] is an alpha1 blocker with selectivity for alpha1 receptors in the prostate and urinary tract. At recommended doses, blockade of alpha1 receptors on blood vessels is weak. Therefore, alfuzosin is indicated only for BPH.
Alfuzosin is formulated in extended-release tablets, and hence absorption is slow. Plasma levels peak 8 hours after dosing. Bioavailability is 49%. Alfuzosin undergoes extensive hepatic metabolism, primarily by CYP3A4, an isoenzyme of cytochrome P450. Most (70%) of each dose is eliminated in the feces as inactive metabolites. A small fraction leaves unchanged in the urine. The half-life is 10 hours.
In patients with moderate to severe hepatic impairment, alfuzosin levels increase threefold to fourfold. The drug is contraindicated for these patients.
Alfuzosin is generally well tolerated. The most common adverse effect is dizziness. Syncope and clinically significant hypotension are rare. Unlike tamsulosin, alfuzosin does not interfere with ejaculation. Doses 4 times greater than recommended can prolong the QT interval and might thereby pose a risk for ventricular dysrhythmias.
Levels of alfuzosin are markedly raised by powerful inhibitors of CYP3A4. Among these are erythromycin, clarithromycin, itraconazole, ketoconazole, nefazodone, and the HIV protease inhibitors, such as ritonavir. Concurrent use of alfuzosin with these drugs is contraindicated.
Although alfuzosin does not lower blood pressure much, combining it with other hypotensive agents could produce a more dramatic reduction. Accordingly, such combinations should be used with caution. Drugs of concern include organic nitrates, antihypertensive agents, and the PDE-5 inhibitors used for sexual dysfunction (e.g., sildenafil [Viagra]).
Silodosin [Rapaflo] is an alpha-adrenergic antagonist that selectively blocks alpha1 receptors in the prostate, bladder, and urethra. Blockade of vascular alpha receptors is weak. The drug is indicated only for BPH.
Silodosin is generally well tolerated. However, like tamsulosin, silodosin can greatly reduce or eliminate release of semen during orgasm. This effect reverses when the drug is discontinued. Although blockade of vascular alpha receptors is usually minimal, silodosin can produce dizziness, lightheadedness, and nasal congestion.
Like prazosin, phentolamine [OraVerse, Rogitine ] is a competitive adrenergic antagonist. However, in contrast to prazosin, phentolamine blocks alpha2 receptors as well as alpha1 receptors. Phentolamine has three approved applications: (1) diagnosis and treatment of pheochromocytoma; (2) prevention of tissue necrosis after extravasation of drugs that produce alpha1-mediated vasoconstriction (e.g., norepinephrine); and (3) reversal of soft tissue anesthesia. (Local anesthetics are often combined with epinephrine, which prolongs anesthetic action by causing alpha1-mediated vasoconstriction. Phentolamine blocks epinephrine-mediated vasoconstriction and thereby increases local blood flow, which increases the rate of anesthetic removal.)
Like prazosin, phentolamine can produce the typical adverse effects associated with alpha-adrenergic blockade: orthostatic hypotension, reflex tachycardia, nasal congestion, and inhibition of ejaculation. Because it blocks alpha2 receptors, phentolamine produces greater reflex tachycardia than prazosin. If reflex tachycardia is especially severe, heart rate can be reduced with a beta blocker. Because tachycardia can aggravate angina pectoris and myocardial infarction (MI), phentolamine is contraindicated for patients with either disorder.
Overdose can produce profound hypotension. If necessary, blood pressure can be elevated with norepinephrine. Epinephrine should not be used because the drug can cause blood pressure to drop even further. In the presence of alpha1 blockade, the ability of epinephrine to promote vasodilation (through activation of vascular beta2 receptors) may outweigh the ability of epinephrine to cause vasoconstriction (through activation of vascular alpha1 receptors). Further lowering of blood pressure is not a significant problem with norepinephrine because norepinephrine does not activate beta2 receptors.
Phenoxybenzamine [Dibenzyline] is an old drug that, like phentolamine, blocks alpha1 and alpha2 receptors. However, unlike all of the other alpha-adrenergic antagonists, phenoxybenzamine is a noncompetitive receptor antagonist. Hence receptor blockade is not reversible. As a result, the effects of phenoxybenzamine are long lasting. (Responses to a single dose can persist for several days.) Effects subside as newly synthesized receptors replace the ones that have been irreversibly blocked. Phenoxybenzamine is approved only for pheochromocytoma.
Like the other alpha-adrenergic antagonists, phenoxybenzamine can produce orthostatic hypotension, reflex tachycardia, nasal congestion, and inhibition of ejaculation. Reflex tachycardia is greater than that caused by prazosin and about equal to that caused by phentolamine.
If dosage is excessive, phenoxybenzamine, like phentolamine, will cause profound hypotension. Furthermore, because hypotension is the result of irreversible alpha1 blockade, it cannot be corrected with an alpha1 agonist. To restore blood pressure, patients must be given intravenous fluids, which elevate blood pressure by increasing blood volume.
In this section we consider the beneficial and adverse responses that can result from blockade of beta-adrenergic receptors. Then we examine the properties of individual beta blockers.
Therapeutic Applications of Beta Blockade
Practically all of the therapeutic effects of the beta-adrenergic antagonists result from blockade of beta1 receptors in the heart. The major consequences of blocking these receptors are (1) reduced heart rate, (2) reduced force of contraction, and (3) reduced velocity of impulse conduction through the atrioventricular (AV) node. Because of these effects, beta blockers are useful in a variety of cardiovascular disorders.
Angina pectoris (cardiac pain due to ischemia) occurs when oxygen supplied to the heart through coronary circulation is insufficient to meet cardiac oxygen demand. Anginal attacks can be precipitated by exertion, intense emotion, and other factors. Beta-adrenergic blockers are a mainstay of antianginal therapy. By blocking beta1 receptors in the heart, these drugs decrease cardiac workload. This reduces oxygen demand, bringing it back into balance with oxygen supply and thereby preventing ischemia and pain.
For years, beta blockers were considered drugs of choice for hypertension. However, more recent data indicate they are less beneficial than previously believed.
The exact mechanism by which beta blockers reduce blood pressure is not known. Older proposed mechanisms include reduction of cardiac output through blockade of beta1 receptors in the heart and suppression of renin release through blockade of beta1 receptors in the kidney (see Chapter 36 for a discussion of the role of renin in blood pressure control). More recently, we have learned that, with long-term use, beta blockers reduce peripheral vascular resistance, which could account for much of their antihypertensive effects.
Beta-adrenergic blocking agents are especially useful for treating dysrhythmias that involve excessive electrical activity in the sinus node and atria. By blocking cardiac beta1 receptors, these drugs can (1) decrease the rate of sinus nodal discharge and (2) suppress conduction of atrial impulses through the AV node, thereby preventing the ventricles from being driven at an excessive rate.
An MI is a region of myocardial necrosis caused by localized interruption of blood flow to the heart wall. Treatment with a beta blocker can reduce pain, infarct size, mortality, and the risk for reinfarction. To be effective, therapy with a beta blocker must begin soon after an MI has occurred and should be continued for several years.
Reduction of Perioperative Mortality
Beta blockers may decrease the risk for mortality associated with noncardiac surgery in high-risk patients. In the DECREASE-IV trial, pretreatment with bisoprolol reduced the incidence of perioperative MI and death. However, for treatment to be both safe and effective, dosing should begin early (several days to weeks before surgery) and doses should be low initially and then titrated up (to achieve a resting heart rate of 60 to 80 beats/minute). In addition, treatment should continue for 1 month after surgery. As shown in an earlier trial, known as POISE, if the beta blocker is started late (just before surgery), and if the doses are large, such treatment can actually increase the risk for perioperative mortality.
Beta blockers are now considered standard therapy for heart failure. This application is relatively new and may come as a surprise to some readers because, until recently, heart failure was considered an absolute contraindication to beta blockers. At this time, only three beta blockers—carvedilol, bisoprolol, and metoprolol—have been shown effective for heart failure.
Hyperthyroidism (excessive production of thyroid hormone) is associated with an increase in the sensitivity of the heart to catecholamines (e.g., norepinephrine, epinephrine). As a result, normal levels of sympathetic activity to the heart can generate tachydysrhythmias and angina pectoris. Blockade of cardiac beta1 receptors suppresses these responses.
When taken prophylactically, beta-adrenergic blocking agents can reduce the frequency and intensity of migraine attacks. However, although beta blockers are effective as prophylaxis, these drugs are not able to abort a migraine headache after it has begun. The mechanism by which beta blockers prevent migraine is not known.
Public speakers and other performers sometimes experience performance anxiety (“stage fright”). Prominent symptoms are tachycardia, tremors, and sweating brought on by generalized discharge of the sympathetic nervous system. Some of you may experience similar symptoms when taking tests. Beta blockers help prevent performance anxiety—including test anxiety—by preventing beta1-mediated tachycardia.
As discussed earlier, a pheochromocytoma secretes large amounts of catecholamines, which can cause excessive stimulation of the heart. Cardiac stimulation can be prevented by beta1 blockade.
Beta blockers are important drugs for treating glaucoma, a condition characterized by elevated intraocular pressure with subsequent injury to the optic nerve. The group of beta blockers used in glaucoma (see Table 14.2) is different from the group of beta blockers discussed here.
Clinical Pharmacology of the Beta-Adrenergic Blocking Agents
|Generic Name||Trade Name||Receptors Blocked||ISA||Lipid Solubility||Half-Life (hr)||Route*||Maintenance Dosage in Hypertension†|
|FIRST-GENERATION: NONSELECTIVE BETA BLOCKERS|
|Carteolol||Cartrol||beta1, beta2||++||Low||6||PO||2.5 mg/day|
|Nadolol||Corgard||beta1, beta2||0||Low||20–24||PO||40 mg/day|
|Pindolol||Visken||beta1, beta2||+++||Moderate||3–4||PO||10 mg twice/day|
|Propranolol (IR)||generic only||beta1, beta2||0||High||3–5||PO, IV||60 mg twice/day|
|Propranolol (ER)||Inderal LA, InnoPran XL||PO||80 mg/day|
|Sotalol||Betapace, Betapace AF||beta1, beta2||0||High||12||PO||Not for hypertension|
|Timolol||Blocadren||beta1, beta2||0||Low||4||PO||20 mg twice/day|
|SECOND-GENERATION: CARDIOSELECTIVE BETA BLOCKERS|
|Atenolol||Tenormin||beta1||0||Low||6–9||PO, IV||50 mg/day|
|Esmolol||Brevibloc||beta1||0||Low||0.15||IV||Not for hypertension|
|Metoprolol (IR)||Lopressor, Betaloc||beta1||0||High||3–7||PO, IV||100 mg/day|
|Metoprolol (SR)||Toprol XL||PO||100 mg/day|
|THIRD-GENERATION: BETA BLOCKERS WITH VASODILATING ACTIONS|
|Carvedilol (IR)||Coreg||beta1, beta2, alpha1||0||Moderate||5–11||PO||12.5 mg twice/day|
|Carvedilol (SR)||Coreg CR||PO||40 mg/day|
|Labetalol||Normodyne, Trandate||beta1, beta2, alpha1||0||Low||6–8||PO, IV||300 mg twice/day|
Adverse Effects of Beta Blockade
Although therapeutic responses to beta blockers are due almost entirely to blockade of beta1 receptors, adverse effects involve both beta1 and beta2 blockade. Consequently, the nonselective beta-adrenergic blocking agents (drugs that block beta1 and beta2 receptors) produce a broader spectrum of adverse effects than do the “cardioselective” beta-adrenergic antagonists (drugs that block only beta1 receptors at therapeutic doses).
Adverse Effects of Beta1 Blockade
All of the adverse effects of beta1 blockade are the result of blocking beta1 receptors in the heart. Blockade of renal beta1 receptors is not a concern.
Blockade of cardiac beta1 receptors can produce bradycardia (excessively slow heart rate). If necessary, heart rate can be increased using a beta-adrenergic agonist, such as isoproterenol, and atropine (a muscarinic antagonist). Isoproterenol competes with the beta blocker for cardiac beta1 receptors, thereby promoting cardiac stimulation. By blocking muscarinic receptors on the heart, atropine prevents slowing of the heart by the parasympathetic nervous system.
Reduced Cardiac Output.
Beta1 blockade can reduce cardiac output by decreasing heart rate and the force of myocardial contraction. Because they can decrease cardiac output, beta blockers must be used with great caution in patients with heart failure or reduced cardiac reserve. In both cases, any further decrease in cardiac output could result in insufficient tissue perfusion.
Precipitation of Heart Failure.
In some patients, suppression of cardiac function with a beta blocker can be so great as to cause heart failure. Patients should be informed about the early signs of heart failure (shortness of breath, night coughs, swelling of the extremities) and instructed to notify the prescriber if these occur. It is important to appreciate that, although beta blockers can precipitate heart failure, they are also used to treat heart failure.
AV Heart Block.
AV heart block is defined as a delay in the conduction of electrical impulses through the AV node. In its most severe form, AV block prevents all atrial impulses from reaching the ventricles. Because blockade of cardiac beta1 receptors can suppress AV conduction, production of AV block is a potential complication of beta-blocker therapy. These drugs are contraindicated for patients with preexisting AV block.
Rebound Cardiac Excitation.
Long-term use of beta blockers can sensitize the heart to catecholamines. As a result, if a beta blocker is withdrawn abruptly, anginal pain or ventricular dysrhythmias may develop. This phenomenon of increased cardiac activity in response to abrupt cessation of beta-blocker therapy is referred to as rebound excitation. The risk for rebound excitation can be minimized by withdrawing these drugs gradually (e.g., by tapering the dosage over a period of 1 to 2 weeks). If rebound excitation occurs, dosing should be temporarily resumed. Patients should be warned against abrupt cessation of treatment. Also, they should be advised to carry an adequate supply of their beta blocker when traveling.