Katzung Chapter 10 Adrenoceptor Antagonist Drugs PDF

10 C H A P T E R Adrenoceptor Antagonist Drugs David Robertson, MD, & Italo Biaggioni...

10 C H A P T E R Adrenoceptor Antagonist Drugs David Robertson, MD, & Italo Biaggioni, MD∗ CASE STUDY A 46-year-old woman sees her physician because of palpita- elicited a sudden and typical episode, with a rise in blood tions and headaches. She enjoyed good health until 1 year ago pressure to 210/120 mm Hg, heart rate to 122 bpm, profuse when spells of rapid heartbeat began. These became more sweating, and facial pallor. This was accompanied by severe severe and were eventually accompanied by throbbing head- headache. What is the likely cause of her episodes? What aches and drenching sweats. Physical examination revealed a caused the blood pressure and heart rate to rise so high dur- blood pressure of 150/90 mm Hg and heart rate of 88 bpm. ing the examination? What treatments might help this During the physical examination, palpation of the abdomen patient? Catecholamines play a role in many physiologic and pathophysi- antagonists are used in primary hypertension and benign prostatic ologic responses as described in Chapter 9. Drugs that block their hyperplasia. Beta-receptor antagonist drugs are useful in a much receptors therefore have important effects, some of which are of wider variety of clinical conditions and are firmly established in great clinical value. These effects vary dramatically according to the treatment of hypertension, ischemic heart disease, arrhyth- the drug’s selectivity for α and β receptors. The classification of mias, endocrinologic and neurologic disorders, glaucoma, and adrenoceptors into α1, α2, and β subtypes and the effects of acti- other conditions. vating 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 dop- BASIC PHARMACOLOGY OF amine receptors is very important; drugs that act on these recep- THE ALPHARECEPTOR tors are discussed in Chapters 21 and 29. This chapter deals with pharmacologic antagonist drugs whose major effect is to occupy ANTAGONIST DRUGS α1, α2, or β receptors outside the central nervous system and pre- vent their activation by catecholamines and related agonists. Mechanism of Action For pharmacologic research, α1- and α2-adrenoceptor antago- Alpha-receptor antagonists may be reversible or irreversible in nist drugs have been very useful in the experimental exploration of their interaction with these receptors. Reversible antagonists dis- autonomic nervous system function. In clinical therapeutics, non- sociate from receptors, and the block can be surmounted with selective α antagonists are used in the treatment of pheochromo- sufficiently high concentrations of agonists; irreversible drugs do cytoma (tumors that secrete catecholamines), and α1-selective not dissociate and cannot be surmounted. Phentolamine and pra- zosin (Figure 10–1) are examples of reversible antagonists. These drugs and labetalol—drugs used primarily for their antihyperten- ∗ sive effects—as well as several ergot derivatives (see Chapter 16) The authors thank Dr Randy Blakely for helpful comments, Dr Brett are also reversible α-adrenoceptor antagonists or partial agonists. English for improving tables, and our students at Vanderbilt for advice on conceptual clarity. Phenoxybenzamine, an agent related to the nitrogen mustards, 151 152 SECTION II Autonomic Drugs HO CH3 N O CH2 CH CH2 CH2 CI R1 CH2 N CH2 C N N+ +CI– N H 3C CH2 R2 CH2 H Phentolamine Phenoxybenzamine Active (ethyleneimonium) intermediate O N CH3O N N C O CH3O N NH2 Prazosin SO2NH2 O CH2 CH2 NH CH CH2 CH3 O CH2 CH3 O CH3 Tamsulosin FIGURE 10–1 Structure of several α-receptor–blocking drugs. forms a reactive ethyleneimonium intermediate (Figure 10–1) that pressor effects of usual doses of α agonists; indeed, in the case of covalently binds to α receptors, resulting in irreversible blockade. agonists with both α and β2 effects (eg, epinephrine), selective Figure 10–2 illustrates the effects of a reversible drug in compari- α-receptor antagonism may convert a pressor to a depressor son with those of an irreversible agent. response (Figure 10–3). This change in response is called epi- As discussed in Chapters 1 and 2, the duration of action of a nephrine reversal; it illustrates how the activation of both α and reversible antagonist is largely dependent on the half-life of the β receptors in the vasculature may lead to opposite responses. drug in the body and the rate at which it dissociates from its recep- Alpha-receptor antagonists often cause orthostatic hypotension tor: The shorter the half-life of the drug in the body, the less time and reflex tachycardia; nonselective (α1 = α2, Table 10–1) blockers it takes for the effects of the drug to dissipate. In contrast, the usually cause significant tachycardia if blood pressure is lowered effects of an irreversible antagonist may persist long after the drug below normal. Orthostatic hypotension is due to antagonism of has been cleared from the plasma. In the case of phenoxyben- sympathetic nervous system stimulation of α1 receptors in vascu- zamine, the restoration of tissue responsiveness after extensive lar smooth muscle; contraction of veins is an important compo- α-receptor blockade is dependent on synthesis of new receptors, nent of the normal capacity to maintain blood pressure in the which may take several days. The rate of return of α1-adrenoceptor upright position since it decreases venous pooling in the periphery. responsiveness may be particularly important in patients having a Constriction of arterioles in the legs also contributes to the normal sudden cardiovascular event or who become candidates for urgent orthostatic response. Tachycardia may be more marked with surgery. agents that block α2-presynaptic receptors in the heart, since the augmented release of norepinephrine will further stimulate β receptors in the heart. Pharmacologic Effects A. Cardiovascular Effects B. Other Effects Because arteriolar and venous tone are determined to a large Blockade of α receptors in other tissues elicits miosis (small extent by α receptors on vascular smooth muscle, α-receptor pupils) and nasal stuffiness. Alpha1 receptors are expressed in the antagonist drugs cause a lowering of peripheral vascular resistance base of the bladder and the prostate, and their blockade decreases and blood pressure (Figure 10–3). These drugs can prevent the resistance to the flow of urine. Alpha blockers, therefore, are used  CHAPTER 10 Adrenoceptor Antagonist Drugs 153 Competitive antagonist Irreversible antagonist 100 100 Percent of maximum tension Percent of maximum tension Control Control 50 50 10 μmol/L 0.4 μmol/L 0.8 μmol/L 20 μmol/L 0 0 2.4 20 160 1.2 10 80 Norepinephrine (μmol/L) Norepinephrine (μmol/L) FIGURE 10–2 Dose-response curves to norepinephrine in the presence of two different α-adrenoceptor–blocking drugs. The tension pro- duced in isolated strips of cat spleen, a tissue rich in α receptors, was measured in response to graded doses of norepinephrine. Left: Tolazoline, a reversible blocker, shifted the curve to the right without decreasing the maximum response when present at concentrations of 10 and 20 μmol/L. Right: Dibenamine, an analog of phenoxybenzamine and irreversible in its action, reduced the maximum response attainable at both concentrations tested. (Modified and reproduced, with permission, from Bickerton RK: The response of isolated strips of cat spleen to sympathomimetic drugs and their antagonists. J Pharmacol Exp Ther 1963;142:99.) FIGURE 10–3 Top: Effects of phentolamine, an α-receptor–blocking drug, on blood pressure in an anesthetized dog. Epinephrine reversal is demonstrated by tracings showing the response to epinephrine before (middle) and after (bottom) phentolamine. All drugs given intrave- nously. BP, blood pressure; HR, heart rate. 154 SECTION II Autonomic Drugs TABLE 10–1 Relative selectivity of antagonists for Most adverse effects of phenoxybenzamine derive from its adrenoceptors. α-receptor–blocking action; the most important are orthostatic hypotension and tachycardia. Nasal stuffiness and inhibition of Receptor Affinity ejaculation also occur. Since phenoxybenzamine enters the central Alpha antagonists nervous system, it may cause less specific effects, including fatigue, Prazosin, terazosin, doxazosin α1 >>>> α2 sedation, and nausea. Because phenoxybenzamine is an alkylating agent, it may have other adverse effects that have not yet been characterized. Phenoxybenzamine α1 > α2 Phentolamine is a potent competitive antagonist at both α1 Phentolamine α1 = α2 and α2 receptors (Table 10–1). Phentolamine reduces peripheral Yohimbine, tolazoline α2 >> α1 resistance through blockade of α1 receptors and possibly α2 recep- Mixed antagonists tors on vascular smooth muscle. Its cardiac stimulation is due to antagonism of presynaptic α2 receptors (leading to enhanced Labetalol, carvedilol β1 = β2 ≥ α1 > α2 release of norepinephrine from sympathetic nerves) and sympa- Beta antagonists thetic activation from baroreflex mechanisms. Phentolamine also Metoprolol, acebutolol, β1 >>> β2 has minor inhibitory effects at serotonin receptors and agonist alprenolol, atenolol, betaxolol, effects at muscarinic and H1 and H2 histamine receptors. celiprolol, esmolol, nebivolol Phentolamine’s principal adverse effects are related to cardiac Propranolol, carteolol, β1 = β2 stimulation, which may cause severe tachycardia, arrhythmias, and penbutolol, pindolol, timolol myocardial ischemia. Phentolamine has been used in the treat- Butoxamine β2 >>> β1 ment of pheochromocytoma. In addition it is sometimes used to reverse local anesthesia in soft tissue sites; local anesthetics are often given with vasoconstrictors that slow their removal. Local phentolamine permits reversal at the end of the procedure. therapeutically for the treatment of urinary retention due to pros- Unfortunately oral and intravenous formulations of phentolamine tatic hyperplasia (see below). Individual agents may have other are no longer consistently available in the United States. important effects in addition to α-receptor antagonism (see Prazosin is a piperazinyl quinazoline effective in the manage- below). ment of hypertension (see Chapter 11). It is highly selective for α1 receptors and typically 1000-fold less potent at α2 receptors. This SPECIFIC AGENTS may partially explain the relative absence of tachycardia seen with prazosin compared with that of phentolamine and phenoxyben- Phenoxybenzamine binds covalently to α receptors, causing irre- zamine. Prazosin relaxes both arterial and venous vascular smooth versible blockade of long duration (14–48 hours or longer). It is muscle, as well as smooth muscle in the prostate, due to blockade somewhat selective for α1 receptors but less so than prazosin (Table of α1 receptors. Prazosin is extensively metabolized in humans; 10–1). The drug also inhibits reuptake of released norepinephrine because of metabolic degradation by the liver, only about 50% of by presynaptic adrenergic nerve terminals. Phenoxybenzamine the drug is available after oral administration. The half-life is nor- blocks histamine (H1), acetylcholine, and serotonin receptors as mally about 3 hours. well as α receptors (see Chapter 16). Terazosin is another reversible α1-selective antagonist that is The pharmacologic actions of phenoxybenzamine are primarily effective in hypertension (see Chapter 11); it is also approved for use related to antagonism of α-receptor–mediated events. The most in men with urinary symptoms due to benign prostatic hyperplasia significant effect is attenuation of catecholamine-induced vasocon- (BPH). Terazosin has high bioavailability but is extensively metabo- striction. While phenoxybenzamine causes relatively little fall in lized in the liver, with only a small fraction of unchanged drug blood pressure in normal supine individuals, it reduces blood pres- excreted in the urine. The half-life of terazosin is 9–12 hours. sure when sympathetic tone is high, eg, as a result of upright pos- Doxazosin is efficacious in the treatment of hypertension and ture or because of reduced blood volume. Cardiac output may be BPH. It differs from prazosin and terazosin in having a longer increased because of reflex effects and because of some blockade of half-life of about 22 hours. It has moderate bioavailability and is presynaptic α2 receptors in cardiac sympathetic nerves. extensively metabolized, with very little parent drug excreted in Phenoxybenzamine is absorbed after oral administration, urine or feces. Doxazosin has active metabolites, although their although bioavailability is low and its kinetic properties are not contribution to the drug’s effects is probably small. well known. The drug is usually given orally, starting with dosages Tamsulosin is a competitive α1 antagonist with a structure of 10 mg/d and progressively increasing the dose until the desired quite different from that of most other α1-receptor blockers. It has effect is achieved. A dosage of less than 100 mg/d is usually suffi- high bioavailability and a half-life of 9–15 hours. It is metabolized cient to achieve adequate α-receptor blockade. The major use of extensively in the liver. Tamsulosin has higher affinity for α1A and phenoxybenzamine is in the treatment of pheochromocytoma (see α1D receptors than for the α1B subtype. Evidence suggests that below). tamsulosin has relatively greater potency in inhibiting contraction  CHAPTER 10 Adrenoceptor Antagonist Drugs 155 in prostate smooth muscle versus vascular smooth muscle compared with other α1-selective antagonists. The drug’s efficacy in BPH CLINICAL PHARMACOLOGY OF suggests that the α1A subtype may be the most important α sub- THE ALPHARECEPTOR type mediating prostate smooth muscle contraction. Furthermore, BLOCKING DRUGS compared with other antagonists, tamsulosin has less effect on standing blood pressure in patients. Nevertheless, caution is appro- priate in using any α antagonist in patients with diminished sym- Pheochromocytoma pathetic nervous system function. Patients receiving oral tamsulosin Pheochromocytoma is a tumor of the adrenal medulla or sympa- and undergoing cataract surgery are at increased risk of the intra- thetic ganglion cells. The tumor secretes catecholamines, espe- operative floppy iris syndrome (IFIS), characterized by the billow- cially norepinephrine and epinephrine. The patient in the case ing of a flaccid iris, propensity for iris prolapse, and progressive study at the beginning of this chapter had a left adrenal pheochro- intraoperative pupillary constriction. These effects increase the risk mocytoma that was identified by imaging. In addition, she had of cataract surgery, and complications are more likely in the ensu- elevated plasma and urinary norepinephrine, epinephrine, and ing 14 days if patients are taking these agents. their metabolites, normetanephrine and metanephrine. The diagnosis of pheochromocytoma is confirmed on the basis of elevated plasma or urinary levels of catecholamines, metaneph- OTHER ALPHA-ADRENOCEPTOR rine, and normetanephrine (see Chapter 6). Once diagnosed bio- ANTAGONISTS chemically, techniques to localize a pheochromocytoma include computed tomography and magnetic resonance imaging scans and 131 Alfuzosin is an α1-selective quinazoline derivative that is approved scanning with radiomarkers such as I-meta-iodobenzylguanidine for use in BPH. It has a bioavailability of about 60%, is extensively (MIBG), a norepinephrine transporter substrate that is taken up metabolized, and has an elimination half-life of about 5 hours. It by tumor cells. may increase risk of QT prolongation in susceptible individuals. The major clinical use of phenoxybenzamine is in the manage- Silodosin resembles tamsulosin in blocking the α1A receptor and ment of pheochromocytoma. Patients have many symptoms and is used in treatment of BPH. Indoramin is another α1-selective signs of catecholamine excess, including intermittent or sustained antagonist that also has efficacy as an antihypertensive. It is not hypertension, headaches, palpitations, and increased sweating. available in the USA. Urapidil is an α1 antagonist (its primary Release of stored catecholamines from pheochromocytomas effect) that also has weak α2-agonist and 5-HT1A-agonist actions may occur in response to physical pressure, chemical stimulation, and weak antagonist action at β1 receptors. It is used in Europe as or spontaneously. When it occurs during operative manipulation an antihypertensive agent and for benign prostatic hyperplasia. of pheochromocytoma, the resulting hypertension may be con- Labetalol has both α1-selective and β-antagonistic effects; it is trolled with α-receptor blockade or nitroprusside. Nitroprusside is discussed below. Neuroleptic drugs such as chlorpromazine and preferred because its effects can be more readily titrated and it has haloperidol are potent dopamine receptor antagonists but are also a shorter duration of action. antagonists at α receptors. Their antagonism of α receptors prob- Alpha-receptor antagonists are most useful in the preoperative ably contributes to some of their adverse effects, particularly management of patients with pheochromocytoma (Figure 10–4). hypotension. Similarly, the antidepressant trazodone has the Administration of phenoxybenzamine in the preoperative period capacity to block α1 receptors. Ergot derivatives, eg, ergotamine helps to control hypertension and tends to reverse chronic changes and dihydroergotamine, cause reversible α-receptor blockade, resulting from excessive catecholamine secretion such as plasma probably via a partial agonist action (see Chapter 16). volume contraction, if present. Furthermore, the patient’s opera- Yohimbine, an indole alkaloid, is an α2-selective antagonist. tive course may be simplified. Oral doses of 10 mg/d can be It is sometimes used in the treatment of orthostatic hypotension increased at intervals of several days until hypertension is con- because it promotes norepinephrine release through blockade of trolled. Some physicians give phenoxybenzamine to patients with α2 receptors in both the central nervous system and the periph- pheochromocytoma for 1–3 weeks before surgery. Other surgeons ery. This increases central sympathetic activation and also pro- prefer to operate on patients in the absence of treatment with motes increased norepinephrine release in the periphery. It was phenoxybenzamine, counting on modern anesthetic techniques to once widely used to treat male erectile dysfunction but has been control blood pressure and heart rate during surgery. superseded by phosphodiesterase-5 inhibitors like sildenafil (see Phenoxybenzamine can be very useful in the chronic treatment of Chapter 12). Yohimbine can greatly elevate blood pressure if inoperable or metastatic pheochromocytoma. Although there is administered to patients receiving norepinephrine transport less experience with alternative drugs, hypertension in patients blocking drugs. Yohimbine reverses the antihypertensive effects of with pheochromocytoma may also respond to reversible α1- α2-adrenoceptor agonists such as clonidine. It is used in veterinary selective antagonists or to conventional calcium channel antago- medicine to reverse anesthesia produced by xylazine, an α2 agonist nists. Beta-receptor antagonists may be required after α-receptor used to calm animals. Although yohimbine has been taken off the blockade has been instituted to reverse the cardiac effects of exces- market in the USA solely for financial reasons, it is available as a sive catecholamines. Beta antagonists should not be used prior to “nutritional” supplement. establishing effective α-receptor blockade, since unopposed 156 SECTION II Autonomic Drugs 240 considerable experience is necessary to use α-adrenoceptor antag- onist drugs safely in these settings. 220 Supine Standing 200 Chronic Hypertension Members of the prazosin family of α1-selective antagonists are effica- 180 cious drugs in the treatment of mild to moderate systemic hyperten- sion (see Chapter 11). They are generally well tolerated, but they are 160 not usually recommended as monotherapy for hypertension because Blood pressure (mm Hg) other classes of antihypertensives are more effective in preventing 140 heart failure. Their major adverse effect is orthostatic hypotension, 120 which may be severe after the first few doses but is otherwise uncom- mon. Nonselective α antagonists are not used in primary systemic 100 hypertension. Prazosin and related drugs may also be associated with dizziness. Orthostatic changes in blood pressure should be checked 80 routinely in any patient being treated for hypertension. It is interesting that the use of α-adrenoceptor antagonists such 60 as prazosin has been found to be associated with either no changes Dibenzyline in plasma lipids or increased concentrations of high-density lipo- 40 80 proteins (HDL), which could be a favorable alteration. The mg/d 40 20 0 mechanism for this effect is not known. 0 Peripheral Vascular Disease 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Weeks Alpha-receptor–blocking drugs do not seem to be effective in the treatment of peripheral vascular occlusive disease characterized by FIGURE 10–4 Effects of phenoxybenzamine (Dibenzyline) on morphologic changes that limit flow in the vessels. Occasionally, blood pressure in a patient with pheochromocytoma. Dosage of the individuals with Raynaud’s phenomenon and other conditions drug was begun in the fourth week as shown by the shaded bar. involving excessive reversible vasospasm in the peripheral circula- Supine systolic and diastolic pressures are indicated by the circles, tion do benefit from prazosin or phenoxybenzamine, although and the standing pressures by triangles and the hatched area. Note calcium channel blockers may be preferable for most patients. that the α-blocking drug dramatically reduced blood pressure. The reduction in orthostatic hypotension, which was marked before treatment, is probably due to normalization of blood volume, a vari- Urinary Obstruction able that is sometimes markedly reduced in patients with longstand- Benign prostatic hyperplasia is common in elderly men. Various ing pheochromocytoma-induced hypertension. (Redrawn and surgical treatments are effective in relieving the urinary symptoms reproduced, with permission, from Engelman E, Sjoerdsma A: Chronic medical ther- of BPH; however, drug therapy is efficacious in many patients. apy for pheochromocytoma. Ann Intern Med 1961;61:229.) The mechanism of action in improving urine flow involves partial reversal of smooth muscle contraction in the enlarged prostate and β-receptor blockade could theoretically cause blood pressure eleva- in the bladder base. It has been suggested that some α1-receptor tion from increased vasoconstriction. antagonists may have additional effects on cells in the prostate that Pheochromocytoma is sometimes treated with metyrosine help improve symptoms. (α-methyltyrosine), the α-methyl analog of tyrosine. This agent is Prazosin, doxazosin, and terazosin are all efficacious in patients a competitive inhibitor of tyrosine hydroxylase, the rate-limiting with BPH. These drugs are particularly useful in patients who also step in the synthesis of dopamine, norepinephrine, and epineph- have hypertension. Considerable interest has focused on which rine (see Figure 6–5). Metyrosine is especially useful in symptom- α1-receptor subtype is most important for smooth muscle contrac- atic patients with inoperable or metastatic pheochromocytoma. tion in the prostate: subtype-selective α1A-receptor antagonists may Because it has access to the central nervous system, metyrosine can have improved efficacy and safety in treating this disease. As indi- cause extrapyramidal effects due to reduced dopamine levels. cated above, tamsulosin is also efficacious in BPH and has rela- tively minor effects on blood pressure at a low dose. This drug may Hypertensive Emergencies be preferred in patients who have experienced orthostatic hypoten- sion with other α1-receptor antagonists. The α-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, α-adrenoceptor Erectile Dysfunction antagonists are most useful when increased blood pressure reflects A combination of phentolamine with the nonspecific smooth excess circulating concentrations of α agonists, eg, in pheochro- muscle relaxant papaverine, when injected directly into the penis, mocytoma, overdosage of sympathomimetic drugs, or clonidine may cause erections in men with sexual dysfunction. Long-term withdrawal. However, other drugs are generally preferable, since administration may result in fibrotic reactions. Systemic absorption  CHAPTER 10 Adrenoceptor Antagonist Drugs 157 may lead to orthostatic hypotension; priapism may require direct Sustained-release preparations of propranolol and metoprolol are treatment with an α-adrenoceptor agonist such as phenylephrine. available. Alternative therapies for erectile dysfunction include prostaglan- dins (see Chapter 18), sildenafil and other cGMP phosphodi- B. Bioavailability esterase inhibitors (see Chapter 12), and apomorphine. Propranolol undergoes extensive hepatic (first-pass) metabolism; its bioavailability is relatively low (Table 10–2). The proportion of Applications of Alpha2 Antagonists drug reaching the systemic circulation increases as the dose is Alpha2 antagonists have relatively little clinical usefulness. They increased, suggesting that hepatic extraction mechanisms may have limited benefit in male erectile dysfunction. There has been become saturated. A major consequence of the low bioavailability experimental interest in the development of highly selective antag- of propranolol is that oral administration of the drug leads to onists for treatment of type 2 diabetes (α2 receptors inhibit insulin much lower drug concentrations than are achieved after intrave- secretion), and for treatment of psychiatric depression. It is likely nous injection of the same dose. Because the first-pass effect varies that better understanding of the subtypes of α2 receptors will lead among individuals, there is great individual variability in the to development of clinically useful subtype-selective new drugs. plasma concentrations achieved after oral propranolol. For the same reason, bioavailability is limited to varying degrees for most β antagonists with the exception of betaxolol, penbutolol, pin- BASIC PHARMACOLOGY OF dolol, and sotalol. THE BETARECEPTOR C. Distribution and Clearance ANTAGONIST DRUGS The β antagonists are rapidly distributed and have large volumes of distribution. Propranolol and penbutolol are quite lipophilic and Beta-receptor antagonists share the common feature of antagoniz- readily cross the blood-brain barrier (Table 10–2). Most β antago- ing the effects of catecholamines at β adrenoceptors. Beta-blocking nists have half-lives in the range of 3–10 hours. A major exception drugs occupy β receptors and competitively reduce receptor occu- is esmolol, which is rapidly hydrolyzed and has a half-life of pancy by catecholamines and other β agonists. (A few members of approximately 10 minutes. Propranolol and metoprolol are exten- this group, used only for experimental purposes, bind irreversibly sively metabolized in the liver, with little unchanged drug appear- to β receptors.) Most β-blocking drugs in clinical use are pure ing in the urine. The cytochrome P450 2D6 (CYP2D6) genotype antagonists; that is, the occupancy of a β receptor by such a drug is a major determinant of interindividual differences in metoprolol causes no activation of the receptor. However, some are partial plasma clearance (see Chapter 4). Poor metabolizers exhibit three- agonists; that is, they cause partial activation of the receptor, albeit fold to tenfold higher plasma concentrations after administration less than that caused by the full agonists epinephrine and isoprot- of metoprolol than extensive metabolizers. Atenolol, celiprolol, and erenol. As described in Chapter 2, partial agonists inhibit the pindolol are less completely metabolized. Nadolol is excreted activation of β receptors in the presence of high catecholamine unchanged in the urine and has the longest half-life of any available concentrations but moderately activate the receptors in the β antagonist (up to 24 hours). The half-life of nadolol is prolonged absence of endogenous agonists. Finally, evidence suggests that in renal failure. The elimination of drugs such as propranolol may some β blockers (eg, betaxolol, metoprolol) are inverse agonists— be prolonged in the presence of liver disease, diminished hepatic drugs that reduce constitutive activity of β receptors—in some blood flow, or hepatic enzyme inhibition. It is notable that the tissues. The clinical significance of this property is not known. pharmacodynamic effects of these drugs are sometimes prolonged The β-receptor–blocking drugs differ in their relative affinities well beyond the time predicted from half-life data. for β1 and β2 receptors (Table 10–1). Some have a higher affinity for β1 than for β2 receptors, and this selectivity may have impor- tant clinical implications. Since none of the clinically available Pharmacodynamics of the Beta-Receptor β-receptor antagonists are absolutely specific for β1 receptors, the selectivity is dose-related; it tends to diminish at higher drug con- Antagonist Drugs centrations. Other major differences among β antagonists relate to Most of the effects of these drugs are due to occupation and block- their pharmacokinetic characteristics and local anesthetic mem- ade of β receptors. However, some actions may be due to other brane-stabilizing effects. effects, including partial agonist activity at β receptors and local Chemically, most β-receptor antagonist drugs (Figure 10–5) anesthetic action, which differ among the β blockers (Table 10–2). resemble isoproterenol to some degree (see Figure 9–4). A. Effects on the Cardiovascular System Pharmacokinetic Properties of the Beta-blocking drugs given chronically lower blood pressure in patients with hypertension (see Chapter 11). The mechanisms Beta-Receptor Antagonists involved are not fully understood but probably include suppres- A. Absorption sion of renin release and effects in the central nervous system. Most of the drugs in this class are well absorbed after oral admin- These drugs do not usually cause hypotension in healthy individu- istration; peak concentrations occur 1–3 hours after ingestion. als with normal blood pressure. 158 SECTION II Autonomic Drugs O CH2 CH CH2 NH CH(CH3)2 O CH2 CH CH2 NH CH(CH3)2 OH OH CH2 CH2 O CH3 Propranolol Metoprolol O CH2 CH CH2 NH CH(CH3)2 O CH2 CH CH2 NH C(CH3)3 OH O N OH N N S N Timolol H Pindolol HO CH CH2 NH CH CH2 CH2 O CH2 CH CH2 NH CH(CH3)2 CH3 OH O C NH2 O OH CH2 C NH2 Labetalol Atenolol OH OH O O CH CH2 NH CH2 CH F F Nebivolol FIGURE 10–5 Structures of some β-receptor antagonists. Beta-receptor antagonists have prominent effects on the heart Overall, although the acute effects of these drugs may include (Figure 10–6) and are very valuable in the treatment of angina (see a rise in peripheral resistance, chronic drug administration leads to Chapter 12) and chronic heart failure (see Chapter 13) and fol- a fall in peripheral resistance in patients with hypertension. lowing myocardial infarction (see Chapter 14). The negative ino- tropic and chronotropic effects reflect the role of adrenoceptors in B. Effects on the Respiratory Tract regulating these functions. Slowed atrioventricular conduction Blockade of the β2 receptors in bronchial smooth muscle may lead with an increased PR interval is a related result of adrenoceptor to an increase in airway resistance, particularly in patients with blockade in the atrioventricular node. In the vascular system, asthma. Beta1-receptor antagonists such as metoprolol and atenolol β-receptor blockade opposes β2-mediated vasodilation. This may may have some advantage over nonselective β antagonists when acutely lead to a rise in peripheral resistance from unopposed blockade of β1 receptors in the heart is desired and β2-receptor α-receptor–mediated effects as the sympathetic nervous system blockade is undesirable. However, no currently available β1- discharges in response to lowered blood pressure due to the fall in selective antagonist is sufficiently specific to completely avoid cardiac output. Nonselective and β1-blocking drugs antagonize interactions with β2 adrenoceptors. Consequently, these drugs the release of renin caused by the sympathetic nervous system. should generally be avoided in patients with asthma. On the other  CHAPTER 10 Adrenoceptor Antagonist Drugs 159 TABLE 10–2 Properties of several beta-receptor–blocking drugs. Partial Agonist Local Anesthetic Lipid Elimination Approximate Selectivity Activity Action Solubility Half-life Bioavailability Acebutolol β1 Yes Yes Low 3–4 hours 50 Atenolol β1 No No Low 6–9 hours 40 Betaxolol β1 No Slight Low 14–22 hours 90 Bisoprolol β1 No No Low 9–12 hours 80 Carteolol None Yes No Low 6 hours 85 Carvedilol1 None No No Moderate 7–10 hours 25–35 Celiprolol β1 Yes No Low 4–5 hours 70 Esmolol β1 No No Low 10 minutes 0 Labetalol1 None Yes Yes Low 5 hours 30 Metoprolol β1 No Yes Moderate 3–4 hours 50 Nadolol None No No Low 14–24 hours 33 2 Nebivolol β1 ? No Low 11–30 hours 12–96 Penbutolol None Yes No High 5 hours >90 Pindolol None Yes Yes Moderate 3–4 hours 90 Propranolol None No Yes High 3.5–6 hours 303 Sotalol None No No Low 12 hours 90 Timolol None No No Moderate 4–5 hours 50 1 Carvedilol and labetalol also cause α1-adrenoceptor blockade. 2 β3 agonist. 3 Bioavailability is dose-dependent. Propranolol 0.5 mg/kg 1 μg/kg Epinephrine 1 μg/kg Epinephrine Cardiac contractile force 200 Arterial pressure 100 (mm Hg) 2 0 1 Aortic flow (L/min) 200 0 Heart rate 1 min (beats/min) 100 FIGURE 10–6 The effect in an anesthetized dog of the injection of epinephrine before and after propranolol. In the presence of a β-receptor–blocking agent, epinephrine no longer augments the force of contraction (measured by a strain gauge attached to the ventricular wall) nor increases cardiac rate. Blood pressure is still elevated by epinephrine because vasoconstriction is not blocked. (Reproduced, with permis- sion, from Shanks RG: The pharmacology of β sympathetic blockade. Am J Cardiol 1966;18:312.) 160 SECTION II Autonomic Drugs hand, many patients with chronic obstructive pulmonary disease (COPD) may tolerate these drugs quite well and the benefits, for The Treatment of Glaucoma example in patients with concomitant ischemic heart disease, may outweigh the risks. Glaucoma is a major cause of blindness and of great pharma- cologic interest because the chronic form often responds to drug therapy. The primary manifestation is increased intraoc- C. Effects on the Eye ular pressure not initially associated with symptoms. Without Beta-blocking agents reduce intraocular pressure, especially in treatment, increased intraocular pressure results in damage glaucoma. The mechanism usually reported is decreased aqueous to the retina and optic nerve, with restriction of visual fields humor production. (See Clinical Pharmacology and Box: The and, eventually, blindness. Intraocular pressure is easily mea- Treatment of Glaucoma.) sured as part of the routine ophthalmologic examination. Two major types of glaucoma are recognized: open-angle D. Metabolic and Endocrine Effects and closed-angle (also called narrow-angle). The closed-angle Beta-receptor antagonists such as propranolol inhibit sympathetic form is associated with a shallow anterior chamber, in which nervous system stimulation of lipolysis. The effects on carbohy- a dilated iris can occlude the outflow drainage pathway at the drate metabolism are less clear, though glycogenolysis in the angle between the cornea and the ciliary body (see Figure human liver is at least partially inhibited after β2-receptor block- 6–9). This form is associated with acute and painful increases ade. Glucagon is the primary hormone used to combat hypogly- of pressure, which must be controlled on an emergency basis cemia; it is unclear to what extent β antagonists impair recovery with drugs or prevented by surgical removal of part of the iris from hypoglycemia, but they should be used with caution in (iridectomy). The open-angle form of glaucoma is a chronic insulin-dependent diabetic patients. This may be particularly condition, and treatment is largely pharmacologic. Because important in diabetic patients with inadequate glucagon reserve intraocular pressure is a function of the balance between and in pancreatectomized patients since catecholamines may be fluid input and drainage out of the globe, the strategies for the major factors in stimulating glucose release from the liver in the treatment of open-angle glaucoma fall into two classes: response to hypoglycemia. Beta1-receptor–selective drugs may be reduction of aqueous humor secretion and enhancement of less prone to inhibit recovery from hypoglycemia. Beta-receptor aqueous outflow. Five general groups of drugs—cholinomi- antagonists are much safer in those type 2 diabetic patients who metics, α agonists, β blockers, prostaglandin F2α analogs, and do not have hypoglycemic episodes. diuretics—have been found to be useful in reducing intraoc- The chronic use of β-adrenoceptor antagonists has been associ- ular pressure and can be related to these strategies as shown ated with increased plasma concentrations of very-low-density in Table 10–3. Of the five drug groups listed in Table 10–3, the lipoproteins (VLDL) and decreased concentrations of HDL choles- prostaglandin analogs and the β blockers are the most popu- terol. Both of these changes are potentially unfavorable in terms of lar. This popularity results from convenience (once- or twice- risk of cardiovascular disease. Although low-density lipoprotein daily dosing) and relative lack of adverse effects (except, in (LDL) concentrations generally do not change, there is a variable the case of β blockers, in patients with asthma or cardiac decline in the HDL cholesterol/LDL cholesterol ratio that may pacemaker or conduction pathway disease). Other drugs that increase the risk of coronary artery disease. These changes tend to have been reported to reduce intraocular pressure include occur with both selective and nonselective β blockers, though they prostaglandin E2 and marijuana. The use of drugs in acute may be less likely to occur with β blockers possessing intrinsic sym- closed-angle glaucoma is limited to cholinomimetics, aceta- pathomimetic activity (partial agonists). The mechanisms by which zolamide, and osmotic agents preceding surgery. The onset β-receptor antagonists cause these changes are not understood, of action of the other agents is too slow in this situation. though changes in sensitivity to insulin action may contribute. E. Effects Not Related to Beta-Blockade Partial β-agonist activity was significant in the first β-blocking drug synthesized, dichloroisoproterenol. It has been suggested that Local anesthetic action, also known as “membrane-stabilizing” retention of some intrinsic sympathomimetic activity is desirable action, is a prominent effect of several β blockers (Table 10–2). to prevent untoward effects such as precipitation of asthma or This action is the result of typical local anesthetic blockade of excessive bradycardia. Pindolol and other partial agonists are sodium channels (see Chapter 26) and can be demonstrated noted in Table 10–2. It is not yet clear to what extent partial ago- experimentally in isolated neurons, heart muscle, and skeletal nism is clinically valuable. Furthermore, these drugs may not be as muscle membrane. However, it is unlikely that this effect is effective as the pure antagonists in secondary prevention of myo- important after systemic administration of these drugs, since the cardial infarction. However, they may be useful in patients who concentration in plasma usually achieved by these routes is too develop symptomatic bradycardia or bronchoconstriction in low for the anesthetic effects to be evident. The membrane- response to pure antagonist β-adrenoceptor drugs, but only if they stabilizing β blockers are not used topically on the eye, because are strongly indicated for a particular clinical indication. local anesthesia of the cornea would be highly undesirable. Sotalol  CHAPTER 10 Adrenoceptor Antagonist Drugs 161 TABLE 10–3 Drugs used in open-angle glaucoma. Mechanism Methods of Administration Cholinomimetics Pilocarpine, carbachol, physostigmine, Ciliary muscle contraction, opening of trabecular Topical drops or gel; plastic film slow-release echothiophate, demecarium meshwork; increased outflow insert Alpha agonists Nonselective Increased outflow Topical drops Epinephrine, dipivefrin Alpha2-selective Decreased aqueous secretion Apraclonidine Topical, postlaser only Brimonidine Topical Beta blockers Timolol, betaxolol, carteolol, Decreased aqueous secretion from the ciliary Topical drops levobunolol, metipranolol epithelium Carbonic anhydrase inhibitors Dorzolamide, brinzolamide Decreased aqueous secretion due to lack of HCO3− Topical Acetazolamide, dichlorphenamide, Oral methazolamide Prostaglandins Latanoprost, bimatoprost, travoprost, Increased outflow Topical unoprostone is a nonselective β-receptor antagonist that lacks local anesthetic oxide production. Nebivolol may increase insulin sensitivity and action but has marked class III antiarrhythmic effects, reflecting does not adversely affect lipid profile. potassium channel blockade (see Chapter 14). Nadolol is noteworthy for its very long duration of action; its spectrum of action is similar to that of timolol. Timolol is a non- selective agent with no local anesthetic activity. It has excellent SPECIFIC AGENTS (SEE TABLE 10–2) ocular hypotensive effects when administered topically in the eye. Levobunolol (nonselective) and betaxolol (β1-selective) are also Propranolol is the prototypical β-blocking drug. As noted above, used for topical ophthalmic application in glaucoma; the latter it has low and dose-dependent bioavailability. A long-acting form drug may be less likely to induce bronchoconstriction than non- of propranolol is available; prolonged absorption of the drug may selective antagonists. Carteolol is a nonselective β-receptor occur over a 24-hour period. The drug has negligible effects at α antagonist. and muscarinic receptors; however, it may block some serotonin Pindolol, acebutolol, carteolol, bopindolol,* oxprenolol,* * receptors in the brain, though the clinical significance is unclear. celiprolol, and penbutolol are of interest because they have par- It has no detectable partial agonist action at β receptors. tial β-agonist activity. They are effective in the major cardiovascu- Metoprolol, atenolol, and several other drugs (Table 10–2) are lar applications of the β-blocking group (hypertension and members of the β1-selective group. These agents may be safer in angina). Although these partial agonists may be less likely to cause patients who experience bronchoconstriction in response to pro- bradycardia and abnormalities in plasma lipids than are antago- pranolol. Since their β1 selectivity is rather modest, they should be nists, the overall clinical significance of intrinsic sympathomimetic used with great caution, if at all, in patients with a history of activity remains uncertain. Pindolol, perhaps as a result of actions asthma. However, in selected patients with COPD the benefits on serotonin signaling, may potentiate the action of traditional may exceed the risks, eg, in patients with myocardial infarction. antidepressant medications. Celiprolol is a β1-selective antagonist Beta1-selective antagonists may be preferable in patients with dia- with a modest capacity to activate β2 receptors. betes or peripheral vascular disease when therapy with a β blocker There is limited evidence suggesting that celiprolol may have less is required, since β2 receptors are probably important in liver adverse bronchoconstrictor effect in asthma and may even promote (recovery from hypoglycemia) and blood vessels (vasodilation). bronchodilation. Acebutolol is also a β1-selective antagonist. Nebivolol is the most highly selective β1-adrenergic receptor blocker, though some of its metabolites do not have this level of specificity. Nebivolol has the additional quality of eliciting vasodi- ∗ lation. This is due to an action of the drug on endothelial nitric Not available in the USA 162 SECTION II Autonomic Drugs Labetalol is a reversible adrenoceptor antagonist available as a twice daily and still have an adequate therapeutic effect. Labetalol, racemic mixture of two pairs of chiral isomers (the molecule has a competitive α and β antagonist, is effective in hypertension, two centers of asymmetry). The (S,S)- and (R,S)-isomers are nearly though its ultimate role is yet to be determined. Use of these inactive, the (S,R)-isomer is a potent α blocker, and the (R,R)- agents is discussed in greater detail in Chapter 11. There is some isomer is a potent β blocker. Labetalol’s affinity for α receptors is evidence that drugs in this class may be less effective in the elderly less than that of phentolamine, but labetalol is α1-selective. Its and in individuals of African ancestry. However, these differences β-blocking potency is somewhat lower than that of propranolol. are relatively small and may not apply to an individual patient. Hypotension induced by labetalol is accompanied by less tachy- Indeed, since effects on blood pressure are easily measured, the cardia than occurs with phentolamine and similar α blockers. therapeutic outcome for this indication can be readily detected in Carvedilol, medroxalol,* and bucindolol* are nonselective any patient. β-receptor antagonists with some capacity to block α1-adrenergic receptors. Carvedilol antagonizes the actions of catecholamines Ischemic Heart Disease more potently at β receptors than at α1 receptors. The drug has a Beta-adrenoceptor blockers reduce the frequency of anginal epi- half-life of 6–8 hours. It is extensively metabolized in the liver, and sodes and improve exercise tolerance in many patients with angina stereoselective metabolism of its two isomers is observed. Since (see Chapter 12). These actions relate to the blockade of cardiac β metabolism of (R)-carvedilol is influenced by polymorphisms in receptors, resulting in decreased cardiac work and reduction in oxy- CYP2D6 activity and by drugs that inhibit this enzyme’s activity gen demand. Slowing and regularization of the heart rate may (such as quinidine and fluoxetine, see Chapter 4), drug interac- contribute to clinical benefits (Figure 10–7). Multiple large-scale tions may occur. Carvedilol also appears to attenuate oxygen free prospective studies indicate that the long-term use of timolol, pro- radical–initiated lipid peroxidation and to inhibit vascular smooth pranolol, or metoprolol in patients who have had a myocardial muscle mitogenesis independently of adrenoceptor blockade. infarction prolongs survival (Figure 10–8). At the present time, data These effects may contribute to the clinical benefits of the drug in are less compelling for the use of other than the three mentioned chronic heart failure (see Chapter 13). β-adrenoceptor antagonists for this indication. It is significant that Esmolol is an ultra-short–acting β1-selective adrenoceptor surveys in many populations have indicated that β-receptor antago- antagonist. The structure of esmolol contains an ester linkage; nists are underused, leading to unnecessary morbidity and mortal- esterases in red blood cells rapidly metabolize esmolol to a metab- ity. In addition, β-adrenoceptor antagonists are strongly indicated in olite that has a low affinity for β receptors. Consequently, esmolol the acute phase of a myocardial infarction. In this setting, relative has a short half-life (about 10 minutes). Therefore, during con- contraindications include bradycardia, hypotension, moderate or tinuous infusions of esmolol, steady-state concentrations are severe left ventricular failure, shock, heart block, and active airways achieved quickly, and the therapeutic actions of the drug are ter- disease. It has been suggested that certain polymorphisms in β2- minated rapidly when its infusion is discontinued. Esmolol may adrenoceptor genes may influence survival among patients receiving be safer to use than longer-acting antagonists in critically ill antagonists after acute coronary syndromes. patients who require a β-adrenoceptor antagonist. Esmolol is use- ful in controlling supraventricular arrhythmias, arrhythmias asso- ciated with thyrotoxicosis, perioperative hypertension, and Cardiac Arrhythmias myocardial ischemia in acutely ill patients. Beta antagonists are often effective in the treatment of both Butoxamine is a research drug selective for β2 receptors. supraventricular and ventricular arrhythmias (see Chapter 14). It Selective β2-blocking drugs have not been actively sought because has been suggested that the improved survival following myocardial there is no obvious clinical application for them; none is available infarction in patients using β antagonists (Figure 10–8) is due to for clinical use. suppression of arrhythmias, but this has not been proved. By increasing the atrioventricular nodal refractory period, β antagonists slow ventricular response rates in atrial flutter and fibrillation. These CLINICAL PHARMACOLOGY OF drugs can also reduce ventricular ectopic beats, particularly if the THE BETARECEPTORBLOCKING ectopic activity has been precipitated by catecholamines. Sotalol has DRUGS antiarrhythmic effects involving ion channel blockade in addition to its β-blocking action; these are discussed in Chapter 14. Hypertension Heart Failure The β-adrenoceptor–blocking drugs have proved to be effective Clinical trials have demonstrated that at least three β antagonists— and well tolerated in hypertension. Although many hypertensive metoprolol, bisoprolol, and carvedilol—are effective in reducing patients respond to a β blocker used alone, the drug is often used mortality in selected patients with chronic heart failure. Although with either a diuretic or a vasodilator. In spite of the short half-life administration of these drugs may worsen acute congestive heart of many β antagonists, these drugs may be administered once or failure, cautious long-term use with gradual dose increments in patients who tolerate them may prolong life. Although mecha- ∗ Not available in the USA. nisms are uncertain, there appear to be beneficial effects on  CHAPTER 10 Adrenoceptor Antagonist Drugs 163 Drama Comedy Documentary 110 Heart rate 90 70 50 10 30 50 70 90 110 Time (min) FIGURE 10–7 Heart rate in a patient with ischemic heart disease measured by telemetry while watching television. Measurements were begun 1 hour after receiving placebo (upper line, red) or 40 mg of oxprenolol (lower line, blue), a nonselective β antagonist with partial agonist activity. Not only was the heart rate decreased by the drug under the conditions of this experiment, it also varied much less in response to stimuli. (Modified and reproduced, with permission, from Taylor SH: Oxprenolol in clinical practice. Am J Cardiol 1983;52:34D.) beneficial effect is thought to result from the slowing of ventricu-.30 lar ejection and decreased outflow resistance. Beta antagonists are Cumulative mortality rate.25 useful in dissecting aortic aneurysm to decrease the rate of devel- opment of systolic pressure. Beta antagonists are also useful in.20 selected at-risk patients in the prevention of adverse cardiovascular.15 Placebo outcomes resulting from noncardiac surgery..10.05 Timolol Glaucoma (See Box: The Treatment of p = 0.0028 Glaucoma).00 Systemic administration of β-blocking drugs for other indications 0 12 24 36 48 60 72 was found serendipitously to reduce intraocular pressure in Time (mo) patients with glaucoma. Subsequently, it was found that topical administration also reduces intraocular pressure. The mechanism FIGURE 10–8 Effects of β-blocker therapy on life-table cumu- appears to involve reduced production of aqueous humor by the lated rates of mortality from all causes over 6 years among 1884 patients surviving myocardial infarctions. Patients were randomly ciliary body, which is physiologically activated by cAMP. Timolol assigned to treatment with placebo (dashed red line) or timolol (solid and related β antagonists are suitable for local use in the eye blue line). (Reproduced, with permission, from Pederson TR: Six-year follow-up of because they lack local anesthetic properties. Beta antagonists the Norwegian multicenter study on timolol after acute myocardial infarction. N appear to have an efficacy comparable to that of epinephrine or Engl J Med 1985;313:1055.) 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 myocardial remodeling and in decreasing the risk of sudden death timolol may be absorbed from the eye to cause serious adverse (see Chapter 13). effects on the heart and airways in susceptible individuals. Topical timolol may interact with orally administered verapamil and increase the risk of heart block. Other Cardiovascular Disorders Betaxolol, carteolol, levobunolol, and metipranolol are also Beta-receptor antagonists have been found to increase stroke vol- approved for the treatment of glaucoma. Betaxolol has the poten- ume in some patients with obstructive cardiomyopathy. This tial advantage of being β1-selective; to what extent this potential 164 SECTION II Autonomic Drugs advantage might diminish systemic adverse effects remains to be effective in stable heart failure or in prophylactic therapy after determined. The drug apparently has caused worsening of pulmo- myocardial infarction should be used for those indications. It is nary symptoms in some patients. possible that the beneficial effects of one drug in these settings might not be shared by another drug in the same class. The pos- Hyperthyroidism sible advantages and disadvantages of β-receptor antagonists that are partial agonists have not been clearly defined in clinical set- Excessive catecholamine action is an important aspect of the tings, although current evidence suggests that they are probably pathophysiology of hyperthyroidism, especially in relation to the less efficacious in secondary prevention after a myocardial infarc- heart (see Chapter 38). The β antagonists are beneficial in this tion compared with pure antagonists. condition. The effects presumably relate to blockade of adreno- ceptors and perhaps in part to the inhibition of peripheral conver- sion of thyroxine to triiodothyronine. The latter action may vary CLINICAL TOXICITY OF THE from one β antagonist to another. Propranolol has been used BETA-RECEPTOR ANTAGONIST DRUGS extensively in patients with thyroid storm (severe hyperthyroid- ism); it is used cautiously in patients with this condition to control Many adverse effects have been reported for propranolol but supraventricular tachycardias that often precipitate heart failure. most are minor. Bradycardia is the most common adverse cardiac effect of β-blocking drugs. Sometimes patients note coolness of Neurologic Diseases hands and feet in winter. Central nervous system effects include mild sedation, vivid dreams, and rarely, depression. Discontinuing Propranolol reduces the frequency and intensity of migraine the use of β blockers in any patient who develops psychiatric headache. Other β-receptor antagonists with preventive efficacy depression should be seriously considered if clinically feasible. It include metoprolol and probably also atenolol, timolol, and has been claimed that β-receptor antagonist drugs with low lipid nadolol. The mechanism is not known. Since sympathetic activ- solubility are associated with a lower incidence of central nervous ity may enhance skeletal muscle tremor, it is not surprising that system adverse effects than compounds with higher lipid solubil- β antagonists have been found to reduce certain tremors (see ity (Table 10–2). Further studies designed to compare the central Chapter 28). The somatic manifestations of anxiety may respond nervous system adverse effects of various drugs are required before dramatically to low doses of propranolol, particularly when taken specific recommendations can be made, though it seems reason- prophylactically. For example, benefit has been found in musicians able to try the hydrophilic drugs nadolol or atenolol in a patient with performance anxiety (“stage fright”). Propranolol may who experiences unpleasant central nervous system effects with contribute to the symptomatic treatment of alcohol withdrawal in other β blockers. some patients. The major adverse effects of β-receptor antagonist drugs relate to the predictable consequences of β blockade. Beta2-receptor Miscellaneous blockade associated with the use of nonselective agents commonly Beta-receptor antagonists have been found to diminish portal causes worsening of preexisting asthma and other forms of airway vein pressure in patients with cirrhosis. There is evidence that obstruction without having these consequences in normal indi- both propranolol and nadolol decrease the incidence of the first viduals. Indeed, relatively trivial asthma may become severe after episode of bleeding from esophageal varices and decrease the β blockade. However, because of their lifesaving potential in car- mortality rate associated with bleeding in patients with cirrhosis. diovascular disease, strong consideration should be given to indi- Nadolol in combination with isosorbide mononitrate appears to vidualized therapeutic trials in some classes of patients, eg, those be more efficacious than sclerotherapy in preventing rebleeding with chronic obstructive pulmonary disease who have appropriate in patients who have previously bled from esophageal varices. indications for β blockers. While β1-selective drugs may have less Variceal band ligation in combination with a β antagonist may be effect on airways than nonselective β antagonists, they must be more efficacious. 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 CHOICE OF A BETA-ADRENOCEPTOR vasospastic disorders. ANTAGONIST DRUG Beta-receptor blockade depresses myocardial contractility and excitability. In patients with abnormal myocardial function, car- Propranolol is the standard against which newer β antagonists diac output may be dependent on sympathetic drive. If this developed for systemic use have been compared. In many years of stimulus is removed by β blockade, cardiac decompensation may very wide use, propranolol has been found to be a safe and effec- ensue. Thus, caution must be exercised in starting a β-receptor tive drug for many indications. Since it is possible that some antagonist in patients with compensated heart failure even though actions of a β-receptor antagonist may relate to some other effect long-term use of these drugs in these patients may prolong life. A of the drug, these drugs should not be considered interchangeable life-threatening adverse cardiac effect of a β antagonist may be for all applications. For example, only β antagonists known to be overcome directly with isoproterenol or with glucagon (glucagon  CHAPTER 10 Adrenoceptor Antagonist Drugs 165 stimulates the heart via glucagon receptors, which are not blocked rather than abrupt cessation of dosage when these drugs are dis- by β antagonists), but neither of these methods is without hazard. continued, especially drugs with short half-lives, such as propra- A very small dose of a β antagonist (eg, 10 mg of propranolol) may nolol and metoprolol. provoke severe cardiac failure in a susceptible individual. Beta The incidence of hypoglycemic episodes exacerbated by blockers may interact with the calcium antagonist verapamil; β-blocking agents in diabetics is unknown. Nevertheless, it is severe hypotension, bradycardia, heart failure, and cardiac con- inadvisable to use β antagonists in insulin-dependent diabetic duction abnormalities have all been described. These adverse patients who are subject to frequent hypoglycemic reactions if effects may even arise in susceptible patients taking a topical (oph- alternative therapies are available. Beta1-selective antagonists offer thalmic) β blocker and oral verapamil. some advantage in these patients, since the rate of recovery from Patients with ischemic heart disease or renovascular hyperten- hypoglycemia may be faster compared with that in diabetics sion may be at increased risk if β blockade is suddenly interrupted. receiving nonselective β-adrenoceptor antagonists. There is con- The mechanism of this effect might involve up-regulation of the siderable potential benefit from these drugs in diabetics after a number of β receptors. Until better evidence is available regarding myocardial infarction, so the balance of risk versus benefit must be the magnitude of the risk, prudence dictates the gradual tapering evaluated in individual patients. SUMMARY Sympathetic Antagonists Pharmacokinetics, Subclass Mechanism of Action Effects Clinical Applications Toxicities, Interactions ALPHA-ADRENOCEPTOR ANTAGONISTS Phenoxybenzamine Irreversibly blocks α1 and α2 Lowers blood pressure (BP) Pheochromocytoma high Irreversible blocker duration indirect baroreflex activation heart rate (HR) rises due to catecholamine states > 1 day Toxicity: Orthostatic baroreflex activation hypotension tachycardia myocardial ischemia Phentolamine Reversibly blocks α1 and α2 Blocks α-mediated vasocon- Pheochromocytoma Half-life ~45 min after striction, lowers BP, increases IV injection HR (baroreflex) Prazosin Block α1, but not α2 Lower BP Hypertension benign pro- Larger depressor effect with first Doxazosin static hyperplasia dose may cause orthostatic hypotension Terazosin Tamsulosin Tamsulosin is slightly selective α1A Blockade may relax pros- Benign prostatic hyperpla- Orthostatic hypotension may be for α1A tatic smooth muscles more sia less common with this subtype than vascular smooth muscle Yohimbine Blocks α2 elicits increased cen- Raises BP and HR Male erectile dysfunction May cause anxiety excess pres- tral sympathetic activity hypotension sor effect if norepinephrine increased norepinephrine transporter is blocked release Labetalol (see β > α1 block Lowers BP with limited HR Hypertension Oral, parenteral Toxicity: Less carvedilol section below) increase tachycardia than other α1 agents BETA-ADRENOCEPTOR ANTAGONISTS Propranolol Block β1 and β2 Lower HR and BP reduce Hypertension angina pec- Oral, parenteral Toxicity: Nadolol renin toris arrhythmias Bradycardia worsened asthma migraine hyperthyroidism fatigue vivid dreams cold Timolol hands Metoprolol Block β1 > β2 Lower HR and BP reduce Angina pectoris hyperten- Toxicity: Bradycardia fatigue Atenolol renin may be safer in sion arrhythmias vivid dreams cold hands asthma Alprenolol Betaxolol Nebivolol (continued ) 166 SECTION II Autonomic Drugs Pharmacokinetics, Subclass Mechanism of Action Effects Clinical Applications Toxicities, Interactions 1 Butoxamine Blocks β2 > β1 Increases peripheral resis- No clinical indication Toxicity: Asthma provocation tance Pindolol β1, β2, with intrinsic sympath- Lowers BP modestly lower Hypertension arrhythmias Oral Toxicity: Fatigue vivid Acebutolol omimetic (partial agonist) HR migraine may avoid dreams cold hands effect worsening of bradycardia Carteolol 1 Bopindolol Oxprenolol1 Celiprolol1 Penbutolol Carvedilol β > α1 block Heart failure Oral, long half-life Toxicity: Medroxalol 1 Fatigue Bucindolol1 (see labetalol above) Esmolol β1 > β2 Very brief cardiac β blockade Rapid control of BP and Parenteral only half-life ~ 10 arrhythmias, thyrotoxicosis min Toxicity: Bradycardia and myocardial ischemia hypotension intraoperatively TYROSINE HYDROXYLASE INHIBITOR Metyrosine Blocks tyrosine hydroxylase Lowers BP in central ner- Pheochromocytoma Toxicity: Extrapyramidal symp- reduces synthesis of dopamine, vous system may elicit toms orthostatic hypotension norepinephrine, and extrapyramidal effects (due crystalluria epinephrine to low dopamine) 1 Not available in the USA. P R E P A R A T I O N S A V A I L A B L E * ALPHA BLOCKERS BETA BLOCKERS Alfuzosin (Uroxatral) Acebutolol (generic, Sectral) Oral: 10 mg tablets (extended release) Oral: 200, 400 mg capsules Doxazosin (generic, Cardura) Atenolol (generic, Tenormin) Oral: 1, 2, 4, 8 mg tablets; 4, 8 mg extended-release tablets Oral: 25, 50, 100 mg tablets Phenoxybenzamine (Dibenzyline) Parenteral: 0.5 mg/mL for IV injection Oral: 10 mg capsules Betaxolol Phentolamine (generic) Oral (Kerlone): 10, 20 mg tablets Parenteral: 5 mg/vial for injection Ophthalmic (generic, Betoptic): 0.25%, 0.5% drops Prazosin (generic, Minipress) Bisoprolol (generic, Zebeta) Oral: 1, 2, 5 mg capsules Oral: 5, 10 mg tablets Silodosin (Rapaflow) Carteolol Oral: 4, 8 mg capsules Oral (Cartrol): 2.5, 5 mg tablets