Case Study

A 46-year-old woman sees her physician because of palpitations and headaches. She enjoyed good health until 1 year ago when spells of cardiac palpitations began. These became more severe and were eventually accompanied by throbbing headaches and drenching sweats. Physical examination reveals a blood pressure of 150/90 mm Hg and heart rate of 88 bpm. During the physical examination, palpation of the abdomen elicits a sudden and typical episode, with a rise in blood pressure to 210/120 mm Hg, heart rate to 122 bpm, and facial pallor. This is accompanied by severe headache and profuse sweating. What is the likely cause of her episodes? What caused the blood pressure and heart rate to rise so high during the examination? What treatments might help this patient?

*The authors thank Dr. Brian B. Hoffman, author of this chapter in previous editions, whose work we have modified and updated. We also thank Dr. Brett English and Suzanna Lonce for improving tables and Dr. Randy Blakely for helpful comments.

Adrenoceptor Antagonist Drugs: Introduction

Catecholamines play a role in many physiologic and pathophysiologic responses as described in Chapter 9. Drugs that block their receptors therefore have important effects, some of which are of great clinical value. These effects vary dramatically according to the drug's selectivity for and receptors. The classification of adrenoceptors into ₁, ₂, and subtypes and the effects of activating these receptors are discussed in Chapters 6 and 9. Blockade of peripheral dopamine receptors is of minor clinical importance at present. In contrast, blockade of central nervous system dopamine receptors is very important; drugs that act on these receptors are discussed in Chapters 21 and 29. This chapter deals with pharmacologic antagonist drugs whose major effect is to occupy ₁, ₂, or receptors outside the central nervous system and prevent their activation by catecholamines and related agonists.

For pharmacologic research, ₁- and ₂-adrenoceptor antagonist drugs have been very useful in the experimental exploration of autonomic nervous system function. In clinical therapeutics, nonselective antagonists are used in the treatment of pheochromocytoma (tumors that secrete catecholamines), and ₁-selective antagonists are used in primary hypertension and benign prostatic hyperplasia. Beta-receptor antagonist drugs are useful in a much wider variety of clinical conditions and are firmly established in the treatment of hypertension, ischemic heart disease, arrhythmias, endocrinologic and neurologic disorders, glaucoma, and other conditions.

Basic Pharmacology of the Alpha-Receptor Antagonist Drugs

Mechanism of Action

Alpha-receptor antagonists may be reversible or irreversible in their interaction with these receptors. Reversible antagonists dissociate from receptors and the block can be surmounted with sufficiently high concentrations of agonists; irreversible drugs do not dissociate and cannot be surmounted. Phentolamine and prazosin (Figure 10–1) are examples of reversible antagonists. These drugs and labetalol—drugs used primarily for their antihypertensive effects—as well as several ergot derivatives (see Chapter 16) are also reversible -adrenoceptor antagonists or partial agonists. Phenoxybenzamine, an agent related to the nitrogen mustards, forms a reactive ethyleneimonium intermediate (Figure 10–1) that covalently binds to receptors, resulting in irreversible blockade. Figure 10–2 illustrates the effects of a reversible drug in comparison with those of an irreversible agent.

As discussed in Chapters 1 and 2, the duration of action of a reversible antagonist is largely dependent on the half-life of the drug in the body and the rate at which it dissociates from its receptor: The shorter the half-life of the drug in the body, the less time it takes for the effects of the drug to dissipate. In contrast, the effects of an irreversible antagonist may persist long after the drug has been cleared from the plasma. In the case of phenoxybenzamine, the restoration of tissue responsiveness after extensive -receptor blockade is dependent on synthesis of new receptors, which may take several days. The rate of return of ₁-adrenoceptor responsiveness may be particularly important in patients having a sudden cardiovascular event or who become candidates for urgent surgery.

Pharmacologic Effects

Cardiovascular Effects

Because arteriolar and venous tone are determined to a large extent by receptors on vascular smooth muscle, -receptor antagonist drugs cause a lowering of peripheral vascular resistance and blood pressure (Figure 10–3). These drugs can prevent the pressor effects of usual doses of agonists; indeed, in the case of agonists with both and ₂ effects (eg, epinephrine), selective -receptor antagonism may convert a pressor to a depressor response (Figure 10–3). This change in response is called epinephrine reversal; it illustrates how the activation of both and receptors in the vasculature may lead to opposite responses. Alpha-receptor antagonists often cause orthostatic hypotension and reflex tachycardia; nonselective (₁ = ₂, Table 10–1) blockers usually cause significant tachycardia if blood pressure is lowered below normal. Orthostatic hypotension is due to antagonism of sympathetic nervous system stimulation of ₁ receptors in vascular smooth muscle; contraction of veins is an important component of the normal capacity to maintain blood pressure in the upright position since it decreases venous pooling in the periphery. Constriction of arterioles in the legs also contributes to the normal orthostatic response. Tachycardia may be more marked with agents that block ₂-presynaptic receptors in the heart, since the augmented release of norepinephrine will further stimulate receptors in the heart.

Other Effects

Blockade of receptors in other tissues elicits miosis (small pupils) and nasal stuffiness. Alpha₁ receptors are expressed in the base of the bladder and the prostate, and their blockade decreases resistance to the flow of urine. Alpha blockers, therefore, are used therapeutically for the treatment of urinary retention due to prostatic hyperplasia (see below). Individual agents may have other important effects in addition to -receptor antagonism (see below).

Specific Agents

Phenoxybenzamine binds covalently to receptors, causing irreversible blockade of long duration (14–48 hours or longer). It is somewhat selective for ₁ receptors but less so than prazosin (Table 10–1). The drug also inhibits reuptake of released norepinephrine by presynaptic adrenergic nerve terminals. Phenoxybenzamine blocks histamine (H₁), acetylcholine, and serotonin receptors as well as receptors (see Chapter 16).

The pharmacologic actions of phenoxybenzamine are primarily related to antagonism of -receptor–mediated events. The most significant effect is attenuation of catecholamine-induced vasoconstriction. While phenoxybenzamine causes relatively little fall in blood pressure in normal supine individuals, it reduces blood pressure when sympathetic tone is high, eg, as a result of upright posture or because of reduced blood volume. Cardiac output may be increased because of reflex effects and because of some blockade of presynaptic ₂ receptors in cardiac sympathetic nerves.

Phenoxybenzamine is absorbed after oral administration, although bioavailability is low and its kinetic properties are not well known. The drug is usually given orally, starting with dosages of 10 mg/d and progressively increasing the dose until the desired effect is achieved. A dosage of less than 100 mg/d is usually sufficient to achieve adequate -receptor blockade. The major use of phenoxybenzamine is in the treatment of pheochromocytoma (see below).

Most adverse effects of phenoxybenzamine derive from its -receptor–blocking action; the most important are orthostatic hypotension and tachycardia. Nasal stuffiness and inhibition of ejaculation also occur. Since phenoxybenzamine enters the central nervous system, it may cause less specific effects, including fatigue, sedation, and nausea. Because phenoxybenzamine is an alkylating agent, it may have other adverse effects that have not yet been characterized.

Phentolamine is a potent competitive antagonist at both ₁ and ₂ receptors (Table 10–1). Phentolamine reduces peripheral resistance through blockade of ₁ receptors and possibly ₂ receptors on vascular smooth muscle. Its cardiac stimulation is due to antagonism of presynaptic ₂ receptors (leading to enhanced release of norepinephrine from sympathetic nerves) and sympathetic activation from baroreflex mechanisms. Phentolamine also has minor inhibitory effects at serotonin receptors and agonist effects at muscarinic and H₁ and H₂ histamine receptors. Phentolamine's principal adverse effects are related to cardiac stimulation, which may cause severe tachycardia, arrhythmias, and myocardial ischemia. Phentolamine has been used in the treatment of pheochromocytoma. Unfortunately oral and intravenous formulations of phentolamine are no longer consistently available in the United States.

Prazosin is a piperazinyl quinazoline effective in the management of hypertension (see Chapter 11). It is highly selective for ₁ receptors and typically 1000-fold less potent at ₂ receptors. This may partially explain the relative absence of tachycardia seen with prazosin compared with that of phentolamine and phenoxybenzamine. Prazosin relaxes both arterial and venous vascular smooth muscle, as well as smooth muscle in the prostate, due to blockade of ₁ receptors. Prazosin is extensively metabolized in humans; because of metabolic degradation by the liver, only about 50% of the drug is available after oral administration. The half-life is normally about 3 hours.

Terazosin is another reversible ₁-selective antagonist that is effective in hypertension (see Chapter 11); it is also approved for use in men with urinary symptoms due to benign prostatic hyperplasia (BPH). Terazosin has high bioavailability but is extensively metabolized in the liver, with only a small fraction of unchanged drug excreted in the urine. The half-life of terazosin is 9–12 hours.

Doxazosin is efficacious in the treatment of hypertension and BPH. It differs from prazosin and terazosin in having a longer half-life of about 22 hours. It has moderate bioavailability and is extensively metabolized, with very little parent drug excreted in urine or feces. Doxazosin has active metabolites, although their contribution to the drug's effects is probably small.

Tamsulosin  is a competitive ₁ antagonist with a structure quite different from that of most other ₁-receptor blockers. It has high bioavailability and a half-life of 9–15 hours. It is metabolized extensively in the liver. Tamsulosin has higher affinity for _1A and _1D receptors than for the _1B subtype. Evidence suggests that tamsulosin has relatively greater potency in inhibiting contraction in prostate smooth muscle versus vascular smooth muscle compared with other ₁-selective antagonists. The drug's efficacy in BPH suggests that the _1A subtype may be the most important subtype mediating prostate smooth muscle contraction. Furthermore, compared with other antagonists, tamsulosin has less effect on standing blood pressure in patients. Nevertheless, caution is appropriate in using any antagonist in patients with diminished sympathetic nervous system function.

Other Alpha-Adrenoceptor Antagonists

Alfuzosin is an ₁-selective quinazoline derivative that is approved for use in BPH. It has a bioavailability of about 60%, is extensively metabolized, and has an elimination half-life of about 5 hours. Indoramin is another ₁-selective antagonist that also has efficacy as an antihypertensive. It is not available in the USA. Urapidil is an ₁ antagonist (its primary effect) that also has weak ₂-agonist and 5-HT_1A-agonist actions and weak antagonist action at ₁ receptors. It is used in Europe as an antihypertensive agent and for benign prostatic hyperplasia. Labetalol has both ₁-selective and -antagonistic effects; it is discussed below. Neuroleptic drugs such as chlorpromazine and haloperidol are potent dopamine receptor antagonists but are also antagonists at receptors. Their antagonism of receptors probably contributes to some of their adverse effects, particularly hypotension. Similarly, the antidepressant trazodone has the capacity to block ₁ receptors. Ergot derivatives, eg, ergotamine and dihydroergotamine, cause reversible -receptor blockade, probably via a partial agonist action (see Chapter 16). Yohimbine, an indole alkaloid, is an ₂-selective antagonist. It is sometimes used in the treatment of orthostatic hypotension because it promotes norepinephrine release through blockade of presynaptic ₂ receptors. It was once widely used to improve male erectile dysfunction but has been superseded by phosphodiesterase-5 inhibitors like sildenafil (see Chapter 12). Yohimbine can reverse the antihypertensive effects of an ₂-adrenoceptor agonist such as clonidine.

Clinical Pharmacology of the Alpha-Receptor–Blocking Drugs

Pheochromocytoma

Pheochromocytoma is a tumor of the adrenal medulla or sympathetic ganglion cells. The tumor secretes catecholamines, especially norepinephrine and epinephrine. The patient in the case study at the beginning of the chapter had a left adrenal pheochromocytoma that was identified by imaging. In addition, she had elevated plasma and urinary norepinephrine, epinephrine, and their metabolites, normetanephrine and metanephrine.

The diagnosis of pheochromocytoma is confirmed on the basis of elevated plasma or urinary levels of catecholamines, metanephrine, and normetanephrine (see Chapter 6). Once diagnosed biochemically, techniques to localize a pheochromocytoma include computed tomography and magnetic resonance imaging scans and scanning with radiomarkers such as ¹³¹I-meta-iodobenzylguanidine (MIBG), a norepinephrine transporter substrate that is taken up by tumor cells.

The major clinical use of phenoxybenzamine is in the management of pheochromocytoma. Patients have many symptoms and signs of catecholamine excess, including intermittent or sustained hypertension, headaches, palpitations, and increased sweating.

Release of stored catecholamines from pheochromocytomas may occur in response to physical pressure, chemical stimulation, or spontaneously. When it occurs during operative manipulation of pheochromocytoma, the resulting hypertension may be controlled with -receptor blockade or nitroprusside. Nitroprusside is preferred because its effects can be more readily titrated and it has a shorter duration of action.

Alpha-receptor antagonists are most useful in the preoperative management of patients with pheochromocytoma (Figure 10–4). Administration of phenoxybenzamine in the preoperative period will help control hypertension and will tend to reverse chronic changes resulting from excessive catecholamine secretion such as plasma volume contraction, if present. Furthermore, the patient's operative course may be simplified. Oral doses of 10 mg/d can be increased at intervals of several days until hypertension is controlled. Some physicians give phenoxybenzamine to patients with pheochromocytoma for 1–3 weeks before surgery. Other surgeons prefer to operate on patients in the absence of treatment with phenoxybenzamine, counting on modern anesthetic techniques to control blood pressure and heart rate during surgery. Phenoxybenzamine can be very useful in the chronic treatment of inoperable or metastatic pheochromocytoma. Although there is less experience with alternative drugs, hypertension in patients with pheochromocytoma may also respond to reversible ₁-selective antagonists or to conventional calcium channel antagonists. Beta-receptor antagonists may be required after -receptor blockade has been instituted to reverse the cardiac effects of excessive catecholamines. Beta antagonists should not be used prior to establishing effective -receptor blockade, since unopposed -receptor blockade could theoretically cause blood pressure elevation from increased vasoconstriction.

Pheochromocytoma is sometimes treated with metyrosine (-methyltyrosine), the -methyl analog of tyrosine. This agent is a competitive inhibitor of tyrosine hydroxylase, the rate-limiting step in the synthesis of dopamine, norepinephrine, and epinephrine (see Figure 6–5). Metyrosine is especially useful in symptomatic patients with inoperable or metastatic pheochromocytoma. Because it has access to the central nervous system, metyrosine can cause extrapyramidal effects due to reduced dopamine levels.

Hypertensive Emergencies

The -adrenoceptor antagonist drugs have limited application in the management of hypertensive emergencies, but labetalol has been used in this setting (see Chapter 11). In theory, -adrenoceptor antagonists are most useful when increased blood pressure reflects excess circulating concentrations of agonists, eg, in pheochromocytoma, overdosage of sympathomimetic drugs, or clonidine withdrawal. However, other drugs are generally preferable, since considerable experience is necessary to use -adrenoceptor antagonist drugs safely in these settings.

Chronic Hypertension

Members of the prazosin family of ₁-selective antagonists are efficacious drugs in the treatment of mild to moderate systemic hypertension (see Chapter 11). They are generally well tolerated, but they are not usually recommended as monotherapy for hypertension because other classes of antihypertensives are more effective in preventing heart failure. Their major adverse effect is orthostatic hypotension, which may be severe after the first few doses but is otherwise uncommon. Nonselective antagonists are not used in primary systemic hypertension. Prazosin and related drugs may also be associated with dizziness. Orthostatic changes in blood pressure should be checked routinely in any patient being treated for hypertension.

It is interesting that the use of -adrenoceptor antagonists such as prazosin has been found to be associated with either no changes in plasma lipids or increased concentrations of high-density lipoproteins (HDL), which could be a favorable alteration. The mechanism for this effect is not known.

Peripheral Vascular Disease

Alpha-receptor–blocking drugs do not seem to be effective in the treatment of peripheral vascular occlusive disease characterized by morphologic changes that limit flow in the vessels. Occasionally, individuals with Raynaud's phenomenon and other conditions involving excessive reversible vasospasm in the peripheral circulation do benefit from prazosin or phenoxybenzamine, although calcium channel blockers may be preferable for most patients.

Urinary Obstruction

Benign prostatic hyperplasia is common in elderly men. Various surgical treatments are effective in relieving the urinary symptoms of BPH; however, drug therapy is efficacious in many patients. The mechanism of action in improving urine flow involves partial reversal of smooth muscle contraction in the enlarged prostate and in the bladder base. It has been suggested that some ₁-receptor antagonists may have additional effects on cells in the prostate that help improve symptoms.

Prazosin, doxazosin, and terazosin are all efficacious in patients with BPH. These drugs are particularly useful in patients who also have hypertension. Considerable interest has focused on which ₁-receptor subtype is most important for smooth muscle contraction in the prostate: subtype-selective _1A-receptor antagonists might lead to improved efficacy and safety in treating this disease. As indicated above, tamsulosin is also efficacious in BPH and has relatively minor effects on blood pressure at a low dose. This drug may be preferred in patients who have experienced orthostatic hypotension with other ₁-receptor antagonists.

Erectile Dysfunction

A combination of phentolamine with the nonspecific smooth muscle relaxant papaverine, when injected directly into the penis, may cause erections in men with sexual dysfunction. Long-term administration may result in fibrotic reactions. Systemic absorption may lead to orthostatic hypotension; priapism may require direct treatment with an -adrenoceptor agonist such as phenylephrine. Alternative therapies for erectile dysfunction include prostaglandins (see Chapter 18), sildenafil and other cGMP phosphodiesterase inhibitors (see Chapter 12), and apomorphine.

Applications of Alpha₂ Antagonists

Alpha₂ antagonists have relatively little clinical usefulness. They have limited benefit in male erectile dysfunction. There has been experimental interest in the development of highly selective antagonists for use in Raynaud's phenomenon to inhibit smooth muscle contraction, for treatment of type 2 diabetes (₂ receptors inhibit insulin secretion), and for treatment of psychiatric depression. It is likely that better understanding of the subtypes of ₂ receptors will lead to development of clinically useful subtype-selective new drugs.

Basic Pharmacology of the Beta-Receptor Antagonist Drugs

Beta-receptor antagonists share the common feature of antagonizing the effects of catecholamines at adrenoceptors. Beta-blocking drugs occupy receptors and competitively reduce receptor occupancy by catecholamines and other agonists. (A few members of this group, used only for experimental purposes, bind irreversibly to receptors.) Most -blocking drugs in clinical use are pure antagonists; that is, the occupancy of a receptor by such a drug causes no activation of the receptor. However, some are partial agonists; that is, they cause partial activation of the receptor, albeit less than that caused by the full agonists epinephrine and isoproterenol. As described in Chapter 2, partial agonists inhibit the activation of receptors in the presence of high catecholamine concentrations but moderately activate the receptors in the absence of endogenous agonists. Finally, evidence suggests that some blockers (eg, betaxolol, metoprolol) are inverse agonists—drugs that reduce constitutive activity of receptors—in some tissues. The clinical significance of this property is not known.

The -receptor–blocking drugs differ in their relative affinities for ₁ and ₂ receptors (Table 10–1). Some have a higher affinity for ₁ than for ₂ receptors, and this selectivity may have important clinical implications. Since none of the clinically available -receptor antagonists are absolutely specific for ₁ receptors, the selectivity is dose-related; it tends to diminish at higher drug concentrations. Other major differences among antagonists relate to their pharmacokinetic characteristics and local anesthetic membrane-stabilizing effects.

Chemically, most -receptor-antagonist drugs (Figure 10–5) resemble isoproterenol to some degree (see Figure 9–3).

Pharmacokinetic Properties of the Beta-Receptor Antagonists

Absorption

Most of the drugs in this class are well absorbed after oral administration; peak concentrations occur 1–3 hours after ingestion. Sustained-release preparations of propranolol and metoprolol are available.

Bioavailability

Propranolol undergoes extensive hepatic (first-pass) metabolism; its bioavailability is relatively low (Table 10–2). The proportion of drug reaching the systemic circulation increases as the dose is increased, suggesting that hepatic extraction mechanisms may become saturated. A major consequence of the low bioavailability of propranolol is that oral administration of the drug leads to much lower drug concentrations than are achieved after intravenous injection of the same dose. Because the first-pass effect varies among individuals, there is great individual variability in the plasma concentrations achieved after oral propranolol. For the same reason, bioavailability is limited to varying degrees for most antagonists with the exception of betaxolol, penbutolol, pindolol, and sotalol.

Distribution and Clearance

The antagonists are rapidly distributed and have large volumes of distribution. Propranolol and penbutolol are quite lipophilic and readily cross the blood-brain barrier (Table 10–2). Most antagonists have half-lives in the range of 3–10 hours. A major exception is esmolol, which is rapidly hydrolyzed and has a half-life of approximately 10 minutes. Propranolol and metoprolol are extensively metabolized in the liver, with little unchanged drug appearing in the urine. The cytochrome P450 2D6 (CYP2D6) genotype is a major determinant of interindividual differences in metoprolol plasma clearance (see Chapter 4). Poor metabolizers exhibit three-fold to ten-fold higher plasma concentrations after administration of metoprolol than extensive metabolizers. Atenolol, celiprolol, and pindolol are less completely metabolized. Nadolol is excreted unchanged in the urine and has the longest half-life of any available antagonist (up to 24 hours). The half-life of nadolol is prolonged in renal failure. The elimination of drugs such as propranolol may be prolonged in the presence of liver disease, diminished hepatic blood flow, or hepatic enzyme inhibition. It is notable that the pharmacodynamic effects of these drugs are sometimes prolonged well beyond the time predicted from half-life data.

Pharmacodynamics of the Beta-Receptor Antagonist Drugs

Most of the effects of these drugs are due to occupation and blockade of receptors. However, some actions may be due to other effects, including partial agonist activity at receptors and local anesthetic action, which differ among the blockers (Table 10–2).

Effects on the Cardiovascular System

Beta-blocking drugs given chronically lower blood pressure in patients with hypertension (see Chapter 11). The mechanisms involved are not fully understood but probably include suppression of renin release and effects in the central nervous system. These drugs do not usually cause hypotension in healthy individuals with normal blood pressure.

Beta-receptor antagonists have prominent effects on the heart (Figure 10–6) and are very valuable in the treatment of angina (see Chapter 12) and chronic heart failure (see Chapter 13) and following myocardial infarction (see Chapter 14). The negative inotropic and chronotropic effects reflect the role of adrenoceptors in regulating these functions. Slowed atrioventricular conduction with an increased PR interval is a related result of adrenoceptor blockade in the atrioventricular node. In the vascular system, -receptor blockade opposes ₂-mediated vasodilation. This may acutely lead to a rise in peripheral resistance from unopposed -receptor-mediated effects as the sympathetic nervous system discharges in response to lowered blood pressure due to the fall in cardiac output. Nonselective and ₁-blocking drugs antagonize the release of renin caused by the sympathetic nervous system.

Overall, although the acute effects of these drugs may include a rise in peripheral resistance, chronic drug administration leads to a fall in peripheral resistance in patients with hypertension.

Effects on the Respiratory Tract

Blockade of the ₂ receptors in bronchial smooth muscle may lead to an increase in airway resistance, particularly in patients with asthma. Beta₁-receptor antagonists such as metoprolol and atenolol may have some advantage over nonselective antagonists when blockade of ₁ receptors in the heart is desired and ₂-receptor blockade is undesirable. However, no currently available ₁-selective antagonist is sufficiently specific to completely avoid interactions with ₂ adrenoceptors. Consequently, these drugs should generally be avoided in patients with asthma. On the other hand, many patients with chronic obstructive pulmonary disease (COPD) may tolerate these drugs quite well and the benefits, for example in patients with concomitant ischemic heart disease, may outweigh the risks.

Effects on the Eye

Beta-blocking agents reduce intraocular pressure, especially in glaucoma. The mechanism usually reported is decreased aqueous humor production. (See Clinical Pharmacology and The Treatment of Glaucoma.)

Metabolic and Endocrine Effects

Beta-receptor antagonists such as propranolol inhibit sympathetic nervous system stimulation of lipolysis. The effects on carbohydrate metabolism are less clear, though glycogenolysis in the human liver is at least partially inhibited after ₂-receptor blockade. Glucagon is the primary hormone used to combat hypoglycemia and it is unclear to what extent antagonists impair recovery from hypoglycemia, but they should be used with caution in insulin-dependent diabetic patients. This may be particularly important in diabetic patients with inadequate glucagon reserve and in pancreatectomized patients since catecholamines may be the major factors in stimulating glucose release from the liver in response to hypoglycemia. Beta₁-receptor–selective drugs may be less prone to inhibit recovery from hypoglycemia. Beta-receptor antagonists are much safer in those type 2 diabetic patients who do not have hypoglycemic episodes.

The chronic use of -adrenoceptor antagonists has been associated with increased plasma concentrations of very-low-density lipoproteins (VLDL) and decreased concentrations of HDL cholesterol. Both of these changes are potentially unfavorable in terms of risk of cardiovascular disease. Although low-density lipoprotein (LDL) concentrations generally do not change, there is a variable decline in the HDL cholesterol/LDL cholesterol ratio that may increase the risk of coronary artery disease. These changes tend to occur with both selective and nonselective blockers, though they may be less likely to occur with blockers possessing intrinsic sympathomimetic activity (partial agonists). The mechanisms by which -receptor antagonists cause these changes are not understood, though changes in sensitivity to insulin action may contribute.

Effects Not Related to Beta-Blockade

Partial -agonist activity was significant in the first -blocking drug synthesized, dichloroisoproterenol. It has been suggested that retention of some intrinsic sympathomimetic activity is desirable to prevent untoward effects such as precipitation of asthma or excessive bradycardia. Pindolol and other partial agonists are noted in Table 10–2. It is not yet clear to what extent partial agonism is clinically valuable. Furthermore, these drugs may not be as effective as the pure antagonists in secondary prevention of myocardial infarction. However, they may be useful in patients who develop symptomatic bradycardia or bronchoconstriction in response to pure antagonist -adrenoceptor drugs, but only if they are strongly indicated for a particular clinical indication.

Local anesthetic action, also known as "membrane-stabilizing" action, is a prominent effect of several blockers (Table 10–2). This action is the result of typical local anesthetic blockade of sodium channels (see Chapter 26) and can be demonstrated experimentally in isolated neurons, heart muscle, and skeletal muscle membrane. However, it is unlikely that this effect is important after systemic administration of these drugs, since the concentration in plasma usually achieved by these routes is too low for the anesthetic effects to be evident. These membrane-stabilizing blockers are not used topically on the eye, where local anesthesia of the cornea would be highly undesirable. Sotalol is a nonselective -receptor antagonist that lacks local anesthetic action but has marked class III antiarrhythmic effects, reflecting potassium channel blockade (see Chapter 14).

Specific Agents

See Table 10–2

Propranolol is the prototypical -blocking drug. As noted above, it has low and dose-dependent bioavailability. A long-acting form of propranolol is available; prolonged absorption of the drug may occur over a 24-hour period. The drug has negligible effects at and muscarinic receptors; however, it may block some serotonin receptors in the brain, though the clinical significance is unclear. It has no detectable partial agonist action at receptors.

Metoprolol, atenolol, and several other drugs (Table 10–2) are members of the ₁-selective group. These agents may be safer in patients who experience bronchoconstriction in response to propranolol. Since their ₁ selectivity is rather modest, they should be used with great caution, if at all, in patients with a history of asthma. However, in selected patients with chronic obstructive lung disease the benefits may exceed the risks, eg, in patients with myocardial infarction. Beta₁-selective antagonists may be preferable in patients with diabetes or peripheral vascular disease when therapy with a blocker is required, since ₂ receptors are probably important in liver (recovery from hypoglycemia) and blood vessels (vasodilation).

Nebivolol is the most highly selective ₁-adrenergic receptor blocker, and it has the additional quality of eliciting vasodilation. This may be due to a poorly understood stimulation of the endothelial nitric oxide pathway.

Nadolol is noteworthy for its very long duration of action; its spectrum of action is similar to that of timolol. Timolol is a nonselective agent with no local anesthetic activity. It has excellent ocular hypotensive effects when administered topically in the eye. Levobunolol (nonselective) and betaxolol (₁-selective) are also used for topical ophthalmic application in glaucoma; the latter drug may be less likely to induce bronchoconstriction than nonselective antagonists. Carteolol is a nonselective -receptor antagonist.

Pindolol, acebutolol, carteolol, bopindolol,* oxprenolol,* celiprolol,* and penbutolol are of interest because they have partial -agonist activity. They are effective in the major cardiovascular applications of the -blocking group (hypertension and angina). Although these partial agonists may be less likely to cause bradycardia and abnormalities in plasma lipids than are antagonists, the overall clinical significance of intrinsic sympathomimetic activity remains uncertain. Pindolol, perhaps as a result of actions on serotonin signaling, may potentiate the action of traditional antidepressant medications. Celiprolol is a ₁-selective antagonist with a modest capacity to activate ₂ receptors.

There is limited evidence suggesting that celiprolol may have less adverse bronchoconstrictor effect in asthma and may even promote bronchodilation. Acebutolol is also a ₁-selective antagonist.

Labetalol  is a reversible adrenoceptor antagonist available as a racemic mixture of two pairs of chiral isomers (the molecule has two centers of asymmetry). The (S,S)- and (R,S)-isomers are nearly inactive, (S,R)- is a potent blocker, and the (R,R)-isomer is a potent blocker. Labetalol's affinity for receptors is less than that of phentolamine, but labetalol is ₁-selective. Its -blocking potency is somewhat lower than that of propranolol. Hypotension induced by labetalol is accompanied by less tachycardia than occurs with phentolamine and similar blockers.

Carvedilol, medroxalol,*  and bucindolol*  are nonselective -receptor antagonists with some capacity to block ₁-adrenergic receptors. Carvedilol antagonizes the actions of catecholamines more potently at receptors than at ₁ receptors. The drug has a half-life of 6–8 hours. It is extensively metabolized in the liver, and stereoselective metabolism of its two isomers is observed. Since metabolism of (R)-carvedilol is influenced by polymorphisms in CYP2D6 activity and by drugs that inhibit this enzyme's activity (such as quinidine and fluoxetine, see Chapter 4), drug interactions may occur. Carvedilol also appears to attenuate oxygen free radical–initiated lipid peroxidation and to inhibit vascular smooth muscle mitogenesis independently of adrenoceptor blockade. These effects may contribute to the clinical benefits of the drug in chronic heart failure (see Chapter 13).

Esmolol is an ultra-short–acting ₁-selective adrenoceptor antagonist. The structure of esmolol contains an ester linkage; esterases in red blood cells rapidly metabolize esmolol to a metabolite that has a low affinity for receptors. Consequently, esmolol has a short half-life (about 10 minutes). Therefore, during continuous infusions of esmolol, steady-state concentrations are achieved quickly, and the therapeutic actions of the drug are terminated rapidly when its infusion is discontinued. Esmolol may be safer to use than longer-acting antagonists in critically ill patients who require a -adrenoceptor antagonist. Esmolol is useful in controlling supraventricular arrhythmias, arrhythmias associated with thyrotoxicosis, perioperative hypertension, and myocardial ischemia in acutely ill patients.

Butoxamine is a research drug selective for ₂ receptors. Selective ₂-blocking drugs have not been actively sought because there is no obvious clinical application for them; none is available for clinical use.

*Not available in the USA.

Clinical Pharmacology of the Beta-Receptor–Blocking Drugs

Hypertension

The -adrenoceptor–blocking drugs have proved to be effective and well tolerated in hypertension. Although many hypertensive patients respond to a blocker used alone, the drug is often used with either a diuretic or a vasodilator. In spite of the short half-life of many antagonists, these drugs may be administered once or twice daily and still have an adequate therapeutic effect. Labetalol, a competitive and antagonist, is effective in hypertension, though its ultimate role is yet to be determined. Use of these agents is discussed in greater detail in Chapter 11. There is some evidence that drugs in this class may be less effective in the elderly and in individuals of African ancestry. However, these differences are relatively small and may not apply to an individual patient. Indeed, since effects on blood pressure are easily measured, the therapeutic outcome for this indication can be readily detected in any patient.

Ischemic Heart Disease

Beta-adrenoceptor blockers reduce the frequency of anginal episodes and improve exercise tolerance in many patients with angina (see Chapter 12). These actions relate to the blockade of cardiac receptors, resulting in decreased cardiac work and reduction in oxygen demand. Slowing and regularization of the heart rate may contribute to clinical benefits (Figure 10–7). Multiple large-scale prospective studies indicate that the long-term use of timolol, propranolol, or metoprolol in patients who have had a myocardial infarction prolongs survival (Figure 10–8). At the present time, data are less compelling for the use of other than the three mentioned -adrenoceptor antagonists for this indication. It is significant that surveys in many populations have indicated that -receptor antagonists are underused, leading to unnecessary morbidity and mortality. In addition, -adrenoceptor antagonists are strongly indicated in the acute phase of a myocardial infarction. In this setting, relative contraindications include bradycardia, hypotension, moderate or severe left ventricular failure, shock, heart block, and active airways disease. It has been suggested that certain polymorphisms in ₂-adrenoceptor genes may influence survival among patients receiving antagonists after acute coronary syndromes.

Cardiac Arrhythmias

Beta antagonists are often effective in the treatment of both supraventricular and ventricular arrhythmias (see Chapter 14). It has been suggested that the improved survival following myocardial infarction in patients using antagonists (Figure 10–8) is due to suppression of arrhythmias, but this has not been proved. By increasing the atrioventricular nodal refractory period, antagonists slow ventricular response rates in atrial flutter and fibrillation. These drugs can also reduce ventricular ectopic beats, particularly if the ectopic activity has been precipitated by catecholamines. Sotalol has antiarrhythmic effects involving ion channel blockade in addition to its -blocking action; these are discussed in Chapter 14.

Heart Failure

Clinical trials have demonstrated that at least three antagonists—metoprolol, bisoprolol, and carvedilol—are effective in reducing mortality in selected patients with chronic heart failure. Although administration of these drugs may worsen acute congestive heart failure, cautious long-term use with gradual dose increments in patients who tolerate them may prolong life. Although mechanisms are uncertain, there appear to be beneficial effects on myocardial remodeling and in decreasing the risk of sudden death (see Chapter 13).

Other Cardiovascular Disorders

Beta-receptor antagonists have been found to increase stroke volume in some patients with obstructive cardiomyopathy. This beneficial effect is thought to result from the slowing of ventricular ejection and decreased outflow resistance. Beta antagonists are useful in dissecting aortic aneurysm to decrease the rate of development of systolic pressure. Beta antagonists are also useful in selected at-risk patients in the prevention of adverse cardiovascular outcomes resulting from noncardiac surgery.

Glaucoma

See The Treatment of Glaucoma

Systemic administration of -blocking drugs for other indications was found serendipitously to reduce intraocular pressure in patients with glaucoma. Subsequently, it was found that topical administration also reduces intraocular pressure. The mechanism appears to involve reduced production of aqueous humor by the ciliary body, which is physiologically activated by cAMP. Timolol and related antagonists are suitable for local use in the eye because they lack local anesthetic properties. Beta antagonists appear to have an efficacy comparable to that of epinephrine or pilocarpine in open-angle glaucoma and are far better tolerated by most patients. While the maximal daily dose applied locally (1 mg) is small compared with the systemic doses commonly used in the treatment of hypertension or angina (10–60 mg), sufficient timolol may be absorbed from the eye to cause serious adverse effects on the heart and airways in susceptible individuals. Topical timolol may interact with orally administered verapamil and increase the risk of heart block.

Betaxolol, carteolol, levobunolol, and metipranolol are -receptor antagonists approved for the treatment of glaucoma. Betaxolol has the potential advantage of being ₁-selective; to what extent this potential advantage might diminish systemic adverse effects remains to be determined. The drug apparently has caused worsening of pulmonary symptoms in some patients.

Hyperthyroidism

Excessive catecholamine action is an important aspect of the pathophysiology of hyperthyroidism, especially in relation to the heart (see Chapter 38). The antagonists are beneficial in this condition. The effects presumably relate to blockade of adrenoceptors and perhaps in part to the inhibition of peripheral conversion of thyroxine to triiodothyronine. The latter action may vary from one antagonist to another. Propranolol has been used extensively in patients with thyroid storm (severe hyperthyroidism); it is used cautiously in patients with this condition to control supraventricular tachycardias that often precipitate heart failure.

Neurologic Diseases

Propranolol reduces the frequency and intensity of migraine headache. Other -receptor antagonists with preventive efficacy include metoprolol and probably also atenolol, timolol, and nadolol. The mechanism is not known. Since sympathetic activity may enhance skeletal muscle tremor, it is not surprising that antagonists have been found to reduce certain tremors (see Chapter 28). The somatic manifestations of anxiety may respond dramatically to low doses of propranolol, particularly when taken prophylactically. For example, benefit has been found in musicians with performance anxiety ("stage fright"). Propranolol may contribute to the symptomatic treatment of alcohol withdrawal in some patients.

Miscellaneous

Beta-receptor antagonists have been found to diminish portal vein pressure in patients with cirrhosis. There is evidence that both propranolol and nadolol decrease the incidence of the first episode of bleeding from esophageal varices and decrease the mortality rate associated with bleeding in patients with cirrhosis. Nadolol in combination with isosorbide mononitrate appears to be more efficacious than sclerotherapy in preventing rebleeding in patients who have previously bled from esophageal varices. Variceal band ligation in combination with a antagonist may be more efficacious.

Choice of a Beta-Adrenoceptor Antagonist Drug

Propranolol is the standard against which newer antagonists developed for systemic use have been compared. In many years of very wide use, propranolol has been found to be a safe and effective drug for many indications. Since it is possible that some actions of a -receptor antagonist may relate to some other effect of the drug, these drugs should not be considered interchangeable for all applications. For example, only antagonists known to be effective in stable heart failure or in prophylactic therapy after myocardial infarction should be used for those indications. It is possible that the beneficial effects of one drug in these settings might not be shared by another drug in the same class. The possible advantages and disadvantages of -receptor antagonists that are partial agonists have not been clearly defined in clinical settings, although current evidence suggests that they are probably less efficacious in secondary prevention after a myocardial infarction compared with pure antagonists.

Clinical Toxicity of the Beta-Receptor Antagonist Drugs

Many adverse effects have been reported for propranolol but most are minor. Bradycardia is the most common adverse cardiac effect of -blocking drugs. Sometimes patients note coolness of hands and feet in winter. Central nervous system effects include mild sedation, vivid dreams, and rarely, depression. Discontinuing the use of blockers in any patient who develops psychiatric depression should be seriously considered if clinically feasible. It has been claimed that -receptor antagonist drugs with low lipid solubility are associated with a lower incidence of central nervous system adverse effects than compounds with higher lipid solubility (Table 10–2). Further studies designed to compare the central nervous system adverse effects of various drugs are required before specific recommendations can be made, though it seems reasonable to try the hydrophilic drugs nadolol or atenolol in a patient who experiences unpleasant central nervous system effects with other blockers.

The major adverse effects of -receptor antagonist drugs relate to the predictable consequences of blockade. Beta₂-receptor blockade associated with the use of nonselective agents commonly causes worsening of preexisting asthma and other forms of airway obstruction without having these consequences in normal individuals. Indeed, relatively trivial asthma may become severe after blockade. However, because of their life-saving potential in cardiovascular disease, strong consideration should be given to individualized therapeutic trials in some classes of patients, eg, those with chronic obstructive pulmonary disease who have appropriate indications for blockers. While ₁-selective drugs may have less effect on airways than nonselective antagonists, they must be used very cautiously in patients with reactive airway disease. Beta₁-selective antagonists are generally well tolerated in patients with mild to moderate peripheral vascular disease, but caution is required in patients with severe peripheral vascular disease or vasospastic disorders.

Beta-receptor blockade depresses myocardial contractility and excitability. In patients with abnormal myocardial function, cardiac output may be dependent on sympathetic drive. If this stimulus is removed by blockade, cardiac decompensation may ensue. Thus, caution must be exercised in starting a -receptor antagonist in patients with compensated heart failure even though long-term use of these drugs in these patients may prolong life. A life-threatening adverse cardiac effect of a antagonist may be overcome directly with isoproterenol or with glucagon (glucagon stimulates the heart via glucagon receptors, which are not blocked by antagonists), but neither of these methods is without hazard. A very small dose of a antagonist (eg, 10 mg of propranolol) may provoke severe cardiac failure in a susceptible individual. Beta blockers may interact with the calcium antagonist verapamil; severe hypotension, bradycardia, heart failure, and cardiac conduction abnormalities have all been described. These adverse effects may even arise in susceptible patients taking a topical (ophthalmic) blocker and oral verapamil.

Patients with ischemic heart disease or renovascularhypertension may be at increased risk if blockade is suddenly interrupted. The mechanism of this effect might involve up-regulation of the number of receptors. Until better evidence is available regarding the magnitude of the risk, prudence dictates the gradual tapering rather than abrupt cessation of dosage when these drugs are discontinued, especially drugs with short half-lives, such as propranolol and metoprolol.

The incidence of hypoglycemic episodes exacerbated by -blocking agents in diabetics is unknown. Nevertheless, it is inadvisable to use antagonists in insulin-dependent diabetic patients who are subject to frequent hypoglycemic reactions if alternative therapies are available. Beta₁-selective antagonists offer some advantage in these patients, since the rate of recovery from hypoglycemia may be faster compared with diabetics receiving nonselective -adrenoceptor antagonists. There is considerable potential benefit from these drugs in diabetics after a myocardial infarction, so the balance of risk versus benefit must be evaluated in individual patients.

Summary: Sympathetic Antagonists

Preparations Available

Alpha Blockers

Beta Blockers

Tyrosine Hydroxylase Inhibitor

References