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9 C H A P T E R Adrenoceptor Agonists & Sympathomimetic Drugs...

9 C H A P T E R Adrenoceptor Agonists & Sympathomimetic Drugs ∗ Italo Biaggioni, MD, & David Robertson, MD CASE STUDY A 68-year-old man presents with a complaint of light-headedness standing. There was an inadequate compensatory increase in on standing that is worse after meals and in hot environments. heart rate (from 84 to 88 bpm), considering the degree of Symptoms started about 4 years ago and have slowly pro- orthostatic hypotension. Physical examination is otherwise gressed to the point that he is disabled. He has fainted several unremarkable with no evidence of peripheral neuropathy or times, but always recovers consciousness almost as soon as he parkinsonian features. Laboratory examinations are negative falls. Review of symptoms reveals slight worsening of constipa- except for plasma norepinephrine, which is low at 98 pg/mL tion, urinary retention out of proportion to prostate size, and (normal is 250–400 pg/mL for his age). A diagnosis of pure decreased sweating. He is otherwise healthy with no history of autonomic failure is made, based on the clinical picture and hypertension, diabetes, or Parkinson’s disease. Because of his the absence of drugs that could induce orthostatic hypoten- urinary retention, he was placed on the α1 antagonist tamsu- sion and diseases commonly associated with autonomic neu- losin but he could not tolerate it because of worsening of ropathy (eg, diabetes, Parkinson’s disease). What precautions orthostatic hypotension. Physical examination revealed a should this patient observe in using sympathomimetic drugs? blood pressure of 167/84 mm Hg supine and 106/55 mm Hg Can such drugs be used in his treatment? The sympathetic nervous system is an important regulator of vir- Drugs that mimic the actions of epinephrine or norepineph- tually all organ systems. This is particularly evident in the regula- rine have traditionally been termed sympathomimetic drugs. tion of blood pressure. As illustrated in the case study, the The sympathomimetics can be grouped by mode of action and by autonomic nervous system is crucial for the maintenance of blood the spectrum of receptors that they activate. Some of these drugs pressure even under relatively minor situations of stress (eg, the (eg, norepinephrine and epinephrine) are direct agonists; that is, gravitational stress of standing). they directly interact with and activate adrenoceptors. Others are The ultimate effects of sympathetic stimulation are mediated indirect agonists because their actions are dependent on their abil- by release of norepinephrine from nerve terminals, which then ity to enhance the actions of endogenous catecholamines. These activates adrenoceptors on postsynaptic sites (see Chapter 6). Also, indirect agents may have either of two different mechanisms: (1) in response to a variety of stimuli such as stress, the adrenal they may displace stored catecholamines from the adrenergic medulla releases epinephrine, which is transported in the blood to nerve ending (eg, the mechanism of action of tyramine), or they target tissues. In other words, epinephrine acts as a hormone, may decrease the clearance of released norepinephrine either by whereas norepinephrine acts as a neurotransmitter. (2a) inhibiting reuptake of catecholamines already released (eg, the mechanism of action of cocaine and tricyclic antidepressants) or (2b) preventing the enzymatic metabolism of norepinephrine ∗ The authors thank Drs. Vsevolod Gurevich and Randy Blakely for (monoamine oxidase and catechol-O-methyltransferase inhibi- helpful comments. tors). Some drugs have both direct and indirect actions. Both 129 130 SECTION II Autonomic Drugs types of sympathomimetics, direct and indirect, ultimately cause G protein is a heterotrimer consisting of α, β, and γ subunits. G activation of adrenoceptors, leading to some or all of the charac- proteins are classified on the basis of their distinctive α subunits. teristic effects of endogenous catecholamines. G proteins of particular importance for adrenoceptor function The pharmacologic effects of direct agonists depend on the include Gs, the stimulatory G protein of adenylyl cyclase; Gi and route of administration, their relative affinity for adrenoreceptor Go, the inhibitory G proteins of adenylyl cyclase; and Gq and G11, subtypes, and the relative expression of these receptor subtypes in the G proteins coupling α receptors to phospholipase C. The target tissues. The pharmacologic effects of indirect sympathomi- activation of G protein-coupled receptors by catecholamines pro- metics are greater under conditions of increased sympathetic activ- motes the dissociation of guanosine diphosphate (GDP) from the ity and norepinephrine storage and release. α subunit of the appropriate G protein. Guanosine triphosphate (GTP) then binds to this G protein, and the α subunit dissociates from the β-γ unit. The activated GTP-bound α subunit then MOLECULAR PHARMACOLOGY regulates the activity of its effector. Effectors of adrenoceptor- UNDERLYING THE ACTIONS OF activated α subunits include adenylyl cyclase, cGMP phosphodi- esterase, phospholipase C, and ion channels. The α subunit is SYMPATHOMIMETIC DRUGS inactivated by hydrolysis of the bound GTP to GDP and phos- phate, and the subsequent reassociation of the α subunit with the The effects of catecholamines are mediated by cell-surface recep- β-γ subunit. The β-γ subunits have additional independent effects, tors. Adrenoceptors are typical G protein-coupled receptors acting on a variety of effectors such as ion channels and enzymes. (GPCRs; see Chapter 2). The receptor protein has an extracellular Adrenoreceptors were initially characterized pharmacologically, N-terminus, traverses the membrane seven times (transmembrane with α receptors having the comparative potencies epinephrine ≥ domains) forming three extracellular and three intracellular loops, norepinephrine >> isoproterenol, and β receptors having the com- and has an intracellular C-terminus (Figure 9–1). G protein- parative potencies isoproterenol > epinephrine ≥ norepinephrine. coupled receptors are coupled by G proteins to the various effec- The development of selective antagonists revealed the presence of tor proteins whose activities are regulated by those receptors. Each subtypes of these receptors, which were finally characterized by Agonist Gq Phospholipase C Ptdlns 4,5P2 { DAG β γ αq + αq* Activated GDP PKC PKC Alpha1 GTP receptor IP3 Ca2+-dependent + protein kinase + Free Stored calcium calcium Activated protein kinase FIGURE 9–1 Activation of α1 responses. Stimulation of α1 receptors by catecholamines leads to the activation of a Gq-coupling protein. The activated α subunit (αq*) of this G protein activates the effector, phospholipase C, which leads to the release of IP3 (inositol 1,4,5-trisphosphate) and DAG (diacylglycerol) from phosphatidylinositol 4,5-bisphosphate (PtdIns 4,5P2). IP3 stimulates the release of sequestered stores of calcium, leading to an increased concentration of cytoplasmic Ca2+. Ca2+ may then activate Ca2+-dependent protein kinases, which in turn phosphorylate their substrates. DAG activates protein kinase C (PKC). GTP, guanosine triphosphate; GDP, guanosine diphosphate. See text for additional effects of α1-receptor activation.  CHAPTER 9 Adrenoceptor Agonists & Sympathomimetic Drugs 131 TABLE 9–1 Adrenoceptor types and subtypes. Receptor Agonist Antagonist G Protein Effects Gene on Chromosome `1 type Phenylephrine Prazosin Gq ↑ IP3, DAG common to all α1A C8 α1B C5 α1D C20 `2 type Clonidine Yohimbine Gi ↓ cAMP common to all α2A Oxymetazoline C10 α2B Prazosin C2 α2C Prazosin C4 a type Isoproterenol Propranolol Gs ↑ cAMP common to all β1 Dobutamine Betaxolol C10 β2 Albuterol Butoxamine C5 β3 C8 Dopamine type Dopamine D1 Fenoldopam Gs ↑ cAMP C5 D2 Bromocriptine Gi ↓ cAMP C11 D3 Gi ↓ cAMP C3 D4 Clozapine Gi ↓ cAMP C11 D5 Gs ↑ cAMP C4 molecular cloning. We now know that unique genes encode the membrane. IP3 is sequentially dephosphorylated, which ultimately receptor subtypes listed in Table 9–1. leads to the formation of free inositol. DAG activates protein kinase Likewise, the endogenous catecholamine dopamine produces a C, which modulates activity of many signaling pathways. In addi- variety of biologic effects that are mediated by interactions with tion, α1 receptors activate signal transduction pathways that were specific dopamine receptors (Table 9–1). These receptors are dis- originally described for peptide growth factor receptors that activate tinct from α and β receptors and are particularly important in the tyrosine kinases. For example, α1 receptors have been found to acti- brain (see Chapters 21 and 29) and in the splanchnic and renal vate mitogen-activated kinases (MAP kinases) and polyphospho- vasculature. Molecular cloning has identified several distinct genes inositol-3-kinase (PI-3-kinase). These pathways may have encoding five receptor subtypes, two D1-like receptors (D1 and importance for the α1-receptor–mediated stimulation of cell growth D5) and three D2-like (D2, D3, and D4). Further complexity and proliferation through the regulation of gene expression. occurs because of the presence of introns within the coding region Alpha2 receptors inhibit adenylyl cyclase activity and cause of the D2-like receptor genes, which allows for alternative splicing intracellular cyclic adenosine monophosphate (cAMP) levels to of the exons in this major subtype. There is extensive polymorphic decrease. Alpha2-receptor–mediated inhibition of adenylyl cyclase variation in the D4 human receptor gene. These subtypes may activity is transduced by the inhibitory regulatory protein, Gi have importance for understanding the efficacy and adverse effects (Figure 9–2). It is likely that not only α, but also the β-γ subunits of novel antipsychotic drugs (see Chapter 29). of Gi 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 sig- Receptor Types nal transduction. Indeed, some of the effects of α2 adrenoceptors A. Alpha Receptors are independent of their ability to inhibit adenylyl cyclase; for Alpha1 receptors are coupled via G proteins in the Gq family to example, α2-receptor agonists cause platelet aggregation and a phospholipase C. This enzyme hydrolyzes polyphosphoinositides, decrease in platelet cAMP levels, but it is not clear whether aggre- leading to the formation of inositol 1,4,5-trisphosphate (IP3) and gation is the result of the decrease in cAMP or other mechanisms diacylglycerol (DAG) (Table 9–1, Figure 9–1). IP3 promotes the involving Gi-regulated effectors. 2+ release of sequestered Ca from intracellular stores, which increases 2+ B. Beta Receptors the cytoplasmic concentration of free Ca and the activation of various calcium-dependent protein kinases. Activation of these Activation of all three receptor subtypes (β1, β2, and β3) results in receptors may also increase influx of calcium across the cell’s plasma stimulation of adenylyl cyclase and increased conversion of 132 SECTION II Autonomic Drugs Agonist Agonist GS Adenylyl Gi cyclase { { βγ GS β γ αS αi αS* αi* + – Beta GDP GTP GTP GDP Alpha2 receptor receptor GTP GDP GDP GTP ATP cAMP Enzyme + ATP + 2C R2C2 protein kinase ADP Enzyme-PO4 2R Biologic effect FIGURE 9–2 Activation and inhibition of adenylyl cyclase by agonists that bind to catecholamine receptors. Binding to β adrenoceptors stimulates adenylyl cyclase by activating the stimulatory G protein, Gs, which leads to the dissociation of its α subunit charged with GTP. This activated αs subunit directly activates adenylyl cyclase, resulting in an increased rate of synthesis of cAMP. Alpha2-adrenoceptor ligands inhibit adenylyl cyclase by causing dissociation of the inhibitory G protein, Gi, into its subunits; ie, an activated αi subunit charged with GTP and a β-γ unit. The mechanism by which these subunits inhibit adenylyl cyclase is uncertain. cAMP binds to the regulatory subunit (R ) of cAMP-dependent protein kinase, leading to the liberation of active catalytic subunits (C ) that phosphorylate specific protein substrates and modify their activity. These catalytic units also phosphorylate the cAMP response element binding protein (CREB), which modifies gene expression. See text for other actions of β and α2 adrenoceptors. adenosine triphosphate (ATP) to cAMP (Table 9–1, Figure 9–2). forming multi-subunit complexes within cells, which contain Activation of the cyclase enzyme is mediated by the stimulatory multiple signaling molecules. coupling protein Gs. Cyclic AMP is the major second messenger The β3 adrenoreceptor is a lower affinity receptor compared of β-receptor activation. For example, in the liver of many species, with β1 and β2 receptors but is more resistant to desensitization. It β-receptor–activated cAMP synthesis leads to a cascade of events is found in several tissues, but its physiologic or pathologic role in culminating in the activation of glycogen phosphorylase. In the humans is not clear. Selective agonists and antagonists have been heart, β-receptor–activated cAMP synthesis increases the influx of developed but are not clinically available. 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 C. Dopamine Receptors effect is uncertain, it may involve the phosphorylation of myosin The D1 receptor is typically associated with the stimulation of light-chain kinase to an inactive form (see Figure 12–1). Beta adenylyl cyclase (Table 9–1); for example, D1-receptor–induced adrenoceptors may activate voltage-sensitive calcium channels in smooth muscle relaxation is presumably due to cAMP accumula- the heart via Gs-mediated enhancement independently of changes tion in the smooth muscle of those vascular beds in which dop- in cAMP concentration. Under certain circumstances, β2 recep- amine is a vasodilator. D2 receptors have been found to inhibit tors may couple to Gq proteins. These receptors have been dem- adenylyl cyclase activity, open potassium channels, and decrease onstrated to activate additional kinases, such as MAP kinases, by calcium influx.  CHAPTER 9 Adrenoceptor Agonists & Sympathomimetic Drugs 133 Receptor Selectivity Receptor Selectivity and Physiologic Many clinically available adrenergic agonists have selectivity for Functions of Adrenoceptor Subtypes: the major (α1 and α2 versus β) adrenoreceptor types, but not for the subtypes of these major groups. Examples of clinically useful Lessons from Knockout Mice sympathomimetic agonists that are relatively selective for α1-, α2-, and β-adrenoceptor subgroups are compared with some nonselec- Since pharmacologic tools used to evaluate the function of tive agents in Table 9–2. Selectivity means that a drug may prefer- adrenoceptor subtypes have some limitations, a number of entially bind to one subgroup of receptors at concentrations too knockout mice have been developed with one or more adre- low to interact extensively with another subgroup. However, selec- noceptor genes subjected to loss of function mutations, as tivity is not usually absolute (nearly absolute selectivity has been described in Chapter 1 (see Box: Pharmacology & Genetics). termed “specificity”), and at higher concentrations, a drug may These models have their own complexities, and extrapola- also interact with related classes of receptors. The effects of a given tions from mice to humans may be uncertain. Nonetheless, drug may depend not only on its selectivity to adrenoreceptor these studies have yielded some novel insights. For example, types, but also to the relative expression of receptor subtypes in a α-adrenoceptor subtypes play an important role in cardiac given tissue. (see Box: Receptor Selectivity and Physiologic responses, the α2A-adrenoceptor subtype is critical in trans- Functions of Adrenoceptor Subtypes). ducing the effects of α2 agonists on blood pressure control, and β1 receptors play a predominant role in directly increas- Receptor Regulation ing heart rate in the mouse heart. 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 Other terms such as tolerance, refractoriness, and tachyphylaxis physiologic response to catecholamines and can be important have also been used to denote desensitization. This process has clinically during the course of treatment. One of the best-studied potential clinical significance because it may limit the therapeutic examples of receptor regulation is the desensitization of adreno- response to sympathomimetic agents. ceptors that may occur after exposure to catecholamines and other Many mechanisms have been found to contribute to desensiti- sympathomimetic drugs. After a cell or tissue has been exposed for zation. Some mechanisms function relatively slowly, over the a period of time to an agonist, that tissue often becomes less course of hours or days, and these typically involve transcriptional responsive to further stimulation by that agent (see Figure 2–12). or translational changes in the receptor protein level, or its migra- tion 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 TABLE 9–2 Relative receptor affinities. residues, association of these receptors with other proteins, or changes in their subcellular location. Relative Receptor Affinities There are two major categories of desensitization of responses mediated by G protein-coupled receptors. Homologous desensi- Alpha agonists tization refers to loss of responsiveness exclusively of the receptors Phenylephrine, methoxamine α1 > α2 >>>>> β that have been exposed to repeated or sustained activation by an Clonidine, methylnorepinephrine α2 > α1 >>>>> β agonist. Heterologous desensitization refers to the process by Mixed alpha and beta agonists which desensitization of one receptor by its agonists also results in Norepinephrine α1 = α2; β1 >> β2 desensitization of another receptor that has not been directly acti- vated by the agonist in question. Epinephrine α1 = α2; β1 = β2 A major mechanism of desensitization that occurs rapidly Beta agonists involves phosphorylation of receptors by members of the G protein- 1 Dobutamine β1 > β2 >>>> α coupled receptor kinase (GRK) family, of which there are seven Isoproterenol β1 = β2 >>>> α members. Specific adrenoceptors become substrates for these Albuterol, terbutaline, β2 >> β1 >>>> α kinases only when they are bound to an agonist. This mechanism metaproterenol, ritodrine is an example of homologous desensitization because it specifically Dopamine agonists involves only agonist-occupied receptors. Dopamine D1 = D2 >> β >> α Phosphorylation of these receptors enhances their affinity for arrestins, a family of four widely expressed proteins. Upon Fenoldopam D1 >> D2 binding of arrestin, the capacity of the receptor to activate G 1 See text. proteins is blunted, presumably as a result of steric hindrance 134 SECTION II Autonomic Drugs (see Figure 2–12). Arrestin then interacts with clathrin and (DHPG). Elsewhere in the body similar transporters remove dop- clathrin adaptor AP2, leading to endocytosis of the receptor. In amine (dopamine transporter, DAT), serotonin (serotonin trans- addition to blunting responses requiring the presence of the porter, SERT), and other neurotransmitters. The NET, surprisingly, receptor on the cell surface, these regulatory processes may also has equivalent affinity for dopamine as for norepinephrine, and it contribute to novel mechanisms of receptor signaling via intra- can sometimes clear dopamine in brain areas where DAT is low, cellular pathways. like the cortex. Receptor desensitization may also be mediated by second- Blockade of the NET, eg, by the nonselective psychostimulant messenger feedback. For example, β adrenoceptors stimulate cocaine or the NET selective agents atomoxetine or reboxetine, cAMP accumulation, which leads to activation of protein kinase impairs this primary site of norepinephrine removal and thus A; protein kinase A can phosphorylate residues on β receptors, synaptic norepinephrine levels rise, leading to greater stimulation resulting in inhibition of receptor function. For the β2 receptor, of α and β adrenoceptors. In the periphery this effect may pro- phosphorylation occurs on serine residues both in the third cyto- duce a clinical picture of sympathetic activation, but it is often plasmic loop and in the carboxyl terminal tail of the receptor. counterbalanced by concomitant stimulation of α2 adrenoceptors Similarly, activation of protein kinase C by Gq-coupled receptors in the brainstem that reduces sympathetic activation. may lead to phosphorylation of this class of G protein-coupled However, the function of the norepinephrine and dopamine receptors. This second-messenger feedback mechanism has been transporters is complex, and drugs can interact with the NET to termed heterologous desensitization because activated protein actually reverse the direction of transport and induce the release of kinase A or protein kinase C may phosphorylate any structurally intraneuronal neurotransmitter. This is illustrated in Figure 9–3. similar receptor with the appropriate consensus sites for phospho- Under normal circumstances (panel A), presynaptic NET (red) rylation by these enzymes. inactivates and recycles norepinephrine (NE, red) released by vesicular fusion. In panel B, amphetamine (black) acts as both an NET substrate and a reuptake blocker, eliciting reverse transport Adrenoceptor Polymorphisms and blocking normal uptake, thereby increasing NE levels in and Since elucidation of the sequences of the genes encoding the α1, beyond the synaptic cleft. In panel C, agents such as methylpheni- α2, and β subtypes of adrenoceptors, it has become clear that there date and cocaine (hexagons) block NET-mediated NE reuptake are relatively common genetic polymorphisms for many of these and enhance NE signaling. receptor subtypes in humans. Some of these may lead to changes in critical amino acid sequences that have pharmacologic impor- tance. Often, distinct polymorphisms occur in specific combina- tions termed haplotypes. Some polymorphisms have been shown MEDICINAL CHEMISTRY OF to alter susceptibility to diseases such as heart failure, others to SYMPATHOMIMETIC DRUGS alter the propensity of a receptor to desensitize, and still others to alter therapeutic responses to drugs in diseases such as asthma. Phenylethylamine may be considered the parent compound from This remains an area of active research because studies have which sympathomimetic drugs are derived (Figure 9–4). This reported inconsistent results as to the pathophysiologic impor- compound consists of a benzene ring with an ethylamine side tance of some polymorphisms. chain. Substitutions may be made on (1) the benzene ring, (2) the terminal amino group, and (3) the α or β carbons of the ethylamino The Norepinephrine Transporter chain. Substitution by –OH groups at the 3 and 4 positions yields sympathomimetic drugs collectively known as catecholamines. When norepinephrine is released into the synaptic cleft, it binds The effects of modification of phenylethylamine are to change the to postsynaptic adrenoceptors to elicit the expected physiologic affinity of the drugs for α and β receptors, spanning the range effect. However, just as the release of neurotransmitters is a tightly from almost pure α activity (methoxamine) to almost pure β regulated process, the mechanisms for removal of neurotransmit- activity (isoproterenol), as well as to influence the intrinsic ability ter must also be highly effective. The norepinephrine transporter to activate the receptors. (NET) is the principal route by which this occurs. It is particularly In addition to determining relative affinity to receptor subtype, efficient in the synapses of the heart, where up to 90% of released chemical structure also determines the pharmacokinetic properties norepinephrine is removed by the NET. Remaining synaptic nor- and bioavailability of these molecules. epinephrine may escape into the extrasynaptic space and enter the bloodstream or be taken up into extraneuronal cells and metabo- lized by catecholamine-N-methyltransferase. In other sites such as A. Substitution on the Benzene Ring the vasculature, where synaptic structures are less well developed, Maximal α and β activity is found with catecholamines, ie, drugs removal may still be 60% or more by NET. The NET, often situ- having –OH groups at the 3 and 4 positions on the benzene ring. ated on the presynaptic neuronal membrane, pumps the synaptic The absence of one or the other of these groups, particularly the norepinephrine back into the neuron cell cytoplasm. In the cell, hydroxyl at C3, without other substitutions on the ring may dra- this norepinephrine may reenter the vesicles or undergo metabo- matically reduce the potency of the drug. For example, phe- lism through monoamine oxidase to dihydroxyphenylglycol nylephrine (Figure 9–5) is much less potent than epinephrine;  CHAPTER 9 Adrenoceptor Agonists & Sympathomimetic Drugs 135 A B Postganglionic sympathetic nerve ending NET NET NE VMAT Amphetamine VMAT NE NET NET Reversed transport NE NE Effector cell Effector cell C NET Cocaine VMAT NE NET Blocked transport NE Effector cell FIGURE 9–3 Pharmacologic targeting of monoamine transporters. Commonly used drugs such as antidepressants, amphetamines, and cocaine target monoamine (norepinephrine, dopamine, and serotonin) transporters with different potencies. A shows the mechanism of reuptake of norepinephrine (NE) back into the noradrenergic neuron via the norepinephrine transporter (NET), where a proportion is sequestered in presynaptic vesicles through the vesicular monoamine transporter (VMAT). B and C show the effects of amphetamine and cocaine on these pathways. See text for details. indeed, α-receptor affinity is decreased about 100-fold and β B. Substitution on the Amino Group activity is almost negligible except at very high concentrations. Increasing the size of alkyl substituents on the amino group tends On the other hand, catecholamines are subject to inactivation by to increase β-receptor activity. For example, methyl substitution catechol-O-methyltransferase (COMT), and because this enzyme on norepinephrine, yielding epinephrine, enhances activity at β2 is found in the gut and liver, catecholamines are not active orally receptors. Beta activity is further enhanced with isopropyl substi- (see Chapter 6). Absence of one or both –OH groups on the phe- tution at the amino group (isoproterenol). Beta2-selective agonists nyl ring increases the bioavailability after oral administration and generally require a large amino substituent group. The larger the prolongs the duration of action. Furthermore, absence of ring substituent on the amino group, the lower the activity at α recep- –OH groups tends to increase the distribution of the molecule to tors; for example, isoproterenol is very weak at α receptors. the central nervous system. For example, ephedrine and amphet- amine (Figure 9–5) are orally active, have a prolonged duration of C. Substitution on the Alpha Carbon action, and produce central nervous system effects not typically Substitutions at the α carbon block oxidation by monoamine oxi- observed with the catecholamines. dase (MAO) and prolong the action of such drugs, particularly the 136 SECTION II Autonomic Drugs HO 3 2 β α HO 4 1 CH2 CH2 NH2 5 6 Catechol Phenylethylamine HO HO OH OH HO CH CH2 NH2 HO CH CH2 NH CH3 Norepinephrine Epinephrine HO HO OH CH3 HO CH CH2 NH CH HO CH2 CH2 NH2 CH3 Isoproterenol Dopamine FIGURE 9–4 Phenylethylamine and some important catecholamines. Catechol is shown for reference. noncatecholamines. Ephedrine and amphetamine are examples of α-substituted compounds (Figure 9–5). Alpha-methyl com- CH3O pounds are also called phenylisopropylamines. In addition to HO their resistance to oxidation by MAO, some phenylisopropylam- CH CH NH2 ines have an enhanced ability to displace catecholamines from CH CH2 NH CH3 OH CH3 storage sites in noradrenergic nerves (see Chapter 6). Therefore, a OH OCH3 portion of their activity is dependent on the presence of normal Phenylephrine Methoxamine norepinephrine stores in the body; they are indirectly acting sympathomimetics. CH CH NH CH3 CH2 CH NH2 D. Substitution on the Beta Carbon OH CH3 CH3 Direct-acting agonists typically have a β-hydroxyl group, although Ephedrine Amphetamine dopamine does not. In addition to facilitating activation of adre- noceptors, this hydroxyl group may be important for storage of sympathomimetic amines in neural vesicles. FIGURE 9–5 Some examples of noncatecholamine sympath- omimetic drugs. The isopropyl group is highlighted in color. ORGAN SYSTEM EFFECTS OF SYMPATHOMIMETIC DRUGS not only on its relative selectivity for α or β adrenoceptors and its pharmacologic action at those receptors; any effect these agents Cardiovascular System have on blood pressure is counteracted by compensatory barore- General outlines of the cellular actions of sympathomimetics are flex mechanisms aimed at restoring homeostasis. presented in Tables 6–3 and 9–3. Sympathomimetics have promi- The effects of sympathomimetic drugs on blood pressure can nent cardiovascular effects because of widespread distribution of α be explained on the basis of their effects on heart rate, myocardial and β adrenoceptors in the heart, blood vessels, and neural and function, peripheral vascular resistance, and venous return (see hormonal systems involved in blood pressure regulation. The net Figure 6–7 and Table 9–4). The endogenous catecholamines, nor- effect of a given sympathomimetic in the intact organism depends epinephrine and epinephrine, have complex cardiovascular effects  CHAPTER 9 Adrenoceptor Agonists & Sympathomimetic Drugs 137 TABLE 9–3 Distribution of adrenoceptor subtypes. removed by pretreatment with the ganglionic blocker trimethaphan, the pressor effect of phenylephrine is increased approximately Type Tissue Actions tenfold, and bradycardia is no longer observed (Figure 9–7), con- α1 Most vascular smooth Contraction firming that the decrease in heart rate associated with the increase muscle (innervated) in blood pressure induced by phenylephrine was reflex in nature Pupillary dilator muscle Contraction (dilates pupil) rather than a direct effect of α1-receptor activation. Pilomotor smooth muscle Erects hair Patients who have an impairment of autonomic function (due to Prostate Contraction pure autonomic failure as in the case study or to more common conditions such as diabetic autonomic neuropathy) exhibit this Heart Increases force of con- traction extreme hypersensitivity to most pressor and depressor stimuli, including medications. This is to a large extent due to failure of α2 Postsynaptic CNS neurons Probably multiple baroreflex buffering. Such patients may have exaggerated increases in Platelets Aggregation heart rate or blood pressure when taking sympathomimetics with Adrenergic and cholinergic Inhibits transmitter β- and α-adrenergic activity, respectively. This, however, can be used nerve terminals release as an advantage in their treatment. The α agonist midodrine is com- Some vascular smooth Contraction monly used to ameliorate orthostatic hypotension in these patients. muscle There are major differences in receptor types predominantly Fat cells Inhibits lipolysis expressed in the various vascular beds (Table 9–4). The skin vessels β1 Heart, juxtaglomerular cells Increases force and rate have predominantly α receptors and constrict in response to epi- of contraction; increases nephrine and norepinephrine, as do the splanchnic vessels. Vessels renin release in skeletal muscle may constrict or dilate depending on whether α β2 Respiratory, uterine, and Promotes smooth muscle or β receptors are activated. The blood vessels of the nasal mucosa vascular smooth muscle relaxation express α receptors, and local vasoconstriction induced by sym- Skeletal muscle Promotes potassium pathomimetics explains their decongestant action (see Therapeutic uptake Uses of Sympathomimetic Drugs). Human liver Activates glycogenolysis β3 Fat cells Activates lipolysis B. Effects of Alpha2-Receptor Activation D1 Smooth muscle Dilates renal blood vessels Alpha2 adrenoceptors are present in the vasculature, and their acti- vation leads to vasoconstriction. This effect, however, is observed D2 Nerve endings Modulates transmitter release only when α2 agonists are given locally, by rapid intravenous injec- tion or in very high oral doses. When given systemically, these vascular effects are obscured by the central effects of α2 receptors, which lead to inhibition of sympathetic tone and blood pressure. Hence, α2 agonists are used as sympatholytics in the treatment of hypertension (see Chapter 11). In patients with pure autonomic because they activate both α and β receptors. It is easier to under- failure, characterized by neural degeneration of postganglionic stand these actions by first describing the cardiovascular effect of noradrenergic fibers, clonidine may increase blood pressure because sympathomimetics that are selective for a given adrenoreceptor. the central sympatholytic effects of clonidine become irrelevant, whereas the peripheral vasoconstriction remains intact. A. Effects of Alpha1-Receptor Activation Alpha1 receptors are widely expressed in vascular beds, and their C. Effects of Beta-Receptor Activation activation leads to arterial and venous vasoconstriction. Their The blood pressure response to a β-adrenoceptor agonist depends direct effect on cardiac function is of relatively less importance. A on its contrasting effects on the heart and the vasculature. relatively pure α agonist such as phenylephrine increases periph- Stimulation of β receptors in the heart increases cardiac output by eral arterial resistance and decreases venous capacitance. The increasing contractility and by direct activation of the sinus node enhanced arterial resistance usually leads to a dose-dependent rise to increase heart rate. Beta agonists also decrease peripheral resis- in blood pressure (Figure 9–6). In the presence of normal cardio- tance by activating β2 receptors, leading to vasodilation in certain vascular reflexes, the rise in blood pressure elicits a baroreceptor- vascular beds (Table 9–4). Isoproterenol is a nonselective β agonist; mediated increase in vagal tone with slowing of the heart rate, it activates both β1 and β2 receptors. The net effect is to maintain which may be quite marked (Figure 9–7). However, cardiac out- or slightly increase systolic pressure and to lower diastolic pressure, put may not diminish in proportion to this reduction in rate, since so that mean blood pressure is decreased (Figure 9–6). increased venous return may increase stroke volume. Furthermore, Direct effects on the heart are determined largely by β1 recep- direct α-adrenoceptor stimulation of the heart may have a modest tors, although β2 and to a lesser extent α receptors are also positive inotropic action. The magnitude of the restraining effect involved, especially in heart failure. Beta-receptor activation of the baroreflex is quite dramatic. If baroreflex function is results in increased calcium influx in cardiac cells. This has both 138 SECTION II Autonomic Drugs TABLE 9–4 Cardiovascular responses to sympathomimetic amines. Phenylephrine Epinephrine lsoproterenol Vascular resistance (tone) Cutaneous, mucous membranes (α) ↑↑ ↑↑ 0 Skeletal muscle (β2, α) ↑ ↓ or ↑ ↓↓ Renal (α, D1) ↑ ↑ ↓ Splanchnic (α, β) ↑↑ ↓ or ↑1 ↓ Total peripheral resistance ↑↑↑ ↓ or ↑1 ↓↓ Venous tone (α, β) ↑ ↑ ↓ Cardiac Contractility (β1) 0 or ↑ ↑↑↑ ↑↑↑ Heart rate (predominantly β1) ↓↓ (vagal reflex) ↑ or ↓ ↑↑↑ Stroke volume 0, ↓, ↑ ↑ ↑ Cardiac output ↓ ↑ ↑↑ Blood pressure Mean ↑↑ ↑ ↓ 1 Diastolic ↑↑ ↓ or ↑ ↓↓ Systolic ↑↑ ↑↑ 0 or ↓ Pulse pressure 0 ↑↑ ↑↑ 1 Small doses decrease, large doses increase. ↑ = increase; ↓ = decrease; 0 = no change. electrical and mechanical consequences. Pacemaker activity— norepinephrine release, but it is unclear if this contributes to car- both normal (sinoatrial node) and abnormal (eg, Purkinje diovascular effects of dopamine. In addition, dopamine activates fibers)—is increased (positive chronotropic effect). Conduction β1 receptors in the heart. At low doses, peripheral resistance may velocity in the atrioventricular node is increased (positive dromo- decrease. At higher rates of infusion, dopamine activates vascular tropic effect), and the refractory period is decreased. Intrinsic α receptors, leading to vasoconstriction, including in the renal contractility is increased (positive inotropic effect), and relax- vascular bed. Consequently, high rates of infusion of dopamine ation is accelerated. As a result, the twitch response of isolated may mimic the actions of epinephrine. 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 eas- Noncardiac Effects of Sympathomimetics ily demonstrated in the absence of reflexes evoked by changes in Adrenoceptors are distributed in virtually all organ systems. This blood pressure, eg, in isolated myocardial preparations and in section focuses on the activation of adrenoceptors that are patients with ganglionic blockade. In the presence of normal reflex responsible for the therapeutic effects of sympathomimetics or activity, the direct effects on heart rate may be dominated by a that explain their adverse effects. A more detailed description of reflex response to blood pressure changes. Physiologic stimulation the therapeutic use of sympathomimetics is given later in this of the heart by catecholamines tends to increase coronary blood chapter. flow. Expression of β3 adrenoreceptors has been detected in the Activation of β2 receptors in bronchial smooth muscle leads human heart and may be upregulated in disease states, but its to bronchodilation, and β2 agonists are important in the treat- relevance to human disease is unclear. ment of asthma (see Chapter 20 and Table 9–3). In the eye, the radial pupillary dilator muscle of the iris con- D. Effects of Dopamine-Receptor Activation tains α receptors; activation by drugs such as phenylephrine causes Intravenous administration of dopamine promotes vasodilation of mydriasis (see Figure 6–9). Alpha stimulants also have important renal, splanchnic, coronary, cerebral, and perhaps other resistance effects on intraocular pressure. Alpha agonists increase the outflow vessels, via activation of D1 receptors. Activation of the D1 recep- of aqueous humor from the eye and can be used clinically to tors in the renal vasculature may also induce natriuresis. The renal reduce intraocular pressure. In contrast, β agonists have little effects of dopamine have been used clinically to improve perfusion effect, but β antagonists decrease the production of aqueous to the kidney in situations of oliguria (abnormally low urinary humor. These effects are important in the treatment of glaucoma output). The activation of presynaptic D2 receptors suppresses (see Chapter 10), a leading cause of blindness.  CHAPTER 9 Adrenoceptor Agonists & Sympathomimetic Drugs 139 FIGURE 9–6 Effects of an α-selective (phenylephrine), β-selective (isoproterenol), and nonselective (epinephrine) sympathomimetic, given as an intravenous bolus injection to a dog. Reflexes are blunted but not eliminated in this anesthetized animal. BP, blood pressure; HR, heart rate. In genitourinary organs, the bladder base, urethral sphincter, Sympathomimetic drugs have important effects on intermedi- and prostate contain α receptors that mediate contraction and ary metabolism. Activation of β adrenoceptors in fat cells leads to therefore promote urinary continence. The specific subtype of α1 increased lipolysis with enhanced release of free fatty acids and receptor involved in mediating constriction of the bladder base and glycerol into the blood. Beta3 adrenoceptors play a role in mediat- prostate is uncertain, but α1A receptors probably play an important ing this response in animals, but their role in humans is probably role. This effect explains why urinary retention is a potential minor. Human fat cells also contain α2 receptors that inhibit adverse effect of administration of the α1 agonist midodrine. lipolysis by decreasing intracellular cAMP. Sympathomimetic Alpha-receptor activation in the ductus deferens, seminal vesi- drugs enhance glycogenolysis in the liver, which leads to increased cles, and prostate plays a role in normal ejaculation. The detumes- glucose release into the circulation. In the human liver, the effects cence of erectile tissue that normally follows ejaculation is also of catecholamines are probably mediated mainly by β receptors, brought about by norepinephrine (and possibly neuropeptide Y) though α1 receptors may also play a role. Catecholamines in high released from sympathetic nerves. Alpha activation appears to have concentration may also cause metabolic acidosis. Activation of β2 a similar detumescent effect on erectile tissue in female animals. adrenoceptors by endogenous epinephrine or by sympathomi- The salivary glands contain adrenoceptors that regulate the metic drugs promotes the uptake of potassium into cells, leading secretion of amylase and water. However, certain sympathomi- to a fall in extracellular potassium. This may result in a fall in the metic drugs, eg, clonidine, produce symptoms of dry mouth. The plasma potassium concentration during stress or protect against a mechanism of this effect is uncertain; it is likely that central ner- rise in plasma potassium during exercise. Blockade of these recep- vous system effects are responsible, although peripheral effects tors may accentuate the rise in plasma potassium that occurs dur- may contribute. ing exercise. On the other hand, epinephrine has been used to The apocrine sweat glands, located on the palms of the hands treat hyperkalemia in certain conditions, but other alternatives are and a few other areas, respond to adrenoceptor stimulants with more commonly used. Beta receptors and α2 receptors that are increased sweat production. These are the apocrine nonthermo- expressed in pancreatic islets tend to increase and decrease insulin regulatory glands usually associated with psychological stress. secretion, respectively, although the major regulator of insulin (The diffusely distributed thermoregulatory eccrine sweat glands release is the plasma concentration of glucose. are regulated by sympathetic cholinergic postganglionic nerves that Catecholamines are important endogenous regulators of hor- activate muscarinic cholinoceptors; see Chapter 6.) mone secretion from a number of glands. As mentioned above, 140 SECTION II Autonomic Drugs 80 100 HR bpm 0 0 BP 100 100 mm Hg Phe Phe 75 μg 7.5 μg 0 0 Intact Ganglionic blockade FIGURE 9–7 Effects of ganglionic blockade on the response to phenylephrine (Phe) in a human subject. Left: The cardiovascular effect of the selective α agonist phenylephrine when given as an intravenous bolus to a subject with intact autonomic baroreflex function. Note that the increase in blood pressure (BP) is associated with a baroreflex-mediated compensatory decrease in heart rate (HR). Right: The response in the same subject after autonomic reflexes were abolished by the ganglionic blocker trimethaphan. Note that resting blood pressure is decreased and heart rate is increased by trimethaphan because of sympathetic and parasympathetic withdrawal (HR scale is different). In the absence of baroreflex buffering, approximately a tenfold lower dose of phenylephrine is required to produce a similar increase in blood pressure. Note also the lack of compensatory decrease in heart rate. insulin secretion is stimulated by β receptors and inhibited by α2 produce qualitatively very different CNS effects. These actions vary receptors. Similarly, renin secretion is stimulated by β1 and inhib- from mild alerting, with improved attention to boring tasks; ited by α2 receptors; indeed, β-receptor antagonist drugs may lower through elevation of mood, insomnia, euphoria, and anorexia; to blood pressure in patients with hypertension at least in part by low- full-blown psychotic behavior. These effects are not readily assigned ering plasma renin. Adrenoceptors also modulate the secretion of to either α- or β-mediated actions and may represent enhancement parathyroid hormone, calcitonin, thyroxine, and gastrin; however, of dopamine-mediated processes or other effects of these drugs in the physiologic significance of these control mechanisms is probably the CNS. limited. In high concentrations, epinephrine and related agents cause leukocytosis, in part by promoting demargination of seques- tered white blood cells back into the general circulation. SPECIFIC SYMPATHOMIMETIC DRUGS The action of sympathomimetics on the central nervous sys- tem varies dramatically, depending on their ability to cross the Endogenous Catecholamines blood-brain barrier. The catecholamines are almost completely Epinephrine (adrenaline) is an agonist at both α and β receptors. excluded by this barrier, and subjective CNS effects are noted It is therefore a very potent vasoconstrictor and cardiac stimulant. only at the highest rates of infusion. These effects have been The rise in systolic blood pressure that occurs after epinephrine described as ranging from “nervousness” to “an adrenaline rush” release or administration is caused by its positive inotropic and or “a feeling of impending disaster.” Furthermore, peripheral chronotropic actions on the heart (predominantly β1 receptors) effects of β-adrenoceptor agonists such as tachycardia and tremor and the vasoconstriction induced in many vascular beds (α recep- are similar to the somatic manifestations of anxiety. In contrast, tors). Epinephrine also activates β2 receptors in some vessels (eg, noncatecholamines with indirect actions, such as amphetamines, skeletal muscle blood vessels), leading to their dilation. which readily enter the central nervous system from the circulation, Consequently, total peripheral resistance may actually fall, explaining  CHAPTER 9 Adrenoceptor Agonists & Sympathomimetic Drugs 141 the fall in diastolic pressure that is sometimes seen with epineph- recognized side effect of these drugs, and newer α2-agonists (with rine injection (Figure 9–6; Table 9–4). Activation of β2 receptors activity also at imidazoline receptors) with fewer central nervous in skeletal muscle contributes to increased blood flow during exer- system side effects are available outside the USA for the treatment cise. Under physiologic conditions, epinephrine functions largely of hypertension (moxonidine, rilmenidine). On the other hand, as a hormone; after release from the adrenal medulla into the the primary indication of dexmedetomidine is for sedation of blood, it acts on distant cells. initially intubated and mechanically ventilated patients during Norepinephrine (levarterenol, noradrenaline) is an agonist at treatment in an intensive care setting. It also reduces the require- both α1 and α2 receptors. Norepinephrine also activates β1 recep- ments for opioids in pain control. Finally, tizanidine is used as a tors with similar potency as epinephrine, but has relatively little central muscle relaxant. effect on β2 receptors. Consequently, norepinephrine increases Xylometazoline and oxymetazoline are direct-acting α ago- peripheral resistance and both diastolic and systolic blood pressure. nists. These drugs have been used as topical decongestants because Compensatory baroreflex activation tends to overcome the direct of their ability to promote constriction of the nasal mucosa. When positive chronotropic effects of norepinephrine; however, the posi- taken in large doses, oxymetazoline may cause hypotension, pre- tive inotropic effects on the heart are maintained. sumably because of a central clonidine-like effect (see Chapter Dopamine is the immediate precursor in the synthesis of nor- 11). Oxymetazoline has significant affinity for α2A receptors. epinephrine (see Figure 6–5). Its cardiovascular effects were Isoproterenol (isoprenaline) is a very potent β-receptor agonist described above. Endogenous dopamine may have more impor- and has little effect on α receptors. The drug has positive chrono- tant effects in regulating sodium excretion and renal function. It tropic and inotropic actions; because isoproterenol activates β is an important neurotransmitter in the central nervous system receptors almost exclusively, it is a potent vasodilator. These actions and is involved in the reward stimulus relevant to addiction. Its lead to a marked increase in cardiac output associated with a fall in deficiency in the basal ganglia leads to Parkinson’s disease, which diastolic and mean arterial pressure and a lesser decrease or a slight is treated with its precursor levodopa. Dopamine receptors are also increase in systolic pressure (Table 9–4; Figure 9–6). targets for antipsychotic drugs. Beta-selective agonists are very important because the separa- tion of β1 and β2 effects (Table 9–2), although incomplete, is sufficient to reduce adverse effects in several clinical applications. Direct-Acting Sympathomimetics Beta1-selective agents include dobutamine and a partial ago- Phenylephrine was discussed previously when describing the nist, prenalterol (Figure 9–8). Because they are less effective in actions of a relatively pure α1 agonist (Table 9–2). Because it is not activating vasodilator β2 receptors, they may increase cardiac out- a catechol derivative (Figure 9–4), it is not inactivated by COMT put with less reflex tachycardia than occurs with nonselective β and has a longer duration of action than the catecholamines. It is agonists such as isoproterenol. Dobutamine was initially consid- an effective mydriatic and decongestant and can be used to raise ered a relatively β1-selective agonist, but its actions are more com- the blood pressure (Figure 9–6). plex. Its chemical structure resembles dopamine, but its actions are Midodrine is a prodrug that is enzymatically hydrolyzed to mediated mostly by activation of α and β receptors. Clinical desglymidodrine, a selective α1-receptor agonist. The peak concen- preparations of dobutamine are a racemic mixture of (−) and (+) tration of desglymidodrine is achieved about 1 hour after midodrine isomers, each with contrasting activity at α1 and α2 receptors. The is administered. The primary indication for midodrine is the treat- (+) isomer is a potent β1 agonist and an α1-receptor antagonist. ment of orthostatic hypotension, typically due to impaired auto- The (−) isomer is a potent α1 agonist, which is capable of causing nomic nervous system function. Although the drug has efficacy in significant vasoconstriction when given alone. The resultant car- diminishing the fall of blood pressure when the patient is standing, diovascular effects of dobutamine reflect this complex pharmacol- it may cause hypertension when the subject is supine. The Food and ogy. Dobutamine has a positive inotropic action caused by the Drug Administration considered withdrawing approval of this drug isomer with predominantly β-receptor activity. It has relatively in 2010 because required postapproval studies that verify the clinical greater inotropic than chronotropic effect compared with isopro- benefit of the drug had not been done. Action was suspended in terenol. Activation of α1 receptors probably explains why periph- response to prescriber and patient requests. eral resistance does not decrease significantly. Methoxamine acts pharmacologically like phenylephrine, Beta2-selective agents have achieved an important place in the since it is predominantly a direct-acting α1-receptor agonist. It treatment of asthma and are discussed in Chapter 20. An addi- may cause a prolonged increase in blood pressure due to vasocon- tional application is to achieve uterine relaxation in premature striction; it also causes a vagally mediated bradycardia. Methoxamine labor (ritodrine; see below). Some examples of β2-selective drugs is available for parenteral use, but clinical applications are rare and currently in use are shown in Figures 9–8 and 20–4; many more limited to hypotensive states. are available or under investigation. 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 vasocon- Mixed-Acting Sympathomimetics striction. Such drugs (eg, clonidine, methyldopa, guanfacine, Ephedrine occurs in various plants and has been used in China guanabenz) are useful in the treatment of hypertension (and some for over 2000 years; it was introduced into Western medicine in other conditions) and are discussed in Chapter 11. Sedation is a 1924 as the first orally active sympathomimetic drug. It is found 142 SECTION II Autonomic Drugs BETA1-SELECTIVE HO HO CH2 CH2 NH HO O CH2 CH CH2 NH CH(CH3)2 HO CH2 CH2 CH CH3 OH Dobutamine Prenalterol BETA2-SELECTIVE HO CH CH NH HO OH CH3 CH CH2 NH C(CH3)3 HO CH2 CH2 OH HO Ritodrine Terbutaline FIGURE 9–8 Examples of β1- and β2-selective agonists. in ma huang, a popular herbal medication (see Chapter 64). Ma enter the sympathetic nerve ending and displace stored cate- huang contains multiple ephedrine-like alkaloids in addition to cholamine transmitter. Such drugs have been called amphetamine- ephedrine. Because ephedrine is a noncatechol phenylisopro- like or “displacers.” Second, they may inhibit the reuptake of pylamine (Figure 9–5), it has high bioavailability and a relatively released transmitter by interfering with the action of the norepi- long duration of action—hours rather than minutes. As with nephrine transporter, NET. many other phenylisopropylamines, a significant fraction of the drug is excreted unchanged in the urine. Since it is a weak base, its A. Amphetamine-Like excretion can be accelerated by acidification of the urine. Amphetamine is a racemic mixture of phenylisopropylamine Ephedrine has not been extensively studied in humans despite (Figure 9–5) that is important chiefly because of its use and misuse its long history of use. Its ability to activate β receptors probably as a central nervous system stimulant (see Chapter 32). accounted for its earlier use in asthma. Because it gains access to Pharmacokinetically, it is similar to ephedrine; however, amphet- the central nervous system, it is a mild stimulant. Ingestion of amine even more readily enters the central nervous system, where ephedrine alkaloids contained in ma huang has raised important it has marked stimulant effects on mood and alertness and a safety concerns. Pseudoephedrine, one of four ephedrine depressant effect on appetite. Its D-isomer is more potent than the enantiomers, has been available over the counter as a component L-isomer. Amphetamine’s actions are mediated through the release of many decongestant mixtures. However, the use of pseu- of norepinephrine and, to some extent, dopamine. doephedrine as a precursor in the illicit manufacture of metham- Methamphetamine (N-methylamphetamine) is very similar to phetamine has led to restrictions on its sale. amphetamine with an even higher ratio of central to peripheral Phenylpropanolamine was a common component in over- actions. Phenmetrazine is a variant phenylisopropylamine with the-counter appetite suppressants. It was removed from the mar- amphetamine-like effects. It has been promoted as an anorexiant ket because its use was associated with hemorrhagic strokes in and is also a popular drug of abuse. Methylphenidate is an young women. The mechanism of this potential adverse effect is amphetamine variant whose major pharmacologic effects and unknown, but the drug can increase blood pressure in patients abuse potential are similar to those of amphetamine. with impaired autonomic reflexes. Methylphenidate may be effective in some children with attention deficit hyperactivity disorder (see Therapeutic Uses of Indirect-Acting Sympathomimetics Sympathomimetic Drugs). Modafinil is a psychostimulant that As noted previously, indirect-acting sympathomimetics can have differs from amphetamine in structure, neurochemical profile, and one of two different mechanisms (Figure 9–3). First, they may behavioral effects. Its mechanism of action is not fully known. It  CHAPTER 9 Adrenoceptor Agonists & Sympathomimetic Drugs 143 inhibits both norepinephrine and dopamine transporters, and it B. Catecholamine Reuptake Inhibitors increases synaptic concentrations not only of norepinephrine and Many inhibitors of the amine transporters for norepinephrine, dop- dopamine, but also of serotonin and glutamate, while decreasing amine, and serotonin are used clinically. Although specificity is not GABA levels. It is used primarily to improve wakefulness in nar- absolute, some are highly selective for one of the transporters. Many colepsy and some other conditions. It is often associated with antidepressants, particularly the older tricyclic antidepressants, can increases in blood pressure and heart rate, though these are usually inhibit norepinephrine and serotonin reuptake to different degrees. mild (see Therapeutic Uses of Sympathomimetic Drugs). This may lead to orthostatic tachycardia as a side effect. Some anti- Tyramine (see Figure 6–5) is a normal by product of tyrosine depressants of this class, particularly imipramine, can induce ortho- metabolism in the body and can be produced in high concentra- static hypotension presumably by their clonidine-like effect or by tions in protein-rich foods by decarboxylation of tyrosine during blocking α1 receptors, but the mechanism remains unclear. fermentation (Table 9–5). It is readily metabolized by MAO in the Atomoxetine is a selective inhibitor of the norepinephrine liver and is normally inactive when taken orally because of a very reuptake transporter. Its actions, therefore, are mediated by poten- high first-pass effect, ie, low bioavailability. If administered paren- tiation of norepinephrine levels in noradrenergic synapses. It is terally, it has an indirect sympathomimetic action caused by the used in the treatment of attention deficit disorders (see below). release of stored catecholamines. Consequently, tyramine’s spec- Atomoxetine has surprisingly little cardiovascular effect because it trum of action is similar to that of norepinephrine. In patients has a clonidine-like effect in the central nervous system to decrease treated with MAO inhibitors—particularly inhibitors of the sympathetic outflow while at the same time potentiating the MAO-A isoform—this effect of tyramine may be greatly intensi- effects of norepinephrine in the periphery. However, it may fied, leading to marked increases in blood pressure. This occurs increase blood pressure in some patients. Norepinephrine reuptake because of increased bioavailability of tyramine and increased is particularly important in the heart, especially during sympa- neuronal stores of catecholamines. Patients taking MAO inhibi- thetic stimulation, and this explains why atomoxetine and other tors must be very careful to avoid tyramine-containing foods. norepinephrine reuptake inhibitors frequently cause orthostatic There are differences in the effects of various MAO inhibitors on tachycardia. Reboxetine has similar characteristics as atomox- tyramine bioavailability, and isoform-specific or reversible enzyme etine. Sibutramine is a serotonin and norepinephrine reuptake antagonists may be safer (see Chapters 28 and 30). inhibitor and was initially approved by the FDA as an appetite suppressant for long-term treatment of obesity. It has been taken off the market in the United States and several other countries because it has been associated with a small increase in cardiovascu- TABLE 9–5 Foods reputed to have a high content of lar events including strokes in patients with a history of cardiovas- tyramine or other sympathomimetic cular disease, which outweighed the benefits gained by modest agents. weight reduction. Duloxetine is a widely used antidepressant with Tyramine Content of an balanced serotonin and norepinephrine reuptake inhibitory effects Food Average Serving (see Chapter 30). Increased cardiovascular risk has not been reported with duloxetine. Duloxetine and milnacipran, another Beer 4–45 mg serotonin and norepinephrine transporter blocker, are approved Broad beans, fava beans Negligible (but contains dop- for the treatment of pain in fibromyalgia (see Chapter 30). amine) Cocaine is a local anesthetic with a peripheral sympathomi- Cheese, natural or aged Nil to 130 mg (cheddar, Gruyère, metic action that results from inhibition of transmitter reuptake at and Stilton especially high) noradrenergic synapses (Figure 9-3). It readily enters the central Chicken liver Nil to 9 mg nervous system and produces an amphetamine-like psychological Chocolate Negligible (but contains phenyl- effect that is shorter lasting and more intense than amphetamine. ethylamine) The major action of cocaine in the central nervous system is to Sausage, fermented (eg, salami, Nil to 74 mg inhibit dopamine reuptake into neurons in the “pleasure centers” pepperoni, summer sausage) of the brain. These properties and the fact that a rapid onset of Smoked or pickled fish (eg, pick- Nil to 198 mg action can be obtained when smoked, snorted into the nose, or led herring) injected, has made cocaine a heavily abused drug (see Chapter 32). Snails (No data found) It is interesting that dopamine-transporter knockout mice still Wine (red) Nil to 3 mg self-administer cocaine, suggesting that cocaine may have addi- Yeast (eg, dietary brewer’s yeast 2–68 mg tional pharmacologic targets. supplements) Note: In a patient taking an irreversible monoamine oxidase (MAO) inhibitor drug, Dopamine Agonists 20–50 mg of tyramine in a meal may increase the blood pressure significantly (see also Chapter 30: Antidepressant Agents). Note that only cheese, sausage, pickled fish, Levodopa, which is converted to dopamine in the body, and dop- and yeast supplements contain sufficient tyramine to be consistently dangerous. This amine agonists with central actions are of considerable value in does not rule out the possibility that some preparations of other foods might contain significantly greater than average amounts of tyramine. Amounts in mg as per regular the treatment of Parkinson’s disease and prolactinemia. These food portion. agents are discussed in Chapters 28 and 37. 144 SECTION II Autonomic Drugs Fenoldopam is a D1-receptor agonist that selectively leads to function. Positive inotropic agents such as dopamine or dobutamine peripheral vasodilation in some vascular beds. The primary indica- may provide short-term relief of heart failure symptoms in patients tion for fenoldopam is in the intravenous treatment of severe with advanced ventricular dysfunction. In low to moderate doses, hypertension (see Chapter 11). these drugs may increase cardiac output and, compared with norepi- nephrine, cause relatively little peripheral vasoconstriction. Isoproterenol increases heart rate and work more than either dop- THERAPEUTIC USES OF amine or dobutamine. See Chapter 13 for a discussion of shock SYMPATHOMIMETIC DRUGS associated with myocardial infarction. Unfortunately, the patient with shock may not respond to any Cardiovascular Applications of these therapeutic maneuvers; the temptation is then to use vaso- constrictors to maintain blood pressure. Coronary perfusion may In keeping with the critical role of the sympathetic nervous system be improved, but this gain may be offset by increased myocardial in the control of blood pressure, a major area of application of the oxygen demands as well as more severe vasoconstriction in blood sympathomimetics is in cardiovascular conditions. vessels to the abdominal viscera. Therefore, the goal of therapy in shock should be to optimize tissue perfusion, not blood pressure. A. Treatment of Acute Hypotension Acute hypotension may occur in a variety of settings such as severe B. Chronic Orthostatic Hypotension hemorrhage, decreased blood volume, cardiac arrhythmias, neuro- On standing, gravitational forces induce venous pooling, resulting logic disease or accidents, adverse reactions or overdose of medica- in decreased venous return. Normally, a decrease in blood pressure tions such as antihypertensive drugs, and infection. If cerebral, is prevented by reflex sympathetic activation with increased heart renal, and cardiac perfusion is maintained, hypotension itself does rate, and peripheral arterial and venous vasoconstriction. Impairment not usually require vigorous direct treatment. Rather, placing the of autonomic reflexes that regulate blood pressure can lead to patient in the recumbent position and ensuring adequate fluid chronic orthostatic hypotension. This is more often due to medica- volume while the primary problem is determined and treated is tions that can interfere with autonomic function (eg, imipramine usually the correct course of action. The use of sympathomimetic and other tricyclic antidepressants, α blockers for the treatment of drugs merely to elevate a blood pressure that is not an immediate urinary retention, and diuretics) diabetes, and other diseases causing threat to the patient may increase morbidity. Sympathomimetic peripheral autonomic neuropathies, and less commonly, primary drugs may be used in a hypotensive emergency to preserve cerebral degenerative disorders of the autonomic nervous system, as in the and coronary blood flow. The treatment is usually of short dura- case study described at the beginning of the chapter. tion while the appropriate intravenous fluid or blood is being Increasing peripheral resistance is one of the strategies to treat administered. Direct-acting α agonists such as norepinephrine, chronic orthostatic hypotension, and drugs activating α receptors phenylephrine, and methoxamine have been used in this setting can be used for this purpose. Midodrine, an orally active α1 ago- when vasoconstriction is desired. nist, is frequently used for this indication. Other sympathomimet- Shock is a complex acute cardiovascular syndrome that results ics, such as oral ephedrine or phenylephrine, can be tried. 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 C. Cardiac Applications untreated, shock usually progresses to a refractory deteriorating Catecholamines such as isoproterenol and epinephrine have been state and death. The three major mechanisms responsible for used in the temporary emergency management of complete heart shock are hypovolemia, cardiac insufficiency, and altered vascular block and cardiac arrest. Epinephrine may be useful in cardiac resistance. Volume replacement and treatment of the underlying arrest in part by redistributing blood flow during cardiopulmo- disease are the mainstays of the treatment of shock. Although nary resuscitation to coronaries and to the brain. However, elec- sympathomimetic drugs have been used in the treatment of virtu- tronic pacemakers are both safer and more effective in heart block ally all forms of shock, their efficacy is unclear. and should be inserted as soon as possible if there is any indication In most forms of shock, intense vasoconstriction, mediated by of continued high-degree block. reflex sympathetic nervous system activation, is present. Indeed, Dobutamine injection is used as a pharmacologic cardiac efforts aimed at reducing rather than increasing peripheral resis- stress test. Dobutamine augments myocardial contractility and tance may be more fruitful to improve cerebral, coronary, and promotes coronary and systemic vasodilation. These actions lead renal perfusion. A decision to use vasoconstrictors or vasodilators to increased heart rate and increased myocardial work and can is best made on the basis of information about the underlying reveal areas of ischemia in the myocardium that are detected by cause. Their use may require invasive monitoring. echocardiogram or nuclear medicine techniques. Dobutamine is Cardiogenic shock and acute heart failure, usually due to mas- often used in patients unable to exercise during the stress test. sive myocardial infarction, has a poor prognosis. Mechanically assisted perfusion and emergency cardiac surgery have been utilized D. Inducing Local Vasoconstriction in some settings. Optimal fluid replacement requires monitoring of Reduction of local or regional blood flow is desirable for achieving pulmonary capillary wedge pressure and other parameters of cardiac hemostasis in surgery, for reducing diffusion of local anesthetics  CHAPTER 9 Adrenoceptor Agonists & Sympathomimetic Drugs 145 away from the site of administration, and for reducing mucous Anaphylaxis membrane congestion. In each instance, α-receptor activation is Anaphylactic shock and related immediate (type I) IgE-mediated desired, and the choice of agent depends on the maximal efficacy reactions affect both the respiratory and the cardiovascular sys- required, the desired duration of action, and the route of admin-