Case Study

A 68-year-old man presents with a complaint of light-headedness on standing that is worse after meals and in hot environments. Symptoms started about 4 years ago and have slowly progressed to the point that he is disabled. He has fainted several times, but always recovers consciousness almost as soon as he falls. Review of symptoms reveals slight worsening of constipation, urinary retention out of proportion to prostate size, and decreased sweating. He is otherwise healthy with no history of hypertension, diabetes, or Parkinson's disease. Because of his urinary retention, he was placed on the ₁ antagonist tamsulosin but he could not tolerate it because of worsening of orthostatic hypotension. Physical examination revealed a blood pressure of 167/84 mm Hg supine and 106/55 mm Hg standing. There was an inadequate compensatory increase in heart rate (from 84 to 88 bpm), considering the degree of orthostatic hypotension. Physical examination is otherwise unremarkable with no evidence of peripheral neuropathy or parkinsonian features. Laboratory examinations are negative except for plasma norepinephrine, which is low at 98 pg/mL (normal is 250–400 pg/mL for his age). A diagnosis of pure autonomic failure is made, based on the clinical picture and the absence of drugs that could induce orthostatic hypotension and diseases commonly associated with autonomic neuropathy (eg, diabetes, Parkinson's disease). What precautions should this patient observe in using sympathomimetic drugs? Can such drugs be used in his treatment?

*The authors thank Dr. Brian B. Hoffman, the author of this chapter in previous editions, whose work we have modified and updated. We also thank Dr. Vsevolod Gurevich for helpful comments and Dr. Alfredo Gamboa for providing the data for Figure 9–7.

Adrenoceptor Agonists & Sympathomimetic Drugs: Introduction

The sympathetic nervous system is an important regulator of virtually all organ systems. This is particularly evident in the regulation of blood pressure. As illustrated in the case study, the autonomic nervous system is crucial for the maintenance of blood pressure even under relatively minor situations of stress (eg, the gravitational stress of standing).

The ultimate effects of sympathetic stimulation are mediated by release of norepinephrine from nerve terminals, which then activates adrenoceptors on postsynaptic sites (see Chapter 6). Also, in response to a variety of stimuli such as stress, the adrenal medulla releases epinephrine, which is transported in the blood to target tissues. In other words, epinephrine acts as a hormone, whereas norepinephrine acts as a neurotransmitter.

Drugs that mimic the actions of epinephrine or norepinephrine have traditionally been termed sympathomimetic drugs.  The sympathomimetics can be grouped by mode of action and by the spectrum of receptors that they activate. Some of these drugs (eg, norepinephrine and epinephrine) are direct agonists; that is, they directly interact with and activate adrenoceptors. Others are indirect agonists; their actions are dependent on the release of endogenous catecholamines. These indirect agents may have either of two different mechanisms: (1) displacement of stored catecholamines from the adrenergic nerve ending (eg, the mechanism of action of tyramine) or (2) inhibition of reuptake of catecholamines already released (eg, the mechanism of action of cocaine and tricyclic antidepressants). Some drugs have both direct and indirect actions. Both types of sympathomimetics, direct and indirect, ultimately cause activation of adrenoceptors, leading to some or all of the characteristic effects of endogenous catecholamines.

The pharmacologic effects of direct agonists depend on the route of administration, their relative affinity for adrenoreceptor subtypes, and the relative expression of these receptor subtypes in target tissues. The pharmacologic effects of indirect sympathomimetics are greater under conditions of increased sympathetic activity and norepinephrine storage and release.

Molecular Pharmacology Underlying the Actions of Sympathomimetic Drugs

The effects of catecholamines are mediated by cell-surface receptors. Adrenoceptors are typical G protein-coupled receptors (GPCRs; see Chapter 2). The receptor protein has an extracellular N-terminus, traverses the membrane seven times (transmembrane domains) forming three extracellular and three intracellular loops, and has an intracellular C-terminus (Figure 9–1). G protein-coupled receptors are coupled by G proteins to the various effector proteins whose activities are regulated by those receptors. Each G protein is a heterotrimer consisting of , , and subunits. G proteins are classified on the basis of their distinctive subunits. G proteins of particular importance for adrenoceptor function include G_s, the stimulatory G protein of adenylyl cyclase; G_i and G_o, the inhibitory G proteins of adenylyl cyclase; and G_q and G₁₁, the G proteins coupling receptors to phospholipase C. The activation of G protein-coupled receptors by catecholamines promotes the dissociation of guanosine diphosphate (GDP) from the subunit of the appropriate G protein. Guanosine triphosphate (GTP) then binds to this G protein, and the subunit dissociates from the - unit. The activated GTP-bound subunit then regulates the activity of its effector. Effectors of adrenoceptor-activated subunits include adenylyl cyclase, cGMP phosphodiesterase, phospholipase C, and ion channels. The subunit is inactivated by hydrolysis of the bound GTP to GDP and phosphate, and the subsequent reassociation of the subunit with the - subunit. The - subunits have additional independent effects, acting on a variety of effectors such as ion channels and enzymes.

Adrenoreceptors were initially characterized pharmacologically, with receptors having the comparative potencies epinephrine ≥ norepinephrine >> isoproterenol, and receptors having the comparative potencies isoproterenol > epinephrine ≥ norepinephrine. The development of selective antagonists revealed the presence of subtypes of these receptors, which were finally characterized by molecular cloning. We now know that unique genes encode the receptor subtypes listed in Table 9–1.

Likewise, the endogenous catecholamine dopamine produces a variety of biologic effects that are mediated by interactions with specific dopamine receptors (Table 9–1). These receptors are distinct from and receptors and are particularly important in the brain (see Chapters 21 and 29) and in the splanchnic and renal vasculature. Molecular cloning has identified several distinct genes encoding five receptor subtypes, two D₁-like receptors (D₁ and D₅) and three D₂-like (D₂, D3, and D₄). Further complexity occurs because of the presence of introns within the coding region of the D₂-like receptor genes, which allows for alternative splicing of the exons in this major subtype. There is extensive polymorphic variation in the D₄ human receptor gene. These subtypes may have importance for understanding the efficacy and adverse effects of novel antipsychotic drugs (see Chapter 29).

Receptor Types

Alpha Receptors

Alpha₁ receptors are coupled via G proteins in the G_q family to phospholipase C. This enzyme hydrolyzes polyphosphoinositides, leading to the formation of inositol 1,4,5-trisphosphate (IP₃) and diacylglycerol (DAG) (Table 9–1, Figure 9–1). IP₃ promotes the release of sequestered Ca²⁺ from intracellular stores, which increases the cytoplasmic concentration of free Ca²⁺ and the activation of various calcium-dependent protein kinases. Activation of these receptors may also increase influx of calcium across the cell's plasma membrane. IP₃ is sequentially dephosphorylated, which ultimately leads to the formation of free inositol. DAG activates protein kinase C, which modulates activity of many signaling pathways. In addition, ₁ receptors activate signal transduction pathways that were originally described for peptide growth factor receptors that activate tyrosine kinases. For example, ₁ receptors have been found to activate mitogen-activated kinases (MAP kinases) and polyphosphoinositol-3-kinase (PI-3-kinase). These pathways may have importance for the ₁-receptor-mediated stimulation of cell growth and proliferation through the regulation of gene expression.

Alpha₂ receptors inhibit adenylyl cyclase activity and cause intracellular cyclic adenosine monophosphate (cAMP) levels to decrease. Alpha₂-receptor–mediated inhibition of adenylyl cyclase activity is transduced by the inhibitory regulatory protein, G_i (Figure 9–2). It is likely that not only , but the - subunits of G_I contribute to inhibition of adenylyl cyclase. Alpha₂ receptors use other signaling pathways, including regulation of ion channel activities and the activities of important enzymes involved in signal transduction. Indeed, some of the effects of ₂ adrenoceptors are independent of their ability to inhibit adenylyl cyclase; for example, ₂-receptor agonists cause platelet aggregation and a decrease in platelet cAMP levels, but it is not clear whether aggregation is the result of the decrease in cAMP or other mechanisms involving G_i-regulated effectors.

Beta Receptors

Activation of all three receptor subtypes (₁, ₂, and ₃) results in stimulation of adenylyl cyclase and increased conversion of adenosine triphosphate (ATP) to cAMP (Table 9–1, Figure 9–2). Activation of the cyclase enzyme is mediated by the stimulatory coupling protein G_s. Cyclic AMP is the major second messenger of -receptor activation. For example, in the liver of many species, -receptor-activated cAMP synthesis leads to a cascade of events culminating in the activation of glycogen phosphorylase. In the heart, -receptor-activated cAMP synthesis increases the influx of calcium across the cell membrane and its sequestration inside the cell. Beta-receptor activation also promotes the relaxation of smooth muscle. Although the mechanism of the smooth muscle effect is uncertain, it may involve the phosphorylation of myosin light-chain kinase to an inactive form (see Figure 12–1). Beta adrenoceptors may activate voltage-sensitive calcium channels in the heart via G_s-mediated enhancement independently of changes in cAMP concentration. Under certain circumstances, ₂ receptors may couple to G_q proteins. These receptors have been demonstrated to activate additional kinases, such as MAP kinases, by forming multi-subunit complexes within cells, which contain multiple signaling molecules.

Dopamine Receptors

The D₁ receptor is typically associated with the stimulation of adenylyl cyclase (Table 9–1); for example, D₁-receptor-induced smooth muscle relaxation is presumably due to cAMP accumulation in the smooth muscle of those vascular beds in which dopamine is a vasodilator. D₂ receptors have been found to inhibit adenylyl cyclase activity, open potassium channels, and decrease calcium influx.

Receptor Selectivity

Many clinically available adrenergic agonists have selectivity for the major (₁, ₂ versus ) adrenoreceptor types, but not for the subtypes of these major groups. Examples of clinically useful sympathomimetic agonists that are relatively selective for ₁-, ₂-, and -adrenoceptor subgroups are compared with some nonselective agents in Table 9–2. Selectivity means that a drug may preferentially bind to one subgroup of receptors at concentrations too low to interact extensively with another subgroup. However, selectivity is not usually absolute (nearly absolute selectivity has been termed "specificity"), and at higher concentrations a drug may also interact with related classes of receptors. The effects of a given drug may depend not only on its relative selectivity to adrenoreceptor types, but also to the expression of subtypes in a given tissue. (see Receptor Selectivity and Physiologic Functions of Adrenoceptor Subtypes).

Receptor Regulation

Responses mediated by adrenoceptors are not fixed and static. The number and function of adrenoceptors on the cell surface and their responses may be regulated by catecholamines themselves, other hormones and drugs, age, and a number of disease states (see Chapter 2). These changes may modify the magnitude of a tissue's physiologic response to catecholamines and can be important clinically during the course of treatment. One of the best-studied examples of receptor regulation is the desensitization of adrenoceptors that may occur after exposure to catecholamines and other sympathomimetic drugs. After a cell or tissue has been exposed for a period of time to an agonist, that tissue often becomes less responsive to further stimulation by that agent (see Figure 2–12). Other terms such as tolerance, refractoriness, and tachyphylaxis have also been used to denote desensitization. This process has potential clinical significance because it may limit the therapeutic response to sympathomimetic agents.

Many mechanisms have been found to contribute to desensitization. Some mechanisms function relatively slowly; over the course of hours or days, and these typically involve transcriptional or translational changes in the receptor protein level, or its migration to the cell surface. Other mechanisms of desensitization occur quickly, within minutes. Rapid modulation of receptor function in desensitized cells may involve critical covalent modification of the receptor, especially by phosphorylation on specific amino acid residues, association of these receptors with other proteins, or changes in their subcellular location.

There are two major categories of desensitization of responses mediated by G protein-coupled receptors. Homologous desensitization refers to loss of responsiveness exclusively of the receptors that have been exposed to repeated or sustained activation by an agonist. Heterologous desensitization refers to the process by which desensitization of one receptor by its agonists also results in desensitization of another receptor that has not been directly activated by the agonist in question.

A major mechanism of desensitization that occurs rapidly involves phosphorylation of receptors by members of the G protein-coupled receptor kinase (GRK) family, of which there are seven members. Specific adrenoceptors become substrates for these kinases only when they are bound to an agonist. This mechanism is an example of homologous desensitization because it specifically involves only agonist-occupied receptors.

Phosphorylation of these receptors enhances their affinity for arrestins, a family of four widely expressed proteins. Upon binding of a -arrestin molecule, the capacity of the receptor to activate G proteins is blunted, presumably as a result of steric hindrance (see Figure 2–12). Arrestin then interacts with clathrin and clathrin adaptor AP2, leading to endocytosis of the receptor. In addition to blunting responses requiring the presence of the receptor on the cell surface, these regulatory processes may also contribute to novel mechanisms of receptor signaling via intracellular pathways.

Receptor desensitization may also be mediated by second-messenger feedback. For example, adrenoceptors stimulate cAMP accumulation, which leads to activation of protein kinase A; protein kinase A can phosphorylate residues on receptors, resulting in inhibition of receptor function. For the ₂ receptor, phosphorylation occurs on serine residues both in the third cytoplasmic loop and in the carboxyl terminal tail of the receptor. Similarly, activation of protein kinase C by G_q-coupled receptors may lead to phosphorylation of this class of G protein-coupled receptors. This second-messenger feedback mechanism has been termed heterologous desensitization because activated protein kinase A or protein kinase C may phosphorylate any structurally similar receptor with the appropriate consensus sites for phosphorylation by these enzymes.

Adrenoceptor Polymorphisms

Since elucidation of the sequences of the genes encoding the ₁, ₂, and subtypes of adrenoceptors, it has become clear that there are relatively common genetic polymorphisms for many of these receptor subtypes in humans. Some of these may lead to changes in critical amino acid sequences that have pharmacologic importance. Often, distinct polymorphisms occur in specific combination termed haplotypes. Some of these polymorphisms have been consistently shown to alter the susceptibility to diseases such as heart failure, to alter the propensity of a receptor to desensitize, and to alter therapeutic responses to drugs in diseases such as asthma. This remains an area of active research because studies have reported inconsistent results as to the pathophysiologic importance of some polymorphisms.

The Norepinephrine Transporter

When norepinephrine is released into the synaptic cleft, it binds to or adrenoceptors and elicits the expected physiologic effect. However, just as release mechanisms for neurotransmitters are highly efficient, the mechanisms for removal of neurotransmitters must act rapidly also. The norepinephrine transporter (NET) is the principal route by which this occurs. It is particularly efficient in the synapses of the heart, where up to 90% of released norepinephrine is removed by the NET. Remaining synaptic norepinephrine may escape into the extrasynaptic space and enter the bloodstream or be taken up into extraneuronal cells and metabolized by catecholamine-N-methyltransferase. In other sites such as the vasculature, where synaptic structures are less well developed, removal may still be 60% or more by NET. The NET, often situated on the presynaptic neuronal membrane, pumps the synaptic norepinephrine back into the neuron cell body. In the cell body, this norepinephrine may reenter the vesicles or undergo metabolism through monoamine oxidase to dihydroxy-phenylglycol (DHPG). Elsewhere in the body analogous transporters remove dopamine (dopamine transporter, DAT), serotonin (serotonin transporter), and other substances. The NET, surprisingly, has greater affinity for dopamine than norepinephrine, and it can sometimes clear dopamine in brain areas where DAT is low, like the cortex.

Blockade of the NET, eg, by the nonselective psychostimulant cocaine or the NET selective agents atomoxetine or reBoxetine, impairs this primary site of norepinephrine removal and thus synaptic norepinephrine levels rise, leading to greater stimulation of and adrenoceptors. In the periphery this effect may produce a clinical picture of sympathetic activation, but it is often counterbalanced by concomitant stimulation of ₂ adrenoceptors in the brain stem that reduce sympathetic activation.

However, the function of the norepinephrine and dopamine transporters is far more complex than simple blockade can account for. For example, some interventions may actually reverse the direction of transport so that intraneuronal neurotransmitter is released.

These considerations have important implications for our understanding of the biogenic amine transporters. They may explain some of the divergent actions that are observed when we administer drugs traditionally considered to be NET blocking agents. This is illustrated in Figure 9–3. Under normal circumstances (panel A), presynaptic NET (red) inactivates and recycles norepinephrine (NE, red) released by vesicular fusion. In panel (B), amphetamine (black) acts as both a NET substrate and a reuptake blocker, eliciting reverse transport and blocking normal uptake, thereby increasing NE levels in and beyond the synaptic cleft. In (C), agents such as methylphenidate and cocaine (hexagons) block NET-mediated NE reuptake and enhance NE signaling.

Medicinal Chemistry of Sympathomimetic Drugs

Phenylethylamine may be considered the parent compound from which sympathomimetic drugs are derived (Figure 9–4). This compound consists of a benzene ring with an ethylamine side chain. Substitutions may be made on (1) the benzene ring, (2) the terminal amino group, and (3) the or carbons of the amino chain. Substitution by –OH groups at the 3 and 4 positions yields sympathomimetic drugs collectively known as catecholamines. The effects of modification of phenylethylamine are to change the affinity of the drugs for and receptors, spanning the range from almost pure activity (methoxamine) to almost pure activity (isoproterenol), as well as to influence the intrinsic ability to activate the receptors.

In addition to determining relative affinity to receptor subtype, chemical structure also determines the pharmacokinetic properties of these molecules and their bioavailability.

Substitution on the Benzene Ring

Maximal and activity is found with catecholamines, ie, drugs having –OH groups at the 3 and 4 positions on the benzene ring. The absence of one or the other of these groups, particularly the hydroxyl at C₃, without other substitutions on the ring may dramatically reduce the potency of the drug. For example, phenylephrine (Figure 9–5) is much less potent than epinephrine; indeed, -receptor affinity is decreased about 100-fold and activity is almost negligible except at very high concentrations. On the other hand, catecholamines are subject to inactivation by catechol-O-methyltransferase (COMT), and because this enzyme is found in the gut and liver, catecholamines are not active orally (see Chapter 6). Absence of one or both –OH groups on the phenyl ring increases the bioavailability after oral administration and prolongs the duration of action. Furthermore, absence of ring –OH groups tends to increase the distribution of the molecule to the central nervous system. For example, ephedrine and amphetamine (Figure 9–5) are orally active, have a prolonged duration of action, and produce central nervous system effects not typically observed with the catecholamines.

Substitution on the Amino Group

Increasing the size of alkyl substituents on the amino group tends to increase -receptor activity. For example, methyl substitution on norepinephrine, yielding epinephrine, enhances activity at ₂ receptors. Beta activity is further enhanced with isopropyl substitution at the amino nitrogen (isoproterenol). Beta₂-selective agonists generally require a large amino substituent group. The larger the substituent on the amino group, the lower the activity at receptors; for example, isoproterenol is very weak at receptors.

Substitution on the Alpha Carbon

Substitutions at the carbon block oxidation by monoamine oxidase (MAO) and prolong the action of such drugs, particularly the noncatecholamines. Ephedrine and amphetamine are examples of -substituted compounds (Figure 9–5). Alpha-methyl compounds are also called phenylisopropylamines. In addition to their resistance to oxidation by MAO, some phenylisopropylamines have an enhanced ability to displace catecholamines from storage sites in noradrenergic nerves (see Chapter 6). Therefore, a portion of their activity is dependent on the presence of normal norepinephrine stores in the body; they are indirectly acting sympathomimetics.

Substitution on the Beta Carbon

Direct-acting agonists typically have a -hydroxyl group, although dopamine does not. In addition to facilitating activation of adrenoceptors, this hydroxyl group may be important for storage of sympathomimetic amines in neural vesicles.

Organ System Effects of Sympathomimetic Drugs

Cardiovascular System

General outlines of the cellular actions of sympathomimetics are presented in Tables 6–3 and 9–3. Sympathomimetics have prominent cardiovascular effects because of widespread distribution of and adrenoceptors in the heart, blood vessels, and neural and hormonal systems involved in blood pressure regulation. The net effect of a given sympathomimetic in the intact organism depends not only on its relative selectivity for or adrenoceptors and its pharmacologic action at those receptors; any effect these agents have on blood pressure is counteracted by compensatory baroreflex mechanisms aimed at restoring homeostasis.

The effects of sympathomimetic drugs on blood pressure can be explained on the basis of their effects on heart rate, myocardial function, peripheral vascular resistance, and venous return (see Figure 6–7 and Table 9–4). The endogenous catecholamines, norepinephrine and epinephrine have complex cardiovascular effects because they activate both and receptors. It is easier to understand these actions by first describing the cardiovascular effect of sympathomimetics that are selective for a given adrenoreceptor.

Effects of Alpha₁-Receptor Activation

Alpha₁ receptors are widely expressed in vascular beds, and their activation leads to arterial and venoconstriction. Their direct effect on cardiac function is of relatively less importance. A relatively pure agonist such as phenylephrine increases peripheral arterial resistance and decreases venous capacitance. The enhanced arterial resistance usually leads to a dose-dependent rise in blood pressure (Figure 9–6). In the presence of normal cardiovascular reflexes, the rise in blood pressure elicits a baroreceptor-mediated increase in vagal tone with slowing of the heart rate, which may be quite marked (Figure 9–7). However, cardiac output may not diminish in proportion to this reduction in rate, since increased venous return may increase stroke volume. Furthermore, direct -adrenoceptor stimulation of the heart may have a modest positive inotropic action. The magnitude of the restraining effect of the baroreflex is quite dramatic. If baroreflex function is removed by pretreatment with the ganglionic blocker trimethaphan, the pressor effect of phenylephrine is increased approximately tenfold, and bradycardia is no longer observed (Figure 9–7), confirming that the decrease in heart associated with the increase in blood pressure induced by phenylephrine was reflex in nature rather than a direct effect of ₁-receptor activation.

Patients who have an impairment of autonomic function (due to pure autonomic failure as in the case study or to more common conditions such as diabetic autonomic neuropathy) exhibit this extreme hypersensitivity to most pressor and depressor stimuli, including medications. This is to a large extent due to failure of baroreflex buffering. Such patients may have exaggerated increases in heart rate or blood pressure when taking sympathomimetics with - and -adrenergic activity, respectively. This, however, can be used as an advantage in their treatment. The agonist midodrine is commonly used to ameliorate orthostatic hypotension in these patients.

There are major differences in receptor types predominantly expressed in the various vascular beds (Table 9–4). The skin vessels have predominantly receptors and constrict in response to epinephrine and norepinephrine, as do the splanchnic vessels. Vessels in skeletal muscle may constrict or dilate depending on whether or receptors are activated. The blood vessels of the nasal mucosa express receptors, and local vasoconstriction induced by sympathomimetics explains their decongestant action (see Therapeutic Uses of Sympathomimetic Drugs).

Effects of Alpha₂-Receptor Activation

Alpha₂ adrenoceptors are present in the vasculature, and their activation leads to vasoconstriction. This effect, however, is observed only when ₂ agonists are given locally, by rapid intravenous injection or in very high oral doses. When given systemically, these vascular effects are obscured by the central effects of ₂ receptors, which lead to inhibition of sympathetic tone and blood pressure. Hence, ₂ agonists are used as sympatholytics in the treatment of hypertension (see Chapter 11). In patients with pure autonomic failure, characterized by neural degeneration of postganglionic noradrenergic fibers, clonidine may increase blood pressure because the central sympatholytic effects of clonidine become irrelevant, whereas the peripheral vasoconstriction remains intact.

Effects of Beta-Receptor Activation

The blood pressure response to a -adrenoceptor agonist depends on its contrasting effects on the heart and the vasculature. Stimulation of receptors in the heart increases cardiac output by stimulating contractility and by a direct stimulation of the sinus node to increase heart rate. Beta agonists also decrease peripheral resistance by activating ₂ receptors, leading to vasodilation in certain vascular beds (Table 9–4). Isoproterenol is a nonselective agonist; it activates both ₁ and ₂ receptors. The net effect is to maintain or slightly increase systolic pressure and to lower diastolic pressure, so that mean blood pressure is decreased (Figure 9–6).

Direct effects on the heart are determined largely by ₁ receptors, although ₂ and to a lesser extent receptors are also involved, especially in heart failure. Beta-receptor activation results in increased calcium influx in cardiac cells. This has both electrical and mechanical consequences. Pacemaker activity—both normal (sinoatrial node) and abnormal (eg, Purkinje fibers)—is increased (positive chronotropic effect). Conduction velocity in the atrioventricular node is increased (positive dromotropic effect), and the refractory period is decreased. Intrinsic contractility is increased (positive inotropic effect), and relaxation is accelerated. As a result, the twitch response of isolated cardiac muscle is increased in tension but abbreviated in duration. In the intact heart, intraventricular pressure rises and falls more rapidly, and ejection time is decreased. These direct effects are easily demonstrated in the absence of reflexes evoked by changes in blood pressure, eg, in isolated myocardial preparations and in patients with ganglionic blockade. In the presence of normal reflex activity, the direct effects on heart rate may be dominated by a reflex response to blood pressure changes. Physiologic stimulation of the heart by catecholamines tends to increase coronary blood flow.

Effects of Dopamine-Receptor Activation

Intravenous administration of dopamine promotes vasodilation of renal, splanchnic, coronary, cerebral, and perhaps other resistance vessels, via activation of D₁ receptors. Activation of the D₁ receptors in the renal vasculature may also induce natriuresis. The renal effects of dopamine have been used clinically to improve perfusion to the kidney in situations of oliguria (abnormally low urinary output). The activation of presynaptic D₂ receptors suppresses norepinephrine release, but it is unclear if this contributes to cardiovascular effects of dopamine. In addition, dopamine activates ₁ receptors in the heart. At low doses, peripheral resistance may decrease. At higher rates of infusion, dopamine activates vascular receptors, leading to vasoconstriction, including in the renal vascular bed. Consequently, high rates of infusion of dopamine may mimic the actions of epinephrine.

Noncardiac Effects of Sympathomimetics

Adrenoceptors are distributed in virtually all organ systems. This section focuses on the activation of adrenoceptors that are responsible for the therapeutic effects of sympathomimetics or that explain their adverse effects. A more detailed description of the therapeutic use of sympathomimetics is given later in this chapter.

Activation of ₂ receptors in bronchial smooth muscle leads to bronchodilation, and ₂ agonists are important in the treatment of asthma (see Chapter 20 and Table 9–3).

In the eye,  the radial pupillary dilator muscle of the iris contains receptors; activation by drugs such as phenylephrine causes mydriasis (see Figure 6–9). Alpha stimulants also have important effects on intraocular pressure. Alpha agonists increase the outflow of aqueous humor from the eye and can be used clinically to reduce intraocular pressure. In contrast, agonists have little effect, but antagonists decrease the production of aqueous humor. These effects are important in the treatment of glaucoma (see Chapter 10), a leading cause of blindness.

In genitourinary organs, the bladder base, urethral sphincter, and prostate contain receptors that mediate contraction and therefore promote urinary continence. The specific subtype of ₁ receptor involved in mediating constriction of the bladder base and prostate is uncertain, but _1A receptors probably play an important role. This effect explains why urinary retention is a potential adverse effect of administration of the ₁ agonist midodrine.

Alpha-receptor activation in the ductus deferens, seminal vesicles, and prostate plays a role in normal ejaculation. The detumescence of erectile tissue that normally follows ejaculation is also brought about by norepinephrine (and possibly neuropeptide Y) released from sympathetic nerves. Alpha activation appears to have a similar detumescent effect on erectile tissue in female animals.

The salivary glands contain adrenoceptors that regulate the secretion of amylase and water. However, certain sympathomimetic drugs, eg, clonidine, produce symptoms of dry mouth. The mechanism of this effect is uncertain; it is likely that central nervous system effects are responsible, although peripheral effects may contribute.

The apocrine sweat glands,  located on the palms of the hands and a few other areas, respond to adrenoceptor stimulants with increased sweat production. These are the apocrine nonthermoregulatory glands usually associated with psychological stress. (The diffusely distributed thermoregulatory eccrine sweat glands are regulated by sympathetic cholinergic postganglionic nerves that activate muscarinic cholinoceptors; see Chapter 6.)

Sympathomimetic drugs have important effects on intermediary metabolism. Activation of adrenoceptors in fat cells leads to increased lipolysis with enhanced release of free fatty acids and glycerol into the blood. Beta₃ adrenoceptors play a role in mediating this response in animals, but their role in humans is probably minor. Human fat cells also contain ₂ receptors that inhibit lipolysis by decreasing intracellular cAMP. Sympathomimetic drugs enhance glycogenolysis in the liver, which leads to increased glucose release into the circulation. In the human liver, the effects of catecholamines are probably mediated mainly by receptors, though ₁ receptors may also play a role. Catecholamines in high concentration may also cause metabolic acidosis. Activation of ₂ adrenoceptors by endogenous epinephrine or by sympathomimetic drugs promotes the uptake of potassium into cells, leading to a fall in extracellular potassium. This may lead to a fall in the plasma potassium concentration during stress or protect against a rise in plasma potassium during exercise. Blockade of these receptors may accentuate the rise in plasma potassium that occurs during exercise. On the other hand, epinephrine has been used to treat hyperkalemia in certain conditions, but other alternatives are more commonly used. Beta receptors and ₂ receptors that are expressed in pancreatic islets tend to increase and decrease insulin secretion, respectively, although the major regulator of insulin release is the plasma concentration of glucose.

Catecholamines are important endogenous regulators of hormone secretion from a number of glands. As mentioned above, insulin secretion is stimulated by receptors and inhibited by ₂ receptors. Similarly, renin secretion is stimulated by ₁ and inhibited by ₂ receptors; indeed, -receptor antagonist drugs may lower blood pressure in patients with hypertension at least in part by lowering plasma renin. Adrenoceptors also modulate the secretion of parathyroid hormone, calcitonin, thyroxine, and gastrin; however, the physiologic significance of these control mechanisms is probably limited. In high concentrations, epinephrine and related agents cause leukocytosis, in part by promoting demargination of white blood cells sequestered away from the general circulation.

The action of sympathomimetics on the central nervous system varies dramatically, depending on their ability to cross the blood-brain barrier. The catecholamines are almost completely excluded by this barrier, and subjective central nervous system effects are noted only at the highest rates of infusion. These effects have been described as ranging from "nervousness" to "an adrenaline rush" or "a feeling of impending disaster." Furthermore, peripheral effects of -adrenoceptor agonists such as tachycardia and tremor are similar to the somatic manifestations of anxiety. In contrast, noncatecholamines with indirect actions, such as amphetamines, which readily enter the central nervous system from the circulation, produce qualitatively very different central nervous system effects. These actions vary from mild alerting, with improved attention to boring tasks; through elevation of mood, insomnia, euphoria, and anorexia; to full-blown psychotic behavior. These effects are not readily assigned to either - or -mediated actions and may represent enhancement of dopamine-mediated processes or other effects of these drugs in the central nervous system.

Specific Sympathomimetic Drugs

Endogenous Catecholamines

Epinephrine (adrenaline) is an agonist at both and receptors. It is therefore a very potent vasoconstrictor and cardiac stimulant. The rise in systolic blood pressure that occurs after epinephrine release or administration is caused by its positive inotropic and chronotropic actions on the heart (predominantly ₁ receptors) and the vasoconstriction induced in many vascular beds ( receptors). Epinephrine also activates ₂ receptors in some vessels (eg, skeletal muscle blood vessels), leading to their dilation. Consequently, total peripheral resistance may actually fall, explaining the fall in diastolic pressure that is sometimes seen with epinephrine injection (Figure 9–6; Table 9–4). Activation of ₂ receptors in skeletal muscle contributes to increased blood flow during exercise. Under physiologic conditions, epinephrine functions largely as a hormone; after release from the adrenal medulla into the blood, it acts on distant cells.

Norepinephrine (levarterenol, noradrenaline) is an agonist at both ₁ and ₂ receptors. Norepinephrine also activates ₁ receptors with similar potency as epinephrine, but has relatively little effect on ₂ receptors. Consequently, norepinephrine increases peripheral resistance and both diastolic and systolic blood pressure. Compensatory baroreflex activation tends to overcome the direct positive chronotropic effects of norepinephrine; however, the positive inotropic effects on the heart are maintained (Table 9–4).

Dopamine is the immediate precursor in the synthesis of norepinephrine (see Figure 6–5). Its cardiovascular effects were described above. Endogenous dopamine may have more important effects in regulating sodium excretion and renal function. It is an important neurotransmitter in the central nervous system and is involved in the reward stimulus relevant to addiction. Its deficiency in the basal ganglia leads to Parkinson's disease, which is treated with its precursor levodopa. Dopamine receptors are also targets for antipsychotic drugs.

Direct-Acting Sympathomimetics

Phenylephrine was discussed previously when describing the actions of a relatively pure ₁ agonist (Table 9–2). Because it is not a catechol derivative (Figure 9–4), it is not inactivated by COMT and has a longer duration of action than the catecholamines. It is an effective mydriatic and decongestant and can be used to raise the blood pressure (Figure 9–6).

Midodrine is a prodrug that is enzymatically hydrolyzed to desglymidodrine, a selective ₁-receptor agonist. The peak concentration of desglymidodrine is achieved about 1 hour after midodrine is administered. The primary indication for midodrine is the treatment of orthostatic hypotension, typically due to impaired autonomic nervous system function. Although the drug has efficacy in diminishing the fall of blood pressure when the patient is standing, it may cause hypertension when the subject is supine.

Methoxamine acts pharmacologically like phenylephrine, since it is predominantly a direct-acting ₁-receptor agonist. It may cause a prolonged increase in blood pressure due to vasoconstriction; it also causes a vagally mediated bradycardia. Methoxamine is available for parenteral use, but clinical applications are rare and limited to hypotensive states.

Alpha₂-selective agonists have an important ability to decrease blood pressure through actions in the central nervous system even though direct application to a blood vessel may cause vasoconstriction. Such drugs (eg, clonidine, methyldopa, guanfacine, guanabenz) are useful in the treatment of hypertension (and some other conditions) and are discussed in Chapter 11. Dexmedetomidine is a centrally acting ₂-selective agonist that is indicated for sedation of initially intubated and mechanically ventilated patients during treatment in an intensive care setting. It also reduces the requirements for opioids in pain control.

Xylometazoline and oxymetazoline are direct-acting agonists. These drugs have been used as topical decongestants because of their ability to promote constriction of the nasal mucosa. When taken in large doses, oxymetazoline may cause hypotension, presumably because of a central clonidine-like effect (see Chapter 11). Oxymetazoline has significant affinity for _2A receptors.

Isoproterenol (isoprenaline) is a very potent -receptor agonist and has little effect on receptors. The drug has positive chronotropic and inotropic actions; because isoproterenol activates receptors almost exclusively, it is a potent vasodilator. These actions lead to a marked increase in cardiac output associated with a fall in diastolic and mean arterial pressure and a lesser decrease or a slight increase in systolic pressure (Table 9–4; Figure 9–6).

Beta-selective agonists are very important because the separation of ₁ and ₂ effects (Table 9–2), although incomplete, is sufficient to reduce adverse effects in several clinical applications.

Beta₁-selective agents include dobutamine and a partial agonist, prenalterol (Figure 9–8). Because they are less effective in activating vasodilator ₂ receptors, they may increase cardiac output with less reflex tachycardia than occurs with nonselective agonists such as isoproterenol. Dobutamine was initially considered a relatively ₁-selective agonist, but its actions are more complex. Its chemical structure that resembles dopamine, but its actions are mediated mostly by activation of and receptors. Clinical preparations of dobutamine are a racemic mixture of (–) and (+) isomers, each with contrasting activity at ₁ and ₂ receptors. The (+) isomer is a potent ₁ agonist and an ₁ receptor antagonist. The (–) isomer is a potent ₁ agonist, which is capable of causing significant vasoconstriction when given alone. The resultant cardiovascular effects of dobutamine reflect this complex pharmacology. Dobutamine has a positive inotropic action caused by the isomer with predominantly -receptor activity. It has relatively greater inotropic than chronotropic effect compared with isoproterenol. Activation of ₁ receptors probably explains why peripheral resistance does not decrease significantly.

Beta₂-selective agents have achieved an important place in the treatment of asthma and are discussed in Chapter 20. An additional application is to achieve uterine relaxation in premature labor (ritodrine; see below). Some examples of ₂-selective drugs currently in use are shown in Figures 9–8 and 20–4; many more are available or under investigation.

Mixed-Acting Sympathomimetics

Ephedrine occurs in various plants and has been used in China for over 2000 years; it was introduced into Western medicine in 1924 as the first orally active sympathomimetic drug. It is found in ma huang, a popular herbal medication (see Chapter 64). Ma huang contains multiple ephedrine-like alkaloids in addition to ephedrine. Because ephedrine is a noncatechol phenylisopropylamine (Figure 9–4), it has high bioavailability and a relatively long duration of action—hours rather than minutes. As with many other phenylisopropylamines, a significant fraction of the drug is excreted unchanged in the urine. Since it is a weak base, its excretion can be accelerated by acidification of the urine.

Ephedrine has not been extensively studied in humans despite its long history of use. Its ability to activate receptors probably accounted for its earlier use in asthma. Because it gains access to the central nervous system, it is a mild stimulant. Ingestion of ephedrine alkaloids contained in ma huang has raised important safety concerns. Pseudoephedrine, one of four ephedrine enantiomers, has been available over the counter as a component of many decongestant mixtures. However, the use of pseudoephedrine as a precursor in the illicit manufacture of methamphetamine has led to restrictions on its sale.

Phenylpropanolamine was a common component in over-the-counter appetite suppressants. It was removed from the market because its use was associated with hemorrhagic strokes in young women. The mechanism of this potential adverse effect is unknown, but the drug can increase blood pressure in patients with impaired autonomic reflexes.

Indirect-Acting Sympathomimetics

As noted previously, indirect-acting sympathomimetics can have one of two different mechanisms (Figure 9–3). First, they may enter the sympathetic nerve ending and displace stored catecholamine transmitter. Such drugs have been called amphetamine-like or "displacers." Second, they may inhibit the reuptake of released transmitter by interfering with the action of the norepinephrine transporter, NET.

Amphetamine-Like

Amphetamine  is a racemic mixture of phenylisopropylamine (Figure 9–4) that is important chiefly because of its use and misuse as a central nervous system stimulant (see Chapter 32). Pharmacokinetically, it is similar to ephedrine; however, amphetamine even more readily enters the central nervous system, where it has marked stimulant effects on mood and alertness and a depressant effect on appetite. Its D-isomer is more potent than the L-isomer. Amphetamine's actions are mediated through the release of norepinephrine and, to some extent, dopamine.

Methamphetamine  (N- methylamphetamine) is very similar to amphetamine with an even higher ratio of central to peripheral actions. Phenmetrazine is a variant phenylisopropylamine with amphetamine-like effects. It has been promoted as an anorexiant and is also a popular drug of abuse. Methylphenidate is an amphetamine variant whose major pharmacologic effects and abuse potential are similar to those of amphetamine. Methylphenidate may be effective in some children with attention deficit hyperactivity disorder (see Therapeutic Uses of Sympathomimetic Drugs). Modafinil is a psychostimulant that differs from amphetamine in structure, neurochemical profile, and behavioral effects. Its mechanism of action is not fully known; it inhibits both norepinephrine and dopamine transporters, and it increases interstitial concentrations not only of norepinephrine and dopamine, but also serotonin and glutamate while decreasing GABA levels. It is used primarily to improve wakefulness in narcolepsy and some other conditions. It is often associated with increases in blood pressure and heart rate, though these are usually mild. (see Therapeutic Uses of Sympathomimetic Drugs).

Tyramine (see Figure 6–5) is a normal by-product of tyrosine metabolism in the body and is also found in high concentrations in some fermented foods such as cheese (Table 9–5). It is readily metabolized by MAO in the liver and is normally inactive when taken orally because of a very high first-pass effect, ie, low bioavailability. If administered parenterally, it has an indirect sympathomimetic action caused by the release of stored catecholamines. Consequently, tyramine's spectrum of action is similar to that of norepinephrine. In patients treated with MAO inhibitors—particularly inhibitors of the MAO-A isoform—this effect of tyramine may be greatly intensified, leading to marked increases in blood pressure. This occurs because of increased bioavailability of tyramine and increased neuronal stores of catecholamines. Patients taking MAO inhibitors must be very careful to avoid tyramine-containing foods. There are differences in the effects of various MAO inhibitors on tyramine bioavailability, and isoform-specific or reversible enzyme antagonists may be safer (see Chapters 28 and 30).

Catecholamine Reuptake Inhibitors

Many inhibitors of the amine transporters for norepinephrine, dopamine, and serotonin are used clinically. Although specificity is not absolute, some are highly selective for one of the transporters. Many antidepressants, particularly the older tricyclic antidepressants can inhibit norepinephrine and serotonin reuptake to different degrees. This may lead to orthostatic tachycardia as a side effect. Some antidepressants of this class, particularly imipramine, can induce orthostatic hypotension presumably by their clonidine-like effect or by blocking ₁ receptors, but the mechanism remains unclear.

Atomoxetine is a selective inhibitor of the norepinephrine reuptake transporter. Its actions, therefore, are mediated by potentiation of norepinephrine levels in noradrenergic synapses. It is used in the treatment of attention deficit disorders (see below). Atomoxetine has surprisingly little cardiovascular effect because it has a clonidine-like effect in the central nervous system to decrease sympathetic outflow while at the same time potentiating the effects of norepinephrine in the periphery. However, it may increase blood pressure in some patients. Norepinephrine reuptake is particularly important in the heart, particularly during sympathetic stimulation, and this explains why atomoxetine and other norepinephrine reuptake inhibitors frequently cause orthostatic tachycardia. ReBoxetine has similar characteristics as atomoxetine. Sibutramine is a serotonin and norepinephrine reuptake inhibitor and is the only appetite suppressant approved by the FDA for long-term treatment of obesity. Duloxetine is also a widely used antidepressant with serotonin and norepinephrine reuptake inhibitory effects (see Chapter 30).

Cocaine is a local anesthetic with a peripheral sympathomimetic action that results from inhibition of transmitter reuptake at noradrenergic synapses (see Chapter 6). It readily enters the central nervous system and produces an amphetamine-like psychological effect that is shorter lasting and more intense than amphetamine. The major action of cocaine in the central nervous system is to inhibit dopamine reuptake into neurons in the "pleasure centers" of the brain. These properties and the fact that it can be smoked, snorted into the nose, or injected for rapid onset of effect have made it a heavily abused drug (see Chapter 32). It is interesting that dopamine-transporter knockout mice still self-administer cocaine, suggesting that cocaine may have additional pharmacologic targets.

Dopamine Agonists

Levodopa, which is converted to dopamine in the body, and dopamine agonists with central actions are of considerable value in the treatment of Parkinson's disease and prolactinemia. These agents are discussed in Chapters 28 and 37.

Fenoldopam is a D₁-receptor agonist that selectively leads to peripheral vasodilation in some vascular beds. The primary indication for fenoldopam is in the intravenous treatment of severe hypertension (Chapter 11).

Therapeutic Uses of Sympathomimetic Drugs

Cardiovascular Applications

In keeping with the critical role of the sympathetic nervous system in the control of blood pressure, a major area of application of the sympathomimetics is in cardiovascular conditions.

Treatment of Acute Hypotension

Acute hypotension may occur in a variety of settings such as severe hemorrhage, decreased blood volume, cardiac arrhythmias, neurologic disease or accidents, adverse reactions or overdose of medications such as antihypertensive drugs, and infection. If cerebral, renal, and cardiac perfusion is maintained, hypotension itself does not usually require vigorous direct treatment. Rather, placing the patient in the recumbent position and ensuring adequate fluid volume while the primary problem is determined and treated is usually the correct course of action. The use of sympathomimetic drugs merely to elevate a blood pressure that is not an immediate threat to the patient may increase morbidity. Sympathomimetic drugs may be used in a hypotensive emergency to preserve cerebral and coronary blood flow. The treatment is usually of short duration while the appropriate intravenous fluid or blood is being administered. Direct-acting agonists such as norepinephrine, phenylephrine, and methoxamine have been used in this setting when vasoconstriction is desired.

Shock is a complex acute cardiovascular syndrome that results in a critical reduction in perfusion of vital tissues and a wide range of systemic effects. Shock is usually associated with hypotension, an altered mental state, oliguria, and metabolic acidosis. If untreated, shock usually progresses to a refractory deteriorating state and death. The three major mechanisms responsible for shock are hypovolemia, cardiac insufficiency, and altered vascular resistance. Volume replacement and treatment of the underlying disease are the mainstays of the treatment of shock. Although sympathomimetic drugs have been used in the treatment of virtually all forms of shock, their efficacy is unclear.

In most forms of shock, intense vasoconstriction, mediated by reflex sympathetic nervous system activation, is present. Indeed, efforts aimed at reducing rather than increasing peripheral resistance may be more fruitful to improve cerebral, coronary, and renal perfusion. A decision to use vasoconstrictors or vasodilators is best made on the basis of information about the underlying cause, which may require invasive monitoring.

Cardiogenic shock and acute heart failure, usually due to massive myocardial infarction, has a poor prognosis. Mechanically assisted perfusion and emergency cardiac surgery have been utilized in some settings. Optimal fluid replacement requires monitoring of pulmonary capillary wedge pressure and other parameters of cardiac function. Positive inotropic agents such as dopamine or dobutamine may provide short-term relief of heart failure symptoms in patients with advanced ventricular dysfunction. In low to moderate doses, these drugs may increase cardiac output and, compared with norepinephrine, cause relatively little peripheral vasoconstriction. Isoproterenol increases heart rate and work more than either dopamine or dobutamine. See Chapter 13 and Table 13–4 for a discussion of shock associated with myocardial infarction.

Unfortunately, the patient with shock may not respond to any of these therapeutic maneuvers; the temptation is then to use vasoconstrictors to maintain blood pressure. Coronary perfusion may be improved, but this gain may be offset by increased myocardial oxygen demands as well as more severe vasoconstriction in blood vessels to the abdominal viscera. Therefore, the goal of therapy in shock should be to optimize tissue perfusion, not blood pressure.

Chronic Orthostatic Hypotension

On standing, gravitational forces induce venous pooling, resulting in decreased venous return. Normally, a decrease in blood pressure is prevented by reflex sympathetic activation with increased heart rate, and peripheral arterial and venous vasoconstriction. Impairment of autonomic reflexes that regulate blood pressure can lead to chronic orthostatic hypotension. This is more often due to medications that can interfere with autonomic function (eg, imipramine and other tricyclic antidepressants, blockers for the treatment of urinary retention, and diuretics), diabetes and other diseases causing peripheral autonomic neuropathies, and less commonly, primary degenerative disorders of the autonomic nervous system, as in the case study described at the beginning of the chapter.

Increasing peripheral resistance is one of the strategies to treat chronic orthostatic hypotension, and drugs activating receptors can be used for this purpose. Midodrine, an orally active ₁ agonist, is frequently used for this indication. Other sympathomimetics, such as oral ephedrine or phenylephrine, can be tried.

Cardiac Applications

Catecholamines such as isoproterenol and epinephrine have been used in the temporary emergency management of complete heart block and cardiac arrest. Epinephrine may be useful in cardiac arrest in part by redistributing blood flow during cardiopulmonary resuscitation to coronaries and to the brain. However, electronic pacemakers are both safer and more effective in heart block and should be inserted as soon as possible if there is any indication of continued high-degree block.

Inducing Local Vasoconstriction

Reduction of local or regional blood flow is desirable for achieving hemostasis in surgery, for reducing diffusion of local anesthetics away from the site of administration, and for reducing mucous membrane congestion. In each instance, -receptor activation is desired, and the choice of agent depends on the maximal efficacy required, the desired duration of action, and the route of administration.

Effective pharmacologic hemostasis, often necessary for facial, oral, and nasopharyngeal surgery, requires drugs of high efficacy that can be administered in high concentration by local application. Epinephrine is usually applied topically in nasal packs (for epistaxis) or in a gingival string (for gingivectomy). Cocaine is still sometimes used for nasopharyngeal surgery because it combines a hemostatic effect with local anesthesia. Occasionally, cocaine is mixed with epinephrine for maximum hemostasis and local anesthesia.

Combining agonists with some local anesthetics greatly prolongs the duration of infiltration nerve block; the total dose of local anesthetic (and the probability of toxicity) can therefore be reduced. Epinephrine, 1:200,000, is the favored agent for this application, but norepinephrine, phenylephrine, and other agonists have also been used. Systemic effects on the heart and peripheral vasculature may occur even with local drug administration but are usually minimal.

Mucous membrane decongestants are agonists that reduce the discomfort of hay fever and, to a lesser extent, the common cold by decreasing the volume of the nasal mucosa. These effects are probably mediated by ₁ receptors. Unfortunately, rebound hyperemia may follow the use of these agents, and repeated topical use of high drug concentrations may result in ischemic changes in the mucous membranes, probably as a result of vasoconstriction of nutrient arteries. Constriction of these vessels may involve activation of ₂ receptors. For example, phenylephrine is often used in nasal decongestant sprays. A longer duration of action—at the cost of much lower local concentrations and greater potential for cardiac and central nervous system effects—can be achieved by the oral administration of agents such as ephedrine or one of its isomers, pseudoephedrine. Long-acting topical decongestants include xylometazoline and oxymetazoline. Most of these mucous membrane decongestants are available as over-the-counter products.

Pulmonary Applications

One of the most important uses of sympathomimetic drugs is in the therapy of bronchial asthma. This use is discussed in Chapter 20. Nonselective drugs (epinephrine), -selective agents (isoproterenol), and ₂-selective agents (albuterol, metaproterenol, terbutaline) all are available for this indication. Sympathomimetics other than the ₂–selective drugs are now rarely used because they are likely to have more adverse effects than the selective drugs.

Anaphylaxis

Anaphylactic shock and related immediate (type I) IgE-mediated reactions affect both the respiratory and the cardiovascular systems. The syndrome of bronchospasm, mucous membrane congestion, angioedema, and severe hypotension usually responds rapidly to the parenteral administration of epinephrine, 0.3–0.5 mg (0.3–0.5 mL of a 1:1000 epinephrine solution). Intramuscular injection may be the preferred route of administration, since skin blood flow (and hence systemic drug absorption from subcutaneous injection) is unpredictable in hypotensive patients. In some patients with impaired cardiovascular function, intravenous injection of epinephrine may be required. Extensive experimental and clinical experience with the drug in anaphylaxis supports epinephrine as the agent of choice, presumably because epinephrine activates , ₁, and ₂ receptors, all of which may be important in reversing the pathophysiologic processes underlying anaphylaxis. Glucocorticoids and antihistamines (both H₁- and H₂-receptor antagonists) may be useful as secondary therapy in anaphylaxis; however, epinephrine is the initial treatment. It is recommended that patients at risk for insect sting hypersensitivity, severe food allergies, or other types of anaphylaxis carry epinephrine in an autoinjector for self-administration (EpiPen).

Ophthalmic Applications

Phenylephrine is an effective mydriatic agent frequently used to facilitate examination of the retina. It is also a useful decongestant for minor allergic hyperemia and itching of the conjunctival membranes. Sympathomimetics administered as ophthalmic drops are also useful in localizing the lesion in Horner's syndrome. (See An Application of Basic Pharmacology to a Clinical Problem.)

Glaucoma responds to a variety of sympathomimetic and sympathoplegic drugs. (See in Chapter 10, The Treatment of Glaucoma.) Epinephrine and its prodrug dipivefrin are now rarely used, but -blocking agents are among the most important therapies. Apraclonidine and brimonidine are ₂-selective agonists that also lower intraocular pressure and are approved for use in glaucoma. The mechanism of action of these drugs in treating glaucoma is still uncertain; direct neuroprotective effects may be involved in addition to the benefits of lowering intraocular pressure.

Genitourinary Applications

As noted above, ₂-selective agents relax the pregnant uterus. Ritodrine, terbutaline, and similar drugs have been used to suppress premature labor. The goal is to defer labor long enough to ensure adequate maturation of the fetus. These drugs may delay labor for several days. This may afford time to administer corticosteroid drugs, which decrease the incidence of neonatal respiratory distress syndrome. However, meta-analysis of older trials and a randomized study suggest that -agonist therapy may have no significant benefit on perinatal infant mortality and may increase maternal morbidity.

Oral sympathomimetic therapy is occasionally useful in the treatment of stress incontinence. Ephedrine or pseudoephedrine may be tried.

Central Nervous System Applications

The amphetamines have a mood-elevating (euphoriant) effect; this effect is the basis for the widespread abuse of this drug group (see Chapter 32). The amphetamines also have an alerting, sleep-deferring action that is manifested by improved attention to repetitive tasks and by acceleration and desynchronization of the electroencephalogram. A therapeutic application of this effect is in the treatment of narcolepsy. Modafinil, a new amphetamine substitute, is approved for use in narcolepsy and is claimed to have fewer disadvantages (excessive mood changes, insomnia and abuse potential) than amphetamine in this condition. The appetite-suppressing effect of these agents is easily demonstrated in experimental animals. In obese humans, an encouraging initial response may be observed, but there is no evidence that long-term improvement in weight control can be achieved with amphetamines alone, especially when administered for a relatively short course. A final application of the central nervous system-active sympathomimetics is in the attention-deficit hyperactivity disorder (ADHD), a behavioral syndrome consisting of short attention span, hyperkinetic physical behavior, and learning problems. Some patients with this syndrome respond well to low doses of methylphenidate and related agents or to clonidine. Extended-release formulations of methylphenidate may simplify dosing regimens and increase adherence to therapy, especially in school-age children. Clinical trials suggest that modafinil may also be useful in ADHD, but because the safety profile in children has not been defined, it has not gained approval by the FDA for this indication.

Additional Therapeutic Uses

Although the primary use of the ₂ agonist clonidine is in the treatment of hypertension (see Chapter 11), the drug has been found to have efficacy in the treatment of diarrhea in diabetics with autonomic neuropathy, perhaps because of its ability to enhance salt and water absorption from the intestine. In addition, clonidine has efficacy in diminishing craving for narcotics and alcohol during withdrawal and may facilitate cessation of cigarette smoking. Clonidine has also been used to diminish menopausal hot flushes and is being used experimentally to reduce hemodynamic instability during general anesthesia. Dexmedetomidine is an ₂ agonist used for sedation under intensive care circumstances and during anesthesia (see Chapter 25). It blunts the sympathetic response to surgery, which may be beneficial in some situations. It lowers opioid requirements for pain control and does not depress ventilation. Tizanidine is an ₂ agonist that is used as a muscle relaxant (see Chapter 27).

Summary: Sympathomimetic Drugs

Preparations Available¹

¹₂ Agonists used in hypertension are listed in Chapter 11. ₂ Agonists used in asthma are listed in Chapter 20. NET transporter inhibitors are listed in Chapter 30.

References