonizes effects of 5-HT. In the past, it was used extensively to treat male sexual dysfunction (Tam et al., 2001). Although efficacy never was clearly demonstrated, there is renewed interest in the use of yohimbine in the treatment of male sexual dysfunction. The drug enhances sexual activity in male rats and may benefit some patients with psychogenic erectile dysfunction. However, the efficacies of PDE5 inhibitors (e.g., sildenafil, vardenafil, and tadalafil) and apomorphine (off-label) have been much more conclusively demonstrated in oral treatment of erectile dysfunction. Several small studies suggest that yohimbine also may be useful for diabetic neuropathy and in the treatment of postural hypotension. In the U.S., yohimbine can be legally sold as a dietary supplement; however, labeling claims that it will arouse or increase sexual desire or improve sexual performance are prohibited. Yohimbine (ANTAGONIL, YOBINE) is approved in veterinary medicine for the reversal of xylazine anesthesia.

Non-Selective Adrenergic Antagonists: Phenoxybenzamine and Phentolamine

Phenoxybenzamine and phentolamine are non-selective receptors antagonists. Phenoxybenzamine, a haloalkylamine compound, produces an irreversible antagonism; while phentolamine, an imidazaline, produces a competitive antagonism. Phenoxybenzamine and phentolamine have played an important role in the establishment of the importance of receptors in the regulation of the cardiovascular and other systems. They are sometimes referred to as "classical" blockers to distinguish them from more recently developed compounds such as prazosin.

The actions of phenoxybenzamine and phentolamine on the cardiovascular system are similar. These "classical" blockers cause a progressive decrease in peripheral resistance, due to antagonism of receptors in the vasculature, and an increase in cardiac output that is due in part to reflex sympathetic nerve stimulation. The cardiac stimulation is accentuated by enhanced release of NE from cardiac sympathetic nerve due to antagonism of presynaptic ₂ receptors by these non-selective blockers. Postural hypotension is a prominent feature with these drugs and this, accompanied by reflex tachycardia that can precipitate cardiac arrhythmias, severely limits the use of these drugs to treat essential hypertension. The more recently developed ₁-selective antagonists, such as prazosin, have replaced the "classical" blockers in the management of essential hypertension. Phenoxybenzamine and phentolamine are still marketed for several specialized uses.

Therapeutic Uses

A use of phenoxybenzamine (DIBENZYLINE) is in the treatment of pheochromocytoma. Pheochromocytomas are tumors of the adrenal medulla and sympathetic neurons that secrete enormous quantities of catecholamines into the circulation. The usual result is hypertension, which may be episodic and severe. The vast majority of pheochromocytomas are treated surgically; however, phenoxybenzamine is often used in preparing the patient for surgery. The drug controls episodes of severe hypertension and minimizes other adverse effects of catecholamines, such as contraction of plasma volume and injury of the myocardium. A conservative approach is to initiate treatment with phenoxybenzamine (at a dosage of 10 mg twice daily) 1-3 weeks before the operation. The dose is increased every other day until the desired effect on blood pressure is achieved. Therapy may be limited by postural hypotension; nasal stuffiness is another frequent adverse effect. The usual daily dose of phenoxybenzamine in patients with pheochromocytoma is 40-120 mg given in two or three divided portions. Prolonged treatment with phenoxybenzamine may be necessary in patients with inoperable or malignant pheochromocytoma. In some patients, particularly those with malignant disease, administration of metyrosine may be a useful adjuvant. Metyrosine (DEMSER) is a competitive inhibitor of tyrosine hydroxylase, the rate-limiting enzyme in the synthesis of catecholamines (Chapter 8). Receptor antagonists also are used to treat pheochromocytoma, but only after the administration of an receptor antagonist (described later).

Phentolamine can also be used in short-term control of hypertension in patients with pheochromocytoma. Rapid infusions of phentolamine may cause severe hypotension, so the drug should be administered cautiously. Phentolamine also may be useful to relieve pseudo-obstruction of the bowel in patients with pheochromocytoma; this condition may result from the inhibitory effects of catecholamines on intestinal smooth muscle.

Phentolamine has been used locally to prevent dermal necrosis after the inadvertent extravasation of an receptor agonist. The drug also may be useful for the treatment of hypertensive crises that follow the abrupt withdrawal of clonidine or that may result from the ingestion of tyramine-containing foods during the use of non-selective MAO inhibitors. Although excessive activation of receptors is important in the development of severe hypertension in these settings, there is little information about the safety and efficacy of phentolamine compared with those of other antihypertensive agents in the treatment of such patients. Direct intracavernous injection of phentolamine (in combination with papaverine) has been proposed as a treatment for male sexual dysfunction. The long-term efficacy of this treatment is not known. Intracavernous injection of phentolamine may cause orthostatic hypotension and priapism; pharmacological reversal of drug-induced erections can be achieved with an receptor agonist such as phenylephrine. Repetitive intrapenile injections may cause fibrotic reactions. Buccally or orally administered phentolamine may have efficacy in some men with sexual dysfunction.

In 2008, the FDA approved the use of phentolamine (ORAVERSE) to reverse or shorten the duration of soft-tissue anesthesia. Sympathomimetics are frequently administered with local anesthetics to slow the removal of the anesthetic by causing vasoconstriction. When the need for anesthesia is over, phentolamine can help reverse it by antagonizing the -receptor induced vasoconstriction.

Phenoxybenzamine has been used off-label to control the manifestations of autonomic hyperreflexia in patients with spinal cord transection.

Toxicity and Adverse Effects

Hypotension is the major adverse effect of phenoxybenzamine and phentolamine. In addition, reflex cardiac stimulation may cause alarming tachycardia, cardiac arrhythmias, and ischemic cardiac events, including myocardial infarction. Reversible inhibition of ejaculation may occur due to impaired smooth muscle contraction in the vas deferens and ejaculatory ducts. Phenoxybenzamine is mutagenic in the Ames test, and repeated administration of this drug to experimental animals causes peritoneal sarcomas and lung tumors. The clinical significance of these findings is not known. Phentolamine stimulates GI smooth muscle, an effect antagonized by atropine, and also enhances gastric acid secretion due in part to histamine release. Thus, phentolamine should be used with caution in patients with a history of peptic ulcer.