Goodman and Gilman Manual of Pharmacology and Therapeutics

Section II
Neuropharmacology

chapter 12
Adrenergic Agonists and Antagonists

Catecholamines and Sympathomimetic Drugs

Catecholamines and sympathomimetic drugs are classified as direct-acting, indirect-acting, or mixed-acting sympathomimetics (Figure 12–1).

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Figure 12–1 Classification of adrenergic receptor agonists (sympathomimetic amines) and drugs that produce sympathomimetic-like effects. For each category, a prototypical drug is shown. (*Not actually sympathetic drugs but produce sympathomimetic-like effects.)

Direct-acting sympathomimetic drugs act directly on 1 or more of the adrenergic receptors. These agents may exhibit considerable selectivity for a specific receptor subtype (e.g., phenylephrine for α1, terbutaline for β2) or may have no or minimal selectivity and act on several receptor types (e.g., epinephrine for α1, α2, β1, β2, and β3 receptors; norepinephrine for α1, α2, and β1 receptors).

Indirect-acting drugs increase the availability of norepinephrine (NE) or epinephrine (EPI) to stimulate adrenergic receptors by several mechanisms:

• By releasing or displacing NE from sympathetic nerve varicosities

• By inhibiting the transport of NE into sympathetic neurons (e.g., cocaine), thereby increasing the dwell time of the transmitter at the receptor

• By blocking the metabolizing enzymes, monoamine oxidase (MAO) (e.g., pargyline) or catechol-O-methyltransferase (COMT) (e.g., entacapone), effectively increasing transmitter supply

Drugs that indirectly release NE and also directly activate receptors are referred to as mixed-acting sympathomimetic drugs [e.g., ephedrine, dopamine (DA)].

A feature of direct-acting sympathomimetic drugs is that their responses are not reduced by prior treatment with reserpine or guanethidine, which deplete NE from sympathetic neurons. After transmitter depletion, the actions of direct-acting sympathomimetic drugs actually may increase because the loss of the neurotransmitter induces compensatory changes that upregulate receptors or enhance the signaling pathway. In contrast, the responses of indirect-acting sympathomimetic drugs (e.g., amphetamine, tyramine) are abolished by prior treatment with reserpine or guanethidine. The cardinal feature of mixed-acting sympathomimetic drugs is that their effects are blunted, but not abolished, by prior treatment with reserpine or guanethidine.

Because the actions of NE are more pronounced on α and β1 receptors than on β2 receptors, many non-catecholamines that release NE have predominantly α receptor–mediated and cardiac effects. However, certain non-catecholamines with both direct and indirect effects on adrenergic receptors show significant β2 activity and are used clinically for these effects. Thus, ephedrine, although dependent on release of NE for some of its effects, relieves bronchospasm by its action on β2 receptors in bronchial smooth muscle, an effect not seen with NE. Moreover, some non-catecholamines (e.g., phenylephrine) act primarily and directly on target cells. It therefore is impossible to predict precisely the effects of non-catecholamines solely on their ability to provoke NE release.

CHEMISTRY AND STRUCTURE-ACTIVITY RELATIONSHIP OF SYMPATHOMIMETIC AMINES. β-Phenylethylamine (Table 12–1) can be viewed as the parent compound of the sympathomimetic amines, consisting of a benzene ring and an ethylamine side chain. The structure permits substitutions to be made on the aromatic ring, the α- and β-carbon atoms, and the terminal amino group to yield a variety of compounds with sympathomimetic activity. NE, EPI, DA, isoproterenol, and a few other agents have hydroxyl groups substituted at positions 3 and 4 of the benzene ring. Since o-dihydroxybenzene is also known as catechol, sympathomimetic amines with these hydroxyl substitutions in the aromatic ring are termed catecholamines.

Table 12–1

Chemical Structures and Major Effects of Some Sympathomimetic Drugs

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Many directly acting sympathomimetic drugs influence both α and β receptors, but the ratio of activities varies among drugs in a continuous spectrum from predominantly α activity (phenylephrine) to predominantly β activity (isoproterenol) (see Table 12–1).

Catecholamines have only a brief duration of action and are ineffective when administered orally, because they are rapidly inactivated in the intestinal mucosa and in the liver before reaching the systemic circulation (see Chapter 8). Compounds without 1 or both hydroxyl substituents are not acted on by COMT, and their oral effectiveness and duration of action are enhanced.

PHYSIOLOGICAL BASIS OF ADRENERGIC RECEPTOR FUNCTION. An important factor in the response of any cell or organ to sympathomimetic amines is the density and proportion of α and β adrenergic receptors. For example, NE has relatively little capacity to increase bronchial airflow, since the receptors in bronchial smooth muscle are largely of the β2 subtype. In contrast, isoproterenol and EPI are potent bronchodilators. Cutaneous blood vessels physiologically express almost exclusively α receptors; thus, NE and EPI cause constriction of such vessels, whereas isoproterenol has little effect. The smooth muscle of blood vessels that supply skeletal muscles has both β2 and α receptors; activation of β2receptors causes vasodilation, and stimulation of α receptors constricts these vessels. In such vessels, the threshold concentration for activation of β2 receptors by EPI is lower than that for α receptors, but when both types of receptors are activated at high concentrations of EPI, the response to α receptors predominates. Physiological concentrations of EPI primarily cause vasodilation.

The ultimate response of a target organ to sympathomimetic amines is dictated by the direct effects of the agents and the reflex homeostatic adjustments of the organism. Many sympathomimetic amines produce a rise in arterial blood pressure caused by stimulation of vascular α adrenergic receptors. This stimulation elicits compensatory reflexes that are mediated by the carotid–aortic baroreceptor system. As a result, sympathetic tone is diminished and vagal tone is enhanced; each of these responses leads to slowing of the heart rate. Conversely, when a drug (e.g., a β2 agonist) lowers mean blood pressure at the mechanoreceptors of the carotid sinus and aortic arch, the baroreceptor reflex works to restore pressure by reducing parasympathetic (vagal) outflow from the CNS to the heart, and increasing sympathetic outflow to the heart and vessels.

FALSE-TRANSMITTER CONCEPT. This hypothesis is a possible explanation for some of the effects of MAO inhibitors. Phenylethylamines normally are synthesized in the GI tract as a result of the action of bacterial tyrosine decarboxylase. The tyramine formed in this fashion usually is oxidatively deaminated in the GI tract and the liver. However, when an MAO inhibitor is administered, tyramine may be absorbed systemically and transported into sympathetic nerve terminals, where its catabolism again is prevented because of the inhibition of MAO at this site; the tyramine then is β-hydroxylated tooctopamine, which is stored in vesicles. As a consequence, NE gradually is displaced by octopamine, and stimulation of the nerve terminal results in the release of a relatively small amount of NE along with a fraction of octopamine. The latter amine has relatively little ability to activate either α or β receptors. Thus, a functional impairment of sympathetic transmission parallels long-term administration of MAO inhibitors.

Despite such functional impairment, patients who have received MAO inhibitors may experience severe hypertensive crises if they ingest cheese, beer, or red wine. These and related foods, which are produced by fermentation, contain a large quantity of tyramine, and to a lesser degree, other phenylethylamines. When GI and hepatic MAO are inhibited, the large quantity of tyramine that is ingested is absorbed rapidly and reaches the systemic circulation in high concentration. A massive and precipitous release of NE can result, with consequent hypertension that can be severe enough to cause myocardial infarction or a stroke (see Chapter 15).

ENDOGENOUS CATECHOLAMINES

EPINEPHRINE

EPI (adrenaline) is a potent stimulant of both α and β adrenergic receptors. Most of the responses listed in Table 8–1 are seen after injection of EPI, although the occurrence of sweating, piloerection, and mydriasis depends on the physiological state of the subject. Particularly prominent are the actions on the heart and on vascular and other smooth muscle.

BLOOD PRESSURE. EPI is one of the most potent vasopressor drugs known. If a pharmacological dose is given rapidly by an intravenous route, it evokes a characteristic effect on blood pressure, which rises rapidly to a peak that is proportional to the dose. The increase in systolic pressure is greater than the increase in diastolic pressure, so that the pulse pressure increases. As the response wanes, the mean pressure may fall below normal before returning to control levels.

The mechanism of the rise in blood pressure due to EPI is:

• A direct myocardial stimulation that increases the strength of ventricular contraction (positive inotropic action)

• An increased heart rate (positive chronotropic action)

• Vasoconstriction in many vascular beds—especially in the precapillary resistance vessels of skin, mucosa, and kidney—along with marked constriction of the veins

The pulse rate, at first accelerated, may be slowed markedly at the height of the rise of blood pressure by compensatory vagal discharge (baroreceptor reflex). Small doses of EPI (0.1 μg/kg) may cause the blood pressure to fall. The depressor effect of small doses and the biphasic response to larger doses are due to greater sensitivity to EPI of vasodilator β2receptors than of constrictor α receptors.

Absorption of EPI after subcutaneous injection is slow due to local vasoconstrictor action; the effects of doses as large as 0.5-1.5 mg can be duplicated by intravenous infusion at a rate of 10-30 μg/min. There is a moderate increase in systolic pressure due to increased cardiac contractile force and a rise in cardiac output (Figure 12–2). Peripheral resistance decreases, owing to a dominant action on β2receptors of vessels in skeletal muscle, where blood flow is enhanced; as a consequence, diastolic pressure usually falls. Because the mean blood pressure is not, as a rule, greatly elevated, compensatory baroreceptor reflexes do not appreciably antagonize the direct cardiac actions. Heart rate, cardiac output, stroke volume, and left ventricular work per beat are increased as a result of direct cardiac stimulation and increased venous return to the heart, which is reflected by an increase in right atrial pressure. The details of the effects of intravenous infusion of EPI, NE, and isoproterenol in humans are compared in Table 12–2 and Figure 12–2.

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Figure 12–2 Effects of intravenous infusion of norepinephrine, epinephrine, or isoproterenol in humans. (Modified from Allwood MJ, Cobbold AF, Ginsberg J. Peripheral vascular effects of noradrenaline, isopropylnoradrenaline, and dopamine. Br Med Bull, 1963;19:132-136. With permission from Oxford University Press.)

Table 12–2

Comparative Effects of Infusion of Epinephrine and Norepinephrine in Humansa

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VASCULAR EFFECTS. In the vasculature, EPI acts chiefly on the smaller arterioles and precapillary sphincters, although veins and large arteries also respond to the drug. Various vascular beds react differently, which results in a substantial redistribution of blood flow. Injected EPI markedly decreases cutaneous blood flow, constricting precapillary vessels and small venules. Cutaneous vasoconstriction accounts for a marked decrease in blood flow in the hands and feet. Blood flow to skeletal muscles is increased by therapeutic doses in humans. This is due in part to a powerful β2-mediated vasodilator action that is only partially counterbalanced by a vasoconstrictor action on the α receptors that also are present in the vascular bed.

The effect of EPI on cerebral circulation is related to systemic blood pressure. In usual therapeutic doses, the drug has relatively little constrictor action on cerebral arterioles. Indeed, autoregulatory mechanisms tend to limit the increase in cerebral blood flow caused by increased blood pressure.

Doses of EPI that have little effect on mean arterial pressure consistently increase renal vascular resistance and reduce renal blood flow by as much as 40%. Since the glomerular filtration rate is only slightly and variably altered, the filtration fraction is consistently increased. Excretion of Na+, K+, and Cl is decreased; urine volume may be increased, decreased, or unchanged. Maximal tubular reabsorptive and excretory capacities are unchanged. The secretion of renin is increased as a consequence of a direct action of EPI on β1 receptors in the juxtaglomerular apparatus. Arterial and venous pulmonary pressures are raised. Although direct pulmonary vasoconstriction occurs, redistribution of blood from the systemic to the pulmonary circulation, due to constriction of the more powerful musculature in the systemic great veins, doubtless plays an important part in the increase in pulmonary pressure. Very high concentrations of EPI may cause pulmonary edema precipitated by elevated pulmonary capillary filtration pressure and possibly by “leaky” capillaries.

Coronary blood flow is enhanced by EPI or by cardiac sympathetic stimulation under physiological conditions. The increased flow, which occurs even with doses that do not increase the aortic blood pressure, is the result of 2 factors. The first is the increased relative duration of diastole at higher heart rates; this is partially offset by decreased blood flow during systole because of more forceful contraction of the surrounding myocardium and an increase in mechanical compression of the coronary vessels. The increased flow during diastole is further enhanced if aortic blood pressure is elevated by EPI; as a consequence, total coronary flow may be increased. The second factor is a metabolic dilator effect that results from the increased strength of contraction and myocardial O2 consumption due to the direct effects of EPI on cardiac myocytes. This vasodilation is mediated in part by adenosine released from cardiac myocytes, which tends to override a direct vasoconstrictor effect of EPI that results from activation of α receptors in coronary vessels.

CARDIAC EFFECTS. EPI is a powerful cardiac stimulant. It acts directly on the predominant β1 receptors of the myocardium and of the cells of the pacemaker and conducting tissues; β2, β3, and α receptors also are present in the heart. Direct responses to EPI include increases in contractile force, accelerated rate of rise of isometric tension, enhanced rate of relaxation, decreased time to peak tension, increased excitability, acceleration of the rate of spontaneous beating, and induction of automaticity in specialized regions of the heart. In accelerating the heart, EPI preferentially shortens systole so that the duration of diastole usually is not reduced.

EPI normally shortens the refractory period of the human atrioventricular (AV) node by direct effects on the heart, although doses of EPI that slow the heart through reflex vagal discharge may indirectly tend to prolong it. EPI also decreases the grade of AV block that occurs as a result of disease, drugs, or vagal stimulation. Depression of sinus rate and AV conduction by vagal discharge probably plays a part in EPI-induced ventricular arrhythmias, because various drugs that block the vagal effect confer some protection. The actions of EPI in enhancing cardiac automaticity are effectively antagonized by β receptor antagonists such as propranolol. However, α1 receptors exist in most regions of the heart, and their activation prolongs the refractory period and strengthens myocardial contractions. Cardiac arrhythmias have been seen in patients after inadvertent intravenous administration of conventional subcutaneous doses of EPI. EPI as well as other catecholamines may cause myocardial cell death, particularly after intravenous infusions. Acute toxicity is associated with contraction band necrosis and other pathological changes; prolonged sympathetic stimulation of the heart, such as in congestive cardiomyopathy, may promote apoptosis of cardiomyocytes.

EFFECTS ON SMOOTH MUSCLES. The effects of EPI on the smooth muscles of different organs and systems depend on the type of adrenergic receptor in the muscle (see Table 8–1). In general, EPI relaxes GI smooth muscle due to activation of both α and β receptors. Intestinal tone and the frequency and amplitude of spontaneous contractions are reduced. The stomach usually is relaxed and the pyloric and ileocecal sphincters are contracted, but these effects depend on the preexisting tone of the muscle. If tone already is high, EPI causes relaxation; if low, contraction.

The responses of uterine muscle to EPI vary with species, phase of the sexual cycle, state of gestation, and dose given. During the last month of pregnancy and at parturition, EPI inhibits uterine tone and contractions (see Chapter 66). EPI relaxes the detrusor muscle of the bladder as a result of activation of β receptors and contracts the trigone and sphincter muscles owing to its α-agonist activity. This can result in hesitancy in urination and may contribute to retention of urine in the bladder. Activation of smooth muscle contraction in the prostate promotes urinary retention.

RESPIRATORY EFFECTS. EPI has a powerful bronchodilator action, most evident when bronchial muscle is contracted because of disease, as in bronchial asthma, or in response to drugs or various autacoids.

The beneficial effects of EPI in asthma also may arise from inhibition of antigen-induced release of inflammatory mediators from mast cells, and to a lesser extent from diminution of bronchial secretions and congestion within the mucosa. Inhibition of mast cell secretion is mediated by β2 receptors, while the effects on the mucosa are mediated by α receptors. however, glucocorticoids have much more profound anti-inflammatory effects (see Chapters 33 and 34).

EFFECTS ON THE CNS. EPI, a polar compound, penetrates poorly into the CNS and hence is not a powerful CNS stimulant. While the drug may cause restlessness, apprehension, headache, and tremor in many persons, these effects in part may be secondary to the effects of EPI on the cardiovascular system, skeletal muscles, and intermediary metabolism; that is, they may be the result of somatic manifestations of anxiety.

METABOLIC EFFECTS. EPI elevates the concentrations of glucose and lactate in blood (see Chapter 8). Insulin secretion is inhibited through an interaction with α2 receptors and is enhanced by activation of α2 receptors; the predominant effect seen with EPI is inhibition. Glucagon secretion is enhanced by an action on the β receptors of the α cells of pancreatic islets. EPI also decreases the uptake of glucose by peripheral tissues. EPI stimulates glycogenolysis in most tissues through β receptors. EPI raises the concentration of free fatty acids in blood by stimulating β receptors in adipocytes. The calorigenic action of EPI (increase in metabolism) is reflected in humans by an increase of 20-30% in O2 consumption after conventional doses.

MISCELLANEOUS EFFECTS. EPI reduces circulating plasma volume by loss of protein-free fluid to the extracellular space, thereby increasing hematocrit and plasma protein concentration. EPI rapidly increases the number of circulating polymorphonuclear leukocytes, likely due to β receptor–mediated demargination of these cells. EPI accelerates blood coagulation and promotes fibrinolysis. EPI stimulates lacrimation and a scanty mucus secretion from salivary glands. EPI also acts directly on white, fast-twitch muscle fibers to prolong the active state, thereby increasing peak tension.

EPI promotes a fall in plasma K+, largely due to stimulation of K+ uptake into cells, particularly skeletal muscle, due to activation of β2 receptors. This is associated with decreased renal K+ excretion.

ABSORPTION, FATE, AND EXCRETION. EPI is ineffective after oral administration. Absorption from subcutaneous tissues occurs relatively slowly. Absorption is more rapid after intramuscular injection. When concentrated solutions are nebulized and inhaled, the actions of the drug largely are restricted to the respiratory tract; however, systemic reactions such as arrhythmias may occur, particularly if larger amounts are used. EPI is rapidly inactivated in the liver by COMT and MAO (see Figure 8–7 and Table 8–4).

EPI is available in a variety of formulations geared for different routes of administration, including self-administration for anaphylactic reactions (EpiPen). EPI is unstable in alkaline solution; when exposed to air or light, it turns pink from oxidation to adrenochrome and then brown from formation of polymers. EPI injection is available in 1 mg/mL (1:1000), 0.1 mg/mL (1:10,000), and 0.5 mg/mL (1:2000) solutions. Subcutaneous dose ranges from 0.3-0.5 mg. The intravenous route is used cautiously if an immediate and reliable effect is mandatory. If the solution is given by vein, it must be adequately diluted and injected very slowly.

TOXICITY, ADVERSE EFFECTS, AND CONTRAINDICATIONS. EPI may cause restlessness, throbbing headache, tremor, and palpitations. The effects rapidly subside with rest, quiet, recumbency, and reassurance. More serious reactions include cerebral hemorrhage and cardiac arrhythmias. The use of large doses or the accidental, rapid intravenous injection of EPI may result in cerebral hemorrhage from the sharp rise in blood pressure. Angina may be induced by EPI in patients with coronary artery disease. The use of EPI generally is contraindicated in patients who are receiving nonselective β receptor antagonists, because its unopposed actions on vascular α1 receptors may lead to severe hypertension and cerebral hemorrhage.

THERAPEUTIC USES. A major use of EPI is to provide rapid, emergency relief of hypersensitivity reactions, including anaphylaxis, to drugs and other allergens. EPI also is used to prolong the action of local anesthetics, presumably by decreasing local blood flow (see Chapter 20). Its cardiac effects may be of use in restoring cardiac rhythm in patients with cardiac arrest due to various causes. It also is used as a topical hemostatic agent on bleeding surfaces such as in the mouth or in bleeding peptic ulcers during endoscopy of the stomach and duodenum. Inhalation of EPI may be useful in the treatment of post-intubation and infectious croup.

NOREPINEPHRINE

Norepinephrine (levarterenol, l-noradrenaline, NE) is a major chemical mediator liberated by mammalian postganglionic sympathetic nerves (see Table 12–1).

NE constitutes 10-20% of the catecholamine content of human adrenal medulla and as much as 97% in some pheochromocytomas.

PHARMACOLOGICAL PROPERTIES. The pharmacological actions of NE and EPI are compared in Table 12–2. Both drugs are direct agonists on effector cells; their actions differ mainly in the ratio of their effectiveness in stimulating α and β2 receptors. They are approximately equipotent in stimulating β1 receptors. NE is a potent α agonist, has relatively little action on β2 receptors, and is somewhat less potent than EPI on the α receptors of most organs.

ABSORPTION, FATE, AND EXCRETION. NE, like EPI, is ineffective when given orally and is absorbed poorly from sites of subcutaneous injection. It is rapidly inactivated in the body by uptake and the actions of COMT and MAO. Small amounts normally are found in the urine. The excretion rate may be greatly increased in patients with pheochromocytoma.

CARDIOVASCULAR EFFECTS. In response to infused NE (see Figure 12–2), systolic and diastolic pressures, and usually pulse pressure, are increased. Cardiac output is unchanged or decreased, and total peripheral resistance is raised. Compensatory vagal reflex activity slows the heart, overcoming a direct cardioaccelerator action, and stroke volume is increased. The peripheral vascular resistance increases in most vascular beds, and renal blood flow is reduced. NE constricts mesenteric vessels and reduces splanchnic and hepatic blood flow. Coronary flow usually is increased, probably owing both to indirectly induced coronary dilation, as with EPI, and to elevated blood pressure. Although generally a poor β2 receptor agonist, NE may increase coronary blood flow directly by stimulating β2receptors on coronary vessels. Patients with Prinzmetal variant angina pectoris may be supersensitive to the α adrenergic vasoconstrictor effects of NE.

ADVERSE EFFECTS AND PRECAUTIONS. The untoward effects of NE are similar to those of EPI, although there typically is greater elevation of blood pressure with NE. Care must be taken that necrosis and sloughing do not occur at the site of intravenous injection owing to extravasation of the drug. Impaired circulation at injection sites may be relieved by infiltrating the area with phentolamine, an α receptor antagonist. Blood pressure must be determined frequently during the infusion and particularly during adjustment of the rate of the infusion. Reduced blood flow to organs such as kidney and intestines is a constant danger with the use of NE.

THERAPEUTIC USES AND STATUS. NE (LEVOPHED, others) is used as a vasoconstrictor to raise or support blood pressure under certain intensive care conditions (discussed below).

DOPAMINE

DA (see Table 12–1) is the immediate metabolic precursor of NE and EPI; it is a central neurotransmitter important in the regulation of movement (see Chapters 1416, and 22) and possesses important intrinsic pharmacological properties. In the periphery, it is synthesized in epithelial cells of the proximal tubule and is thought to exert local diuretic and natriuretic effects. DA is a substrate for both MAO and COMT and thus is ineffective when administered orally.

PHARMACOLOGICAL PROPERTIES.

Cardiovascular Effects. The cardiovascular effects of DA are mediated by several distinct types of receptors that vary in their affinity for DA (see Chapter 13). At low concentrations, the primary interaction of DA is with vascular D1 receptors, especially in the renal, mesenteric, and coronary beds. By activating adenylyl cyclase and raising intracellular concentrations of cyclic AMP, D1 receptor stimulation leads to vasodilation. Infusion of low doses of DA causes an increase in glomerular filtration rate, renal blood flow, and Na+ excretion. Activation of D1 receptors on renal tubular cells decreases Na+transport by cyclic AMP-dependent and cyclic AMP-independent mechanisms. The renal tubular actions of DA that cause natriuresis may be augmented by the increase in renal blood flow and the small increase in the glomerular filtration rate that follow its administration. The resulting increase in hydrostatic pressure in the peritubular capillaries and reduction in oncotic pressure may contribute to diminished reabsorption of Na+ by the proximal tubular cells. As a consequence, DA has pharmacologically appropriate effects in the management of states of low cardiac output associated with compromised renal function, such as severe congestive heart failure.

At higher concentrations, DA exerts a positive inotropic effect on the myocardium, acting on β1 adrenergic receptors. DA also causes the release of NE from nerve terminals, which contributes to its effects on the heart. Tachycardia is less prominent during infusion of DA than of isoproterenol. DA usually increases systolic blood pressure and pulse pressure and either has no effect on diastolic blood pressure or increases it slightly. Total peripheral resistance usually is unchanged when low or intermediate doses of DA are given. At high concentrations, DA activates vascular α1 receptors, leading to more general vasoconstriction.

PRECAUTIONS, ADVERSE REACTIONS, AND CONTRAINDICATIONS. Before DA is administered to patients in shock, hypovolemia should be corrected by transfusion of whole blood, plasma, or other appropriate fluid. Untoward effects due to overdosage generally are attributable to excessive sympathomimetic activity (although this also may be the response to worsening shock). Nausea, vomiting, tachycardia, anginal pain, arrhythmias, headache, hypertension, and peripheral vasoconstriction may be encountered during DA infusion. Extravasation of large amounts of DA during infusion may cause ischemic necrosis and sloughing. Rarely, gangrene of the fingers or toes has followed prolonged infusion of the drug. DA should be avoided if the patient has received an MAO inhibitor. Careful adjustment of dosage also is necessary in patients who are taking tricyclic antidepressants.

THERAPEUTIC USES. DA is used in the treatment of severe congestive heart failure, particularly in patients with oliguria and low or normal peripheral vascular resistance. The drug may improve physiological parameters in the treatment of cardiogenic and septic shock. While DA may acutely improve cardiac and renal function in severely ill patients with chronic heart disease or renal failure, there is relatively little evidence supporting long-term benefit in clinical outcome.

Dopamine hydrochloride is used only intravenously, administered at a rate of 2-5 μg/kg/min; this rate may be increased gradually up to 20-50 μg/kg/min as necessary. During the infusion, patients require clinical assessment of myocardial function, perfusion of vital organs such as the brain, and the production of urine. Reduction in urine flow, tachycardia, or the development of arrhythmias may be indications to slow or terminate the infusion. The duration of action of DA is brief, and hence the rate of administration can be used to control the intensity of effect.

Related drugs include fenoldopam and dopexamine. Fenoldopam (CORLOPAM, others), a benzazepine derivative, is a rapidly acting vasodilator used for control of severe hypertension (e.g., malignant hypertension with end-organ damage) in hospitalized patients for ≤48 h. Fenoldopam is an agonist for peripheral D1 receptors and binds with moderate affinity to α2 adrenergic receptors; it has no significant affinity for D2 receptors or α1 or β adrenergic receptors. Fenoldopam is a racemic mixture; the R-isomer is the active component. It dilates a variety of blood vessels, including coronary arteries, afferent and efferent arterioles in the kidney, and mesenteric arteries. Less than 6% of an orally administered dose is absorbed because of extensive first-pass metabolism. The elimination t1/2 of intravenously infused fenoldopam is ~10 min. Adverse effects are related to the vasodilation and include headache, flushing, dizziness, and tachycardia or bradycardia.

Dopexamine (DOPACARD) is a synthetic analog related to DA with intrinsic activity at dopamine D1 and D2 receptors as well as at β2 receptors; it may have other effects such as inhibition of catecholamine uptake. It has favorable hemodynamic actions in patients with severe congestive heart failure, sepsis, and shock. In patients with low cardiac output, dopexamine infusion significantly increases stroke volume with a decrease in systemic vascular resistance. Tachycardia and hypotension can occur, but usually only at high infusion rates. Dopexamine is not currently available in the U.S.

β ADRENERGIC RECEPTOR AGONISTS

β agonists play a major role only in the treatment of bronchoconstriction in patients with asthma (reversible airway obstruction) or chronic obstructive pulmonary disease (COPD). Minor uses include management of preterm labor, treatment of complete heart block in shock, and short-term treatment of cardiac decompensation after surgery or in patients with congestive heart failure or myocardial infarction. β Receptor agonists may be used to stimulate the rate and force of cardiac contraction. The chronotropic effect is useful in the emergency treatment of arrhythmias such as torsade de pointes, bradycardia, or heart block (see Chapter 29).

ISOPROTERENOL

Isoproterenol (see Table 12–1) is a potent, nonselective β receptor agonist with very low affinity for α receptors. Consequently, isoproterenol has powerful effects on all β receptors and almost no action at α receptors.

PHARMACOLOGICAL ACTIONS. The major cardiovascular effects of isoproterenol (compared with EPI and NE) are illustrated in Figure 12–2. IV infusion of isoproterenol lowers peripheral vascular resistance, primarily in skeletal muscle but also in renal and mesenteric vascular beds. Diastolic blood pressure falls. Systolic blood pressure may remain unchanged or rise, although mean arterial pressure typically falls. Cardiac output is increased because of the positive inotropic and chronotropic effects of the drug in the face of diminished peripheral vascular resistance. The cardiac effects of isoproterenol may lead to palpitations, sinus tachycardia, and more serious arrhythmias.

Isoproterenol relaxes almost all varieties of smooth muscle when the tone is high, but this action is most pronounced on bronchial and GI smooth muscle. It prevents or relieves bronchoconstriction. Its effect in asthma may be due in part to an additional action to inhibit antigen-induced release of histamine and other mediators of inflammation; this action is shared by β2-selective stimulants.

ABSORPTION, FATE, AND EXCRETION. Isoproterenol is readily absorbed when given parenterally or as an aerosol. It is metabolized primarily in the liver and other tissues by COMT. Isoproterenol is a relatively poor substrate for MAO and is not taken up by sympathetic neurons to the same extent as are EPI and NE. The duration of action of isoproterenol therefore may be longer than that of EPI, but it still is brief.

TOXICITY AND ADVERSE EFFECTS. Palpitations, tachycardia, headache, and flushing are common. Cardiac ischemia and arrhythmias may occur, particularly in patients with underlying coronary artery disease.

THERAPEUTIC USES. Isoproterenol (ISUPREL, others) may be used in emergencies to stimulate heart rate in patients with bradycardia or heart block, particularly in anticipation of inserting an artificial cardiac pacemaker or in patients with the ventricular arrhythmia torsade de pointes. In disorders such as asthma and shock, isoproterenol largely has been replaced by other sympathomimetic drugs (seebelow and Chapter 36).

DOBUTAMINE

The pharmacological effects of dobutamine (see Table 12–1) are due to direct interactions with α and β receptors and are complex.

Dobutamine possesses a center of asymmetry; both enantiomeric forms are present in the racemic mixture used clinically. The (–) isomer of dobutamine is a potent agonist at α1 receptors and is capable of causing marked pressor responses; (+)-dobutamine is a potent α1 receptor antagonist, which can block the effects of (–)-dobutamine. Both isomers are full agonists at β receptors, but the (+) isomer is a more potent β receptor agonist than the (–) isomer (~10-fold).

CARDIOVASCULAR EFFECTS. The cardiovascular effects of racemic dobutamine are a composite of the pharmacological properties of the (–) and (+) stereoisomers. Dobutamine has relatively more prominent inotropic than chronotropic effects on the heart compared to isoproterenol. Although not completely understood, this useful selectivity may arise because peripheral resistance is relatively unchanged. Alternatively, cardiac α1 receptors may contribute to the inotropic effect. At equivalent inotropic doses, dobutamine enhances automaticity of the sinus node to a lesser extent than does isoproterenol; however, enhancement of atrioventricular and intraventricular conduction is similar for both drugs.

ADVERSE EFFECTS. Blood pressure and heart rate may increase significantly during dobutamine administration requiring reduction of infusion rate. Patients with a history of hypertension may exhibit an exaggerated pressor response more frequently. Because dobutamine facilitates AV conduction, patients with atrial fibrillation are at risk of marked increases in ventricular response rates; digoxin or other measures may be required to prevent this from occurring. Some patients may develop ventricular ectopic activity. As with any inotropic agent, dobutamine may increase the size of a myocardial infarct by increasing myocardial O2 demand. The efficacy of dobutamine over a period of more than a few days is uncertain; there is evidence for the development of tolerance.

THERAPEUTIC USES. Dobutamine (DOBUTREX) is indicated for the short-term treatment of cardiac decompensation that may occur after cardiac surgery or in patients with congestive heart failure or acute myocardial infarction. Dobutamine increases cardiac output and stroke volume in such patients, usually without a marked increase in heart rate. Alterations in blood pressure or peripheral resistance usually are minor. An infusion of dobutamine in combination with echocardiography is useful in the noninvasive assessment of patients with coronary artery disease.

Dobutamine has a t1/2 ~2 min; the onset of effect is rapid, steady-state concentrations are achieved within 10 min, and major metabolites are conjugates of dobutamine and 3-O-methyldobutamine. The rate of infusion required to increase cardiac output is 2.5-10 μg/kg/min; higher infusion rates occasionally are required. The rate and duration of the infusion are determined by the clinical and hemodynamic responses of the patient.

β2-SELECTIVE ADRENERGIC RECEPTOR AGONISTS

In the treatment of asthma or COPD, drugs with preferential affinity for β2 receptors compared with β1 receptors have been developed. The selectivity, however, is not absolute, and is lost at high concentrations of these drugs. Moreover up to 40% of the β receptors in the human heart are β2 receptors, activation of which can cause cardiac stimulation. A useful strategy to enhance preferential activation of pulmonary β2 receptors is the administration by inhalation of small doses of the drug in aerosol form. This approach typically leads to effective activation of β2 receptors in the bronchi but very low systemic drug concentrations. Consequently, there is less potential to activate cardiac β1 or β2 receptors or to stimulate β2 receptors in skeletal muscle, which can cause tremor and thereby limit oral therapy.

Administration of β agonists by aerosol (see Chapter 36) typically leads to a very rapid therapeutic response, generally within minutes, although some agonists such as salmeterol have a delayed onset of action. Only ~10% of an inhaled dose actually enters the lungs; much of the remainder is swallowed and ultimately may be absorbed.

In the treatment of asthma and COPD, β receptor agonists are used to activate pulmonary receptors that relax bronchial smooth muscle and decrease airway resistance. β receptor agonists also may suppress the release of leukotrienes and histamine from mast cells in lung tissue, enhance mucociliary function, and decrease microvascular permeability.

SHORT-ACTING β2 ADRENERGIC AGONISTS

METAPROTERENOL. Metaproterenol (called orciprenaline in Europe), along with terbutaline and fenoterol, belongs to the structural class of resorcinol bronchodilators that have hydroxyl groups at positions 3 and 5 of the phenyl ring (rather than at positions 3 and 4 as in catechols) (see Table 12–1). Consequently, metaproterenol is resistant to methylation by COMT. It is excreted primarily as glucuronic acid conjugates. Metaproterenol is considered to be β2-selective, although it probably is less selective than albuterol or terbutaline and hence is more prone to cause cardiac stimulation.

Effects occur within minutes of inhalation and persist for several hours. After oral administration, onset of action is slower, but effects last 3-4 h. Metaproterenol is used for the long-term treatment of obstructive airway diseases, asthma, and for treatment of acute bronchospasm. Side effects are similar to the short- and intermediate-acting sympathomimetic bronchodilators.

ALBUTEROL. Albuterol (VENTOLIN-HFA, PROVENTIL-HFA, others; see Table 12–1) is a selective β2 receptor agonist with pharmacological properties and therapeutic indications similar to those of terbutaline. It is administered either by inhalation or orally for the symptomatic relief of bronchospasm.

When administered by inhalation, it produces significant bronchodilation within 15 min, and effects persist for 3-4 h. The cardiovascular effects of albuterol are considerably weaker than those of isoproterenol when doses that produce comparable bronchodilation are administered by inhalation. Oral albuterol has the potential to delay preterm labor. Although rare, CNS and respiratory side effects are sometimes observed.

LEVALBUTEROL. Levalbuterol (XOPENEX) is the R-enantiomer of albuterol that is a used to treat asthma and COPD. Levalbuterol is β2-selective and acts like other β2 adrenergic agonists and has similar pharmacokinetic and pharmacodynamics properties to albuterol.

PIRBUTEROL. Pirbuterol is a relatively selective β2 agonist. Pirbuterol acetate (MAXAIR) is available for inhalation therapy; dosing is typically every 4-6 h.

TERBUTALINE. Terbutaline is a β2-selective bronchodilator. It contains a resorcinol ring and thus is not a substrate for COMT methylation. It is effective when taken orally, subcutaneously, or by inhalation (not marketed for inhalation in the U.S.).

Effects are observed rapidly after inhalation or parenteral administration; after inhalation its action may persist 3-6 h. With oral administration, the onset of effect may be delayed 1-2 h. Terbutaline (BRETHINE, others) is used for the long-term treatment of obstructive airway diseases and for treatment of acute bronchospasm, and also is available for parenteral use for the emergency treatment of status asthmaticus (see Chapter 36).

ISOETHARINE. Isoetharine selectivity for β2 receptors may not approach that of some of the other agents. Although resistant to metabolism by MAO, it is a catecholamine and thus is a good substrate for COMT. It is used only by inhalation for the treatment of acute episodes of bronchoconstriction. Isoetharine is not marketed in the U.S.

BITOLTEROL. Bitolterol (TORNALATE) is a β2 agonist in which the hydroxyl groups in the catechol moiety are protected by esterification. Esterases in the lung and other tissues hydrolyze this prodrug to the active form, colterol, or terbutylnorepinephrine. The duration of effect of bitolterol after inhalation ranges from 3-6 h. Bitolterol has been discontinued in the U.S.

FENOTEROL. Fenoterol (BEROTEC) is a β2-selective receptor agonist. After inhalation, it has a prompt onset of action, and its effect typically is sustained for 4-6 h. The possible association of fenoterol use with increased deaths from asthma, although controversial, has led to its withdrawal from the market.

PROCATEROL. Procaterol (MASCACIN, others) is a β2-selective receptor agonist. After inhalation, it has a prompt onset of action that is sustained for ~5 h. Procaterol is not available in the U.S.

LONG-ACTING β2 ADRENERGIC AGONISTS (LABA)

SALMETEROL. Salmeterol (SEREVENT) is a β2-selective agonist with a prolonged duration of action (>12 h); it has at least 50-fold greater selectivity for β2 receptors than albuterol. It provides symptomatic relief and improves lung function and quality of life in patients with COPD. It has additive effects when used in combination with inhaled ipratropium or oral theophylline. It is highly lipophilic and has a sustained duration of action. It also may have anti-inflammatory activity.

Salmeterol is metabolized by CYP3A4 to α-hydroxy-salmeterol, which is eliminated primarily in the feces. The onset of action of inhaled salmeterol is relatively slow, so it is not suitable monotherapy for acute breakthrough attacks of bronchospasm. Salmeterol generally is well tolerated. Salmeterol should not be used more than twice daily (morning and evening) and should not be used to treat acute asthma symptoms, which should be treated with a short-acting β2 agonist (e.g., albuterol) when breakthrough symptoms occur despite twice-daily use of salmeterol. The use of LABA is recommended only for patients in whom inhaled corticosteroids alone either have failed to achieve good asthma control or for initial therapy.

FORMOTEROL. Formoterol (FORADIL, others) is a long-acting β2-selective receptor agonist. Significant bronchodilation occurs within minutes of inhalation of a therapeutic dose, which may persist for up to 12 h. It is highly lipophilic and has high affinity for β2 receptors. Its major advantage over many other β2-selective agonists is this prolonged duration of action. Formoterol is FDA-approved for treatment of asthma, bronchospasm, prophylaxis of exercise-induced bronchospasm, and COPD. It can be used concomitantly with short-acting β2 agonists, glucocorticoids (inhaled or systemic), and theophylline.

ARFORMOTEROL. Arformoterol (BROVANA), the (R, R) enantiomer of formoterol, is a selective long-acting β2 agonist that has twice the potency of racemic formoterol. It is used for the long-term treatment of bronchoconstriction in patients with COPD, including chronic bronchitis and emphysema. Systemic exposure to arformoterol is due to pulmonary absorption with plasma levels reaching peak levels in 0.25-1 h. Plasma protein binding is 52-65%. It is primarily metabolized by CYP2D6 and CYP2C19. It does not inhibit any of the common CYPs.

INDACATEROL. Indacaterol is a once-daily long-acting β adrenergic agonist, classified as an ultra-LABA, was recently approved for treatment of COPD.

It has a fast onset of action, long duration, and appears well tolerated. Indacaterol behaves as a potent β2 agonist with high intrinsic efficacy, which, in contrast to salmeterol, does not antagonize the bronchorelaxant effect of short-acting β2 adrenergic agonists. Evidence indicates that indacaterol has a longer duration of action than salmeterol and formoterol. Indacaterol is not indicated for the treatment of asthma.

Carmoterol is also an ultra-LABA that is currently in phase III clinical trials in the U.S.

RITODRINE. Ritodrine is a β2-selective agonist that was developed specifically for use as a uterine relaxant. Nevertheless, its pharmacological properties closely resemble those of the other agents in this group.

The pharmacokinetic properties of ritodrine are complex and incompletely defined, especially in pregnant women. Ritodrine may be administered intravenously to selected patients to arrest premature labor. However, β2-selective agonists may not have clinically significant benefits on perinatal mortality and may actually increase maternal morbidity. Ritodrine is not available in the U.S. See Chapter 66 for the pharmacology of tocolytic agents.

ADVERSE EFFECTS OF β2-SELECTIVE AGONISTS. The major adverse effects of β receptor agonists occur as a result of excessive activation of β receptors. Patients with underlying cardiovascular disease are particularly at risk for significant reactions. However, the likelihood of adverse effects can be greatly decreased in patients with lung disease by administering the drug by inhalation.

Tremor is a relatively common adverse effect of the β2-selective receptor agonists. Tolerance generally develops to this effect. This adverse effect can be minimized by starting oral therapy with a low dose of drug and progressively increasing the dose as tolerance to the tremor develops. Feelings of restlessness, apprehension, and anxiety may limit therapy with these drugs, particularly oral or parenteral administration.

Tachycardia is a common adverse effect of systemically administered β receptor agonists. Stimulation of heart rate occurs primarily by means of β1 receptors. During a severe asthma attack, heart rate actually may decrease during therapy with a β agonist, presumably because of improvement in pulmonary function with consequent reduction in endogenous cardiac sympathetic stimulation. In patients without cardiac disease, β agonists rarely cause significant arrhythmias or myocardial ischemia; however, patients with underlying coronary artery disease or preexisting arrhythmias are at greater risk. The risk of adverse cardiovascular effects also is increased in patients who are receiving MAO inhibitors. In general, at least 2 weeks should elapse between the use of MAO inhibitors and administration of β2agonists or other sympathomimetics.

When given parenterally, these drugs may increase the concentrations of plasma glucose, lactate, and free fatty acids and decrease the concentration of K+. The decrease in K+ concentration is especially important in patients with cardiac disease taking digoxin and diuretics. In some diabetic patients, hyperglycemia may be worsened and higher doses of insulin may be required. These adverse effects are far less likely with inhalation therapy.

β3-SELECTIVE ADRENERGIC RECEPTOR AGONISTS

MIRABEGRON. (MYRBETRIQ), a selective β3 adrenergic agonist, is approved for the treatment of overactive bladder (urinary urgency, frequency, urge incontinence). The drug activates β3 adrenergic receptors on the detrusor muscle of the bladder to facilitate filling of the bladder and storage of urine. The drug is administered orally with a starting dose of 25 mg once daily. Side effects may include hypertension, nasopharyngitis, urinary tract infection, and headache. Mirabegron is an inhibitor of CYPs 2D6 and 3A.

α1-SELECTIVE ADRENERGIC RECEPTOR AGONISTS

Activation of α adrenergic receptors in vascular smooth muscle results in contraction, causing increases in peripheral vascular resistance and increases in blood pressure. Although the clinical utility of these drugs is limited, they may be useful in the treatment of some patients with hypotension, including orthostatic hypotension, or shock. Phenylephrine andmethoxamine (discontinued in the U.S.) are direct-acting vasoconstrictors and are selective activators of α1 receptors. Mephentermine and metaraminol act both directly and indirectly.Midodrine is a prodrug that is converted, after oral administration, to desglymidodrine, a direct-acting α1 agonist.

PHENYLEPHRINE. Phenylephrine (NEO-SYNEPHRINE, others) is a α1-selective agonist; it activates β receptors only at much higher concentrations. The drug causes marked arterial vasoconstriction during intravenous infusion. Phenylephrine (NEO-SYNEPHRINE, others) also is used as a nasal decongestant and as a mydriatic in various nasal and ophthalmic formulations (see Chapter 64).

MEPHENTERMINE. Mephentermine acts both directly and indirectly. After an intramuscular injection, the onset of action is prompt (within 5-15 min), and effects may last for several hours. Because the drug releases NE, cardiac contraction is enhanced, and cardiac output and systolic and diastolic pressures usually are increased. The change in heart rate is variable, depending on the degree of vagal tone. Adverse effects are related to CNS stimulation, excessive rises in blood pressure, and arrhythmias. Mephentermine is used to prevent hypotension, which frequently accompanies spinal anesthesia. The drug has been discontinued in the U.S.

METARAMINOL. Metaraminol exerts direct effects on vascular α adrenergic receptors. Metaraminol also is an indirectly acting agent that stimulates the release of NE. The drug has been used in the treatment of hypotensive states or off-label to relieve attacks of paroxysmal atrial tachycardia, particularly those associated with hypotension (see Chapter 29).

MIDODRINE. Midodrine (PROAMATINE, others) is an orally effective α1 receptor agonist. It is a prodrug, converted to an active metabolite, desglymidodrine. Midodrine-induced rises in blood pressure are associated with both arterial and venous smooth muscle contraction. A frequent complication in these patients is supine hypertension. This can be minimized by administering the drug during periods when the patient will remain upright, and elevating the head of the bed. Typical dosing, achieved by careful titration of blood pressure responses, varies between 2.5 and 10 mg thrice daily.

α2-SELECTIVE ADRENERGIC RECEPTOR AGONISTS

α2-Selective adrenergic agonists are used primarily for the treatment of systemic hypertension. Their efficacy as antihypertensive agents is somewhat surprising, as many blood vessels contain postsynaptic α2 adrenergic receptors that promote vasoconstriction (see Chapter 8). Clonidine, the prototypic α2 agonist, lowers blood pressure by activation of α2receptors in the CNS. Some α2 agonists are used to reduce intraocular pressure.

CLONIDINE

Intravenous infusion of clonidine causes an acute rise in blood pressure, because of activation of postsynaptic α2 receptors in vascular smooth muscle. This transient vasoconstriction (not usually seen with oral administration) is followed by a more prolonged hypotensive response that results from decreased sympathetic outflow from the CNS. The effect appears to result, at least in part, from activation of α2 receptors in the lower brainstem region. Clonidine also stimulates parasympathetic outflow, which may contribute to the slowing of heart rate. In addition, some of the antihypertensive effects of clonidine may be mediated by activation of presynaptic α2 receptors that suppress the release of NE, ATP, and NPY from postganglionic sympathetic nerves. Clonidine decreases the plasma concentration of NE and reduces its excretion in the urine.

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ABSORPTION, FATE, AND EXCRETION. Clonidine is well absorbed after oral administration, with bioavailability ~100%. Peak concentration in plasma and the maximal hypotensive effect are observed 1-3 h after an oral dose. The elimination t1/2 is 6-24 h (mean of ~12 h). About half of an administered dose can be recovered unchanged in the urine; the t1/2 of the drug may increase with renal failure. A transdermal delivery patch permits continuous administration of clonidine as an alternative to oral therapy. The drug is released at an approximately constant rate for a week; 3-4 days are required to reach steady-state concentrations in plasma. When the patch is removed, plasma concentrations remain stable for ~8 h and then decline gradually over a period of several days; this decrease is associated with a rise in blood pressure.

ADVERSE EFFECTS. The major adverse effects of clonidine are dry mouth and sedation, which may diminish in intensity after several weeks of therapy. Sexual dysfunction also may occur. Marked bradycardia is observed in some patients. These effects of clonidine frequently are related to dose, and their incidence may be lower with transdermal administration of clonidine. About 15-20% of patients develop contact dermatitis when using the transdermal system. Withdrawal reactions follow abrupt discontinuation of long-term therapy with clonidine in some hypertensive patients (see Chapter 27).

THERAPEUTIC USES. The major therapeutic use of clonidine (CATAPRES, others) is in the treatment of hypertension (see Chapter 27). Clonidine also has apparent efficacy in the off-label treatment of a range of other disorders: in reducing diarrhea in some diabetic patients with autonomic neuropathy, in treating and preparing addicted subjects for withdrawal from narcotics, alcohol, and tobacco (seeChapter 24) by ameliorating some of the adverse sympathetic nervous activity associated with withdrawal and decreasing craving for the drug, in reducing the incidence of menopausal hot flashes (transdermal application of CATAPRES). Acute administration of clonidine has been used in the differential diagnosis of patients with hypertension and suspected pheochromocytoma. Among the other off-label uses of clonidine are atrial fibrillation, attention deficit hyperactivity disorder (ADHD), constitutional growth delay in children, cyclosporine-associated nephrotoxicity, Tourette syndrome, hyperhidrosis, mania, posthepatic neuralgia, psychosis, restless leg syndrome, ulcerative colitis, and allergy-induced inflammatory reactions in patients with extrinsic asthma.

APRACLONIDINE. Apraclonidine (IOPIDINE) is a relatively selective α2 receptor agonist that is used topically to reduce intraocular pressure with minimal systemic effects.

Apraclonidine does not cross the blood-brain barrier and is more useful than clonidine for ophthalmic therapy. Apraclonidine is useful as short-term adjunctive therapy in glaucoma patients whose intraocular pressure is not well controlled by other pharmacological agents. The drug also is used to control or prevent elevations in intraocular pressure that occur in patients after laser trabeculoplasty or iridotomy (see Chapter 64).

BRIMONIDINE. Brimonidine (ALPHAGAN, others) is a clonidine derivative and α2-selective agonist that is administered ocularly to lower intraocular pressure in patients with ocular hypertension or open-angle glaucoma. Unlike apraclonidine, brimonidine can cross the blood-brain barrier and can produce hypotension and sedation, although these CNS effects are slight compared to those of clonidine.

GUANFACINE. Guanfacine (TENEX, others) is an α2 receptor agonist that is more selective for α2 receptors than is clonidine. Guanfacine lowers blood pressure by activation of brainstem receptors with resultant suppression of sympathetic activity. A sustained-release form (INTUNIV) is FDA-approved for treatment of ADHD in children ages 6-17 years. Guanfacine and clonidine appear to have similar efficacy for the treatment of hypertension and similar pattern of adverse effects. A withdrawal syndrome may occur after the abrupt discontinuation, but it is less frequent and milder than the syndrome that follows clonidine withdrawal; this difference may relate to the longer t1/2 of guanfacine.

GUANABENZ. Guanabenz (WYTENSIN, others) is a centrally acting α2 agonist that decreases blood pressure by a mechanism similar to those of clonidine and guanfacine. Guanabenz has a t1/2 of 4-6 h and is extensively metabolized by the liver; dosage adjustment may be necessary in patients with hepatic cirrhosis. The adverse effects caused by guanabenz are similar to those seen with clonidine.

METHYLDOPA. Methyldopa (α-methyl-3,4-dihydroxyphenylalanine) is a centrally acting antihypertensive agent. It is metabolized to α-methylnorepinephrine in the brain, and this compound is thought to activate central α2 receptors and lower blood pressure in a manner similar to that of clonidine (see Chapter 27).

TIZANIDINE. Tizanidine (ZANAFLEX, others) is a muscle relaxant used for the treatment of spasticity associated with cerebral and spinal disorders. It is also an α2 agonist with some properties similar to those of clonidine.

MISCELLANEOUS SYMPATHOMIMETIC AGONISTS

AMPHETAMINE

Amphetamine, racemic β-phenylisopropylamine (see Table 12–1), has powerful CNS stimulant actions and α and β receptor stimulation in the periphery. Unlike EPI, it is effective after oral administration and its effects last for several hours.

CARDIOVASCULAR SYSTEM. Amphetamine given orally raises both systolic and diastolic blood pressure. Heart rate often is reflexly slowed; with large doses, cardiac arrhythmias may occur.

OTHER SMOOTH MUSCLES. In general, smooth muscles respond to amphetamine as they do to other sympathomimetic amines. The contractile effect on the sphincter of the urinary bladder is particularly marked, and for this reason amphetamine has been used in treating enuresis and incontinence. Pain and difficulty in micturition occasionally occur. The GI effects of amphetamine are unpredictable. If enteric activity is pronounced, amphetamine may cause relaxation and delay the movement of intestinal contents; if the gut already is relaxed, the opposite effect may occur. The response of the human uterus varies, but there usually is an increase in tone.

CNS. Amphetamine is one of the most potent sympathomimetic amines in stimulating the CNS. It stimulates the medullary respiratory center, lessens the degree of central depression caused by various drugs, and produces other signs of CNS stimulation. In eliciting of CNS excitatory effects, the d-isomer (dextroamphetamine) is 3-4 times more potent than the l-isomer. The psychic effects depend on the dose and the mental state and personality of the individual. The main results of an oral dose of 10-30 mg include wakefulness, alertness, and a decreased sense of fatigue; elevation of mood, with increased initiative, self-confidence, and ability to concentrate; often, elation and euphoria; and increase in motor and speech activities. Performance of simple mental tasks is improved, but, although more work may be accomplished, the number of errors may increase. Physical performance (e.g., in athletes) is improved, and the drug often is abused for this purpose. These effects are variable and may be reversed by overdosage or repeated usage. Prolonged use or large doses are nearly always followed by depression and fatigue. Many individuals given amphetamine experience headache, palpitation, dizziness, vasomotor disturbances, agitation, confusion, dysphoria, apprehension, delirium, or fatigue (see Chapter 24).

FATIGUE AND SLEEP. In general, amphetamine prolongs the duration of adequate performance before fatigue appears, and the effects of fatigue are at least partly reversed. Amphetamine reduces the frequency of attention lapses that impair performance after prolonged sleep deprivation and thus improves execution of tasks requiring sustained attention. The need for sleep may be postponed, but it cannot be avoided indefinitely. When the drug is discontinued after long use, the pattern of sleep may take as long as 2 months to return to normal.

ANALGESIA. Amphetamine and some other sympathomimetic amines have a small analgesic effect, but it is not sufficiently pronounced to be therapeutically useful. However, amphetamine can enhance the analgesia produced by opiates.

Respiration. Amphetamine stimulates the respiratory center, increasing the rate and depth of respiration. In normal individuals, usual doses of the drug do not appreciably increase respiratory rate or minute volume. Nevertheless, when respiration is depressed by centrally acting drugs, amphetamine may stimulate respiration.

Depression of Appetite. Amphetamine and similar drugs have been used for the treatment of obesity. Weight loss is almost entirely due to reduced food intake and only in small measure to increased metabolism. In humans, tolerance to the appetite suppression develops rapidly.

Mechanisms of Action in the CNS. Amphetamine exerts its effects in the CNS by releasing biogenic amines from their storage sites in nerve terminals. The neuronal dopamine transporter (DAT) and the vesicular monoamine transporter 2 (VMAT2) appear to be 2 of the principal targets of amphetamine’s action. The alerting effect of amphetamine, its anorectic effect, and at least a component of its locomotor-stimulating action presumably are mediated by release of NE from central noradrenergic neurons. Some aspects of locomotor activity and the stereotyped behavior induced by amphetamine probably are a consequence of the release of DA from dopaminergic nerve terminals, particularly in the neostriatum. Higher doses are required to produce the behavioral effects. With still higher doses of amphetamine, disturbances of perception and overt psychotic behavior occur, possibly due to release of 5HT from serotonergic neurons and of DA in the mesolimbic system.

TOXICITY AND ADVERSE EFFECTS. The acute toxic effects of amphetamine usually are extensions of its therapeutic actions, and as a rule result from overdosage. CNS effects commonly include restlessness, dizziness, tremor, hyperactive reflexes, talkativeness, tenseness, irritability, weakness, insomnia, fever, and sometimes euphoria. Confusion, aggressiveness, changes in libido, anxiety, delirium, paranoid hallucinations, panic states, and suicidal or homicidal tendencies occur, especially in mentally ill patients. However, these psychotic effects can be elicited in any individual if sufficient quantities of amphetamine are ingested for a prolonged period. Fatigue and depression usually follow central stimulation. Cardiovascular effects are common and include headache, chilliness, pallor or flushing, palpitation, cardiac arrhythmias, anginal pain, hypertension or hypotension, and circulatory collapse. Excessive sweating occurs. GI symptoms include dry mouth, metallic taste, anorexia, nausea, vomiting, diarrhea, and abdominal cramps. Fatal poisoning usually terminates in convulsions and coma, and cerebral hemorrhages are the main pathological findings.

The toxic dose of amphetamine varies widely; occasionally occurring after as little as 2 mg, but rare with <15 mg. Severe reactions have occurred with 30 mg, yet doses of 400-500 mg are not uniformly fatal. Larger doses can be tolerated after chronic use of the drug. Treatment of acute amphetamine intoxication may include acidification of the urine by administration of ammonium chloride to enhance the rate of elimination. Sedatives may be required for the CNS symptoms. Severe hypertension may require administration of sodium nitroprusside or an α adrenergic receptor antagonist. Chronic intoxication with amphetamine causes symptoms similar to those of acute overdosage. Weight loss may be marked. A psychotic reaction with vivid hallucinations and paranoid delusions, often mistaken for schizophrenia, is the most common serious effect. Recovery is rapid after withdrawal of the drug, but occasionally the condition becomes chronic, with amphetamine hastening the onset of incipient schizophrenia. Amphetamines are schedule II drugs and should be used only under medical supervision. Amphetamine use is inadvisable in patients with anorexia, insomnia, asthenia, psychopathic personality, or a history of homicidal or suicidal tendencies.

DEPENDENCE AND TOLERANCE. Psychological dependence often occurs when amphetamine or dextroamphetamine is used chronically, as discussed in Chapter 24. Tolerance almost invariably develops to the anorexigenic effect of amphetamines, and often is seen also in the need for increasing doses to maintain improvement of mood in psychiatric patients. Development of tolerance is not invariable, and cases of narcolepsy have been treated for years without requiring an increase in the initially effective dose.

THERAPEUTIC USES. Amphetamine is used chiefly for its CNS effects. Dextroamphetamine is FDA-approved for the treatment of narcolepsy and ADHD (see below).

METHAMPHETAMINE

Methamphetamine (DESOXYN; see Table 12–1) acts centrally to release DA and other biogenic amines, and to inhibit neuronal and vesicular monoamine transporters as well as MAO. Small doses have prominent central stimulant effects without significant peripheral actions; somewhat larger doses produce a sustained rise in systolic and diastolic blood pressures, due mainly to cardiac stimulation. Methamphetamine is a schedule II drug and has high potential for abuse (see Chapter 24).

METHYLPHENIDATE

Methylphenidate is structurally related to amphetamine.

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Methylphenidate (RITALIN, others) is a mild CNS stimulant with more prominent effects on mental than on motor activities. However, large doses produce signs of generalized CNS stimulation that may lead to convulsions. In pharmacological properties, it resembles amphetamines. Methylphenidate also shares the abuse potential of the amphetamines and is listed as a schedule II controlled substance in the U.S. Methylphenidate is effective in the treatment of narcolepsy and ADHD. The use of methylphenidate is contraindicated in patients with glaucoma.

DEXMETHYLPHENIDATE. Dexmethylphenidate (FOCALIN) is the d-threo enantiomer of racemic methylphenidate. It is FDA-approved as a schedule II drug for the treatment of ADHD.

PEMOLINE. Pemoline (CYLERT, others) is structurally dissimilar to methylphenidate but elicits similar changes in CNS function with minimal effects on the cardiovascular system. It is employed in treating ADHD. It can be given once daily because of its long t1/2. Clinical improvement may require treatment for 3-4 weeks. Use of pemoline has been associated with severe hepatic failure and was discontinued in the U.S. in 2006.

EPHEDRINE

Ephedrine is an agonist at both α and β receptors; in addition, it enhances release of NE from sympathetic neurons and thus is a mixed-acting sympathomimetic (see Table 12–1 andFigure 12–1).

Only l-ephedrine and racemic ephedrine are used clinically. Ephedrine is effective after oral administration. The drug stimulates heart rate and cardiac output and variably increases peripheral resistance; as a result, ephedrine usually increases blood pressure. Activation of β receptors in the lungs promotes bronchodilation. Ephedrine is a potent CNS stimulant. After oral administration, the effects of the drug persist for several hours.

THERAPEUTIC USES AND TOXICITY. The use of ephedrine as a bronchodilator in patients with asthma has become less extensive with the development of β2-selective agonists. Ephedrine has been used to promote urinary continence. Ephedrine also has been used to treat the hypotension that may occur with spinal anesthesia.

Untoward effects of ephedrine include hypertension and insomnia. Concerns have been raised about the safety of ephedrine. Large amounts of herbal preparations containing ephedrine (ma huang, ephedra) are used around the world. The considerable variability in the content of ephedrine in these preparations is a cause for concern and can lead to inadvertent consumption of dangerous doses of ephedrine and its isomers. The Combat Methamphetamine Epidemic Act of 2005 regulates the sale of ephedrine, phenylpropanolamine, and pseudoephedrine, which can be used as precursors in the illicit manufacture of amphetamine and methamphetamine.

OTHER SYMPATHOMIMETIC AGENTS

Several sympathomimetic drugs are used primarily as vasoconstrictors for local application to the nasal mucous membrane or the eye: propylhexedrine (BENZEDREX, others), naphazoline (PRIVINE, NAPHCON, others), oxymetazoline (AFRIN, OCUCLEAR, others), and xylometazoline (OTRIVIN, others). Phenylephrine, pseudoephedrine (SUDAFED, others) (a stereoisomer of ephedrine), and phenylpropanolamine have been used most commonly in oral preparations for the relief of nasal congestion. Phenylpropanolamine shares the pharmacological properties of ephedrine and is approximately equal in potency except that it causes less CNS stimulation. Because phenylpropanolamine may increase the risk of hemorrhagic stroke, the drug is no longer licensed for marketing in the U.S.

THERAPEUTIC USES OF SYMPATHOMIMETIC DRUGS

SHOCK. Shock is an immediately life-threatening impairment of delivery of oxygen and nutrients to the organs of the body. Causes of shock include hypovolemia (due to dehydration or blood loss), cardiac failure (extensive myocardial infarction, severe arrhythmia), obstruction to cardiac output, and peripheral circulatory dysfunction (sepsis or anaphylaxis). The treatment of shock consists of reversing the underlying pathogenesis as well as nonspecific measures aimed at correcting hemodynamic abnormalities. The accompanying fall in blood pressure generally leads to marked activation of the sympathetic nervous system. This, in turn, causes peripheral vasoconstriction and an increase in the rate and force of cardiac contraction. In the initial stages of shock these mechanisms may maintain blood pressure and cerebral blood flow, although blood flow to the kidneys, skin, and other organs may be decreased, leading to impaired production of urine and metabolic acidosis.

The initial therapy of shock involves basic life-support measures. It is essential to maintain blood volume, which often requires monitoring of hemodynamic parameters. Specific therapy (e.g., antibiotics for patients in septic shock) should be initiated immediately. If these measures do not lead to an adequate therapeutic response, it may be necessary to use vasoactive drugs. Many of these pharmacological approaches, while apparently clinically reasonable, are of uncertain efficacy. Adrenergic receptor agonists may be used in an attempt to increase myocardial contractility or to modify peripheral vascular resistance. In general terms, β receptor agonists increase heart rate and force of contraction, α receptor agonists increase peripheral vascular resistance, and DA promotes dilation of renal and splanchnic vascular beds, in addition to activating β and α receptors.

Cardiogenic shock due to myocardial infarction has a poor prognosis; therapy is aimed at improving peripheral blood flow. Medical intervention is designed to optimize cardiac filling pressure (preload), myocardial contractility, and peripheral resistance (afterload). Preload may be increased by administration of intravenous fluids or reduced with drugs such as diuretics and nitrates. A number of sympathomimetic amines have been used to increase the force of contraction of the heart. Some of these drugs have disadvantages: isoproterenol is a powerful chronotropic agent and can greatly increase myocardial O2 demand; NE intensifies peripheral vasoconstriction; and EPI increases heart rate and may predispose the heart to dangerous arrhythmias. DA is an effective inotropic agent that causes less increase in heart rate than does isoproterenol. DA also promotes renal arterial dilation; this may be useful in preserving renal function. When given in high doses (>10-20 μg/kg/min), DA activates α receptors, causing peripheral and renal vasoconstriction. Dobutamine has complex pharmacological actions that are mediated by its stereoisomers; the clinical effects of the drug are to increase myocardial contractility with little increase in heart rate or peripheral resistance.

In some patients, hypotension is so severe that vasoconstricting drugs are required to maintain a blood pressure that is adequate for CNS perfusion. α Agonists have been used for this purpose. This approach may be advantageous in patients with hypotension due to failure of the sympathetic nervous system (e.g., after spinal anesthesia or injury). However, in patients with other forms of shock, such as cardiogenic shock, reflex vasoconstriction generally is intense, and α receptor agonists may further compromise blood flow to organs such as the kidneys and gut and adversely increase the work of the heart. Vasodilating drugs such as nitroprusside are more likely to improve blood flow and decrease cardiac work in such patients by decreasing afterload if a minimally adequate blood pressure can be maintained.

The hemodynamic abnormalities in septic shock are complex and poorly understood. Most patients with septic shock initially have low or barely normal peripheral vascular resistance, possibly owing to excessive effects of endogenously produced NO as well as normal or increased cardiac output. If the syndrome progresses, myocardial depression, increased peripheral resistance, and impaired tissue oxygenation occur. The primary treatment of septic shock is antibiotics. Therapy with drugs such as DA or dobutamine is guided by hemodynamic monitoring.

HYPOTENSION. Drugs with predominantly α agonist activity can be used to raise blood pressure in patients with decreased peripheral resistance in conditions such as spinal anesthesia or intoxication with antihypertensive medications. However, hypotension per se is not an indication for treatment with these agents unless there is inadequate perfusion of organs such as the brain, heart, or kidneys. Furthermore, adequate replacement of fluid or blood may be more appropriate than drug therapy for many patients with hypotension.

Patients with orthostatic hypotension often represent a pharmacological challenge. Therapeutic approaches include physical maneuvers and a variety of drugs (fludrocortisone, prostaglandin synthesis inhibitors, somatostatin analogs, caffeine, vasopressin analogs, DA antagonists, and some sympathomimetic drugs). The ideal agent would enhance venous constriction prominently and produce relatively little arterial constriction so as to avoid supine hypertension. No such agent currently is available. Drugs used include α1 agonists and indirect-acting agents. Midodrine shows promise in treating this disorder.

HYPERTENSION. Centrally acting α2 agonists such as clonidine are useful in the treatment of hypertension. Drug therapy of hypertension is discussed in Chapter 27.

ALLERGIC REACTIONS. EPI is the drug of choice to reverse the manifestations of serious acute hypersensitivity reactions (e.g., from food, bee sting, or drug allergy).

A subcutaneous injection of EPI rapidly relieves itching, hives, and swelling of lips, eyelids, and tongue. In some patients, careful intravenous infusion of EPI may be required to ensure prompt pharmacological effects. In addition to its cardiovascular effects, EPI is thought to activate β receptors that suppress the release from mast cells of mediators such as histamine and leukotrienes. EPI auto-injectors (EPIPEN, others) are employed widely for the emergency self-treatment of anaphylaxis.

CARDIAC ARRHYTHMIAS. Cardiopulmonary resuscitation in patients with cardiac arrest due to ventricular fibrillation, electromechanical dissociation, or asystole may be facilitated by drug treatment. EPI is an important therapeutic agent in patients with cardiac arrest. α Agonists also help to preserve cerebral blood flow during resuscitation. Consequently, during external cardiac massage, EPI facilitates distribution of the limited cardiac output to the cerebral and coronary circulations. The optimal dose of EPI in patients with cardiac arrest is unclear. Once a cardiac rhythm has been restored, it may be necessary to treat arrhythmias, hypotension, or shock.

LOCAL VASCULAR EFFECTS. EPI is used in many surgical procedures in the nose, throat, and larynx to shrink the mucosa and improve visualization by limiting hemorrhage. Simultaneous injection of EPI with local anesthetics retards the absorption and increases the duration of anesthesia (see Chapter 20). Injection of α agonists into the penis may be useful in reversing priapism, a complication of the use of α receptor antagonists or PDE5 inhibitors (e.g., sildenafil) in the treatment of erectile dysfunction. Both phenylephrine and oxymetazoline are efficacious vasoconstrictors when applied locally during sinus surgery.

NASAL DECONGESTION. α Receptor agonists are used extensively as nasal decongestants. Agonists may be administered either orally or topically. Sympathomimetic decongestants should be used with great caution in patients with hypertension and in men with prostatic enlargement, and they are contraindicated in patients who are taking MAO inhibitors. Oral decongestants are much less likely to cause rebound congestion but carry a greater risk of inducing adverse systemic effects. Patients with uncontrolled hypertension or ischemic heart disease generally should avoid the oral consumption of OTC products or herbal preparations containing sympathomimetic drugs.

ASTHMA. Use of β adrenergic agonists in the treatment of asthma and COPD is discussed in Chapter 36.

OPHTHALMIC USES. Ophthalmic use is discussed in Chapter 64.

NARCOLEPSY AND RELATED SYNDROMES. Narcolepsy is characterized by hypersomnia. Some patients respond to treatment with tricyclic antidepressants or MAO inhibitors. Alternatively, CNS stimulants such as amphetamine, dextroamphetamine, or methamphetamine may be useful. Therapy with amphetamines is complicated by the risk of abuse and the likelihood of the development of tolerance and behavioral changes. Modafinil (PROVIGIL), a CNS stimulant, may have benefit in narcolepsy. In the U.S., it is a schedule IV controlled substance. Its mechanism of action in narcolepsy is unclear. Armodafinil (NUVIGIL), the R-enantiomer of modafinil (a mixture of R- and S-enantiomers) is also indicated for narcolepsy.

WEIGHT REDUCTION. Amphetamine promotes weight loss by suppressing appetite rather than by increasing energy expenditure. Other anorexic drugs include methamphetamine, dextroamphetamine, phentermine, benzphetamine, phendimetrazine, phenmetrazine, diethylpropion, mazindol, phenylpropanolamine, and sibutramine (a mixed adrenergic/serotonergic drug). Phenmetrazine, mazindol, and phenylpropanolamine have been discontinued in the U.S. Available evidence does not support the isolated use of these drugs in the absence of a more comprehensive program that stresses exercise and modification of diet.

ATTENTION DEFICIT HYPERACTIVITY DISORDER. This syndrome, usually first evident in childhood, is characterized by excessive motor activity, difficulty in sustaining attention, and impulsiveness. A variety of stimulant drugs have been used in the treatment of ADHD, and they are particularly indicated in moderate-to-severe cases. Methylphenidate is effective in children with ADHD and is the most common intervention. Treatment may start with a dose of 5 mg of methylphenidate in the morning and at lunch; the dose is increased gradually over a period of weeks depending on the response as judged by parents, teachers, and the clinician. The total daily dose generally should not exceed 60 mg; because of its short duration of action, most children require 2 or 3 doses of methylphenidate each day. Sustained-release preparations of dextroamphetamine, methylphenidate (RITALIN SR, CONCERTA, METADATE), methylphenidate hydrochlorideisk (QUILLIVANT XR)dexmethylphenidate (FOCALIN XR), and amphetamine (ADDERALL XR) may be used once daily in children and adults. Lisdexamfetamine (VYVANSE) can be administered once daily and a transdermal formulation of methylphenidate (DAYTRANA) is marketed for daytime use. Potential adverse effects of these medications include insomnia, abdominal pain, anorexia, and weight loss that may be associated with suppression of growth in children. A sustained release formulation of guanfacine (INTUNIV), an α2A receptor agonist, has been approved for use in children (ages 6-17 years) in treating ADHD.

Adrenergic Receptor Antagonists

Adrenergic receptor antagonists inhibit the interaction of NE, EPI, and other sympathomimetic drugs with α and β receptors (Figure 12–3). Additional background material is presented in Chapter 8. Agents that block DA receptors are considered in Chapter 13.

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Figure 12–3 Classification of adrenergic receptor antagonists. Drugs marked by an asterisk (*) also block α1 receptors.

α ADRENERGIC RECEPTOR ANTAGONISTS

The α1 receptors mediate contraction of arterial, venous, and visceral smooth muscle, while the α2 receptors are involved in suppressing sympathetic output, increasing vagal tone, facilitating platelet aggregation, inhibiting NE and ACh release from nerve endings, and regulating metabolic effects (e.g., suppression of insulin secretion and inhibition of lipolysis). The α2 receptors also mediate contraction of some arteries and veins.

Some of the most important effects of α receptor antagonists observed clinically are on the cardiovascular system. α Receptor antagonists have a wide spectrum of pharmacological specificities and are chemically heterogeneous. Some of these drugs have markedly different affinities for α1 and α2 receptors. More recently, agents that discriminate among the various subtypes of a particular receptor have become available; e.g., tamsulosin has higher potency at α1A than at α1B receptors.

α1 RECEPTOR ANTAGONISTS

GENERAL PHARMACOLOGICAL PROPERTIES. Blockade of α1 receptors inhibits vasoconstriction induced by endogenous catecholamines; vasodilation may occur in both arteriolar resistance vessels and veins. The result is a fall in blood pressure due to decreased peripheral resistance. The magnitude of such effects depends on the activity of the sympathetic nervous system at the time the antagonist is administered, and thus is less in supine than in upright subjects. For most α receptor antagonists, the fall in blood pressure is opposed by baroreceptor reflexes that cause increases in heart rate and cardiac output, as well as fluid retention (effects largely inhibited by β antagonists). These reflexes are exaggerated if the antagonist also blocks α2 receptors on peripheral sympathetic nerve endings, leading to enhanced release of NE and increased stimulation of postsynaptic β1receptors in the heart and on juxtaglomerular cells (see Chapter 8). Blockade of α1 receptors can alleviate some of the symptoms of benign prostatic hyperplasia (BPH). The prostate and lower urinary tract tissues exhibit a high proportion of α1A receptors.

AVAILABLE AGENTS

PRAZOSIN AND RELATED DRUGS. Due in part to its greater α1 receptor selectivity, this class of α receptor antagonists exhibits greater clinical utility and has largely replaced the nonselective haloalkylamine (e.g., phenoxybenzamine) and imidazoline (e.g., phentolamine) α receptor antagonists. Prazosin is the prototypical α1-selective antagonist.

The affinity of prazosin for α1 adrenergic receptors is ~1000-fold greater than that for α2 adrenergic receptors. Prazosin has similar potencies at α1A, α1B, and α1D subtypes. Prazosin, doxazosin, and tamsulosin, frequently are used for the treatment of hypertension (see Chapter 27).

PHARMACOLOGICAL PROPERTIES

The major effects of prazosin result from its blockade of α1 receptors in arterioles and veins. This leads to a fall in peripheral vascular resistance and in venous return to the heart. Unlike the case with many vasodilating drugs, administration of prazosin usually does not increase heart rate. Prazosin decreases cardiac preload and has little effect on cardiac output and rate. Prazosin also may act in the CNS to suppress sympathetic outflow. Prazosin and related drugs decrease low-density lipoproteins (LDLs) and triglycerides and increase the concentrations of high-density lipoproteins (HDLs).

Prazosin (MINIPRESS, others) is well absorbed after oral administration, and bioavailability is ~50-70%. Peak concentrations in plasma generally are reached 1-3 h after an oral dose. The drug is tightly bound to plasma proteins and only 5% of the drug is free in the circulation; diseases that modify the concentration of this protein (e.g., inflammatory processes) may change the free fraction. Prazosin is extensively metabolized in the liver, and little unchanged drug is excreted by the kidneys. The plasma t1/2 is ~3 h. The initial dose should be 1 mg, usually given at bedtime. The dose is titrated upward depending on the blood pressure. In the off-label treatment of BPH, doses from 1-5 mg twice daily typically are used.

TERAZOSIN. Terazosin (HYTRIN, others) is a structural analog of prazosin. It is less potent than prazosin but retains high specificity for α1 receptors; terazosin does not discriminate among α1A, α1B, and α1D receptors. Terazosin is more soluble in water than is prazosin, and its bioavailability is high (>90%). The t1/2 is ~12 h, and its duration of action is >18 h. Terazosin and doxazosin induce apoptosis in prostate smooth muscle cells. This apoptosis may lessen the symptoms associated with chronic BPH. The apoptotic effect of terazosin and doxazosin appears to be related to the quinazoline moiety rather than α1 receptor antagonism. An initial first dose of 1 mg is recommended, that is titrated upward depending on the therapeutic response. Doses of 10 mg/day may be required for maximal effect in BPH.

DOXAZOSIN. Doxazosin (CARDURA, others) is a structural analog of prazosin and a highly selective antagonist at α1 receptors. It is nonselective among α1 receptor subtypes. The t1/2 of doxazosin is ~20 h, and its duration of action may extend to 36 h. Bioavailability and extent of metabolism of doxazosin and prazosin are similar. Doxazosin is given initially as a 1-mg dose in the treatment of hypertension or BPH. Doxazosin also may have beneficial actions in the long-term management of BPH related to apoptosis.

ALFUZOSIN. Alfuzosin (UROXATRAL) is α1 receptor antagonist with similar affinity at all of the α1 receptor subtypes. It is used in treating BPH but not for treatment of hypertension. Its bioavailability is ~64%; it has a t1/2 of 3-5 h. Alfuzosin is a substrate of CYP3A4. The recommended dosage is one 10-mg extended-release tablet daily to be taken after the same meal each day.

TAMSULOSIN. Tamsulosin (FLOMAX), is an α1 receptor antagonist with some selectivity for α1A (and α1D) subtypes compared to the α1B subtype. This selectivity may favor blockade of α1A receptors in prostate. Tamsulosin is efficacious in the treatment of BPH with little effect on blood pressure. Tamsulosin is well absorbed, is extensively metabolized by CYPs, and has a t1/2 of 5-10 h. Tamsulosin may be administered at a 0.4-mg starting dose. Abnormal ejaculation is an adverse effect of tamsulosin.

SILODOSIN. Silodosin (RAPAFLO) exhibits selectivity for the α1A over the α1B receptor. The drug is metabolized by UGT2B7; coadministration with inhibitors of this enzyme (e.g., probenecid, valproic acid, fluconazole) increases systemic exposure to silodosin. The drug is approved for the treatment of BPH. The chief side effect of silodosin is retrograde ejaculation (in 28% of those treated). Silodosin is available as 4-mg and 8-mg capsules.

ADVERSE EFFECTS

An adverse effect of prazosin and its congeners is the first-dose effect; marked postural hypotension and syncope sometimes are seen 30-90 min after the initial dose of prazosin. The risk of the first-dose phenomenon is minimized by limiting the initial dose (e.g., 1 mg at bedtime), by increasing the dosage slowly, and by introducing additional antihypertensive drugs cautiously. Nonspecific adverse effects such as headache, dizziness, and asthenia rarely limit treatment with prazosin.

THERAPEUTIC USES

Hypertension. Prazosin and its congeners have been used successfully in the treatment of essential hypertension (see Chapter 27).

Congestive Heart Failure. α Receptor antagonists have been used in the treatment of congestive heart failure, but are not the drugs of choice.

Benign Prostatic Hyperplasia. BPH produces symptomatic urethral obstruction that leads to weak stream, urinary frequency, and nocturia. α1 Receptors in the trigone muscle of the bladder and urethra contribute to the resistance to outflow of urine; prazosin reduces this. Finasteride (PROPECIA, PROSCAR, others) and dutasteride (AVODART), 2 drugs that inhibit conversion of testosterone to dihydrotestosterone (see Chapter 41) and can reduce prostate volume in some patients, are approved as monotherapy and in combination with α receptor antagonists. α1-Selective antagonists have efficacy in BPH owing to relaxation of smooth muscle in the bladder neck, prostate capsule, and prostatic urethra. Combination therapy with doxazosin and finasteride reduces the risk of overall clinical progression of BPH significantly more than treatment with either drug alone. Tamsulosin at the recommended dose of 0.4 mg daily and silodosin at 0.8 mg are less likely to cause orthostatic hypotension than are the other drugs. The predominant α1 subtype expressed in the human prostate is the α1A receptor.

Other Disorders. Some studies indicate that prazosin can decrease the incidence of digital vasospasm in patients with Raynaud’s disease; however, its relative efficacy as compared with Ca2+ channel blockers is not known. Prazosin may have some benefit in patients with other vasospastic disorders. Prazosin may be useful for the treatment of patients with mitral or aortic valvular insufficiency, presumably by reducing afterload.

α2 ADRENERGIC RECEPTOR ANTAGONISTS

Activation of presynaptic α2 receptors inhibits the release of NE and other cotransmitters from peripheral sympathetic nerve endings. Activation of α2 receptors in the CNS inhibits sympathetic nervous system activity and leads to a fall in blood pressure. Blockade of α2 receptors with selective antagonists such as yohimbine thus can increase sympathetic outflow and potentiate the release of NE from nerve endings. Antagonists that also block α1 receptors give rise to similar effects on sympathetic outflow and release of NE, but the net increase in blood pressure is prevented by inhibition of vasoconstriction.

Although certain vascular beds contain α2 receptors that promote contraction of smooth muscle, these receptors are preferentially stimulated by circulating catecholamines, whereas α1 receptors are activated by NE released from sympathetic nerve fibers. The physiological role of vascular α2 receptors in the regulation of blood flow within various vascular beds is uncertain. The α2 receptors contribute to smooth muscle contraction in the human saphenous vein, whereas α1 receptors are more prominent in dorsal hand veins. The effects of α2receptor antagonists on the cardiovascular system are dominated by actions in the CNS and on sympathetic nerve endings.

YOHIMBINE. Yohimbine (YOCON, APHRODYNE) is a competitive antagonist that is selective for α2 receptors. Yohimbine enters the CNS, where it acts to increase blood pressure and heart rate; it also enhances motor activity and produces tremors. Yohimbine also antagonizes effects of 5HT.

In the past, it was used to treat male sexual dysfunction. Some studies suggest that yohimbine also may be useful for diabetic neuropathy and postural hypotension. In the U.S., yohimbine may be sold as a dietary supplement; however, labeling claims that it will increase sexual desire or performance are prohibited.

NONSELECTIVE α ADRENERGIC ANTAGONISTS: PHENOXYBENZAMINE AND PHENTOLAMINE

Phenoxybenzamine and phentolamine are nonselective α receptors antagonists. Phenoxybenzamine produces an irreversible antagonism; phentolamine produces a competitive antagonism.

Phenoxybenzamine and phentolamine cause a progressive decrease in peripheral resistance, an increase in cardiac output (due in part to reflex sympathetic nerve stimulation), and enhanced release of NE from cardiac sympathetic nerve due to antagonism of presynaptic α2 receptors. Postural hypotension, a prominent feature accompanied by reflex tachycardia that can precipitate cardiac arrhythmias, severely limits the use of these drugs to treat essential hypertension. The α1-selective antagonists have replaced the classical α-blockers in the management of essential hypertension. Phenoxybenzamine and phentolamine are still marketed for several specialized uses.

Therapeutic Uses. A use of phenoxybenzamine (DIBENZYLINE) is in the treatment of pheochromocytoma, which are tumors of the adrenal medulla and sympathetic neurons that secrete enormous quantities of catecholamines. Phenoxybenzamine is often used in preparing the patient for surgical removal of the tumor. A conservative approach is to initiate treatment with phenoxybenzamine (at a dosage of 10 mg twice daily) 1-3 weeks before the operation. The dose is increased every other day until the desired effect on blood pressure is achieved. Prolonged treatment with phenoxybenzamine may be necessary in patients with inoperable or malignant pheochromocytoma. In some patients, particularly those with malignant disease, administration of metyrosine, a competitive inhibitor of tyrosine hydroxylase, may be a useful adjuvant (see Chapter 8). β Receptor antagonists also are used but only after the administration of an α receptor antagonist.

Phentolamine can also be used in short-term control of hypertension in patients with pheochromocytoma. Phentolamine has been used locally to prevent dermal necrosis after the inadvertent extravasation of an α receptor agonist.

Toxicity and Adverse Effects. Hypotension is the major adverse effect of phenoxybenzamine and phentolamine. In addition, reflex cardiac stimulation may cause alarming tachycardia, cardiac arrhythmias, and ischemic cardiac events, including myocardial infarction. Reversible inhibition of ejaculation may occur due to impaired smooth muscle contraction in the vas deferens and ejaculatory ducts. Phenoxybenzamine is mutagenic in the Ames test.

ADDITIONAL α ADRENERGIC RECEPTOR ANTAGONISTS

Ergot Alkaloids. The ergot alkaloids were the first adrenergic receptor antagonists to be discovered. Information about the ergot alkaloids can be found in Chapter 13.

INDORAMIN. Indoramin is a selective, competitive α1 receptor antagonist that also antagonizes H1- and 5HT receptors. As an α1-selective antagonist, indoramin lowers blood pressure with minimal tachycardia. The drug also decreases the incidence of attacks of Raynaud phenomenon. Some of the adverse effects of indoramin include sedation, dry mouth, and failure of ejaculation. Indoramin is not available in the U.S.

KETANSERIN. Ketanserin, a 5HT/α1 receptor antagonist not available in the U.S., is discussed in Chapter 13.

URAPIDIL. Urapidil is a selective α1 receptor antagonist that is not commercially available in the U.S. Blockade of peripheral α1 receptors appears to be primarily responsible for the hypotension produced by urapidil, although it has actions in the CNS as well.

BUNAZOSIN. Bunazosin is an α1-selective antagonist of the quinazoline class that can lower blood pressure in patients with hypertension; this agent is not available in the U.S.

NEUROLEPTIC AGENTS. Chlorpromazine, haloperidol, and other neuroleptic drugs of the phenothiazine and butyrophenone types produce significant blockade of both α and D2 receptors.

β ADRENERGIC RECEPTOR ANTAGONISTS

β Antagonists can be distinguished by the following properties:

• Relative affinity for β1 and β2 receptors

• Intrinsic sympathomimetic activity

• Blockade of α receptors

• Differences in lipid solubility

• Capacity to induce vasodilation

• Pharmacokinetic parameters

β Adrenergic receptor antagonists are classified as non–subtype-selective (first generation), β1-selective (second generation), and non–subtype or subtype-selective with additional cardiovascular actions (third generation). These latter drugs have additional cardiovascular properties (especially vasodilation) that seem unrelated to β blockade. Table 12–3summarizes important pharmacological and pharmacokinetic properties of β receptor antagonists.

Table 12–3

Pharmacological/Pharmacokinetic Properties of β Adrenergic Receptor Blocking Agents

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Several β receptor antagonists also have local anesthetic or membrane-stabilizing activity that is independent of β-blockade. Such drugs include propranolol, acebutolol, and carvedilol. Pindolol, metoprolol, betaxolol, and labetalol have slight membrane-stabilizing effects.

CARDIOVASCULAR SYSTEM. The major therapeutic effects of β receptor antagonists are on the cardiovascular system. It is important to distinguish the effects in normal subjects from those in subjects with cardiovascular disease such as hypertension or myocardial ischemia.

Because catecholamines have positive chronotropic and inotropic actions, β receptor antagonists slow the heart rate and decrease myocardial contractility. When tonic stimulation of β receptors is low, this effect is correspondingly modest. However, when the sympathetic nervous system is activated, as during exercise or stress, β receptor antagonists attenuate the expected rise in heart rate. Short-term administration of β receptor antagonists such as propranolol decreases cardiac output; peripheral resistance increases in proportion to maintain blood pressure as a result of blockade of vascular β2 receptors and compensatory reflexes, such as increased sympathetic nervous system activity, leading to activation of vascular α receptors. With long-term use of β antagonists, total peripheral resistance returns to initial values or decreases in patients with hypertension. With β antagonists that also are α1receptor antagonists (e.g., labetalol, carvedilol, and bucindolol), cardiac output is maintained with a greater fall in peripheral resistance.

β Receptor antagonists have significant effects on cardiac rhythm and automaticity, which involves blockade of both β1 receptors and β2 receptors. β Receptor antagonists reduce sinus rate, decrease the spontaneous rate of depolarization of ectopic pacemakers, slow conduction in the atria and in the AV node, and increase the functional refractory period of the AV node.

ACTIVITY AS ANTIHYPERTENSIVE AGENTS. β Receptor antagonists generally do not reduce blood pressure in patients with normal blood pressure. However, these drugs lower blood pressure in patients with hypertension. Reduction of β1-stimulated renin release from the juxtaglomerular cells is a putative contributing mechanism (see Chapter 26). Because presynaptic β receptors enhance the release of NE from sympathetic neurons, diminished release of NE from β blockade is a possible response. Long-term administration of β-blockers to hypertensive patients ultimately leads to a fall in peripheral vascular resistance.

Some β antagonists have additional effects that may contribute to their capacity to lower blood pressure. These drugs all produce peripheral vasodilation; properties that have been proposed to contribute to this effect include production of NO, activation of β2 receptors, blockade of α1 receptors, blockade of Ca2+ entry, opening of K+ channels, and antioxidant activity (Table 12–4 and Figure 12–4). These mechanisms appear to contribute to the antihypertensive effects by enhancing hypotension, increasing peripheral blood flow, and decreasing afterload. Celiprolol and nebivolol also have been observed to produce vasodilation and thereby reduce preload.

Table 12–4

Third-Generation β Receptor Antagonists with Putative Additional Mechanisms of Vasodilation

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Figure 12–4 Mechanisms underlying actions of vasodilating β blockers in blood vessels. (ROS, reactive oxygen species; sGC, soluble guanylyl cyclase; AC adenylyl cyclase; L-type VGCC, L-type voltage-gated Ca2+ channel.) (Modified with permission from Toda N. Vasodilating β-adrenoreceptor blockers as cardiovascular therapeutics. Pharmacol Ther, 2003;100:215-234. Copyright © Elsevier.)

Propranolol and other nonselective β receptor antagonists inhibit the vasodilation caused by isoproterenol and augment the pressor response to EPI. This is particularly significant in patients with pheochromocytoma, in whom β receptor antagonists should be used only after adequate α receptor blockade has been established.

PULMONARY SYSTEM. Nonselective β receptor antagonists such as propranolol block β2 receptors in bronchial smooth muscle. This usually has little effect on pulmonary function in normal individuals. However, in patients with COPD, such blockade can lead to life-threatening bronchoconstriction. Although β1-selective antagonists or antagonists with intrinsic sympathomimetic activity are less likely than propranolol to increase airway resistance in patients with asthma, these drugs should be used only with great caution, if at all, in patients with bronchospastic diseases.

METABOLIC EFFECTS. Catecholamines promote glycogenolysis and mobilize glucose in response to hypoglycemia. Nonselective β blockers may delay recovery from hypoglycemia in type 1 (insulin-dependent) diabetes mellitus, but infrequently in type 2 diabetes mellitus. β Receptor antagonists can interfere with the counter-regulatory effects of catecholamines secreted during hypoglycemia by blunting the perception of symptoms such as tremor, tachycardia, and nervousness. Use β adrenergic receptor antagonists with great caution in patients with labile diabetes and frequent hypoglycemic reactions; if such a drug is indicated, use a β1-selective antagonist.

β Receptor antagonists can attenuate the release of free fatty acids from adipose tissue. Nonselective β receptor antagonists consistently reduce HDL cholesterol, increase LDL cholesterol, and increase triglycerides. In contrast, β1-selective antagonists, including celiprolol, carteolol, nebivolol, carvedilol, and bevantolol, reportedly improve the serum lipid profile of dyslipidemic patients. Propranolol and atenolol increase triglycerides, whereas chronic celiprolol, carvedilol, and carteolol reduce plasma triglycerides. In contrast to classical β-blockers, which decrease insulin sensitivity, the vasodilating β receptor antagonists (e.g., celiprolol, nipradilol, carteolol, carvedilol, and dilevalol) increase insulin sensitivity in patients with insulin resistance.

Other Effects. β Receptor antagonists block catecholamine-induced tremor. They also block inhibition of mast-cell degranulation by catecholamines.

ADVERSE EFFECTS AND PRECAUTIONS

The most common adverse effects of β receptor antagonists arise as pharmacological consequences of blockade of β receptors. β Receptor blockade may cause or exacerbate heart failure in patients with compensated heart failure, acute myocardial infarction, or cardiomegaly. Nonetheless, there is convincing evidence that chronic administration of β receptor antagonists is efficacious in prolonging life in the therapy of heart failure in selected patients (see Chapter 28). The use of β adrenergic receptor antagonists is contraindicated in patients with asthma, COPD, sinus bradycardia, and cardiogenic shock.

Bradycardia is a normal response to β receptor blockade; however, in patients with partial or complete AV conduction defects, β antagonists may cause life-threatening bradyarrhythmias. Abrupt discontinuation of β receptor antagonists after long-term treatment can exacerbate angina and may increase the risk of sudden death. A major adverse effect of β receptor antagonists is caused by blockade of β2 receptors in bronchial smooth muscle. Because the selectivity of current β blockers for β1 receptors is modest, these drugs should be avoided if at all possible in patients with asthma. As noted above, β blockade may blunt recognition of hypoglycemia by patients.

DRUG INTERACTIONS. Aluminum salts, cholestyramine, and colestipol may decrease the absorption of β-blockers. Drugs such as phenytoin, rifampin, and phenobarbital, as well as smoking, induce hepatic biotransformation enzymes and may decrease plasma concentrations of β receptor antagonists. Cimetidine and hydralazine may increase the bioavailability of propranolol and metoprolol by affecting hepatic blood flow. β Receptor antagonists can impair the clearance of lidocaine. The antihypertensive effects of β receptor antagonists can be opposed by indomethacin and other NSAIDs (seeChapter 34).

THERAPEUTIC USES

CARDIOVASCULAR DISEASES. β Receptor antagonists are used extensively in the treatment of hypertension, angina and acute coronary syndromes, and congestive heart failure (see Chapters 27 and 28). These drugs also are used frequently in the treatment of supraventricular and ventricular arrhythmias (see Chapter 29).

β Receptor antagonists, particularly propranolol, are used in the treatment of hypertrophic obstructive cardiomyopathy. Propranolol is useful for relieving angina, palpitations, and syncope in patients with this disorder. β-blockers also may attenuate catecholamine-induced cardiomyopathy in pheochromocytoma.

GLAUCOMA. β Receptor antagonists are very useful in the treatment of chronic open-angle glaucoma.

Six drugs are currently available: carteolol (OCUPRESS, others), betaxolol (BETOPTIC, others), levobunolol (BETAGAN, others), metipranolol (OPTIPRANOLOL, others), timolol (TIMOPTIC, others), and levobetaxolol (BETAXON). These agents decrease the production of aqueous humor. Glaucoma and therapies are presented in Chapter 64.

OTHER USES. β Receptor antagonists control many of the cardiovascular signs and symptoms of hyperthyroidism and are useful adjuvants to more definitive therapy. In addition, propranolol inhibits the peripheral conversion of thyroxine to triiodothyronine, an effect that may be independent of β receptor blockade (see Chapter 39). Propranolol, timolol, and metoprolol are effective for the prophylaxis of migraine. Tachycardia, muscle tremors, and other evidence of increased sympathetic activity are reduced by β-blockers.

NONSELECTIVE β ADRENERGIC RECEPTOR ANTAGONISTS

PROPRANOLOL

Propranolol interacts with β1 and β2 receptors with equal affinity, lacks intrinsic sympathomimetic activity, and does not block α receptors.

Propranolol is used for the treatment of hypertension and angina. The initial oral dose is 40-80 mg/day, titrated upward until the optimal response is obtained (typically <320 mg/day). Propranolol also is used for supraventricular arrhythmias/tachycardias, ventricular arrhythmias/tachycardias, premature ventricular contractions, digitalis-induced tachyarrhythmias, myocardial infarction, pheochromocytoma, essential tremor, and the prophylaxis of migraine. It also is used for several off-label indications including parkinsonian tremors (sustained-release only), akathisia induced by antipsychotic drugs, variceal bleeding in portal hypertension, and anxiety disorder.

Propranolol is highly lipophilic and is almost completely absorbed after oral administration. The drug is highly metabolized by the liver during its first passage through the portal circulation; on average, only ~25% reaches the systemic circulation. Individual variation in hepatic clearance of propranolol contributes to enormous variability in plasma concentrations (~20-fold) after oral administration. The degree of hepatic extraction of propranolol declines as the dose is increased. The bioavailability of propranolol may be increased by the concomitant ingestion of food. Propranolol readily enters the CNS. Sustained-release formulations of propranolol (INDERAL LA, others) have been developed to maintain therapeutic concentrations of propranolol in plasma throughout a 24-h period.

NADOLOL

Nadolol (CORGARD, others) is a long-acting antagonist with equal affinity for β1 and β2 receptors.

A distinguishing characteristic of nadolol is its relatively long t1/2. It can be used to treat hypertension and angina pectoris. Unlabeled uses have included migraine prophylaxis, parkinsonian tremors, and variceal bleeding in portal hypertension. The t1/2 of the drug in plasma is ~20 h. Nadolol is largely excreted intact in the urine and may accumulate in patients with renal failure.

TIMOLOL

Timolol (BLOCADREN, others) is a potent, nonselective β receptor antagonist used for hypertension, congestive heart failure, acute myocardial infarction, and migraine prophylaxis.

The ocular formulation of timolol (TIMOPTIC, others), used for the treatment of glaucoma, may be extensively absorbed systemically (see Chapter 64); adverse effects can occur in susceptible patients, such as those with asthma or congestive heart failure.

PINDOLOL

Pindolol (VISKEN, others) is a nonselective β receptor antagonist with intrinsic sympathomimetic activity.

Pindolol has low membrane-stabilizing activity and low lipid solubility. It is a weak partial β agonist; such drugs may be preferred as antihypertensive agents in individuals with diminished cardiac reserve or a propensity for bradycardia. It is used to treat angina pectoris and hypertension.

β1-SELECTIVE ADRENERGIC RECEPTOR ANTAGONISTS

METOPROLOL

Metoprolol (LOPRESSOR, others) is a β1-selective receptor antagonist.

It is highly absorbed after oral administration, but bioavailability is relatively low (~40%) because of first-pass metabolism. Plasma concentrations of the drug vary widely (up to 17-fold) possibly due to genetically determined differences in the rate of metabolism in the liver by CYP2D6. The t1/2 of metoprolol is 3-4 h, but can double in CYP2D6 poor metabolizers who have a 5X higher risk for developing adverse effects. An extended-release formulation (TOPROL XL) is available for once-daily administration.

For the treatment of hypertension, the usual initial dose is 100 mg/day. The drug sometimes is effective when given once daily, although it frequently is used in 2 divided doses. Dosage may be increased at weekly intervals until optimal reduction of blood pressure is achieved. Metoprolol generally is used in 2 divided doses for the treatment of stable angina. For the initial treatment of patients with acute myocardial infarction, an intravenous formulation of metoprolol tartrate is available. Metoprolol generally is contraindicated for the treatment of acute myocardial infarction in patients with heart rates of <45 beats/min, heart block greater than first-degree (PR interval ≥0.24 second), systolic blood pressure <100 mm Hg, or moderate to severe heart failure. Metoprolol also has been proven to be effective in chronic heart failure.

ATENOLOL

Atenolol (TENORMIN, others) is a β1-selective antagonist.

Atenolol is incompletely absorbed (~50%) and is excreted largely unchanged in the urine with elimination t1/2 5-8 h. The drug accumulates in patients with renal failure, and dosage should be adjusted for patients whose creatinine clearance is <35 mL/min. The initial dose of atenolol for the treatment of hypertension usually is 50 mg/day, given once daily, and may be increased to 100 mg. Atenolol has been shown to be efficacious, in combination with a diuretic, in elderly patients with isolated systolic hypertension.

ESMOLOL

Esmolol (BREVIBLOC, others) is a β1-selective antagonist with a rapid onset and a very short duration of action.

Esmolol is used when β-blockade of short duration is desired or in critically ill patients in whom adverse effects of bradycardia, heart failure, or hypotension may necessitate rapid withdrawal of the drug. Esmolol is given by slow IV injection. The drug is hydrolyzed rapidly by esterases in erythrocytes and has a t1/2 of ~8 min. Peak hemodynamic effects occur within 6-10 min of administration of a loading dose, and there is substantial attenuation of β blockade within 20 min of stopping an infusion. Because esmolol is used in urgent settings where immediate onset of β blockade is warranted, a partial loading dose typically is administered, followed by a continuous infusion of the drug. If an adequate therapeutic effect is not observed within 5 min, the same loading dose is repeated, followed by a maintenance infusion at a higher rate. This process may need to be repeated to approach desired end point (e.g., lowered heart rate or blood pressure).

ACEBUTOLOL. Acebutolol (SECTRAL, others) is a β1-selective antagonist with some intrinsic sympathomimetic and membrane-stabilizing activity. Acebutolol is well absorbed, and undergoes significant first-pass metabolism to an active metabolite, diacetolol, which accounts for most of the drug’s activity. Acebutolol has been used to treat hypertension, cardiac arrhythmias, and acute myocardial infarction. The initial dose in hypertension is 400 mg/day; given as a single or 2 divided doses. Optimal responses usually occur with doses of 400-800 mg per day (range, 200-1200 mg).

BISOPROLOL. Bisoprolol (ZEBETA) is a highly selective β1 receptor antagonist that is approved for the treatment of hypertension. Bisoprolol can be considered a standard treatment option when selecting a β-blocker for use in combination with ACE inhibitors and diuretics in patients with chronic heart failure and in treating hypertension. Bisoprolol generally is well tolerated; side effects include dizziness, bradycardia, hypotension, and fatigue. It is eliminated by renal excretion (50%) and liver metabolism (50%).

BETAXOLOL. Betaxolol (BETOPTIC, LOKERN, KERLONE, others) is a selective β1 receptor antagonist with slight membrane-stabilizing properties. Betaxolol is used to treat hypertension, angina pectoris, and glaucoma. It is usually well tolerated and side effects are mild and transient. In glaucoma it reduces intraocular pressure.

β RECEPTOR ANTAGONISTS WITH ADDITIONAL CARDIOVASCULAR EFFECTS (THIRD-GENERATION β-BLOCKERS)

Third-generation β-blockers possess vasodilating actions produced through a variety of mechanisms (see Table 12–4 and Figure 12–4).

LABETALOL

Labetalol (NORMODYNE, TRANDATE, others) is representative of a class of drugs that act as competitive antagonists at both α1 and β receptors. The pharmacological properties of the drug are complex, because each isomer displays different relative activities.

The properties of the mixture include selective blockade of α1 receptors (as compared with the α2 subtype), blockade of β1 and β2 receptors, partial agonist activity at β2 receptors, and inhibition of neuronal uptake of NE (cocaine-like effect) (see Chapter 8). The potency of the mixture for β blockade is 5-10 fold that for α1 blockade. The actions of labetalol on both α1 and β receptors contribute to the fall in blood pressure observed in patients with hypertension. α1 Receptor blockade leads to relaxation of arterial smooth muscle and vasodilation. β1 Blockade contributes to a fall in blood pressure, in part by blocking reflex sympathetic stimulation of the heart. The intrinsic sympathomimetic activity of labetalol at β2 receptors may contribute to vasodilation.

Labetalol is available in oral form for therapy of chronic hypertension and as an intravenous formulation for use in hypertensive emergencies. Labetalol has been associated with hepatic injury in a limited number of patients.

CARVEDILOL

Carvedilol (COREG) blocks β1, β2, and α1 receptors, and also has antioxidant and anti-inflammatory effects. Carvedilol produces vasodilation.

Carvedilol is extremely liphophic and is able to protect cell membranes from lipid peroxidation. At high doses, carvedilol exerts Ca2+ channel-blocking activity. Carvedilol does not increase β receptor density. Carvedilol improves ventricular function and reduces mortality and morbidity in patients with mild to severe congestive heart failure. Carvedilol is rapidly absorbed following oral administration, with peak plasma concentrations occurring in 1-2 h. No significant changes in the pharmacokinetics of carvedilol are seen in elderly patients with hypertension, and no change in dosage is needed in patients with moderate to severe renal insufficiency. Due to its extensive oxidative metabolism by the liver, carvedilol’s pharmacokinetics can be profoundly affected by drugs that induce or inhibit oxidation. These include the inducer, rifampin, and inhibitors such as cimetidine, quinidine, fluoxetine, and paroxetine.

BUCINDOLOL. Bucindolol (SANDONORM) is a third-generation nonselective β adrenergic antagonist with weak α1 adrenergic blocking properties. Bucindolol reduces afterload and increases plasma HDL cholesterol, but does not affect plasma triglycerides. Bucindolol is extensively metabolized by the liver and has a t1/2 of ~8 h. A new drug application is under review with the FDA.

CELIPROLOL. Celiprolol (SELECTOL) is a cardioselective β receptor antagonist with weak vasodilating and bronchodilating effects attributed to partial selective β2 agonist activity. It may antagonize peripheral α2 adrenergic receptor activity, promote NO production, and inhibit oxidative stress. It is largely unmetabolized and is excreted unchanged in the urine and feces. Celiprolol is used for treatment of hypertension and angina.

NEBIVOLOL. Nebivolol (BYSTOLIC) is a selective β1 receptor antagonist, has endothelial NO-mediated vasodilator activity, and is approved for treatment of hypertension. The d-isomer is the active β-blocking component; the l-isomer is responsible for enhancing production of NO. It is lipophilic, and concomitant administration of chlorthalidone, hydrochlorothiazide, theophylline, or digoxin with nebivolol may reduce its extent of absorption. The NO-dependent vasodilating action of nebivolol and its high β1 adrenergic receptor selectivity likely contribute to the drug’s efficacy and improved tolerability (e.g., less fatigue and sexual dysfunction) as an antihypertensive agent. Metabolism occurs via CYP2D6.

OTHER β ADRENERGIC RECEPTOR ANTAGONISTS. There are numerous β adrenergic receptor antagonists on the market as ophthalmologic preparations for the treatment of glaucoma (see Chapter 64).