The adrenergic antagonists (also called blockers or sympatholytic agents) bind to adrenoceptors but do not trigger the usual receptor-mediated intracellular effects. These drugs act by either reversibly or irreversibly attaching to the receptor, thus preventing its activation by endogenous catecholamines. Like the agonists, the adrenergic antagonists are classified according to their relative affinities for ? or ? receptors in the peripheral nervous system.
These drugs will interfere with the functions of the sympathetic nervous system. Numerous adrenergic antagonists have important roles in clinical medicine, primarily to treat diseases associated with the cardiovascular system. [Note: Antagonists that block dopamine receptors are most important in the central nervous system (CNS) and are, therefore, considered in that section (see Chapter 13).] The receptor-blocking drugs discussed in this chapter are summarized in Figure 7.1.
Figure 7.1. Summary of blocking agents and drugs affecting neurotransmitter uptake or release.
?-Adrenergic Blocking Agents
Drugs that block ? adrenoceptors profoundly affect blood pressure. Because normal sympathetic control of the vasculature occurs in large part through agonist actions on ?-adrenergic receptors, blockade of these receptors reduces the sympathetic tone of the blood vessels, resulting in decreased peripheral vascular resistance. This induces a reflex tachycardia resulting from the lowered blood pressure.
The magnitude of the response depends on the sympathetic tone of the individual when the agent is given. Effects are more profound in an individual who is standing and less in a person who is supine. Hypovolemic patients will also have a more marked response as well. [Note: ? receptors, including ?1 adrenoceptors on the heart, are not affected by ? blockade.] The ?-adrenergic blocking agents, phenoxybenzamine and phentolamine, have limited clinical applications.
Phenoxybenzamine [fen-ox-ee-BEN-za-meen] is nonselective, linking covalently to both ?1- and ?2-receptors (Figure 7.2). The block is irreversible and noncompetitive, and the only mechanism the body has for overcoming the block is to synthesize new adrenoceptors, which requires a day or longer. Therefore, the actions of phenoxybenzamine last about 24 hours after a single administration. After the drug is injected, a delay of a few hours occurs before ? blockade develops.
Figure 7.2. Covalent inactivation of ?1 adrenoceptor by phenoxybenzamine.
a. Cardiovascular effects
By blocking ? receptors, phenoxybenzamine prevents vasoconstriction of peripheral blood vessels by endogenous catecholamines. The decreased peripheral resistance provokes a reflex tachycardia. Furthermore, the ability to block presynaptic inhibitory ?2 receptors in the heart can contribute to an increased cardiac output. [Note: These receptors, when blocked, will result in more norepinephrine release, which stimulates ? receptors on the heart, increasing cardiac output.] Thus, the drug has been unsuccessful in maintaining lowered blood pressure in hypertension, and its use has been discontinued for this purpose.
b. Epinephrine reversal
All ?-adrenergic blockers reverse the ?-agonist actions of epinephrine. For example, the vasoconstrictive action of epinephrine is interrupted, but vasodilation of other vascular beds caused by stimulation of ? receptors is not blocked. Therefore, in the presence of phenoxybenzamine, the systemic blood pressure decreases in response to epinephrine (Figure 7.3). [Note: The actions of norepinephrine are not reversed, but are diminished because norepinephrine lacks significant ?-agonist action on the vasculature.] Phenoxybenzamine has no effect on the actions of isoproterenol, which is a pure ? agonist (see Figure 7.3).
Figure 7.3. Summary of effects of adrenergic blockers on the changes in blood pressure induced by isoproterenol, epinephrine, and norepinephrine.
2. Therapeutic uses
Phenoxybenzamine is used in the treatment of pheochromocytoma, a catecholamine-secreting tumor of cells derived from the adrenal medulla. Prior to surgical removal of the tumor, patients are treated with phenoxybenzamine to preclude the hypertensive crisis that can result from manipulation of the tissue. This drug is also useful in the chronic management of these tumors, particularly when the catecholamine-secreting cells are diffuse and, therefore, inoperable. Phenoxybenzamine is sometimes effective in treating Raynaud disease, frostbite, and acrocyanosis. Autonomic hyperreflexia, which predisposes paraplegic patients to strokes, can be managed with phenoxybenzamine.
3. Adverse effects
Phenoxybenzamine can cause postural hypotension, nasal stuffiness, nausea, and vomiting. It may inhibit ejaculation. It also may induce reflex tachycardia, which is mediated by the baroreceptor reflex. Phenoxybenzamine is contraindicated in patients with decreased coronary perfusion.
In contrast to phenoxybenzamine, phentolamine [fen-TOLE-a-meen] produces a competitive block of ?1 and ?2 receptors. This drug’s action lasts for approximately 4 hours after a single administration. Like phenoxybenzamine, it produces postural hypotension and causes epinephrine reversal. Phentolamine-induced reflex cardiac stimulation and tachycardia are mediated by the baroreceptor reflex and by blocking the ?2 receptors of the cardiac sympathetic nerves. The drug can also trigger arrhythmias and anginal pain, and phentolamine is contraindicated in patients with decreased coronary perfusion.
Phentolamine is used for the short-term management of pheochromocytoma. It is also used locally to prevent dermal necrosis and extravasation due to norepinephrine administration as well as being used to treat hypertensive crisis due to abrupt withdrawal of clonidine and from ingesting tyramine-containing foods in patients taking nonselective monoamine oxidase inhibitors. Phentolamine is now rarely used for the treatment of impotence (it can be injected intracavernosally to produce vasodilation of penile arteries).
C. Prazosin, terazosin, doxazosin, tamsulosin, and alfuzosin
Prazosin [PRAY-zoe-sin], terazosin [ter-AY-zoe-sin], doxazosin [dox-AY-zoe-sin], and tamsulosin [tam-SUE-loh-sin] are selective competitive blockers of the ?1 receptor. In contrast to phenoxybenzamine and phentolamine, the first three drugs are useful in the treatment of hypertension. Tamsulosin and alfuzosin [al-FYOO-zoe-sin] are indicated for the treatment of benign prostatic hypertrophy (also known as benign prostatic hyperplasia, or BPH). Metabolism leads to inactive products that are excreted in urine except for those of doxazosin, which appear in feces. Doxazosin is the longest acting of these drugs.
1. Cardiovascular effects
All of these agents decrease peripheral vascular resistance and lower arterial blood pressure by causing the relaxation of both arterial and venous smooth muscle. Tamsulosin has the least effect on blood pressure. These drugs, unlike phenoxybenzamine and phentolamine, cause minimal changes in cardiac output, renal blood flow, and the glomerular filtration rate.
2. Therapeutic uses
Individuals with elevated blood pressure who have been treated with one of these drugs do not become tolerant to its action. However, the first dose of these drugs produces an exaggerated orthostatic hypotensive response (Figure 7.4) that can result in syncope (fainting). This action, termed a “first-dose” effect, may be minimized by adjusting the first dose to one-third or one-fourth of the normal dose and by giving the drug at bedtime. These drugs improve lipid profiles and glucose metabolism in hypertensive patients. Prazosin and others are used to treat congestive heart failure. By dilating both arteries and veins, these agents decrease preload and afterload, leading to an increase in cardiac output and a reduction in pulmonary congestion. Unlike ? blockers, these agents have not been found to prolong life in patients with heart failure.
The ?1-receptor antagonists have been used as an alternative to surgery in patients with symptomatic BPH (Figure 7.5). Blockade of the ? receptors decreases tone in the smooth muscle of the bladder neck and prostate and improves urine flow. Tamsulosin is an inhibitor (with some selectivity) of the ?1A receptors found on the smooth muscle of the prostate. This selectivity accounts for tamsulosin’s relatively minimal effect on blood pressure and its use in BPH, though dizziness (orthostasis) may rarely occur. [Note: Finasteride and dutasteride inhibit 5?-reductase, preventing the conversion of testosterone to dihydrotestosterone. These drugs are approved for the treatment of BPH by reducing prostate volume in selected patients (see Antiandrogens).]
Figure 7.4. First dose of ?1 receptor blocker may produce an orthostatic hypotensive response that can result in syncope (fainting).
Figure 7.5. Comparisons of treatments for benign prostatic hyperplasia.
PSA = Prostate specific antigen.
3. Adverse effects
?1 Blockers may cause dizziness, a lack of energy, nasal congestion, headache, drowsiness, and orthostatic hypotension (although to a lesser degree than that observed with phenoxybenzamine and phentolamine). These agents do not trigger reflex tachycardia to the same extent as the nonselective ?-receptor blockers. An additive antihypertensive effect occurs when prazosin is given with either a diuretic or a ? blocker, thereby necessitating a reduction in its dose.
Due to a tendency to retain sodium (Na+) and fluid, prazosin is frequently used along with a diuretic. These drugs do not affect male sexual function as severely as phenoxybenzamine and phentolamine. However, by blocking ? receptors in the ejaculatory ducts and impairing smooth muscle contraction, inhibition of ejaculation and retrograde ejaculation have been reported. Tamsulosin has a caution about “floppy iris syndrome,” a condition in which the iris billows in response to intraoperative eye surgery. Figure 7.6 summarizes some adverse effects observed with ? blockers.
Figure 7.6. Some adverse effects commonly observed with nonselective ?-adrenergic blocking agents.
Yohimbine [yo-HIM-bean] is a selective competitive ?2 blocker. It is found dysfunction as a component of the bark of the yohimbe tree and is sometimes used as a sexual stimulant. [Efficacy of yohimbine for the treatment of impotence has never been clearly demonstrated.] Yohimbine works at the level of the CNS to increase sympathetic outflow to the periphery. It directly blocks ?2 receptors and has been used to relieve vasoconstriction associated with Raynaud disease. Yohimbine is contraindicated in CNS and cardiovascular conditions because it is a CNS and cardiovascular stimulant.
?-Adrenergic Blocking Agents
All the clinically available ? blockers are competitive antagonists. Nonselective ? blockers act at both ?1 and ?2 receptors, whereas cardioselective ? antagonists primarily block ?1 receptors [Note: There are no clinically useful ?2 antagonists.] These drugs also differ in intrinsic sympathomimetic activity, in CNS effects, blockade of sympathetic receptors, vasodilation, and in pharmacokinetics (Figure 7.7).
Although all ? blockers lower blood pressure in hypertension, they do not induce postural hypotension, because the ? adrenoceptors remain functional. Therefore, normal sympathetic control of the vasculature is maintained. ? blockers are also effective in treating angina, cardiac arrhythmias, myocardial infarction, congestive heart failure, hyperthyroidism, and glaucoma as well as serving in the prophylaxis of migraine headaches. [Note: The names of all ? blockers end in “-olol” except for labetalol and carvedilol.]
Figure 7.7.Elimination half-lives for some ? blockers.
A. Propranolol: A nonselective ? antagonist
Propranolol [proe-PRAN-oh-lole] is the prototype ?-adrenergic antagonist and blocks both ?1 and ?2 receptors with equal affinity. Sustained-release preparations for once-a-day dosing are available.
Propranolol diminishes cardiac output, having both negative inotropic and chronotropic effects (Figure 7.8). It directly depresses sinoatrial and atrioventricular activity. The resulting bradycardia usually limits the dose of the drug. During exercise or stress, when the sympathetic nervous system is activated, ? blockers will attenuate the expected increase in heart rate. Cardiac output, work, and oxygen consumption are decreased by a blockade of ?1 receptors, and these effects are useful in the treatment of angina (see ?-Adrenergic Blockers).
The ? blockers are effective in attenuating supraventricular cardiac arrhythmias, but generally are not effective against ventricular arrhythmias (except those induced by exercise). At high doses, propranolol may cause a membrane-stabilizing effect on the heart, but this effect is insignificant if the drug is given at therapeutic doses.
Figure 7.8.Actions of propranolol and other ? blockers.
b. Peripheral vasoconstriction
Blockade of ? receptors prevents ?2-mediated vasodilation (see Figure 7.8). The reduction in cardiac output leads to decreased blood pressure. This hypotension triggers a reflex peripheral vasoconstriction that is reflected in reduced blood flow to the periphery. In patients with hypertension, total peripheral resistance returns to normal or decreases with long term use of propranolol. On balance, there is a gradual reduction of both systolic and diastolic blood pressures in hypertensive patients. No postural hypotension occurs, because the ?1-adrenergic receptors that control vascular resistance are unaffected.
Blocking ?2 receptors in the lungs of susceptible patients causes contraction of the bronchiolar smooth muscle (see Figure 7.8). This can precipitate a respiratory crisis in patients with chronic obstructive pulmonary disease (COPD) or asthma. Therefore, ? blockers, particularly, nonselective ones, are contraindicated in patients with COPD or asthma.
d. Increased Na+ retention
Reduced blood pressure causes a decrease in renal perfusion, resulting in an increase in Na+ retention and plasma volume (see Figure 7.8). In some cases, this compensatory response tends to elevate the blood pressure. For these patients, ? blockers are often combined with a diuretic to prevent Na+ retention.
e. Disturbances in glucose metabolism
? Blockade leads to decreased glycogenolysis and decreased glucagon secretion. Therefore, if a patient with type 1 (formerly insulin-dependent) diabetes is to be given propranolol, very careful monitoring of blood glucose is essential, because pronounced hypoglycemia may occur after insulin injection. ? Blockers also attenuate the normal physiologic response to hypoglycemia.
f. Blocked action of isoproterenol
All ? blockers, including propranolol, have the ability to block the actions of isoproterenol on the cardiovascular system. Thus, in the presence of a ? blocker, isoproterenol does not produce either the typical cardiac stimulation or reductions in mean arterial pressure and diastolic pressure (see Figure 7.3). [Note: In the presence of a ? blocker, epinephrine no longer lowers diastolic blood pressure or stimulates the heart, but its vasoconstrictive action (mediated by ? receptors) remains unimpaired. The actions of norepinephrine on the cardiovascular system are mediated primarily by ? receptors and are, therefore, unaffected.]
After oral administration, propranolol is almost completely absorbed because it is highly lipophilic. It is subject to first-pass effect, and only about 25 percent of an administered dose reaches the circulation. The volume of distribution of orally administered propranolol is quite large (4 liters/Kg), and the drug readily crosses the blood-brain barrier. Propranolol is extensively metabolized, and most metabolites are excreted in the urine.
3. Therapeutic effects
Propranolol does not reduce blood pressure in people with normal blood pressure. Propranolol lowers blood pressure in hypertension by several different mechanisms of action. Decreased cardiac output is the primary mechanism, but inhibition of renin release from the kidney, decrease in total peripheral resistance with long term use, and decreased sympathetic outflow from the CNS also contribute to propranolol’s antihypertensive effects (see ?-Adrenoceptor–Blocking Agents).
Propranolol is also effective in reducing migraine episodes when used prophylactically (see Prophylaxis). ? Blockers are valuable in the treatment of chronic migraine, because these agents decrease the incidence and severity of the attacks. [Note: During an attack, sumatriptan is used, as well as other drugs.]
Propranolol and other ? blockers are effective in blunting the widespread sympathetic stimulation that occurs in hyperthyroidism. In acute hyperthyroidism (thyroid storm), ? blockers may be lifesaving in protecting against serious cardiac arrhythmias.
d. Angina pectoris
Propranolol decreases the oxygen requirement of heart muscle and, therefore, is effective in reducing the chest pain on exertion that is common in angina. Propranolol is, thus, useful in the chronic management of stable angina but not for acute treatment. Tolerance to moderate exercise is increased, and this is measurable by improvement in the electrocardiogram. However, treatment with propranolol does not allow strenuous physical exercise such as tennis.
e. Myocardial infarction
Propranolol and other ? blockers have a protective effect on the myocardium. Thus, patients who have had one myocardial infarction appear to be protected against a second heart attack by prophylactic use of ? blockers. In addition, administration of a ? blocker immediately following a myocardial infarction reduces infarct size and hastens recovery. The mechanism for these effects may be a blocking of the actions of circulating catecholamines, which would increase the oxygen demand in an already ischemic heart muscle. Propranolol also reduces the incidence of sudden arrhythmic death after myocardial infarction.
4. Adverse effects
Propranolol has a serious and potentially lethal side effect when administered to a patient with asthma (Figure 7.9). An immediate contraction of the bronchiolar smooth muscle prevents air from entering the lungs. Death by asphyxiation has been reported for patients with asthma whom were inadvertently administered the drug. Therefore, propranolol must never be used in treating any individual with COPD or asthma.
Figure 7.9.Adverse effects commonly observed in individuals treated with propranolol.
Treatment with ? blockers must never be stopped quickly because of the risk of precipitating cardiac arrhythmias, which may be severe. The ? blockers must be tapered off gradually for at least a few weeks. Long-term treatment with a ? antagonist leads to up-regulation of the ? receptor. On suspension of therapy, the increased receptors can worsen angina or hypertension.
c. Sexual impairment
Because sexual function in the male occurs through ?-adrenergic activation, ? blockers do not affect normal ejaculation or the internal bladder sphincter function. On the other hand, some men do complain of impaired sexual activity. The reasons for this are not clear and may be independent of ?-receptor blockade.
d. Metabolic disturbances
? Blockade leads to decreased glycogenolysis and decreased glucagon secretion. Fasting hypoglycemia may occur. In addition, ? blockers can prevent the counterregulatory effects of catecholamines during hypoglycemia. The perception of symptoms such as tremor, tachycardia, and nervousness are blunted. [Note: Cardioselective ? blockers are preferred in treating asthma patients who use insulin (see ?1-selective antagonists).]
A major role of ? receptors is to mobilize energy molecules such as free fatty acids. [Note: Lipases in fat cells are activated, leading to the metabolism of triglycerides into free fatty acids.] Patients administered nonselective ? blockers have increased low-density lipoprotein (“bad”cholesterol), increased triglycerides, and reduced high-density lipoprotein (“good” cholesterol). On the other hand, the serum lipid profile in dyslipidemia patients improves with the use of ?1-selective antagonists such as metoprolol.
e. CNS effects
Propranolol has numerous CNS-mediated effects, including depression, dizziness, lethargy, fatigue, weakness, visual disturbances, hallucinations, short-term memory loss, emotional lability, vivid dreams (including nightmares), decreased performance, and depression manifested by insomnia.
f. Drug interactions
Drugs that interfere with, or inhibit, the metabolism of propranolol, such as cimetidine, fluoxetine, paroxetine, and ritonavir, may potentiate its antihypertensive effects. Conversely, those that stimulate or induce its metabolism, such as barbiturates, phenytoin, and rifampin, can decrease its effects.