Chapter 12: Adrenergic Agonists and Antagonists

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 up-regulate 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.

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, epinephrine, 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.

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). Despite the multiplicity of the sites of action of sympathomimetic amines, several generalizations can be made (Table 12–1).

Separation of Aromatic Ring and Amino Group. By far the greatest sympathomimetic activity occurs when two carbon atoms separate the ring from the amino group. This rule applies with few exceptions to all types of action.

Substitution on the Amino Group. The effects of amino substitution are most readily seen in the actions of catecholamines on α and β receptors. Increase in the size of the alkyl substituent increases β receptor activity (e.g., isoproterenol). NE has, in general, rather feeble β₂ activity; this activity is greatly increased in epinephrine by the addition of a methyl group. A notable exception is phenylephrine, which has an N-methyl substituent but is an α-selective agonist. β₂-Selective compounds require a large amino substituent, but depend on other substitutions to define selectivity for β₂ rather than for β₁ receptors. In general, the smaller the substitution on the amino group, the greater the selectivity for α activity, although N-methylation increases the potency of primary amines. Thus, α activity is maximal in epinephrine, less in NE and almost absent in isoproterenol.

Substitution on the Aromatic Nucleus. Maximal α and β activity depends on the presence of hydroxyl groups on positions 3 and 4. When one or both of these groups are absent, with no other aromatic substitution, the overall potency is reduced. Phenylephrine is thus less potent than epinephrine at both α and β receptors, with β₂ activity almost completely absent. Studies of the β adrenergic receptor suggest that the hydroxyl groups on serine residues 204 and 207 probably form hydrogen bonds with the catechol hydroxyl groups at positions 3 and 4, respectively. It also appears that aspartate 113 is a point of electrostatic interaction with the amine group on the ligand. Since the serines are in the fifth membrane-spanning region and the aspartate is in the third (Chapter 8), it is likely that catecholamines bind parallel to the plane of the membrane, forming a bridge between the two membrane spans. However, models involving DA receptors suggest alternative possibilities.

Hydroxyl groups in positions 3 and 5 confer β₂ receptor selectivity on compounds with large amino substituents. Thus, metaproterenol, terbutaline, and other similar compounds relax the bronchial musculature in patients with asthma, but cause less direct cardiac stimulation than do the non-selective drugs. The response to non-catecholamines is partly determined by their capacity to release NE from storage sites. These agents thus cause effects that are mostly mediated by α and β₁ receptors, since NE is a weak β₂ agonist. Phenylethylamines that lack hydroxyl groups on the ring and the β-hydroxyl group on the side chain act almost exclusively by causing the release of NE from sympathetic nerve terminals.

Since substitution of polar groups on the phenylethylamine structure makes the resultant compounds less lipophilic, unsubstituted or alkyl-substituted compounds cross the blood-brain barrier more readily and have more central activity. Thus, ephedrine, amphetamine, and methamphetamine exhibit considerable CNS activity. In addition, as noted, the absence of polar hydroxyl groups results in a loss of direct sympathomimetic activity.

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 (Chapter 8). Compounds without one or both hydroxyl substituents are not acted upon by COMT, and their oral effectiveness and duration of action are enhanced.

Groups other than hydroxyls have been substituted on the aromatic ring. In general, potency at α receptors is reduced and β receptor activity is minimal; the compounds may even block β receptors. For example, methoxamine, with methoxy substituents at positions 2 and 5, has highly selective α-stimulating activity, and in large doses blocks β receptors. Albuterol, a β₂-selective agonist, has a substituent at position 3 and is an important exception to the general rule of low β receptor activity.

Substitution on the α-Carbon Atom. This substitution blocks oxidation by MAO, greatly prolonging the duration of action of non-catecholamines because their degradation depends largely on the action of this enzyme. The duration of action of drugs such as ephedrine or amphetamine is thus measured in hours rather than in minutes. Similarly, compounds with an α-methyl substituent persist in the nerve terminals and are more likely to release NE from storage sites. Agents such as metaraminol exhibit a greater degree of indirect sympathomimetic activity.

Substitution on the β-Carbon Atom. Substitution of a hydroxyl group on the β carbon generally decreases actions within the CNS, largely because it lowers lipid solubility. However, such substitution greatly enhances agonist activity at both α and β adrenergic receptors. Although ephedrine is less potent than methamphetamine as a central stimulant, it is more powerful in dilating bronchioles and increasing blood pressure and heart rate.

Optical Isomerism. Substitution on either α- or β-carbon yields optical isomers. Levorotatory substitution on the β-carbon confers the greater peripheral activity, so that the naturally occurring l-epinephrine and l-NE are at least 10 times as potent as their unnatural d-isomers. Dextrorotatory substitution on the α-carbon generally results in a more potent compound. d-Amphetamine is more potent than l-amphetamine in central but not peripheral activity.

False-Transmitter Concept. Indirectly acting amines are taken up into sympathetic nerve terminals and storage vesicles, where they replace NE in the storage complex. Phenylethylamines that lack a β-hydroxyl group are retained there poorly, but β-hydroxylated phenylethylamines and compounds that subsequently become hydroxylated in the synaptic vesicle by dopamine β-hydroxylase are retained in the synaptic vesicle for relatively long periods of time. Such substances can produce a persistent diminution in the content of NE at functionally critical sites. When the nerve is stimulated, the contents of a relatively constant number of synaptic vesicles are apparently released by exocytosis. If these vesicles contain phenylethylamines that are much less potent than NE, activation of postsynaptic α and β receptors will be diminished.

This hypothesis, known as the false-transmitter concept, 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, and the amine does not reach the systemic circulation in significant concentrations. 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 to octopamine and stored in the vesicles in this form. As a consequence, NE gradually is displaced, 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. The properties of various MAO inhibitors (reversible or irreversible; selective or non-selective at MAO-A and MAO-B) are discussed in Chapter 15.

The effects are somewhat different when the drug is given by slow intravenous infusion or by subcutaneous injection. Absorption of epinephrine 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 β₂ receptors of vessels in skeletal muscle, where blood flow is enhanced; as a consequence, diastolic pressure usually falls. Since 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. At slightly higher rates of infusion, there may be no change or a slight rise in peripheral resistance and diastolic pressure, depending on the dose and the resultant ratio of α to β responses in the various vascular beds; compensatory reflexes also may come into play. The details of the effects of intravenous infusion of epinephrine, NE, and isoproterenol in humans are compared in Table 12–2 and Figure 12–2.

The effect of epinephrine on cerebral circulation is related to systemic blood pressure. In usual therapeutic doses, the drug has relatively little constrictor action on cerebral arterioles. It is physiologically advantageous that the cerebral circulation does not constrict in response to activation of the sympathetic nervous system by stressful stimuli. Indeed, autoregulatory mechanisms tend to limit the increase in cerebral blood flow caused by increased blood pressure.

Doses of epinephrine that have little effect on mean arterial pressure consistently increase renal vascular resistance and reduce renal blood flow by as much as 40%. All segments of the renal vascular bed contribute to the increased resistance. 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 epinephrine 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 epinephrine may cause pulmonary edema precipitated by elevated pulmonary capillary filtration pressure and possibly by "leaky" capillaries.

Coronary blood flow is enhanced by epinephrine 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 two factors. The first is the increased relative duration of diastole at higher heart rates (described later); 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 epinephrine; 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 epinephrine on cardiac myocytes. This vasodilation is mediated in part by adenosine released from cardiac myocytes, which tends to override a direct vasoconstrictor effect of epinephrine that results from activation of α receptors in coronary vessels.

In accelerating the heart, epinephrine preferentially shortens systole so that the duration of diastole usually is not reduced. Indeed, activation of β receptors increases the rate of relaxation of ventricular muscle. Epinephrine speeds the heart by accelerating the slow depolarization of sinoatrial (SA) nodal cells that takes place during diastole, that is, during phase 4 of the action potential (Chapter 29). Consequently, the transmembrane potential of the pacemaker cells rises more rapidly to the threshold level of action potential initiation. The amplitude of the action potential and the maximal rate of depolarization (phase 0) also are increased. A shift in the location of the pacemaker within the SA node often occurs, owing to activation of latent pacemaker cells. In Purkinje fibers, epinephrine also accelerates diastolic depolarization and may activate latent pacemaker cells. These changes do not occur in atrial and ventricular muscle fibers, where epinephrine has little effect on the stable, phase 4 membrane potential after repolarization. If large doses of epinephrine are given, premature ventricular contractions occur and may herald more serious ventricular arrhythmias. This rarely is seen with conventional doses in humans, but ventricular extrasystoles, tachycardia, or even fibrillation may be precipitated by release of endogenous epinephrine when the heart has been sensitized to this action of epinephrine by certain anesthetics or by myocardial ischemia. The mechanism of induction of these cardiac arrhythmias is not clear.

Some effects of epinephrine on cardiac tissues are largely secondary to the increase in heart rate and are small or inconsistent when the heart rate is kept constant. For example, the effect of epinephrine on repolarization of atrial muscle, Purkinje fibers, or ventricular muscle is small if the heart rate is unchanged. When the heart rate is increased, the duration of the action potential is consistently shortened, and the refractory period is correspondingly decreased.

Conduction through the Purkinje system depends on the level of membrane potential at the time of excitation. Excessive reduction of this potential results in conduction disturbances, ranging from slowed conduction to complete block. Epinephrine often increases the membrane potential and improves conduction in Purkinje fibers that have been excessively depolarized.

Epinephrine normally shortens the refractory period of the human atrioventricular (AV) node by direct effects on the heart, although doses of epinephrine that slow the heart through reflex vagal discharge may indirectly tend to prolong it. Epinephrine also decreases the grade of AV block that occurs as a result of disease, drugs, or vagal stimulation. Supraventricular arrhythmias are apt to occur from the combination of epinephrine and cholinergic stimulation. Depression of sinus rate and AV conduction by vagal discharge probably plays a part in epinephrine-induced ventricular arrhythmias, since various drugs that block the vagal effect confer some protection. The actions of epinephrine in enhancing cardiac automaticity and in causing arrhythmias 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 epinephrine. Premature ventricular contractions can appear, which may be followed by multifocal ventricular tachycardia or ventricular fibrillation. Pulmonary edema also may occur.

Epinephrine decreases the amplitude of the T wave of the electrocardiogram (ECG) in normal persons. In animals given relatively larger doses, additional effects are seen on the T wave and the ST segment. After decreasing in amplitude, the T wave may become biphasic, and the ST segment can deviate either above or below the isoelectric line. Such ST-segment changes are similar to those seen in patients with angina pectoris during spontaneous or epinephrine-induced attacks of pain. These electrical changes therefore have been attributed to myocardial ischemia. Also, epinephrine 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. Recent interest has focused on the possibility that prolonged sympathetic stimulation of the heart, such as in congestive cardiomyopathy, may promote apoptosis of cardiomyocytes.

The responses of uterine muscle to epinephrine vary with species, phase of the sexual cycle, state of gestation, and dose given. Epinephrine contracts strips of pregnant or nonpregnant human uterus in vitro by interaction with α receptors. The effects of epinephrine on the human uterus in situ, however, differ. During the last month of pregnancy and at parturition, epinephrine inhibits uterine tone and contractions. Effects of adrenergic agents and other drugs on the uterus are discussed later in this chapter and in Chapter 66.

Epinephrine 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.

Miscellaneous Effects. Epinephrine reduces circulating plasma volume by loss of protein-free fluid to the extracellular space, thereby increasing hematocrit and plasma protein concentration. However, conventional doses of epinephrine do not significantly alter plasma volume or packed red cell volume under normal conditions, although such doses are reported to have variable effects in the presence of shock, hemorrhage, hypotension, or anesthesia. Epinephrine rapidly increases the number of circulating polymorphonuclear leukocytes, likely due to β receptor–mediated demargination of these cells. Epinephrine accelerates blood coagulation in laboratory animals and humans and promotes fibrinolysis.

The effects of epinephrine on secretory glands are not marked; in most glands secretion usually is inhibited, partly owing to the reduced blood flow caused by vasoconstriction. Epinephrine stimulates lacrimation and a scanty mucus secretion from salivary glands. Sweating and pilomotor activity are minimal after systemic administration of epinephrine, but occur after intradermal injection of very dilute solutions of either epinephrine or NE. Such effects are inhibited by α receptor antagonists.

Mydriasis is readily seen during physiological sympathetic stimulation but not when epinephrine is instilled into the conjunctival sac of normal eyes. However, epinephrine usually lowers intraocular pressure; the mechanism of this effect is not clear but probably reflects reduced production of aqueous humor due to vasoconstriction and enhanced outflow (Chapter 64).

Although epinephrine does not directly excite skeletal muscle, it facilitates neuromuscular transmission, particularly that following prolonged rapid stimulation of motor nerves. In apparent contrast to the effects of α receptor activation at presynaptic nerve terminals in the autonomic nervous system (α₂ receptors), stimulation of α receptors causes a more rapid increase in transmitter release from the somatic motor neuron, perhaps as a result of enhanced influx of Ca²⁺. These responses likely are mediated by α₁ receptors. These actions may explain in part the ability of epinephrine (given intra-arterially) to briefly increase strength of the injected limb of patients with myasthenia gravis. Epinephrine also acts directly on white, fast-twitch muscle fibers to prolong the active state, thereby increasing peak tension. Of greater physiological and clinical importance is the capacity of epinephrine and selective β₂ agonists to increase physiological tremor, at least in part due to β receptor–mediated enhancement of discharge of muscle spindles.

Epinephrine 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. These receptors have been exploited in the management of hyperkalemic familial periodic paralysis, which is characterized by episodic flaccid paralysis, hyperkalemia, and depolarization of skeletal muscle. The β₂-selective agonist albuterol apparently is able to ameliorate the impairment in the ability of the muscle to accumulate and retain K⁺.

The administration of large or repeated doses of epinephrine or other sympathomimetic amines to experimental animals damages arterial walls and myocardium, even inducing necrosis in the heart indistinguishable from myocardial infarction. The mechanism of this injury is not yet clear, but α and β receptor antagonists and Ca²⁺ channel blockers may afford substantial protection against the damage. Similar lesions occur in many patients with pheochromocytoma or after prolonged infusions of NE.

Epinephrine is rapidly inactivated in the body. The liver, which is rich in both of the enzymes responsible for destroying circulating epinephrine (COMT and MAO), is particularly important in this regard (see Figure 8–7 and Table 8–4). Although only small amounts appear in the urine of normal persons, the urine of patients with pheochromocytoma may contain relatively large amounts of epinephrine, NE and their metabolites.

Epinephrine is available in a variety of formulations geared for different clinical indications and routes of administration, including self-administration for anaphylactic reactions (EpiPen). Several practical points are worth noting. First, epinephrine 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. Epinephrine injection is available in 1 mg/mL (1:1000), 0.1 mg/mL (1:10,000), and 0.5 mg/mL (1:2,000) solutions. The usual adult dose given subcutaneously ranges from 0.3-0.5 mg. Fatal medication errors have occurred as a consequence of confusing these dilutions. 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. The dose is seldom as much as 0.25 mg, except for cardiac arrest, when larger doses may be required.

Other Effects. Other responses to NE are not prominent in humans. The drug causes hyperglycemia and other metabolic effects similar to those produced by epinephrine, but these are observed only when large doses are given because NE is not as effective a "hormone" as epinephrine. Intradermal injection of suitable doses causes sweating that is not blocked by atropine.

Absorption, Fate, and Excretion. NE, like epinephrine, is ineffective when given orally and is absorbed poorly from sites of subcutaneous injection. It is rapidly inactivated in the body by the same enzymes that methylate and oxidatively deaminate epinephrine (discussed earlier). Small amounts normally are found in the urine. The excretion rate may be greatly increased in patients with pheochromocytoma.

Toxicity, Adverse Effects, and Precautions. The untoward effects of NE are similar to those of epinephrine, although there typically is greater elevation of blood pressure with NE. Excessive doses can cause severe hypertension, so careful blood pressure monitoring generally is indicated during systemic administration of this agent.

Care must be taken that necrosis and sloughing do not occur at the site of intravenous injection owing to extravasation of the drug. The infusion should be made high in the limb, preferably through a long plastic cannula extending centrally. Impaired circulation at injection sites, with or without extravasation of NE, 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. The use of it and other sympathomimetic amines in shock is discussed later in this chapter. In the treatment of low blood pressure, the dose is titrated to the desired pressor response.

At somewhat 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 (discussed later). 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, probably because of the ability of DA to reduce regional arterial resistance in some vascular beds, such as mesenteric and renal, while causing only minor increases in others. At high concentrations, DA activates vascular α₁ receptors, leading to more general vasoconstriction.

Other Effects. Although there are specific DA receptors in the CNS, injected DA usually has no central effects because it does not readily cross the blood-brain barrier.

Dopamine hydrochloride is used only intravenously, preferably into a large vein to prevent perivasular infiltration; extravasation may cause necrosis and sloughing of the surrounding tissue. The use of a calibrated infusion pump or other device capable of controlling the rate of flow is necessary. The drug initially is administered at a rate of 2-5 μg/kg per minute; this rate may be increased gradually up to 20-50 μg/kg per minute or more as the clinical situation dictates. During the infusion, patients require clinical assessment of myocardial function, perfusion of vital organs such as the brain, and the production of urine. Most patients should receive intensive care, with monitoring of arterial and venous pressures and the ECG. 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 not more than 48 hours. 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 (Murphy et al., 2001). Fenoldopam must be administered using a calibrated infusion pump; the usual dose rate ranges from 0.01-1.6 μg/kg per minute.

Less than 6% of an orally administered dose is absorbed because of extensive first-pass formation of sulfate, methyl, and glucuronide conjugates. The elimination t_1/2 of intravenously infused fenoldopam, estimated from the decline in plasma concentration in hypertensive patients after the cessation of a 2-hour infusion, is 10 minutes. 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 (Fitton and Benfield, 1990). It appears to have 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.

Epinephrine first was used as a bronchodilator at the beginning of the past century, and ephedrine was introduced into western medicine in 1924, although it had been used in China for thousands of years. The next major advance was the development in the 1940s of isoproterenol, a β receptor–selective agonist; this provided a drug for asthma that lacked α receptor activity. The recent development of β₂-selective agonists has resulted in drugs with even more valuable characteristics, including adequate oral bioavailability, lack of α adrenergic activity, and diminished likelihood of some adverse cardiovascular effects.

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 epinephrine and NE. The duration of action of isoproterenol therefore may be longer than that of epinephrine, 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 torsades de pointes. In disorders such as asthma and shock, isoproterenol largely has been replaced by other sympathomimetic drugs (discussed later in this chapter and in Chapter 36).

Although dobutamine originally was thought to be a relatively selective β₁ receptor agonist, it now is clear that its pharmacological effects 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. In contrast, (+)-dobutamine is a potent α₁ receptor antagonist, which can block the effects of (−)-dobutamine. The effects of these two isomers are mediated by β receptors. The (+) isomer is a more potent β receptor agonist than the (−) isomer (~10-fold). Both isomers appear to be full agonists.

In animals, administration of dobutamine at a rate of 2.5-15 μg/kg per minute increases cardiac contractility and cardiac output. Total peripheral resistance is not greatly affected. The relatively constant peripheral resistance presumably reflects counterbalancing of α₁ receptor–mediated vasoconstriction and β₂ receptor–mediated vasodilation (Ruffolo, 1987). Heart rate increases only modestly when the rate of administration of dobutamine is maintained at < 20 μg/kg per minute. After administration of β receptor antagonists, infusion of dobutamine fails to increase cardiac output, but total peripheral resistance increases, confirming that dobutamine has modest direct effects on α adrenergic receptors in the vasculature.

Adverse Effects. In some patients, blood pressure and heart rate increase significantly during dobutamine administration; this may require reduction of the rate of infusion. Patients with a history of hypertension may exhibit such an exaggerated pressor response more frequently. Since dobutamine facilitates atrioventricular 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 potentially may increase the size of a myocardial infarct by increasing myocardial O₂ demand. This risk must be balanced against the patient's overall clinical status. 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, although some patients may have marked increases in blood pressure or heart rate. Clinical evidence of longer-term efficacy remains uncertain. An infusion of dobutamine in combination with echocardiography is useful in the noninvasive assessment of patients with coronary artery disease. Stressing of the heart with dobutamine may reveal cardiac abnormalities in carefully selected patients.

Dobutamine has a t_1/2 ≈2 minutes; the major metabolites are conjugates of dobutamine and 3-O-methyldobutamine. The onset of effect is rapid. Consequently, a loading dose is not required, and steady-state concentrations generally are achieved within 10 minutes of initiation of the infusion by calibrated infusion pump. The rate of infusion required to increase cardiac output typically is between 2.5 and 10 μg/kg per minute, although higher infusion rates occasionally are required. The rate and duration of the infusion are determined by the clinical and hemodynamic responses of the patient.

Modifications have included placing the hydroxyl groups at positions 3 and 5 of the phenyl ring or substituting another moiety for the hydroxyl group at position 3. This has yielded drugs such as metaproterenol, terbutaline, and albuterol, which are not substrates for COMT. Bulky substituents on the amino group of catecholamines contribute to potency at β receptors with decreased activity at α receptors and decreased metabolism by MAO. A final 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 receptor agonists by aerosol (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 (discussed later). While subcutaneous injection also causes prompt bronchodilation, the peak effect of a drug given orally may be delayed for several hours. Aerosol therapy depends on the delivery of drug to the distal airways. This, in turn, depends on the size of the particles in the aerosol and respiratory parameters such as inspiratory flow rate, tidal volume, breath-holding time, and airway diameter. Only ~10% of an inhaled dose actually enters the lungs; much of the remainder is swallowed and ultimately may be absorbed. Successful aerosol therapy requires that each patient master the technique of drug administration. Many patients, particularly children and the elderly, do not use optimal techniques, often because of inadequate instructions or incoordination. In these patients, spacer devices may enhance the efficacy of inhalation therapy.

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. Although this action appears to be a major therapeutic effect of these drugs in patients with asthma, evidence suggests that β receptor agonists also may suppress the release of leukotrienes and histamine from mast cells in lung tissue, enhance mucociliary function, decrease microvascular permeability, and possibly inhibit phospholipase A₂ (Seale, 1988). These additional actions seem to contribute to the beneficial effects of β agonists in the treatment of human asthma It is becoming increasingly clear that airway inflammation is also directly involved in airway hyper-responsiveness; consequently, the use of anti-inflammatory drugs such as inhaled steroids has primary importance. Most authorities recommend that long-acting β agonists should not be used without concomitant anti-inflammatory therapy in the treatment of asthma (Drazen and O'Byrne, 2009; Fanta, 2009). The use of β agonists for the treatment of asthma and COPD is discussed in Chapter 36.

Effects occur within minutes of inhalation and persist for several hours. After oral administration, onset of action is slower, but effects last 3-4 hours. Metaproterenol is used for the long-term treatment of obstructive airway diseases, asthma, and for treatment of acute bronchospasm (Chapter 36). Side effects are similar to the short- and intermediate-acting sympathomimetic bronchodilators.

When administered by inhalation, it produces significant bronchodilation within 15 minutes, and effects persist for 3-4 hours. 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.

Albuterol has been made available in a metered dose inhaler free of chlorofluorcarbons (CFC); CFC-containing albuterol inhalers have been taken off the market. Like CFCs, the alternate propellant, hydrofluoroalkane (HFA) is inert in the human airway, but unlike CFCs, it does not contribute to depletion of the stratospheric ozone layer.

Levalbuterol. Levalbuterol (xopenex) is the R-enantiomer of albuterol which is a racemic drug used to treat asthma and COPD. Although originally available only as a solution for nebulizer, it is now available as a CFC-free metered dose inhaler. Levalbuterol is β₂-selective and acts like other β₂ adrenergic agonists. In general, levalbuterol has similar pharmacokinetic and pharmacodynamics properties to albuterol. Although it has been claimed to have fewer side effects than albuterol, these claims have not been supported by clinical trials.

Pirbuterol. Pirbuterol is a relatively selective β₂ agonist. Its structure is identical to albuterol except for the substitution of a pyridine ring for the benzene ring. Pirbuterol acetate (maxair) is available for inhalation therapy; dosing is typically every 4-6 hours. Pirbuterol is the only preparation available in a breath-activated meter-dose inhaler, a device meant to optimize medication delivery by releasing a spray of medication only on the patient's initiation of inspiration.

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 hours. With oral administration, the onset of effect may be delayed 1-2 hours. 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 (Chapter 36).

Isoetharine. Isoetharine was the first β₂-selective drug widely used for the treatment of airway obstruction. However, its degree of 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 (Table 12–1). Consequently, it is used only by inhalation for the treatment of acute episodes of bronchoconstriction. Isoetharine is no longer marketed in the U.S.

Bitolterol. Bitolterol (tornalate) is a novel β₂ agonist in which the hydroxyl groups in the catechol moiety are protected by esterification with 4-methylbenzoate. Esterases in the lung and other tissues hydrolyze this prodrug to the active form, colterol, or terbutylnorepinephrine (Table 12–1). Animal studies suggest that these esterases are present in higher concentrations in lung than in tissues such as the heart. The duration of effect of bitolterol after inhalation ranges from 3-6 hours. 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 hours. The possible association of fenoterol use with increased deaths from asthma, although controversial (Pearce et al., 1995; Suissa and Ernst, 1997), has led to its withdrawal from the market. It is thought that the dysrhythmias and cardiac effects are due to effects on β₁ adrenergic receptors.

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

Like formoterol, it is highly lipophilic and has a sustained duration of action; for salmeterol, this long action reflects binding to a specific site within the β₂ receptor that allows for its prolonged activation. It also may have anti-inflammatory activity. Salmeterol is metabolized by CYP3A4 to α-hydroxy-salmeterol, which is eliminated primarily in the feces. Since the onset of action of inhaled salmeterol is relatively slow, it is not suitable monotherapy for acute breakthrough attacks of bronchospasm. Salmeterol or formoterol are the agents of choice for nocturnal asthma in patients who remain symptomatic despite anti-inflammatory agents and other standard management.

Salmeterol generally is well tolerated but has the potential to increase heart rate and plasma glucose concentration, to produce tremors, and to decrease plasma potassium concentration through effects on extrapulmonary β₂ receptors. 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 (Redington, 2001).

Many patients with moderate or severe persistent asthma have benefited immensely with the use of long-acting β agonists like salmeterol together with an inhaled corticosteroid. These benefits have to be counterbalanced against the results of the Salmeterol Multicenter Asthma Research Trial (SMART), in which the addition of a long acting β agonist to "usual therapy" was associated with an increased risk of fatal or near-fatal asthmatic attacks, as compared with "usual therapy" alone. This study is controversial and often criticized because only a minority of subjects in SMART were taking inhaled corticosteroids and there is a lack of reports of increased asthma mortality among patients taking both a long-acting β agonist and an inhaled corticosteroid (Fanta, 2009). Nevertheless, the FDA has placed a black-box warning in the labeling information for salmeterol, formoterol, and arformoterol. Moreover, national and international expert panels (Fanta, 2009) have recommended the use of long-acting agonists only for patients in whom inhaled corticosteroids alone either have failed to achieve good asthma control or for initial therapy.

A substantial portion of systemic exposure to arformoterol is due to pulmonary absorption with plasma levels reaching peak levels in 0.25-1 hour. Plasma protein binding is 52-65%. It is primarily metabolized by direct conjugation to glucuronide or sulfate conjugates and secondarily by O-demethylation by CYP2D6 and CYP2C19. It does not inhibit any of the common CYPs. The drug is well tolerated and the most common side effects are skeletal muscle tremor and cramps, insomnia, tachycardia, decreases in plasma potassium, and increases in plasma glucose. As mentioned previously, a black-box warning has been instituted in response to findings of the SMART trials (Fanta, 2009; Lipworth, 2007).

Carmoterol. Carmoterol is a pure (R,R)-isomer and a non-catechol with a p-methoxyphenyl group on the carbostyril aromatic ring. It is a potent and selective β₂ adrenergic agonist with a selectivity for β₂ over β₁ receptors of 53. It is claimed to be 5 times more selective for the β₂ adrenergic receptor in tracheal preparations than those in the right atrium. Carmoterol has a rapid onset and long duration of action and shows a bronchodilator effect over 24 hours with once a day dosing. Indications for carmoterol include asthma and COPD (Cazzola and Matera, 2008; Matera and Cazzola, 2007).

Indacaterol. Indacaterol is a once-daily long-acting β adrenergic agonist in development for asthma and COPD. It has a fast onset of action, appears well tolerated, and has been shown to be effective in both asthma and COPD with little tachyphalaxis upon continued use. 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.

Both indacaterol and carmoterol are currently in Phase III clinical trials in the U.S. (Cazzola and Matera, 2008; Matera and Cazzola, 2007).

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.

Ritodrine is rapidly but incompletely (30%) absorbed following oral administration, and 90% of the drug is excreted in the urine as inactive conjugates; ~50% of ritodrine is excreted unchanged after intravenous administration. 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. Ritodrine and related drugs can prolong pregnancy. 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.

Tremor is a relatively common adverse effect of the β₂-selective receptor agonists. Tolerance generally develops to this effect; it is not clear whether tolerance reflects desensitization of the β₂ receptors of skeletal muscle or adaptation within the CNS. 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. It is uncertain to what extent the increase in heart rate also is due to activation of cardiac β₂ receptors or to reflex effects that stem from β₂ receptor–mediated peripheral vasodilation. However, β₂ receptors are also present in the human myocardium and all β₂ adrenergic agonists have the potential to produce cardiac stimulation. 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 β₂ agonists or other sympathomimetics.

Large doses of β receptor agonists cause myocardial necrosis in laboratory animals. When given parenterally, these drugs also may increase the concentrations of glucose, lactate, and free fatty acids in plasma and decrease the concentration of K⁺. The decrease in K⁺ concentration may be especially important in patients with cardiac disease, particularly those taking digoxin and diuretics. In some diabetic patients, hyperglycemia may be worsened by these drugs, and higher doses of insulin may be required. All these adverse effects are far less likely with inhalation therapy than with parenteral or oral therapy.

Mephentermine. Mephentermine is a sympathomimetic drug that acts both directly and indirectly; it has many similarities to ephedrine (discussed later). After an intramuscular injection, the onset of action is prompt (within 5-15 minutes), and effects may last for several hours. Since 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 is a sympathomimetic drug with prominent 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 for preferable treatments of this arrhythmia).

Midodrine. Midodrine (proamatine, others) is an orally effective α₁ receptor agonist. It is a prodrug; its activity is due to its conversion to an active metabolite, desglymidodrine, which achieves peak concentrations ~1 hour after a dose of midodrine. The t_1/2 of desglymidodrine is ~3 hours. Consequently, the duration of action is ~4-6 hours. Midodrine-induced rises in blood pressure are associated with both arterial and venous smooth muscle contraction. This is advantageous in the treatment of patients with autonomic insufficiency and postural hypotension (McClellan et al., 1998). 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, avoiding dosing within 4 hours of bedtime, and elevating the head of the bed. Very cautious use of a short-acting antihypertensive drug at bedtime may be useful in some patients. Typical dosing, achieved by careful titration of blood pressure responses, varies between 2.5 and 10 mg three times daily.

In addition, α₂ agonists reduce intraocular pressure by decreasing the production of aqueous humor. This action first was reported for clonidine and suggested a potential role for α₂ receptor agonists in the management of ocular hypertension and glaucoma. Unfortunately, clonidine lowered systemic blood pressure even if applied topically to the eye (Alward, 1998). Two derivatives of clonidine, apraclonidine and brimonidine, have been developed that retain the ability to decrease intraocular pressure with little or no effect on systemic blood pressure.

Questions remain about whether the sympatho-inhibitory action of clonidine results solely from its α₂ receptor agonism or whether part or all of its actions are mediated by imidazoline receptors. Imidazoline receptors include three subtypes (I₁, I₂, and I₃) and are widely distributed in the body, including the CNS. Clonidine, as an imidazoline, binds to these imidazoline receptors, in addition to its well-described binding to α₂ receptors. Two newer antihypertensive imidazolines, rilmenidine and moxonidine, have profiles of action similar to clonidine's, suggesting a role for I₁ receptors. However, the lack of an antihypertensive effect of clonidine in knockout mice lacking α_2A receptors supports a key role for these receptors in blood pressure regulation (Zhu et al., 1999). Others argue that, while the action of clonidine may be mediated by α₂ receptors, the I₁ receptor mediates the effects of moxonidine and rilmenidine. Finally, α₂ and imidazoline receptors may cooperatively regulate vasomotor tone and may jointly mediate the hypotensive actions of centrally acting drugs with affinity for both receptor types.

Clonidine decreases discharges in sympathetic preganglionic fibers in the splanchnic nerve and in postganglionic fibers of cardiac nerves. These effects are blocked by α₂-selective antagonists such as yohimbine. Clonidine also stimulates parasympathetic outflow, which may contribute to the slowing of heart rate as a consequence of increased vagal tone and diminished sympathetic drive. 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.

Absorption, Fate, and Excretion. Clonidine is well absorbed after oral administration, and its bioavailability is nearly 100%. The peak concentration in plasma and the maximal hypotensive effect are observed 1-3 hours after an oral dose. The elimination t_1/2 of the drug ranges from 6-24 hours, with a mean of ~12 hours. About half of an administered dose can be recovered unchanged in the urine, and the t_1/2 of the drug may increase with renal failure. There is good correlation between plasma concentrations of clonidine and its pharmacological effects. 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 hours 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. These responses occur in at least 50% of patients and may require drug discontinuation. However, they may diminish in intensity after several weeks of therapy. Sexual dysfunction also may occur. Marked bradycardia is observed in some patients. These and some of the other adverse effects of clonidine frequently are related to dose, and their incidence may be lower with transdermal administration of clonidine, since antihypertensive efficacy may be achieved while avoiding the relatively high peak concentrations that occur after oral administration of the drug. About 15-20% of patients develop contact dermatitis when using clonidine in the transdermal system. Withdrawal reactions follow abrupt discontinuation of long-term therapy with clonidine in some hypertensive patients (Chapter 27).

Therapeutic Uses. The major therapeutic use of clonidine (catapres, others) is in the treatment of hypertension (Chapter 27). Clonidine also has apparent efficacy in the off-label treatment of a range of other disorders. Stimulation of α₂ receptors in the GI tract may increase absorption of sodium chloride and fluid and inhibit secretion of bicarbonate. This may explain why clonidine has been found to be useful in reducing diarrhea in some diabetic patients with autonomic neuropathy. Clonidine also is useful in treating and preparing addicted subjects for withdrawal from narcotics, alcohol, and tobacco (Chapter 24). Clonidine may help ameliorate some of the adverse sympathetic nervous activity associated with withdrawal from these agents, as well as decrease craving for the drug. The long-term benefits of clonidine in these settings and in neuropsychiatric disorders remain to be determined. Clonidine may be useful in selected patients receiving anesthesia because it may decrease the requirement for anesthetic and increase hemodynamic stability (Hayashi and Maze, 1993; Chapter 19). Other potential benefits of clonidine and related drugs such as dexmedetomidine (precedex; a relatively selective α₂ receptor agonist with sedative properties) in anesthesia include preoperative sedation and anxiolysis, drying of secretions, and analgesia. Transdermal administration of clonidine (cataprestts) may be useful in reducing the incidence of menopausal hot flashes.

Acute administration of clonidine has been used in the differential diagnosis of patients with hypertension and suspected pheochromocytoma. In patients with primary hypertension, plasma concentrations of NE are markedly suppressed after a single dose of clonidine; this response is not observed in many patients with pheochromocytoma. The capacity of clonidine to activate postsynaptic α₂ receptors in vascular smooth muscle has been exploited in a limited number of patients whose autonomic failure is so severe that reflex sympathetic responses on standing are absent; postural hypotension is thus marked. Since the central effect of clonidine on blood pressure is unimportant in these patients, the drug can elevate blood pressure and improve the symptoms of postural hypotension. Among the other off-label uses of clonidine are atrial fibrillation, attention-deficit/hyperactivity disorder, constitutional growth delay in children, cyclosporine-associated nephrotoxicity, Tourette's syndrome, hyperhidrosis, mania, posthepatic neuralgia, psychosis, restless leg syndrome, ulcerative colitis, and allergy-induced inflammatory reactions in patients with extrinsic asthma.

The clinical utility of apraclonidine is most apparent as short-term adjunctive therapy in glaucoma patients whose intraocular pressure is not well controlled by other pharmacological agents such as β receptor antagonists, parasympathomimetics, or carbonic anhydrase inhibitors. The drug also is used to control or prevent elevations in intraocular pressure that occur in patients after laser trabeculoplasty or iridotomy (Chapter 64).

The drug is well absorbed after oral administration and has a large volume of distribution (4-6 L/kg). About 50% of guanfacine appears unchanged in the urine; the rest is metabolized. The t_1/2 for elimination ranges from 12-24 hours. Guanfacine and clonidine appear to have similar efficacy for the treatment of hypertension. The pattern of adverse effects also is similar for the two drugs, although it has been suggested that some of these effects may be milder and occur less frequently with guanfacine. A withdrawal syndrome may occur after the abrupt discontinuation of guanfacine, but it appears to be less frequent and milder than the syndrome that follows clonidine withdrawal. Part of this difference may relate to the longer t_1/2 of guanfacine.

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.

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—in athletes, e.g.—is improved, and the drug often is abused for this purpose. These effects are not invariable 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 (Chapter 24).

Fatigue and Sleep. Prevention and reversal of fatigue by amphetamine have been studied extensively in the laboratory, in military field studies, and in athletics. In general, the duration of adequate performance is prolonged before fatigue appears, and the effects of fatigue are at least partly reversed. The most striking improvement appears to occur when performance has been reduced by fatigue and lack of sleep. Such improvement may be partly due to alteration of unfavorable attitudes toward the task. However, 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, although the wisdom of this use is at best questionable. Weight loss in obese humans treated with amphetamine is almost entirely due to reduced food intake and only in small measure to increased metabolism. The site of action probably is in the lateral hypothalamic feeding center; injection of amphetamine into this area, but not into the ventromedial region, suppresses food intake. Neurochemical mechanisms of action are unclear but may involve increased release of NE and/or DA. In humans, tolerance to the appetite suppression develops rapidly. Hence, continuous weight reduction usually is not observed in obese individuals without dietary restriction.

Mechanisms of Action in the CNS. Amphetamine appears to exert most or all of its effects in the CNS by releasing biogenic amines from their storage sites in nerve terminals. In addition, the neuronal dopamine transporter (DAT) and the vesicular monoamine transporter 2 (VMAT2) appear to be two of the principal targets of amphetamine's action (Fleckenstein, 2007). These mechanisms include amphetamine-induced exchange diffusion, reverse transport, channel-like transport phenomena, and effects resulting from the weakly basic properties of amphetamine. Amphetamine analogs affect monamine transporters through phosphorylation, transporter trafficking, and the production of reactive oxygen and nitrogen species. These mechanisms may have potential implications for neurotoxicity as well as dopaminergic neurodegenerative diseases (discussed later) (Fleckenstein, 2007).

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. These effects can be prevented in experimental animals by treatment with metyrosine (α-methyltyrosine), an inhibitor of tyrosine hydroxylase, and therefore of catecholamine synthesis. 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 these behavioral effects, and this correlates with the higher concentrations of amphetamine required to release DA from brain slices or synaptosomes in vitro. With still higher doses of amphetamine, disturbances of perception and overt psychotic behavior occur. These effects may be due to release of 5-hydroxytryptamine (serotonin, 5-HT) from serotonergic neurons and of DA in the mesolimbic system. In addition, amphetamine may exert direct effects on CNS receptors for 5-HT (Chapter 13).

The toxic dose of amphetamine varies widely. Toxic manifestations occasionally occur as an idiosyncratic reaction after as little as 2 mg, but are rare with doses of < 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; this enhances 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, but abnormal mental conditions are more common. 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 usually is rapid after withdrawal of the drug, but occasionally the condition becomes chronic. In these persons, amphetamine may act as a precipitating factor hastening the onset of incipient schizophrenia.

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. Tolerance is striking in individuals who are dependent on the drug; a daily intake of 1.7 g without apparent ill effects has been reported. 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 (dexedrine, others), with greater CNS action and less peripheral action, was used off-label for obesity (but no longer is approved for this purpose because of the risk of abuse) and is FDA-approved for the treatment of narcolepsy and attention-deficit/hyperactivity disorder (see below, "Therapeutic Uses of Sympathomimetic Drugs").

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. Cardiac output is increased, although the heart rate may be reflexly slowed. Venous constriction causes peripheral venous pressure to increase. These factors tend to increase the venous return, and thus cardiac output. Pulmonary arterial pressure is raised, probably owing to increased cardiac output. Methamphetamine is a schedule II drug under federal regulations and has high potential for abuse (Chapter 24). It is widely used as a cheap, accessible recreational drug and its abuse is a widespread phenomenon. Illegal production of methamphetamine in clandestine laboratories throughout the U.S. is common. It is used principally for its central effects, which are more pronounced than those of amphetamine and are accompanied by less prominent peripheral actions (see below, Therapeutic Uses of Sympathomimetic Drugs).

Its pharmacological properties are essentially the same as those of the 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 attention-deficit/hyperactivity disorder, as described in the subsequent paragraphs.

Methylphenidate is readily absorbed after oral administration and reaches peak concentrations in plasma in ~2 hours. The drug is a racemate; its more potent (+) enantiomer has a t_1/2 of ~6 hours, and the less potent (−) enantiomer has a t_1/2 of ~4 hours. Concentrations in the brain exceed those in plasma. The main urinary metabolite is a de-esterified product, ritalinic acid, which accounts for 80% of the dose. 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 for the treatment of attention-deficit/hyperactivity disorder and is listed as a schedule II controlled substance in the U.S.

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 attention-deficit/hyperactivity disorder. It can be given once daily because of its long t_1/2. Clinical improvement may require treatment for 3-4 weeks. Use of pemoline has been associated with severe hepatic failure. The drug was discontinued in the U.S. in 2006.

Therapeutic Uses and Toxicity. In the past, ephedrine was used to treat Stokes-Adams attacks with complete heart block and as a CNS stimulant in narcolepsy and depressive states. It has been replaced by alternate treatments in each of these disorders. In addition, its use as a bronchodilator in patients with asthma has become much less extensive with the development of β₂-selective agonists. Ephedrine has been used to promote urinary continence, although its efficacy is not clear. Indeed, the drug may cause urinary retention, particularly in men with benign prostatic hyperplasia. Ephedrine also has been used to treat the hypotension that may occur with spinal anesthesia.

Untoward effects of ephedrine include hypertension, particularly after parenteral administration or with higher-than-recommended oral dosing. Insomnia is a common CNS adverse effect. Tachyphylaxis may occur with repetitive dosing. Concerns have been raised about the safety of ephedrine. Usual or higher-than-recommended doses may cause important adverse effects in susceptible individuals and are especially of concern in patients with underlying cardiovascular disease that might be unrecognized. Of potentially greater cause for concern, large amounts of herbal preparations containing ephedrine (ma huang, ephedra) are utilized around the world. There can be considerable variability in the content of ephedrine in these preparations, which may lead to inadvertent consumption of higher-than-usual doses of ephedrine and its isomers. Because of this, the FDA has banned the sale of dietary supplements containing ephedra. In addition, 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. The structures of propylhexedrine (benzedrex, others), naphazoline (privine, naphcon, others), oxymetazoline (afrin, ocu-clear, others), and xylometazoline (otrivin, others) are depicted in Table 12–1 and Figure 12–4.

Phenylephrine (described earlier), pseudoephedrine (sudafed, others) (a stereoisomer of ephedrine), and phenylpropanolamine are the sympathomimetic drugs that have been used most commonly in oral preparations for the relief of nasal congestion. Pseudoephedrine is available without a prescription in a variety of solid and liquid dosage forms. Phenylpropanolamine shares the pharmacological properties of ephedrine and is approximately equal in potency except that it causes less CNS stimulation. Due to concern about the possibility that phenylpropanolamine increases the risk of hemorrhagic stroke, the drug is no longer licensed for marketing in the U.S.

Shock. Shock is a clinical syndrome characterized by inadequate perfusion of tissues; it usually is associated with hypotension and ultimately with the failure of organ systems (Hollenberg et al., 1999). 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, or cardiac mechanical defects such as ventricular septal defect), obstruction to cardiac output (due to pulmonary embolism, pericardial tamponade, or aortic dissection), and peripheral circulatory dysfunction (sepsis or anaphylaxis). Recent research on shock has focused on the accompanying increased permeability of the GI mucosa to pancreatic proteases, and on the role of these degradative enzymes on microvascular inflammation and multi-organ failure (Schmid-Schoenbein and Hugli, 2005). The treatment of shock consists of specific efforts to reverse the underlying pathogenesis as well as nonspecific measures aimed at correcting hemodynamic abnormalities. Regardless of etiology, 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 in an effort to improve abnormalities in blood pressure and flow. This therapy generally is empirically based on response to hemodynamic measurements. 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 (Breslow and Ligier, 1991).

Cardiogenic shock due to myocardial infarction has a poor prognosis; therapy is aimed at improving peripheral blood flow. Definitive therapy, such as emergency cardiac catheterization followed by surgical revascularization or angioplasty, may be very important. Mechanical left ventricular assist devices also may help to maintain cardiac output and coronary perfusion in critically ill patients. In the setting of severely impaired cardiac output, falling blood pressure leads to intense sympathetic outflow and vasoconstriction. This may further decrease cardiac output as the damaged heart pumps against a higher peripheral resistance. 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 epinephrine 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 per minute), 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 in shock, hypotension is so severe that vasoconstricting drugs are required to maintain a blood pressure that is adequate for CNS perfusion. Alpha agonists such as NE, phenylephrine, metaraminol, mephentermine, midodrine, ephedrine, epinephrine, DA, and methoxamine all 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. Indeed, 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. Data on the comparative value of various adrenergic agents in the treatment of septic shock are limited. Therapy with drugs such as DA or dobutamine is guided by hemodynamic monitoring, with individualization of therapy depending on the patient's overall clinical condition.

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. In patients with spinal anesthesia that interrupts sympathetic activation of the heart, injections of ephedrine increase heart rate as well as peripheral vascular resistance; tachyphylaxis may occur with repetitive injections, necessitating the use of a directly acting drug.

Patients with orthostatic hypotension (excessive fall in blood pressure with standing) often represent a pharmacological challenge. There are diverse causes for this disorder, including the Shy-Drager syndrome and idiopathic autonomic failure. Therapeutic approaches include physical maneuvers and a variety of drugs (fludrocortisone, prostaglandin synthesis inhibitors, somatostatin analogs, caffeine, vasopressin analogs, and DA antagonists). A number of sympathomimetic drugs also have been used in treating this disorder. 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 in this disorder to activate α₁ receptors include both direct- and indirect-acting agents. Midodrine shows promise in treating this challenging disorder.

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

Cardiac Arrhythmias. Cardiopulmonary resuscitation in patients with cardiac arrest due to ventricular fibrillation, electromechanical dissociation, or asystole may be facilitated by drug treatment. Epinephrine is an important therapeutic agent in patients with cardiac arrest; epinephrine and other α agonists increase diastolic pressure and improve coronary blood flow. Alpha agonists also help to preserve cerebral blood flow during resuscitation. Cerebral blood vessels are relatively insensitive to the vasoconstricting effects of catecholamines, and perfusion pressure is increased. Consequently, during external cardiac massage, epinephrine facilitates distribution of the limited cardiac output to the cerebral and coronary circulations. Although it had been thought that the β adrenergic effects of epinephrine on the heart made ventricular fibrillation more susceptible to conversion with electrical countershock, tests in animal models have not confirmed this hypothesis. The optimal dose of epinephrine in patients with cardiac arrest is unclear. Once a cardiac rhythm has been restored, it may be necessary to treat arrhythmias, hypotension, or shock.

In patients with paroxysmal supraventricular tachycardias, particularly those associated with mild hypotension, careful infusion of an α agonist (e.g., phenylephrine) to raise blood pressure to ~160 mm Hg may end the arrhythmia by increasing vagal tone. However, this method of treatment has been replaced largely by Ca²⁺ channel blockers with clinically significant effects on the AV node,β antagonists, adenosine, and electrical cardioversion (Chapter 29). Beta agonists such as isoproterenol may be used as adjunctive or temporizing therapy with atropine in patients with marked bradycardia who are compromised hemodynamically; if long-term therapy is required, a cardiac pacemaker usually is the treatment of choice.

Congestive Heart Failure. Sympathetic stimulation of β receptors in the heart is an important compensatory mechanism for maintenance of cardiac function in patients with congestive heart failure. Responses mediated by β receptors are blunted in the failing human heart. While β agonists may increase cardiac output in acute emergency settings such as shock, long-term therapy with β agonists as inotropic agents is not efficacious. Indeed, interest has grown in the use of β receptor antagonists in the treatment of patients with congestive heart failure (Chapter 28).

Local Vascular Effects of α Adrenergic Receptor Agonists. Epinephrine 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 epinephrine with local anesthetics retards the absorption of the anesthetic and increases the duration of anesthesia (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 in patients with allergic or vasomotor rhinitis and in acute rhinitis in patients with upper respiratory infections. These drugs probably decrease resistance to airflow by decreasing the volume of the nasal mucosa; this may occur by activation of α receptors in venous capacitance vessels in nasal tissues that have erectile characteristics. The receptors that mediate this effect appear to be α₁ receptors. Interestingly, α₂ receptors may mediate contraction of arterioles that supply nutrition to the nasal mucosa. Intense constriction of these vessels may cause structural damage to the mucosa. A major limitation of therapy with nasal decongestants is loss of efficacy, "rebound" hyperemia, and worsening of symptoms with chronic use or when the drug is stopped. Although mechanisms are uncertain, possibilities include receptor desensitization and damage to the mucosa. Agonists that are selective for α₁ receptors may be less likely to induce mucosal damage.

For decongestion, α agonists may be administered either orally or topically. Oral ephedrine often causes CNS adverse effects. Pseudoephedrine is a stereoisomer of ephedrine that is less potent than ephedrine in producing tachycardia, increased blood pressure, and CNS stimulation. 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. A variety of compounds (see under Ephedrine, earlier) are available for topical use in patients with rhinitis. Topical decongestants are particularly useful in acute rhinitis because of their more selective site of action, but they are apt to be used excessively by patients, leading to rebound congestion. Oral decongestants are much less likely to cause rebound congestion but carry a greater risk of inducing adverse systemic effects. Indeed, patients with uncontrolled hypertension or ischemic heart disease generally should carefully avoid the oral consumption of over-the-counter products or herbal preparations containing sympathomimetic drugs.

Asthma. Use of β adrenergic agonists in the treatment of asthma and chronic obstructive pulmonary disease (COPD) is discussed in Chapter 36.

Allergic Reactions. Epinephrine 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 epinephrine rapidly relieves itching, hives, and swelling of lips, eyelids, and tongue. In some patients, careful intravenous infusion of epinephrine may be required to ensure prompt pharmacological effects. This treatment may be life-saving when edema of the glottis threatens airway patency or when there is hypotension or shock in patients with anaphylaxis. In addition to its cardiovascular effects, epinephrine is thought to activate β receptors that suppress the release from mast cells of mediators such as histamine and leukotrienes. Although glucocorticoids and antihistamines frequently are administered to patients with severe hypersensitivity reactions, epinephrine remains the mainstay. Epinephrine auto-injectors (epipen, others) are employed widely for the emergency self-treatment of anaphylaxis.

Ophthalmic Uses. Application of various sympathomimetic amines for diagnostic and therapeutic ophthalmic use is discussed in Chapter 64.

Narcolepsy and Related Syndromes. Narcolepsy is characterized by hypersomnia, including attacks of sleep that may occur suddenly under conditions that are not normally conducive to sleep. Some patients respond to treatment with tricyclic antidepressants or MAO inhibitors. Alternatively, CNS stimulants such as amphetamine, dextroamphetamine, or methamphetamine may be useful. 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 and may not involve adrenergic receptors. Therapy with amphetamines is complicated by the risk of abuse and the likelihood of the development of tolerance. Depression, irritability, and paranoia also may occur. Amphetamines may disturb nocturnal sleep, which increases the difficulty of avoiding daytime attacks of sleep in these patients. Armodafinil (nuvigil), the R-enantiomer of modafinil (a mixture of R- and S-enantiomers) is also indicated for narcolepsy, to improve wakefulness in shift workers, and to combat excessive sleepiness in patients with obstructive sleep apnea-hypopnea syndrome.

Narcolepsy in rare individuals is caused by mutations in the related orexin neuropeptides (also called hypocretins), which are expressed in the lateral hypothalamus, or in their G protein–coupled receptors (Mignot, 2004). Although such mutations are not present in most subjects with narcolepsy, the levels of orexins in the CSF are markedly diminished, suggesting that deficient orexin signaling may play a pathogenic role. The association of these neuropeptides and their cognate GPCRs with narcolepsy provides an attractive target for the development of novel pharmacotherapies for this disorder.

Weight Reduction. Obesity arises as a consequence of positive caloric balance. Optimally, weight loss is achieved by a gradual increase in energy expenditure from exercise combined with dieting to decrease the caloric intake. However, this obvious approach has a relatively low success rate. Consequently, alternative forms of treatment, including surgery or medications, have been developed in an effort to increase the likelihood of achieving and maintaining weight loss. Amphetamine was found to produce weight loss in early studies of patients with narcolepsy and was subsequently used in the treatment of obesity. The drug promotes weight loss by suppressing appetite rather than by increasing energy expenditure. Other anorexic drugs include methamphetamine, dextroamphetamine (and a prodrug form, lisdexamfetamine), 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. In short-term (up to 20 weeks), double-blind controlled studies, amphetamine-like drugs have been shown to be more effective than placebo in promoting weight loss; the rate of weight loss typically is increased by ~ 0.5 pound per week with these drugs. There is little to choose among these drugs in terms of efficacy. However, long-term weight loss has not been demonstrated unless these drugs are taken continuously. In addition, other important issues have not yet been resolved, including the selection of patients who might benefit from these drugs, whether the drugs should be administered continuously or intermittently, and the duration of treatment. Adverse effects of treatment include the potential for drug abuse and habituation, serious worsening of hypertension (although in some patients blood pressure actually may fall, presumably as a consequence of weight loss), sleep disturbances, palpitations, and dry mouth. These agents may be effective adjuncts in the treatment of obesity. However, 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. β₃ Receptor agonists have remarkable anti-obesity and anti-diabetic effects in rodents. However, pharmaceutical companies have not yet succeeded in developing β₃ receptor agonists for the treatment of these conditions in humans, perhaps because of important differences in β₃ receptors between humans and rodents. With the cloning of the human β₃ receptor, compounds with favorable metabolic effects have been developed. The use of β₃ agonists in the treatment of obesity remains a possibility for the future (Fernandez-Lopez et al., 2002; Robidoux et al., 2004).

Attention-Deficit/Hyperactivity Disorder (ADHD). This syndrome, usually first evident in childhood, is characterized by excessive motor activity, difficulty in sustaining attention, and impulsiveness. Children with this disorder frequently are troubled by difficulties in school, impaired interpersonal relationships, and excitability. Academic underachievement is an important characteristic. A substantial number of children with this syndrome have characteristics that persist into adulthood, although in modified form. Behavioral therapy may be helpful in some patients. Catecholamines may be involved in the control of attention at the level of the cerebral cortex. A variety of stimulant drugs have been utilized in the treatment of ADHD, and they are particularly indicated in moderate-to-severe cases. Dextroamphetamine has been demonstrated to be more effective than placebo. Methylphenidate is effective in children with ADHD and is the most common intervention (Swanson and Volkow, 2003). 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 two or three doses of methylphenidate each day. The timing of doses is adjusted individually in accordance with rapidity of onset of effect and duration of action. Methylphenidate, dextroamphetamine, and amphetamine probably have similar efficacy in ADHD and are the preferred drugs in this disorder. Sustained-release preparations of dextroamphaetamine, methylphenidate (ritalin sr, concerta, meta-date), dexmethylphenidate (focalin xr), and amphetamine (adderal 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. Minor symptoms may be transient or may respond to adjustment of dosage or administration of the drug with meals. Other drugs that have been utilized include tricyclic antidepressants, antipsychotic agents, and clonidine. A sustained release formulation of guanfacine (intuniv), an α_2A receptor agonist, has recently been approved for use in children (ages 6-17 years) in treating ADHD.

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 other vasodilating drugs, administration of prazosin usually does not increase heart rate. Since prazosin has little or no α₂ receptor–blocking effect at concentrations achieved clinically, it probably does not promote the release of NE from sympathetic nerve endings in the heart. In addition, prazosin decreases cardiac preload and thus has little tendency to increase cardiac output and rate, in contrast to vasodilators such as hydralazine that have minimal dilatory effects on veins. Although the combination of reduced preload and selective α₁ receptor blockade might be sufficient to account for the relative absence of reflex tachycardia, prazosin also may act in the CNS to suppress sympathetic outflow. Prazosin appears to depress baroreflex function in hypertensive patients. Prazosin and related drugs in this class tend to have favorable effects on serum lipids in humans, decreasing low-density lipoproteins (LDL) and triglycerides while increasing concentrations of high-density lipoproteins (HDL). Prazosin and related drugs may have effects on cell growth unrelated to antagonism of α₁ receptors (Hu et al., 1998).

Prazosin (minipress, others) is well absorbed after oral administration, and bioavailability is ~ 50-70%. Peak concentrations of prazosin in plasma generally are reached 1-3 hours after an oral dose. The drug is tightly bound to plasma proteins (primarily α₁-acid glycoprotein), 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 t_1/2 is ~3 hours (may be prolonged to 6-8 hours in congestive heart failure). The duration of action of the drug typically is 7-10 hours in the treatment of hypertension.

The initial dose should be 1 mg, usually given at bedtime so that the patient will remain recumbent for at least several hours to reduce the risk of syncopal reactions that may follow the first dose of prazosin. Therapy is begun with 1 mg given two or three times daily, and the dose is titrated upward depending on the blood pressure. A maximal effect generally is observed with a total daily dose of 20 mg in patients with hypertension. In the off-label treatment of benign prostatic hyperplasia (BPH), doses from 1-5 mg twice daily typically are used.

Terazosin. Terazosin (hytrin, others) is a close structural analog of prazosin. It is less potent than prazosin but retains high specificity for α₁ receptors; terazosin does not discriminate among α_1A, α_1B, and α_1D receptors. The major distinction between the two drugs is in their pharmacokinetic properties.

Terazosin is more soluble in water than is prazosin, and its bioavailability is high (>90%). The t_1/2 of elimination of terazosin is ~12 hours, and its duration of action usually extends beyond 18 hours. Consequently, the drug may be taken once daily to treat hypertension and BPH in most patients. Terazosin has been found more effective than finasteride in treatment of BPH (Lepor et al., 1996). An interesting aspect of the action of terazosin and doxazosin in the treatment of lower urinary tract problems in men with BPH is the induction of apoptosis in prostate smooth muscle cells. This apoptosis may lessen the symptoms associated with chronic BPH by limiting cell proliferation. The apoptotic effect of terazosin and doxazosin appears to be related to the quinazoline moiety rather than α₁ receptor antagonism; tamsulosin, a non-quinazoline α₁ receptor antagonist, does not produce apoptosis (Kyprianou, 2003). Only ~10% of terazosin is excreted unchanged in the urine. An initial first dose of 1 mg is recommended. Doses are slowly 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 another structural analog of prazosin and a highly selective antagonist at α₁ receptors. It is non-selective among α₁ receptor subtypes, and differs from prazosin in its pharmacokinetic profile.

The t_1/2 of doxazosin is ~20 hours, and its duration of action may extend to 36 hours. The bioavailability and extent of metabolism of doxazosin and prazosin are similar. Most doxazosin metabolites are eliminated in the feces. The hemodynamic effects of doxazosin appear to be similar to those of prazosin. As in the cases of prazosin and terazosin, doxazosin should be 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 that are independent of α₁ receptor antagonism. Doxazosin is typically administered once daily. An extended-release formulation marketed for BPH is not recommended for the treatment of hypertension.

Alfuzosin. Alfuzosin (uroxatral) is a quinazoline-based α₁ receptor antagonist with similar affinity at all of the α₁ receptor subtypes. It has been used extensively in treating BPH; it is not approved for treatment of hypertension. Its bioavailability is ~64%; it has a t_1/2 of 3-5 hours. Alfuzosin is a substrate of CYP3A4 and the concomitant administration of CPY3A4 inhibitors (e.g., ketoconazole, clarithromycin, itraconazole, ritonavir) is contraindicated. Alfuzosin should be avoided in patients at risk for prolonged QT syndrome. The recommended dosage is one 10-mg extended-release tablet daily to be taken after the same meal each day.

Tamsulosin. Tamsulosin (flomax), a benzenesulfonamide, is an α₁ receptor antagonist with some selectivity for α_1A (and α_1D) subtypes compared to the α_1B subtype (Kenny et al., 1996). This selectivity may favor blockade of α_1A receptors in prostate. Tamsulosin is efficacious in the treatment of BPH with little effect on blood pressure (Beduschi et al., 1998); tamsulosin is not approved for the treatment of hypertension. Tamsulosin is well absorbed and has a t_1/2 of 5-10 hours. It is extensively metabolized by CYPs. Tamsulosin may be administered at a 0.4-mg starting dose; a dose of 0.8 mg ultimately will be more efficacious in some patients. Abnormal ejaculation is an adverse effect of tamsulosin, experienced by ~18% of patients receiving the higher dose.

Silodosin. Silidosin (rapaflo) also exhibits selectivity for the α_1A, over the α_1B adrenergic receptor. The drug is metabolized by several pathways; the main metabolite is a glucuronide formed by UGT2B7; co-administration 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 and is reported, as is tamsulosin, to have lesser effects on blood pressure than the non-α₁ subtype selective antagonists. Nevertheless, dizziness and orthostatic hypotension can occur. The chief side effect of silodosin is retrograde ejaculation (in 28% of those treated). Silodosin is available as 4-mg and 8-mg capsules.

Syncopal episodes also have occurred with a rapid increase in dosage or with the addition of a second antihypertensive drug to the regimen of a patient who already is taking a large dose of prazosin. The mechanisms responsible for such exaggerated hypotensive responses or for the development of tolerance to these effects are not clear. An action in the CNS to reduce sympathetic outflow may contribute (described earlier). 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.

Since orthostatic hypotension may be a problem during long-term treatment with prazosin or its congeners, it is essential to check standing as well as recumbent blood pressure. Nonspecific adverse effects such as headache, dizziness, and asthenia rarely limit treatment with prazosin. The nonspecific complaint of dizziness generally is not due to orthostatic hypotension. Although not extensively documented, the adverse effects of the structural analogs of prazosin appear to be similar to those of the parent compound. For tamsulosin, at a dose of 0.4 mg daily, effects on blood pressure are not expected, although impaired ejaculation may occur.

α₁ receptors in the trigone muscle of the bladder and urethra contribute to the resistance to outflow of urine. Prazosin reduces this resistance in some patients with impaired bladder emptying caused by prostatic obstruction or parasympathetic decentralization from spinal injury. The efficacy and importance of α receptor antagonists in the medical treatment of benign prostatic hyperplasia have been demonstrated in multiple controlled clinical trials. Transurethral resection of the prostate is the accepted surgical treatment for symptoms of urinary obstruction in men with BPH; however, there are some serious potential complications (e.g., risk of impotence), and improvement may not be permanent. Other, less invasive procedures also are available.

Medical therapy has utilized α receptor antagonists for many years. Finasteride (propecia, proscar, others) and dutasteride (avodart), two drugs that inhibit conversion of testosterone to dihydrotestosterone (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. These drugs rapidly improve urinary flow, whereas the actions of finasteride are typically delayed for months. Combination therapy with doxazosin and finasteride reduces the risk of overall clinical progression of BPH significantly more than treatment with either drug alone (McConnell et al., 2003). 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. There is growing evidence that the predominant α₁ receptor subtype expressed in the human prostate is the α_1A receptor (Michel and Vrydag, 2006). Developments in this area will provide the basis for the selection of α receptor antagonists with specificity for the relevant subtype of α₁ receptor. However, the possibility remains that some of the symptoms of BPH are due to α₁ receptors in other sites, such as bladder, spinal cord, or brain.

Other Disorders. Though anecdotal evidence suggested that prazosin might be useful in the treatment of patients with variant angina (Prinzmetal's angina) due to coronary vasospasm, several small controlled trials have failed to demonstrate a clear benefit. Some studies have indicated that prazosin can decrease the incidence of digital vasospasm in patients with Raynaud's disease; however, its relative efficacy as compared with other vasodilators (e.g., Ca²⁺ channel blockers) is not known. Prazosin may have some benefit in patients with other vasospastic disorders. Prazosin decreases ventricular arrhythmias induced by coronary artery ligation or reperfusion in laboratory animals; the therapeutic potential for this use in humans is not known. Prazosin also may be useful for the treatment of patients with mitral or aortic valvular insufficiency, presumably because of reduction of afterload.

Although certain vascular beds contain α₂ receptors that promote contraction of smooth muscle, it is thought that these receptors are preferentially stimulated by circulating catecholamines, whereas α₁ receptors are activated by NE released from sympathetic nerve fibers. In other vascular beds, α₂ receptors reportedly promote vasodilation by stimulating the release of NO from endothelial cells. 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 α₂ receptor 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. The compound is an indolealkylamine alkaloid and is found in the bark of the tree Pausinystalia yohimbe and in Rauwolfia root; its structure resembles that of reserpine. Yohimbine readily enters the CNS, where it acts to increase blood pressure and heart rate; it also enhances motor activity and produces tremors. These actions are opposite to those of clonidine, an α₂ agonist. Yohimbine also antagonizes effects of 5-HT. In the past, it was used extensively to treat male sexual dysfunction (Tam et al., 2001). Although efficacy never was clearly demonstrated, there is renewed interest in the use of yohimbine in the treatment of male sexual dysfunction. The drug enhances sexual activity in male rats and may benefit some patients with psychogenic erectile dysfunction. However, the efficacies of PDE5 inhibitors (e.g., sildenafil, vardenafil, and tadalafil) and apomorphine (off-label) have been much more conclusively demonstrated in oral treatment of erectile dysfunction. Several small studies suggest that yohimbine also may be useful for diabetic neuropathy and in the treatment of postural hypotension. In the U.S., yohimbine can be legally sold as a dietary supplement; however, labeling claims that it will arouse or increase sexual desire or improve sexual performance are prohibited. Yohimbine (antagonil, yobine) is approved in veterinary medicine for the reversal of xylazine anesthesia.

Non-selective α Adrenergic Antagonists: Phenoxybenzamine and Phentolamine. Phenoxybenzamine and phentolamine are non-selective α receptors antagonists. Phenoxybenzamine, a haloalkylamine compound, produces an irreversible antagonism; while phentolamine, an imidazaline, produces a competitive antagonism. Phenoxybenzamine and phentolamine have played an important role in the establishment of the importance of α receptors in the regulation of the cardiovascular and other systems. They are sometimes referred to as "classical" α blockers to distinguish them from more recently developed compounds such as prazosin.

The actions of phenoxybenzamine and phentolamine on the cardiovascular system are similar. These "classical" α blockers cause a progressive decrease in peripheral resistance, due to antagonism of α receptors in the vasculature, and an increase in cardiac output that is due in part to reflex sympathetic nerve stimulation. The cardiac stimulation is accentuated by enhanced release of NE from cardiac sympathetic nerve due to antagonism of presynaptic α₂ receptors by these non-selective α blockers. Postural hypotension is a prominent feature with these drugs and this, accompanied by reflex tachycardia that can precipitate cardiac arrhythmias, severely limits the use of these drugs to treat essential hypertension. The more recently developed α₁-selective antagonists, such as prazosin, 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. Pheochromocytomas are tumors of the adrenal medulla and sympathetic neurons that secrete enormous quantities of catecholamines into the circulation. The usual result is hypertension, which may be episodic and severe. The vast majority of pheochromocytomas are treated surgically; however, phenoxybenzamine is often used in preparing the patient for surgery. The drug controls episodes of severe hypertension and minimizes other adverse effects of catecholamines, such as contraction of plasma volume and injury of the myocardium. 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. Therapy may be limited by postural hypotension; nasal stuffiness is another frequent adverse effect. The usual daily dose of phenoxybenzamine in patients with pheochromocytoma is 40-120 mg given in two or three divided portions. 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 may be a useful adjuvant. Metyrosine (demser) is a competitive inhibitor of tyrosine hydroxylase, the rate-limiting enzyme in the synthesis of catecholamines (Chapter 8). β Receptor antagonists also are used to treat pheochromocytoma, but only after the administration of an α receptor antagonist (described later).

Phentolamine can also be used in short-term control of hypertension in patients with pheochromocytoma. Rapid infusions of phentolamine may cause severe hypotension, so the drug should be administered cautiously. Phentolamine also may be useful to relieve pseudo-obstruction of the bowel in patients with pheochromocytoma; this condition may result from the inhibitory effects of catecholamines on intestinal smooth muscle.

Phentolamine has been used locally to prevent dermal necrosis after the inadvertent extravasation of an α receptor agonist. The drug also may be useful for the treatment of hypertensive crises that follow the abrupt withdrawal of clonidine or that may result from the ingestion of tyramine-containing foods during the use of non-selective MAO inhibitors. Although excessive activation of α receptors is important in the development of severe hypertension in these settings, there is little information about the safety and efficacy of phentolamine compared with those of other antihypertensive agents in the treatment of such patients. Direct intracavernous injection of phentolamine (in combination with papaverine) has been proposed as a treatment for male sexual dysfunction. The long-term efficacy of this treatment is not known. Intracavernous injection of phentolamine may cause orthostatic hypotension and priapism; pharmacological reversal of drug-induced erections can be achieved with an α receptor agonist such as phenylephrine. Repetitive intrapenile injections may cause fibrotic reactions. Buccally or orally administered phentolamine may have efficacy in some men with sexual dysfunction.

In 2008, the FDA approved the use of phentolamine (oraverse) to reverse or shorten the duration of soft-tissue anesthesia. Sympathomimetics are frequently administered with local anesthetics to slow the removal of the anesthetic by causing vasoconstriction. When the need for anesthesia is over, phentolamine can help reverse it by antagonizing the α-receptor induced vasoconstriction.

Phenoxybenzamine has been used off-label to control the manifestations of autonomic hyperreflexia in patients with spinal cord transection.

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, and repeated administration of this drug to experimental animals causes peritoneal sarcomas and lung tumors. The clinical significance of these findings is not known. Phentolamine stimulates GI smooth muscle, an effect antagonized by atropine, and also enhances gastric acid secretion due in part to histamine release. Thus, phentolamine should be used with caution in patients with a history of peptic ulcer.

Additional α Adrenergic Receptor Antagonists

Ergot Alkaloids. The ergot alkaloids were the first adrenergic receptor antagonists to be discovered, and most aspects of their general pharmacology were disclosed in the classic studies of Dale. Ergot alkaloids exhibit a complex variety of pharmacological properties. To varying degrees, these agents act as partial agonists or antagonists at α receptors, DA receptors, and serotonin receptors. Additional information about the ergot alkaloids can be found in Chapter 13 and in previous editions of this book.

Indoramin. Indoramin is a selective, competitive α₁ receptor antagonist that is used outside the U.S. for the treatment of hypertension, BPH, and in the prophylaxis of migraine. Competitive antagonism of histamine H₁ and 5-HT receptors also is evident. As an α₁-selective antagonist, indoramin lowers blood pressure with minimal tachycardia. The drug also decreases the incidence of attacks of Raynaud's phenomenon.

The bioavailability of indoramin generally is < 30% (with considerable variability), and it undergoes extensive first-pass metabolism. Little unchanged drug is excreted in the urine, and some of the metabolites may be biologically active. The elimination t_1/2 is ~5 hours. Some of the adverse effects of indoramin include sedation, dry mouth, and failure of ejaculation. Although indoramin is an effective antihypertensive agent, it has complex pharmacokinetics and lacks a well-defined place in current therapy.

Ketanserin. Although developed as a 5-HT-receptor antagonist, ketanserin also blocks α₁ receptors. Ketanserin (not available in the U.S.) is discussed in Chapter 13.

Urapidil. Urapidil is a novel, selective α₁ receptor antagonist that has a chemical structure distinct from those of prazosin and related compounds; the drug 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. The drug is extensively metabolized and has a t_1/2 of 3 hours. The role of urapidil in the treatment of hypertension remains to be determined.

Bunazosin. Bunazosin is an α₁-selective antagonist of the quinazoline class that has been shown to lower blood pressure in patients with hypertension. Bunazosin is available in Germany, Japan, Thailand, and Indonesia.

Neuroleptic Agents. Natural and synthetic compounds of several other chemical classes developed primarily because they are antagonists of D₂ dopamine receptors also exhibit α receptor blocking activity. Chlorpromazine, haloperidol, and other neuroleptic drugs of the phenothiazine and butyrophenone types produce significant α receptor blockade in both laboratory animals and humans.

History. Ahlquist's hypothesis that the effects of catecholamines were mediated by activation of distinct α and β receptors provided the initial impetus for the synthesis and pharmacological evaluation of β receptor antagonists (Chapter 8). The first such selective agent was dichloroisoproterenol, a partial agonist. Sir James Black and his colleagues initiated a program in the late 1950s to develop additional β blockers, with the resulting synthesis and characterization of propranolol.

Chemistry. The structural formulas of some β receptor antagonists in general use are shown in Figures 12–7 and 12–8. The structural similarities between agonists and antagonists that act on β receptors are closer than those between α receptor agonists and antagonists. Substitution of an isopropyl group or other bulky substituent on the amino nitrogen favors interaction with β receptors. There is a rather wide tolerance for the nature of the aromatic moiety in the non-selective β receptor antagonists; however, the structural tolerance for β₁-selective antagonists is far more constrained.

In this chapter, 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 12–3 summarizes important pharmacological and pharmacokinetic properties of β receptor antagonists.

β Receptor antagonists have significant effects on cardiac rhythm and automaticity. Although it had been thought that these effects were due exclusively to blockade of β₁ receptors, β₂ receptors likely also regulate heart rate in humans (Altschuld and Billman, 2000; Brodde and Michel, 1999). β₃ Receptors also have been identified in normal myocardial tissue in several species, including humans (Moniotte et al., 2001). Signal transduction for β₃ receptors is complex and includes G_s but also G_i/G_o; stimulation of cardiac β₃ receptors inhibits cardiac contraction and relaxation. The physiological role of β₃ receptors in the heart remains to be established (Morimoto et al., 2004). 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.

Although high concentrations of many β blockers produce quinidine-like effects (membrane-stabilizing activity), it is doubtful that this is significant at usual doses of these agents. However, this effect may be important when there is overdosage. Interestingly, d-propranolol may suppress ventricular arrhythmias independently of β receptor blockade.

The cardiovascular effects of β receptor antagonists are most evident during dynamic exercise. In the presence of β receptor blockade, exercise-induced increases in heart rate and myocardial contractility are attenuated. However, the exercise-induced increase in cardiac output is less affected because of an increase in stroke volume. The effects of β receptor antagonists on exercise are somewhat analogous to the changes that occur with normal aging. In healthy elderly persons, catecholamine-induced increases in heart rate are smaller than in younger individuals; however, the increase in cardiac output in older people may be preserved because of an increase in stroke volume during exercise. β Blockers tend to decrease work capacity, as assessed by their effects on intense short-term or more prolonged steady-state exertion. Exercise performance may be impaired to a lesser extent by β₁-selective agents than by non-selective antagonists. Blockade of β₂ receptors tends to blunt the increase in blood flow to active skeletal muscle during submaximal exercise. Blockade of β receptors also may attenuate catecholamine-induced activation of glucose metabolism and lipolysis.

Coronary artery blood flow increases during exercise or stress to meet the metabolic demands of the heart. By increasing heart rate, contractility, and systolic pressure, catecholamines increase myocardial oxygen demand. However, in patients with coronary artery disease, fixed narrowing of these vessels attenuates the expected increase in flow, leading to myocardial ischemia. β Receptor antagonists decrease the effects of catecholamines on the determinants of myocardial O₂ consumption. However, these agents may tend to increase the requirement for oxygen by increasing end-diastolic pressure and systolic ejection period. Usually, the net effect is to improve the relationship between cardiac O₂ supply and demand; exercise tolerance generally is improved in patients with angina, whose capacity to exercise is limited by the development of chest pain (Chapter 28).

Presynaptic β receptors enhance the release of NE from sympathetic neurons, but the importance of diminished release of NE to the antihypertensive effects of β antagonists is unclear. Although β blockers would not be expected to decrease the contractility of vascular smooth muscle, long-term administration of these drugs to hypertensive patients ultimately leads to a fall in peripheral vascular resistance (Man in't Veld et al., 1988). The mechanism for this important effect is not known, but this delayed fall in peripheral vascular resistance in the face of a persistent reduction of cardiac output appears to account for much of the antihypertensive effect of these drugs. Although it has been hypothesized that central actions of β blockers also may contribute to their antihypertensive effects, there is relatively little evidence to support this possibility, and drugs that poorly penetrate the blood-brain barrier are effective antihypertensive agents.

As indicated, some β receptor antagonists have additional effects that may contribute to their capacity to lower blood pressure. These drugs all produce peripheral vasodilation; at least six properties have been proposed to contribute to this effect, including production of nitric oxide, activation of β₂ receptors, blockade of α₁ receptors, blockade of Ca²⁺ entry, opening of K⁺ channels, and antioxidant activity. The ability of vasodilating β receptor antagonists to act through one or more of these mechanisms is depicted in Table 12–4 and Figure 12–9. These mechanisms appear to contribute to the antihypertensive effects by enhancing hypotension, increasing peripheral blood flow, and decreasing afterload. Two of these agents (e.g., celiprolol and nebivolol) also have been observed to produce vasodilation and thereby reduce preload.

Although further clinical trials are needed, these agents may be associated with a lower incidence of bronchospasm, impaired lipid metabolism, impotence, reduced regional blood flow, increased vascular resistance, and withdrawal symptoms. A lower incidence of these adverse effects would be particularly beneficial in patients who have insulin resistance and diabetes mellitus in addition to hypertension (Toda, 2003). The clinical significance in humans of some of these relatively subtle differences in pharmacological properties still is unclear. Particular interest has focused on patients with congestive heart failure or peripheral arterial occlusive disease.

Propranolol and other non-selective β receptor antagonists inhibit the vasodilation caused by isoproterenol and augment the pressor response to epinephrine. 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. This avoids uncompensated α receptor–mediated vasoconstriction caused by epinephrine secreted from the tumor.

The β receptors mediate activation of hormone-sensitive lipase in fat cells, leading to release of free fatty acids into the circulation (Chapter 8). This increased flux of fatty acids is an important source of energy for exercising muscle. β Receptor antagonists can attenuate the release of free fatty acids from adipose tissue. Non-selective 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. While drugs such as propranolol and atenolol increase triglycerides, plasma triglycerides are reduced with chronic celiprolol, carvedilol, and carteolol (Toda, 2003).

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. Together with their cardioprotective effects, improvement in insulin sensitivity from vasodilating β receptor antagonists may partially counterbalance the hazard from worsened lipid abnormalities associated with diabetes. If β blockers are to be used, β₁-selective or vasodilating β receptor antagonists are preferred. In addition, it may be necessary to use β receptor antagonists in conjunction with other drugs, (e.g., HMGCoA reductase inhibitors) to ameliorate adverse metabolic effects (Dunne et al., 2001).

β Receptor agonists decrease the plasma concentration of K⁺ by promoting the uptake of the ion, predominantly into skeletal muscle. At rest, an infusion of epinephrine causes a decrease in the plasma concentration of K⁺. The marked increase in the concentration of epinephrine that occurs with stress (such as myocardial infarction) may cause hypokalemia, which could predispose to cardiac arrhythmias. The hypokalemic effect of epinephrine is blocked by an experimental antagonist, ICI 118551, which has a high affinity for β₂ and β₃ receptors. Exercise causes an increase in the efflux of K⁺ from skeletal muscle. Catecholamines tend to buffer the rise in K⁺ by increasing its influx into muscle. β Blockers negate this buffering effect.

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

Some patients complain of cold extremities while taking β receptor antagonists. Symptoms of peripheral vascular disease may worsen, although this is uncommon, or Raynaud's phenomenon may develop. The risk of worsening intermittent claudication probably is very small with this class of drugs, and the clinical benefits of β antagonists in patients with peripheral vascular disease and coexisting coronary artery disease may be very important.

Abrupt discontinuation of β receptor antagonists after long-term treatment can exacerbate angina and may increase the risk of sudden death. The underlying mechanism is unclear, but it is well established that there is enhanced sensitivity to β receptor agonists in patients who have undergone long-term treatment with certain β receptor antagonists after the blocker is withdrawn abruptly. For example, chronotropic responses to isoproterenol are blunted in patients who are receiving β receptor antagonists; however, abrupt discontinuation of propranolol leads to greater-than-normal sensitivity to isoproterenol. This increased sensitivity is evident several days after stopping propranolol and may persist for at least 1 week. Such enhanced sensitivity can be attenuated by tapering the dose of the β blocker for several weeks before discontinuation. Supersensitivity to isoproterenol also has been observed after abrupt discontinuation of metoprolol, but not of pindolol. This enhanced β responsiveness may result from up-regulation of β receptors. The number of β receptors on circulating lymphocytes is increased in subjects who have received propranolol for long periods; pindolol has the opposite effect. Optimal strategies for discontinuation of β blockers are not known, but it is prudent to decrease the dose gradually and to restrict exercise during this period.

Metabolism. As already described, β adrenergic blockade may blunt recognition of hypoglycemia by patients; it also may delay recovery from insulin-induced hypoglycemia. β Receptor antagonists should be used with great caution in patients with diabetes who are prone to hypoglycemic reactions; β₁-selective agents may be preferable for these patients. The benefits of β receptor antagonists in type 1 diabetes with myocardial infarction may outweigh the risk in selected patients (Gottlieb et al., 1998).

Miscellaneous. The incidence of sexual dysfunction in men with hypertension who are treated with β receptor antagonists is not clearly defined. Although experience with the use of β adrenergic receptor antagonists in pregnancy is increasing, information about the safety of these drugs during pregnancy still is limited.

Overdosage. The manifestations of poisoning with β receptor antagonists depend on the pharmacological properties of the ingested drug, particularly its β₁ selectivity, intrinsic sympathomimetic activity, and membrane-stabilizing properties. Hypotension, bradycardia, prolonged AV conduction times, and widened QRS complexes are common manifestations of overdosage. Seizures and depression may occur. Hypoglycemia and bronchospasm can occur. Significant bradycardia should be treated initially with atropine, but a cardiac pacemaker often is required. Large doses of isoproterenol or an α receptor agonist may be necessary to treat hypotension. Glucagon, acting through its own GPCR and independently of the β adrenergic receptor, has positive chronotropic and inotropic effects on the heart, and the drug has been useful in some patients suffering from an overdose of a β receptor antagoinst.

Drug Interactions. Both pharmacokinetic and pharmacodynamic interactions have been noted between β receptor antagonists and other drugs. Interactions with sympathomimetics, α blockers, and β agonists are predictable from the pharmacology. 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 that are metabolized extensively (e.g., propranolol). Cimetidine and hydralazine may increase the bioavailability of agents such as propranolol and metoprolol by affecting hepatic blood flow. β Receptor antagonists can impair the clearance of lidocaine.

Other drug interactions have pharmacodynamic explanations. For example, β antagonists and Ca²⁺ channel blockers have additive effects on the cardiac conducting system. Additive effects on blood pressure between β blockers and other antihypertensive agents often are employed to clinical advantage. However, the antihypertensive effects of β receptor antagonists can be opposed by indomethacin and other nonsteroidal anti-inflammatory drugs (Chapter 34).

Large trials have been conducted with carvedilol, bisoprolol, metoprolol, xamoterol, bucindolol, betaxol, nebivolol, and talinolol (Cleland, 2003). Carvedilol, metoprolol, and bisoprolol all have been shown to reduce the mortality rate in large cohorts of patients with stable chronic heart failure regardless of severity (Bolger and Al-Nasser, 2003; Cleland, 2003). In the initial use of β blockers for treating heart failure, the beginning effects often are neutral or even adverse. Benefits accumulate gradually over a period of weeks to months, although benefits from the third-generation vasodilator β blocker carvedilol may be seen within days in patients with severe heart failure. There also is a reduction in the hospitalization of patients along with a reduction in mortality with fewer sudden deaths and deaths caused by progressive heart failure. These benefits extend to patients with asthma and with diabetes mellitus (Cruickshank, 2002; Dunne et al., 2001; Salpeter, 2003; Self et al., 2003). Patients in atrial fibrillation and heart failure can also benefit from β blockade (Kühlkamp et al., 2002). On the other hand, patients with heart failure and atrial fibrillation are associated with a higher mortality, and the benefit derived from β blockers may not be comparable to those in sinus rhythm (Fung et al., 2003). Long-term β blockade reduces cardiac volume, myocardial hypertrophy, and filling pressure, and increases ejection fraction (e.g., ventricular remodeling). β Receptor antagonists impact mortality even before beneficial effects on ventricular function are observed, possibly due to prevention of arrhythmias or a reduction in acute vascular events.

Some patients are unable to tolerate β blockers. Hopefully, ongoing trials will identify the common characteristics that define this population so that β blockers can be avoided in these patients (Bolger and Al-Nasser, 2003). Because of the real possibility of acutely worsening cardiac function, β receptor antagonists should be initiated only by clinicians experienced in patients with congestive heart failure. As might be anticipated, starting with very low doses of drug and advancing doses slowly over time, depending on each patient's response, are critical for the safe use of these drugs in patients with congestive heart failure.

It is unknown whether it is necessary to block only the β₁ adrenergic receptor or whether non-selective agents would be more desirable in the management of heart failure. Blockade of β₂ adrenergic receptors can enhance peripheral vasoconstriction and bronchoconstriction and therefore have a deleterious effect. On the other hand, blocking β₂ receptors might be advantageous due to more effectively protecting cardiac cells from catecholamine excess and hypokalemia. Some propose that non-selective β antagonists that block both β₁ and β₂ receptors and also have peripheral vasodilatory actions (third-generation β blockers) may offer the best myocardial, metabolic, and hemodynamic benefit (Chapter 28) (Cleland, 2003). Some experts have recommended that β blockers be considered as part of the standard treatment regimen for all patients with mild to moderate heart failure (Goldstein, 2002; Maggioni et al., 2003).

It is of potential interest that expression of β₂ receptors is relatively maintained in these settings of heart failure. While both β₁ and β₂ receptors activate adenylyl cyclase by means of G_s, there is evidence suggesting that β₂ receptors also stimulate G_i, which may attenuate contractile responses and lead to activation of other effector pathways downstream of G_i (Lefkowitz et al., 2000). Overexpression of β₂ adrenergic receptors in mouse heart is associated with increased cardiac force without the development of cardiomyopathy (Liggett et al., 2000). The stimulation of β₃ adrenergic receptors inhibits contraction and relaxation (Gauthier et al., 2000). In contrast to β₁ and β₂ receptors, β₃ receptors are upregulated in heart failure (Moniotte et al., 2001). This has led to the hypothesis that in severe congestive heart failure, as β₁ and β₂ receptor pathways by G_s become less responsive, the inhibitory effects of the β₃ receptor pathway may contribute to the detrimental effects of sympathetic stimulation in congestive heart failure (Morimoto et al., 2004). Thus, the blockade of β₃ receptors by β antagonists (e.g., carvedilol) could improve the acute tolerability and benefit of β₁ and β₂ receptor antagonists (Moniotte et al., 2001; Morimoto et al., 2004).

The mechanisms by which β receptor antagonists decrease mortality in patients with congestive heart failure are still unclear. Perhaps this is not surprising, given that the mechanism by which this class of drugs lowers blood pressure in patients with hypertension remains elusive despite years of investigation (Chapter 27). This is much more than an academic undertaking; a deeper understanding of involved pathways could lead to selection of the most appropriate drugs available as well as the development of novel compounds with especially desirable properties. The potential differences among β₁, β₂, and β₃ receptor function in heart failure is one example of the complexity of adrenergic pharmacology of this syndrome. There is evidence for multiple affinity states of the β₁ receptor, for cell–type specific coupling of β receptor subtypes to signalling pathways other than G_s-adenylyl cyclase–cyclic AMP, and form altered receptor properties when β₂ and β₃ receptors for hetero-oligomers (Breit et al., 2004; Rozec et al., 2003). Such findings suggest opportunities for the development of more focused β-antagonist therapy in the future.

A number of mechanisms have been proposed to play a role in the beneficial effects of β receptor antagonists in heart failure. Since excess effects of catecholamines may be toxic to the heart, especially through activation of β₁ receptors, inhibition of the pathway may help preserve myocardial function. Also, antagonism of β receptors in the heart may attenuate cardiac remodeling, which ordinarily might have deleterious effects on cardiac function. Interestingly, activation of β receptors and elevation of cellular cyclic AMP may promote myocardial cell death by apoptosis (Singh et al., 2000; Brunton, 2005; Ding et al., 2005). In addition, properties of certain β receptor antagonists that are due to other, unrelated properties of these drugs may be potentially important. For example, afterload reduction by drugs such as carvedilol may be relevant. The potential importance of the α₁-antagonistic and antioxidant properties of carvedilol in its beneficial effects in patients with heart failure is not clear (Ma et al., 1996).

Use of β Antagonists in Other Cardiovascular Diseases. 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. Efficacy probably is related to partial relief of the pressure gradient along the outflow tract. β Blockers also may attenuate catecholamine-induced cardiomyopathy in pheochromocytoma.

β Blockers are used frequently in the medical management of acute dissecting aortic aneurysm; their usefulness comes from reduction in the force of myocardial contraction and the rate of development of such force. Nitroprusside is an alternative, but when given in the absence of β receptor blockade, it causes an undesirable tachycardia. Patients with Marfan's syndrome may develop progressive dilation of the aorta, which may lead to aortic dissection and regurgitation, a major cause of death in these patients. Chronic treatment with propranolol may be efficacious in slowing the progression of aortic dilation and its complications in patients with Marfan's syndrome (Shores et al., 1994).

β Receptor antagonists generally are administered as eye drops and have an onset in ~30 minutes with a duration of 12-24 hours. While topically administered β blockers usually are well tolerated, systemic absorption can lead to adverse cardiovascular and pulmonary effects in susceptible patients. They therefore should be used with great caution in glaucoma patients at risk for adverse systemic effects of β receptor antagonists (e.g., patients with bronchial asthma, severe COPD, or those with bradyarrhythmias). The use of topically administered β blockers for treatment of glaucoma is discussed further in Chapter 64. Three β blockers (betaxolol, metipranolol, and timolol) also have been observed to confer protection to retinal neurons, apparently related to their ability to attenuate neuronal Ca²⁺ and Na⁺ influx (Wood et al., 2003). Betaxolol is the most effective antiglaucoma drug at reducing Na⁺/Ca²⁺ influx. β Blockers may be able to blunt ganglion cell death in glaucoma and that levobetaxolol may be a more important neuroprotectant than timolol because of its greater capacity to block Na⁺ and Ca²⁺ influx (Osborne et al., 2004).

Other Uses. Many of the signs and symptoms of hyperthyroidism are reminiscent of the manifestations of increased sympathetic nervous system activity. Indeed, excess thyroid hormone increases the expression of β receptors in some types of cells. 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. However, caution is advised in treating patients with cardiac enlargement, since the use of β receptor antagonists may precipitate congestive heart failure (see Chapter 39 for further discussion of the treatment of hyperthyroidism).

Propranolol, timolol, and metoprolol are effective for the prophylaxis of migraine (Tfelt-Hansen, 1986); the mechanism of this effect is not known, and these drugs are not useful for treatment of acute attacks of migraine.

Propranolol and other β blockers are effective in controlling acute panic symptoms in individuals who are required to perform in public or in other anxiety-provoking situations. Public speakers may be calmed by the prophylactic administration of the drug, and the performance of musicians may be improved. Tachycardia, muscle tremors, and other evidence of increased sympathetic activity are reduced. Propranolol also may be useful in the treatment of essential tremor.

β Blockers may be of some value in the treatment of patients undergoing withdrawal from alcohol or those with akathisia. Propranolol and nadolol are efficacious in the primary prevention of variceal bleeding in patients with portal hypertension caused by cirrhosis of the liver (Bosch, 1998; Villanueva et al., 1996). Isosorbide mononitrate may augment the fall in portal pressure seen in some patients treated with β receptor antagonists. These drugs also may be beneficial in reducing the risk of recurrent variceal bleeding.

Absorption, Fate, and Excretion. Propranolol is highly lipophilic and is almost completely absorbed after oral administration. However, much of the drug is metabolized by the liver during its first passage through the portal circulation; on average, only ~25% reaches the systemic circulation. In addition, there is great inter-individual variation in the presystemic clearance of propranolol by the liver; this contributes to enormous variability in plasma concentrations (~20-fold) after oral administration of the drug and contributes to the wide dosage range for clinical efficacy. A clinical disadvantage of propranolol is that multiple increases in drug dose may be required over time. 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 and during long-term administration of the drug.

Propranolol has a large volume of distribution (4 L/kg) and readily enters the CNS. Approximately 90% of the drug in the circulation is bound to plasma proteins. It is extensively metabolized, with most metabolites appearing in the urine. One product of hepatic metabolism is 4-hydroxypropranolol, which has some β adrenergic antagonist activity.

Analysis of the distribution of propranolol, its clearance by the liver, and its activity is complicated by the stereospecificity of these processes (Walle et al., 1988). The (−)-enantiomers of propranolol and other β blockers are the active forms of the drug. The (−)-enantiomer of propranolol appears to be cleared more slowly from the body than is the inactive enantiomer. The clearance of propranolol may vary with hepatic blood flow and liver disease and also may change during the administration of other drugs that affect hepatic metabolism. Monitoring of plasma concentrations of propranolol has found little application, since the clinical end points (reduction of blood pressure and heart rate) are readily determined. The relationships between the plasma concentrations of propranolol and its pharmacodynamic effects are complex; for example, despite its short t_1/2 in plasma (~4 hours), its antihypertensive effect is sufficiently long-lived to permit administration twice daily in some patients. Some of the (−)-enantiomer of propranolol and other β blockers is taken up into sympathetic nerve endings and is released upon sympathetic nerve stimulation (Walle et al., 1988).

Sustained-release formulations of propranolol (inderal la, others) have been developed to maintain therapeutic concentrations of propranolol in plasma throughout a 24-hour period. Suppression of exercise-induced tachycardia is maintained throughout the dosing interval, and patient compliance may be improved.

Therapeutic Uses. For the treatment of hypertension and angina, the initial oral dose of propranolol generally is 40-80 mg per day. The dose may then be titrated upward until the optimal response is obtained. For the treatment of angina, the dose may be increased at intervals of < 1 week, as indicated clinically. In hypertension, the full blood-pressure response may not develop for several weeks. Typically, doses are < 320 mg/day. If propranolol is taken twice daily for hypertension, blood pressure should be measured just prior to a dose to ensure that the duration of effect is sufficiently prolonged. Adequacy of β adrenergic blockade can be assessed by measuring suppression of exercise-induced tachycardia. 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 has been used for several off-label indications including parkinsonian tremors (sustained-release only), akathisia induced by antipsychotic drugs, variceal bleeding in portal hypertension, and generalized anxiety disorder (Table 12–4).

Propranolol may be administered intravenously for the management of life-threatening arrhythmias or to patients under anesthesia. Under these circumstances, the usual dose is 1-3 mg, administered slowly (< 1 mg/min) with careful and frequent monitoring of blood pressure, ECG, and cardiac function. If an adequate response is not obtained, a second dose may be given after several minutes. If bradycardia is excessive, atropine should be administered to increase heart rate. Change to oral therapy should be initiated as soon as possible. Use of propranolol was associated with a 26% reduction in mortality in the β Blocker Heart Attack Trial (BHAT) (Dobre et al., 2007)

Absorption, Fate, and Excretion. Nadolol is very soluble in water and is incompletely absorbed from the gut; its bioavailability is ~35%. Interindividual variability is less than with propranolol. The low lipid solubility of nadolol may result in lower concentrations of the drug in the brain as compared with more lipid-soluble β receptor antagonists. Although it frequently has been suggested that the incidence of CNS adverse effects is lower with hydrophilic β receptor antagonists, data from controlled trials to support this contention are limited. Nadolol is not extensively metabolized and is largely excreted intact in the urine. The t_1/2 of the drug in plasma is ~20 hours; consequently, it generally is administered once daily. Nadolol may accumulate in patients with renal failure, and dosage should be reduced in such individuals.

Absorption, Fate, and Excretion. Timolol is well absorbed from the GI tract. It is metabolized extensively by CYP2D6 in the liver and undergoes first-pass metabolism. Only a small amount of unchanged drug appears in the urine. The t_1/2 in plasma is ~4 hours. Interestingly, the ocular formulation of timolol (timoptic, others), used for the treatment of glaucoma, may be extensively absorbed systemically (Chapter 64); adverse effects can occur in susceptible patients, such as those with asthma or congestive heart failure. The systemic administration of cimetidine with topical ocular timolol increases the degree of β blockade, resulting in a reduction of resting heart rate, intraocular pressure, and exercise tolerance (Ishii et al., 2000). For ophthalmic use timolol is available combined with other medications (e.g., with dorzolamide or travoprost). Timolol also provide benefits to patients with coronary heart disease: in the acute post MI period, timolol produced a 39% reduction in mortality in the Norwegian Multicenter Study.

Although only limited data are available, β blockers with slight partial agonist activity may produce smaller reductions in resting heart rate and blood pressure. Hence, such drugs may be preferred as antihypertensive agents in individuals with diminished cardiac reserve or a propensity for bradycardia. Nonetheless, the clinical significance of partial agonism has not been substantially demonstrated in controlled trials but may be of importance in individual patients. Agents such as pindolol block exercise-induced increases in heart rate and cardiac output.

Absorption, Fate, and Excretion. Pindolol is almost completely absorbed after oral administration and has moderately high bioavailability. These properties tend to minimize interindividual variation in the plasma concentrations of the drug that are achieved after its oral administration. Approximately 50% of pindolol ultimately is metabolized in the liver. The principal metabolites are hydroxylated derivatives that subsequently are conjugated with either glucuronide or sulfate before renal excretion. The remainder of the drug is excreted unchanged in the urine. The plasma t_1/2 of pindolol is ~4 hours; clearance is reduced in patients with renal failure.

Absorption, Fate, and Excretion. Metoprolol is almost completely 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), perhaps because of genetically determined differences in the rate of metabolism. Metoprolol is extensively metabolized in the liver, with CYP2D6 the major enzyme involved, and only 10% of the administered drug is recovered unchanged in the urine. The t_1/2 of metoprolol is 3-4 hours, but can increase to 7-8 hours in CYP2D6 poor metabolizers. It recently has been reported that CYP2D6 poor metabolizers have a 5-fold higher risk for developing adverse effects during metoprolol treatment than patients who are not poor metabolizers (Wuttke et al., 2002). An extended-release formulation (toprol xl) is available for once-daily administration.

Therapeutic Uses. Metoprolol has been used to treat essential hypertension, angina pectoris, tachycardia, heart failure, vasovagal syncope, and as secondary prevention after myocardial infarction, an adjunct in treatment of hyperthyroidism, and for migraine prophylaxis. 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 two divided doses. Dosage may be increased at weekly intervals until optimal reduction of blood pressure is achieved. If the drug is taken only once daily, it is important to confirm that blood pressure is controlled for the entire 24-hour period. Metoprolol generally is used in two 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. Oral dosing is initiated as soon as the clinical situation permits. Metoprolol generally is contraindicated for the treatment of acute myocardial infarction in patients with heart rates of < 45 beats per minute, 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. Its use is associated with a striking reduction in all-cause mortality and hospitalization for worsening heart failure and a modest reduction in all-cause hospitalization (MERIT-HF Study Group, 1999; Prakash and Markham, 2000).

Absorption, Fate, and Excretion. Atenolol is incompletely absorbed (~50%), but most of the absorbed dose reaches the systemic circulation. There is relatively little interindividual variation in the plasma concentrations of atenolol; peak concentrations in different patients vary over only a 4-fold range. The drug is excreted largely unchanged in the urine, and the elimination t_1/2 is 5-8 hours. The drug accumulates in patients with renal failure, and dosage should be adjusted for patients whose creatinine clearance is < 35 mL/min.

Therapeutic Uses. Atenol can be used to treat hypertension, coronary heart disease, arrhythmias, and angina pectoris, and to treat or reduce the risk of heart complications following myocardial infarction. It is also used to treat Graves disease until anti-thyroid medication can take effect. The initial dose of atenolol for the treatment of hypertension usually is 50 mg/day, given once daily. If an adequate therapeutic response is not evident within several weeks, the daily dose may be increased to 100 mg; higher doses are unlikely to provide any greater antihypertensive effect. Atenolol has been shown to be efficacious, in combination with a diuretic, in elderly patients with isolated systolic hypertension. Atenolol causes fewer CNS side effects (depression, nightmares) than most β blockers and few bronchospatic reactions due to its pharmacological and pharmacokinetic profile (Varon, 2008).

Absorption, Fate, and Excretion. Esmolol is given by slow IV injection and has a t_1/2 of ~8 minutes and an apparent volume of distribution of ~2 L/kg. The drug contains an ester linkage, and it is hydrolyzed rapidly by esterases in erythrocytes. The t_1/2 of the carboxylic acid metabolite of esmolol is far longer (4 hours), and it accumulates during prolonged infusion of esmolol. However, this metabolite has very low potency as a β receptor antagonist (1/500 of the potency of esmolol); it is excreted in the urine.

Esmolol is commonly used in patients during surgery to prevent or treat tachycardia and in the treatment of supraventricular tachycardia. The onset and cessation of β receptor blockade with esmolol are rapid; peak hemodynamic effects occur within 6-10 minutes of administration of a loading dose, and there is substantial attenuation of β blockade within 20 minutes of stopping an infusion. Esmolol may have striking hypotensive effects in normal subjects, although the mechanism of this effect is unclear.

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 minutes, the same loading dose is repeated, followed by a maintenance infusion at a higher rate. This process, including progressively greater infusion rates, may need to be repeated until the desired end point (e.g., lowered heart rate or blood pressure) is approached. Esmolol is particularly useful in severe postoperative hypertension and is a suitable agent in situations where cardiac output, heart rate, and blood pressure are increased. The American Heart Association/American College of Cardiology guidelines recommend against using esmolol in patients already on β blocker therapy, bradycardiac patients, and decompensated heart failure patients, as the drug may compromise their myocardial function (Varon, 2008).

Absorption, Fate, and Excretion. Acebutolol is well absorbed, and undergoes significant first-pass metabolism to an active metabolite, diacetolol, which accounts for most of the drug's activity. Overall bioavailability is 35-50%. The elimination t_1/2 of acebutolol typically is ~3 hours, but the t_1/2 of diacetolol is 8-12 hours; it is excreted largely in the urine. Acebutolol has lipophilic properties and crosses the blood-brain barrier. It has no negative impact on serum lipids (cholesterol, triglycerides, or HDL).

Therapeutic Uses. Acebutol has been used to treat hypertension, ventricular and atrial cardiac arrhythmias, acute myocardial infarction in high-risk patients, and Smith-Magenis syndrome. The initial dose of acebutolol in hypertension usually is 400 mg/day; it may be given as a single dose, but two divided doses may be required for adequate control of blood pressure. Optimal responses usually occur with doses of 400-800 mg per day (range, 200-1200 mg).

Bisoprolol generally is well tolerated; side effects include dizziness, bradycardia, hypotension, and fatigue. Bisoprolol is well absorbed following oral administration, with bioavailability of ~90%. It is eliminated by renal excretion (50%) and liver metabolism to pharmacologically inactive metabolites (50%). Bisoprolol has a plasma t_1/2 of 11-17 hours. 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 stable, moderate to severe chronic heart failure and in treating hypertension (McGavin and Keating, 2002; Simon et al., 2003). It has also been used to treat arrhythmias and ischemic heart disease. Bisoprolol was associated with a 34% mortality benefit in the Cardiac Insufficiency Bisoprolol Study-II (CIBIS-II).

Absorption, Fate, and Excretion. Betaxolol is well absorbed with high bioavailability and an elimination t_1/2 of 14-22 hours.

Therapeutic Uses. 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 by reducing the production of aqueous humor in the eye.

The pharmacological effects of labetalol have become clearer since the four isomers were separated and tested individually. The R,R isomer is about four times more potent as a β receptor antagonist than is racemic labetalol and accounts for much of the β blockade produced by the mixture of isomers; it no longer is in development as a separate drug (dilevalol). As an α₁ antagonist, this isomer is < 20% as potent as the racemic mixture. The R,S isomer is almost devoid of both α and β blocking effects. The S,R isomer has almost no β blocking activity, yet is about five times more potent as an α₁ blocker than is racemic labetalol. The S,S isomer is devoid of β blocking activity and has a potency similar to that of racemic labetalol as an α₁ receptor antagonist. The R,R isomer has some intrinsic sympathomimetic activity at β₂ adrenergic receptors; this may contribute to vasodilation. Labetalol also may have some direct vasodilating capacity.

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, particularly in the upright position. The β₁ blockade also contributes to a fall in blood pressure, in part by blocking reflex sympathetic stimulation of the heart. In addition, 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. Labetalol is one of the few β adrenergic antagonists that has been recommended as treatment for acute severe hypertension (hypertensive emergency). Its hypotensive action begins within 2-5 minutes after IV administration, reaching its peak at 5-15 minutes and lasting ~2-4 hours. Heart rate is either maintained or slightly reduced and cardiac output is maintained. Labetalol reduces systemic vascular resistance without reducing total peripheral blood flow. Cerebral, renal, and coronary blood flow is maintained. It can be used in the setting of pregnancy-induced hypertensive crisis because little placental transfer occurs due to the poor lipid solubility of labetalol.

Absorption, Fate, and Excretion. Although labetalol is completely absorbed from the gut, there is extensive first-pass clearance; bioavailability is only ~20-40%, is highly variable, and may be increased by food intake. The drug is rapidly and extensively metabolized in the liver by oxidative biotransformation and glucuronidation; very little unchanged drug is found in the urine. The rate of metabolism of labetalol is sensitive to changes in hepatic blood flow. The elimination t_1/2 of the drug is ~8 hours. The t_1/2 of the R,R isomer of labetalol (dilevalol) is ~15 hours. Labetalol provides an interesting and challenging example of pharmacokinetic-pharmacodynamic modeling applied to a drug that is a racemic mixture of isomers with different kinetics and pharmacological actions (Donnelly and Macphee, 1991).

Carvedilol possesses two distinct antioxidant properties: it is a chemical antioxidant that can bind to and scavenge reactive oxygen species (ROS), and it can suppress the biosynthesis of ROS and oxygen radicals. Carvedilol is extremely liphophic and is able to protect cell membranes from lipid peroxidation. It prevents low density lipoprotein (LDL) oxidation, which in turn induces the uptake of LDL into the coronary vasculature. Carvedilol also inhibits ROS-mediated loss of myocardial contractility, stress-induced hypertrophy, apoptosis, and the accumulation and activation of neutrophils. At high doses, carvedilol exerts Ca²⁺ channel-blocking activity. Carvedilol does not increase β receptor density and is not associated with high levels of inverse agonist activity (Cheng et al., 2001; Dandona et al., 2007; Keating and Jarvis, 2003).

Carvedilol has been tested in numerous double-blind, randomized studies, including the U.S. Carvedilol Heart Failure Trials Program, Carvedilol or Metoprolol European Trial (COMET) (Poole-Wilson et al., 2003), Carvedilol Prospective Randomised Cumulative Survival (COPERNICUS) trial, and the Carvedilol Post Infarct Survival Control in LV Dysfunction (CAPRICORN) trial (Cleland, 2003). These trials showed that carvedilol improves ventricular function and reduces mortality and morbidity in patients with mild to severe congestive heart failure. Several experts recommend it as the standard treatment option in this setting. In addition, carvedilol combined with conventional therapy reduces mortality and attenuates myocardial infarction. In patients with chronic heart failure, carvedilol reduces cardiac sympathetic drive, but it is not clear if blockade of α₁ receptor–mediated vasodilation is maintained over long periods of time.

Absorption, Fate, and Excretion. Carvedilol is rapidly absorbed following oral administration, with peak plasma concentrations occurring in 1-2 hours. It is highly lipophilic and thus is extensively distributed into extravascular tissues. It is > 95% protein bound and is extensively metabolized in the liver, predominantly by CYP2D6 and CYP2C9. The t_1/2 is 7-10 hours. Stereoselective first-pass metabolism results in more rapid clearance of S(−)-carvedilol than R(+)-carvedilol. No significant changes in the pharmacokinetics of carvedilol were seen in elderly patients with hypertension, and no change in dosage is needed in patients with moderate to severe renal insufficiency (Cleland, 2003; Keating and Jarvis, 2003). Because of carvedilol's extensive oxidative metabolism by the liver, its 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 increases left ventricular systolic ejection fraction and decreases peripheral resistance, thereby reducing afterload. It increases plasma HDL cholesterol, but does not affect plasma triglycerides. A large comprehensive clinical trial, the β Blocker Evaluation of Survival Trial (BEST), was terminated early because of the inability to demonstrate a survival benefit with bucindolol versus placebo. In subsequent analyses from BEST, however, benefits have been demonstrated in discrete subgroups, including a genetically identified subgroup. An evaluation was made of the therapeutic responses to bucindolol among patients with genetic variations or polymorphisms in two adrenergic receptors: β₁ 389 arg/gly and α_2C 322-325 WT/Del. Researchers identified three distinct genotypes that predict the effect of bucindolol: very favorable (47% of BEST patients), favorable (40%), and unfavorable (13%). In the study, patients with the very favorable genotype experienced significant improvements in clinical end points compared to placebo, including reductions in all-cause mortality, cardiovascular mortality, heart failure hospitalization, and cardiovascular hospitalization. A New Drug Application (NDA) has been filed with the FDA and is currently under review.

Bucindolol is well absorbed after oral administration, reaching maximum plasma levels in 2 hours. It is highly protein bound (87%), extensively metabolized by the liver to 5-hydroxybucindolol, and has a t_1/2 of ~8 hours.

Celiprolol reduces heart rate and blood pressure and can increase the functional refractory period of the atrioventricular node. Oral bioavailability ranges from 30-70%, and peak plasma levels are seen at 2-4 hours. It is largely unmetabolized and is excreted unchanged in the urine and feces. Celiprolol does not undergo first-pass metabolism. The predominant mode of excretion is renal. Celiprolol is used for treatment of hypertension and angina (Felix et al., 2001; Witchitz et al., 2000).

Nebivolol is administered as the racemate containing equal amounts of the d and l-enantiomers. The d-isomer is the active β blocking component; the l-isomer is responsible for enhancing production of NO. Nebivolol is devoid of intrinsic sympathomimetic effects as well as membrane stabilizing activity and α₁ receptor blocking properties. 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 (deBoer et al., 2007; Gupta and Wright, 2008; Moen and Wagstaff, 2006; Rosei and Rizzoni, 2007). Metabolism occurs via CYP2D6, and the influence of polymorphisms in the CYP2D6 gene on the bioavailability and duration of nebivolol's actions is being evaluated (Lefebvre et al., 2006), as is the influence of plasma concentration of receptor selectivity.

Other β Adrenergic Receptor Antagonists. There are numerous β adrenergic receptor antagonists on the market as ophthalmologic preparations for the treatment of glaucoma or other causes of high blood pressure inside the eye (Chapter 64). These include carteolol (ocupress, others), metipranolol (optipranolol), nipradilol (hypadil; not available in the U.S.), levobunolol (betagan, liquifilm, others), betaxolol (betoptic, others), and timolol (timoptic, others) (Henness et al., 2007). The use of β adrenergic receptor antagonists in glaucoma is contraindicated in patients with asthma, COPD, sympathomatic sinus bradycardia, and cardiogenic shock.