10 Adrenomimetic Drugs Tony J.-F. Lee and Robert E. Stitzel DRUG LIST GENERIC NAME PAGE GENERIC NAME PAGE Albuterol 105 Isoproterenol 102 Amphetamine 106 Metaraminol 105 Dobutamine 105 Methoxamine 105 Dopamine 103 Norepinephrine 101 Ephedrine 105 Phenylephrine 105 Epinephrine 101 Terbutaline 105 The adrenomimetic drugs mimic the effects of adren- tal structure of the catecholamines is shown in Figure ergic sympathetic nerve stimulation on sympathetic 10.1. effectors; these drugs are also referred to as sympatho- The L-isomers are the naturally occurring forms mimetic agents. The adrenergic transmitter norepineph- of epinephrine and norepinephrine and possess consid- rine and the adrenal medullary hormone epinephrine erably greater pharmacological effects than do the also are included under this broad heading. The D-isomers. Throughout most of the world, epinephrine adrenomimetic drugs are an important group of thera- and norepinephrine are known as adrenaline and nora- peutic agents that can be used to maintain blood pres- drenaline, respectively. sure or to relieve a life-threatening attack of acute Noncatecholamine adrenomimetic drugs differ from bronchial asthma. They are also present in many over- the basic catecholamine structure primarily by having the-counter cold preparations because they constrict substitutions on their benzene ring. mucosal blood vessels and thus relieve nasal congestion. MECHANISM OF ACTION CHEMISTRY Many adrenomimetic drugs produce responses by inter- The adrenomimetic drugs can be divided into two ma- acting with the adrenoceptors on sympathetic effector jor groups on the basis of their chemical structure: the cells. An examination of Table 9.1 reveals that sympa- catecholamines and the noncatecholamines. The cate- thetic effectors have activity at 1-, 2-, 1-, or 2- cholamines include norepinephrine, epinephrine, and adrenoreceptors or in some cases, combinations of these dopamine, all of which are naturally occurring, and sev- adrenoceptors. Adrenomimetic drugs vary in their afﬁni- eral synthetic substances, the most important of which ties for each subgroup of adrenoceptors. Some, like epi- is isoproterenol (isopropyl norepinephrine). The skele- nephrine, have a high afﬁnity for all of the adrenocep- 96 10 Adrenomimetic Drugs 97 OH (para) An important characteristic of indirectly acting adrenomimetic drugs is that repeated injections or pro- OH (meta) Catechol longed infusion can lead to tachyphylaxis (gradually di- minished responses to repeated administration). This is a result of a gradually diminishing availability of re- leasable norepinephrine stores on repeated drug ad- C ministration. The time frame of the tachyphylaxis will C vary with individual agents. Ethylamine The actions of many indirectly acting adreno- N mimetic drugs are reduced or abolished by the prior ad- ministration of either cocaine or tricyclic antidepressant FIGURE 10.1 drugs (e.g., imipramine). These compounds can block Skeletal structure of catecholamines. the adrenergic neuronal transport system and thereby prevent the indirectly acting drug from being taken up into the nerve and reaching the norepinephrine storage tors. Others are relatively selective. For example, isopro- vesicles. Lipophilic drugs (e.g., amphetamine), however, terenol has a high afﬁnity for 1- and 2-adrenoceptors can enter nerves by diffusion and do not need mem- but a very low afﬁnity for -adrenoceptors; isopro- brane transport systems. terenol is considered a nearly pure -agonist. Nor- Destruction or surgical interruption of the adrener- epinephrine has a high afﬁnity for - and 1-adrenocep- gic nerves leading to an effector tissue renders indirectly tors but a relatively low afﬁnity for 2-receptors. acting adrenomimetic drugs ineffective because neu- The effect of a given adrenomimetic drug on a partic- ronal norepinephrine is no longer available for release ular type of effector cell depends on the receptor selectiv- since the nerves have degenerated. Also, patients being ity of the drug, the response characteristics of the effector treated for hypertension with reserpine or guanethidine, cells, and the predominant type of adrenoceptor found on which deplete the norepinephrine stores in adrenergic the cells. For example, the smooth muscle cells of many neurons (see Chapter 20), respond poorly to administra- blood vessels have only or predominantly -adrenocep- tion of indirectly acting adrenomimetic drugs. tors. The interaction of compounds with these adreno- Some adrenomimetic drugs act both directly and in- ceptors initiates a chain of events in the vascular smooth directly; that is, they release some norepinephrine from muscle cells that leads to activation of the contractile storage sites and also directly activate tissue receptors. process. Thus, norepinephrine and epinephrine, which Such drugs are called mixed-action adrenomimetics. have high afﬁnities for -adrenoceptors, cause the vas- However, most therapeutically important adreno- cular muscle to contract and the blood vessels to con- mimetic drugs in humans act either directly or indirectly. strict. Since bronchial smooth muscle contains 2- adrenoceptors, the response in this tissue elicited by the Structure–Activity Relationships Among action of 2-adrenoceptor agonists is relaxation of Adrenomimetic Drugs smooth muscle cells. Epinephrine and isoproterenol, which have high afﬁnities for 2-adrenoceptors, cause re- The nature of the substitutions made on the basic laxation of bronchial smooth muscle. Norepinephrine phenylethylamine skeleton at the para and meta positions has a lower afﬁnity for 2-adrenoceptors and has rela- of the benzene ring or on the -carbon of the side chain tively weak bronchiolar relaxing properties. determine whether an adrenomimetic drug will act di- Adrenomimetic drugs can be divided into two major rectly or indirectly. Directly acting adrenomimetic drugs, groups on the basis of their mechanism of action. which have two or more carbon atoms (e.g., isopro- Norepinephrine, epinephrine, and some closely related terenol) added to their amino group, are virtually pure adrenomimetics produce responses in effector cells by -adrenoceptor agonists. Directly acting drugs, which have directly stimulating - or -adrenoceptors and are re- only small substitutions on their amino groups (e.g., nor- ferred to as directly acting adrenomimetic drugs. epinephrine and epinephrine), are usually -adrenocep- Many other adrenomimetic drugs, such as ampheta- tor agonists, but may be -adrenoceptor agonists as well. mine, do not themselves interact with adrenoceptors, yet Norepinephrine has very weak actions on 2-adrenocep- they produce sympathetic effects by releasing norepi- tors but strong 1-adrenoceptor actions. Epinephrine has nephrine from neuronal storage sites (vesicles). The a high afﬁnity for both 1- and 2-adrenoceptors. norepinephrine that is released by these compounds Adrenomimetic drugs with no substitutions on their interacts with the receptors on the effector cells. These benzene ring (e.g., amphetamine and ephedrine) are adrenomimetics are called indirectly acting adreno- generally quite lipid soluble, readily cross the blood- mimetic drugs. The effects elicited by indirectly acting brain barrier, and can cause central nervous system drugs resemble those produced by norepinephrine. (CNS) stimulation. 98 II DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM The structure of a particular adrenomimetic drug will for example contraction, secretion, relaxation, or al- inﬂuence its susceptibility to metabolism by catechol- tered metabolism. The total process of converting the O-methyltransferase (COMT) and monoamine oxidase action of an external signal (e.g., norepinephrine inter- (MAO). The actions of COMT are speciﬁc for the cate- acting with its receptor) to a physiological response chol structure. If either the meta or para hydroxyl group (e.g., vascular smooth muscle contraction) is called sig- is absent, COMT will not metabolize the drug. The pres- nal transduction. ence of a substitution, such as a methyl group, on the - Following the binding of the agonist (the ﬁrst mes- carbon of the side chain reduces the afﬁnity of the senger) to its appropriate receptor on the external sur- adrenomimetic drug for MAO. Also, drugs with a large face of the effector cell, a second messenger is generated substitution on the terminal nitrogen will not be de- (or synthesized) and participates in a particular series of graded by MAO. A noncatecholamine that has a methyl biochemical reactions that ultimately result in the gen- group attached to its -carbon will not be metabolized eration of a speciﬁc physiological response by that cell by either enzyme and will have a greatly prolonged du- (Figs. 10.2 and 10.3). For both - and -adrenoceptors, ration of action (e.g., amphetamine). the signal transduction process seems to involve the participation of G proteins (see Chapter 2). The speciﬁc second-messenger pathways constitute a The Role of Second Messengers in highly versatile signaling system that can modify (stimu- Receptor-mediated Responses late or inhibit) numerous cellular processes including The adrenomimetic drugs, including the naturally oc- secretion, contraction and relaxation, metabolism, neu- curring catecholamines, initiate their responses by com- ronal excitability, cell growth, and apoptosis. The sec- bining with -, -, or dopamine adrenoceptors. This in- ond messengers that participate in signal transduction teraction triggers a series of biochemical events starting include cyclic adenosine monophosphate (cAMP), within the effector cell membrane that eventually cul- diacylglycerol, and inositol triphosphate. Once liberated minates in the production of a physiological response, within the cell, second messengers will activate speciﬁc Catecholamine Calcium Adenylyl channel –adrenoceptor cyclase Cell GS GS Membrane protein protein phosphorylation of other proteins ATP Cyclic AMP (e.g., ion channels) phosphorylation Protein Protein Protein kinaseA kinaseA kinaseA phosphorylation phosphorylation Inactive Active Phosphory- Phosphory- lipase lipase lase b lase a Fat Free Glycogen Glucose - 1 - PO4 fatty acids Glucose Lactate (liver) (muscle) FIGURE 10.2 The role of cyclic 3 ,5 -adenosine monophosphate (cAMP) as a second messenger in the actions , of catecholamines acting on -receptors. ATP adenosine triphosphate. Catecholamines Ca2 channel Phospholipase C G-protein 1-adrenoceptor e ran e mb Ce ll m Ptdins 4, 5 P2 DAG OH Ca2 Pro kin tein um P ase C i cu l P c ret Ser ine mi Ca2 store P plas P P P do P En Ins 1, 3, 4, 5 P4 Ins 1, 4, 5 P3 Protein Protein-P Metabolism Ca2 Calmodulin Secretion 10 Adrenomimetic Drugs Contraction Synaptic transmission Protein-P Cell growth Protein Ca2 Calmodulin Kinase FIGURE 10.3 The role of diacylglycerol (DAG) and inositol triphosphate (Ins 1,4,5 P3) as second messengers linked to agonist-receptor ( 1-adrenoceptor) interactions. Ptdins 4,5 P2 is a phosphatidylinositol precursor in cell membranes that is hydrolyzed following receptor activation to form the two second messengers, Ins 1,4,5 P3 and DAG. Once liberated within the cell, these second messengers activate separate but interacting pathways. Ins 1,4,5 P3 releases Ca stored in cells and can be phosphorylated to form a tetraphosphate (Ins 1,3,4,5 P4), which can open Ca channels in the membrane. DAG triggers protein phosphorylation through the activation of protein kinase C. Ca -induced activation of the enzyme calmodulin also phosphorylates protein. Adenylyl cyclase traverses the membrane. Cyclic AMP–dependent protein kinase can phosphorylate and inactivate the -adrenoceptors. This kinase may have a role in homologous desensitization of Gs-protein–coupled -adrenoceptors. -Receptor stimulation can (1) activate Ca channels through an action of Gs proteins without the participation of cAMP and (2) affect other ion channels through phosphorylation via kinases. (Modiﬁed from Berridge MJ. Inositol triphosphate and diacylglycerol: Two interacting second messengers. ISI Atlas of Science: Pharmacology, 1:91, 1987.) 99 100 II DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM signal pathways. For example, inositol triphosphate afﬁnities possessed by the catecholamines for - and functions by mobilizing calcium from intracellular stores -adrenoceptors and to differences in the relative dis- or opening channels; the calcium can be used to initi- tribution of the receptors in a particular vascular bed. ate vascular smooth muscle contraction, probably The hemodynamic responses of the major vascular beds through a protein phosphorylation pathway (Fig. 10.3). to these amines are shown in Table 10.2. Diacylglycerol is known to stimulate an enzyme, protein The blood vessels of the skin and mucous mem- kinase C, that phosphorylates speciﬁc intracellular pro- branes predominantly contain -adrenoceptors. Both teins, some of which regulate ionic mechanisms such as epinephrine and norepinephrine produce a powerful the Na /H exchanger and potassium channels. constriction in these tissues, substantially reducing The basic features of the signaling system found in blood ﬂow through them. Isoproterenol, which is almost different cells are remarkably similar. It appears that a pure -adrenoceptor agonist, has little effect on the protein phosphorylation is a ﬁnal common pathway in vasculature of the skin and mucous membranes. The the molecular mechanisms through which neurotrans- blood vessels in visceral organs, including the kidneys, mitters, hormones, and the nerve impulse produce many contain predominantly -adrenoceptors, although some of their biological effects in target cells. 2-adrenoceptors are also present. Consequently, epi- nephrine and norepinephrine cause vasoconstriction PHARMACODYNAMIC ACTIONS OF and reduced blood ﬂow through the kidneys and other NOREPINEPHRINE, EPINEPHRINE, visceral organs. Isoproterenol produces either no effect AND ISOPROTERENOL or weak vasodilation. The blood vessels in skeletal muscle contain both - and 2-adrenoceptors. Norepinephrine constricts these Vascular Effects blood vessels and reduces blood ﬂow through an inter- The cardiovascular effects of norepinephrine, epineph- action with -adrenoceptors. Isoproterenol dilates the rine, and isoproterenol are shown in Table 10.1. vessels in skeletal muscle and consequently increases Differences in the action of these three catecholamines blood ﬂow through the tissue by interaction with the on various vascular beds are due both to the different 2-adrenoceptors. Epinephrine has a more complex ac- TA B L E 1 0 . 1 Cardiovascular Effects of Catecholamines in Humans (in therapeutic doses of 0.1-0.4 g/kg/min IV or 0.5–1.0 mg SC) Cardiovascular function Epinephrine Norepinephrine Isoproterenol Systolic blood pressure 0 Diastolic blood pressure Mean blood pressure 0 Total peripheral resistance Heart rate (chronotropic effect) Stroke output (inotropic effect) Cardiac output 0 Key: 0 no effect; increased; decreased. The number of symbols indicates the approximate magnitude of the response. TA B L E 1 0 . 2 Response of the Major Vascular Beds to Usual Doses of the Catecholamines Vascular bed Receptor type* Norepinephrine Epinephrine Isoproterenol Cutaneous blood vessels Constriction Constriction None Visceral blood vessels Constriction Constriction None (weak dilation) Renal blood vessels Constriction Constriction None (weak dilation) Coronary blood vessels , Dilation Dilation Dilation Skeletal muscle blood vessels , 2 Constriction Dilation Dilation Pial blood vessels , 1 Constriction/dilation Constriction/dilation Dilation *While virtually all blood vessels have -receptors, some also have 1 -receptors. Stimulation of either subtype generally results in vasocon- 2 striction. 10 Adrenomimetic Drugs 101 tion on these blood vessels because of its high afﬁnity The net effect of norepinephrine administration on for both - and 2-adrenoceptors. Whether epinephrine heart rate and ventricular contractile force therefore produces vasodilation or vasoconstriction in skeletal varies with the dose of norepinephrine, the physical ac- muscle depends on the dose administered. Low doses of tivity of the subject, any prior cardiovascular and baro- epinephrine will dilate the blood vessels; larger doses receptor pathology, and the presence of other drugs that will constrict them. may alter reﬂexes. Although several factors can inﬂuence the ﬂow of In a normal resting subject who is receiving no blood through the coronary vessels, the most important drugs, there is a moderate parasympathetic tone to the of these is the local production of vasodilator metabolites heart, and sympathetic activity is relatively low. The that results from stimulation-induced increased work by ventricular muscle receives little, if any, parasympathetic the heart. -Adrenoreceptors and -adrenoceptors in innervation. As the blood pressure rises in response to the coronary vascular beds do not play a major role in norepinephrine, the baroreceptor reﬂex is activated, determining the vasodilator effects of the administra- parasympathetic impulses (which are inhibitory) to the tion of epinephrine or norepinephrine. heart increase in frequency, and what little sympathetic outﬂow there is may be reduced. Heart rate is slowed so much that the direct effect of norepinephrine to in- Effects on the Intact Cardiovascular System crease the rate is masked and there is a net decrease in An increase in sympathetic neuronal activity causes an rate. Under the conditions described, however, the im- increase in heart rate (positive chronotropic effect, or pact of the reﬂex on the ventricles is very slight because tachycardia) and an increase in cardiac contractile force there is no parasympathetic innervation and the preex- (positive inotropic effect) such that the stroke output is isting level of sympathetic activity is already low. A fur- increased. Cardiac output, which is a function of rate ther decrease in sympathetic activity therefore would and stroke output, is thus increased. A physiological in- have little further effect on contractility in this subject. crease in sympathetic tone is almost always accompanied Thus, a decrease in heart rate and an increase in stroke by a diminution of parasympathetic vagal tone; this al- volume will occur, and cardiac output will change very lows full expression of the effects of increased sympa- little. thetic tone on the activity of the heart. The reﬂex nature of the bradycardia induced by An increase in sympathetic tone constricts blood parenterally administered norepinephrine can readily vessels in most vascular beds and therefore causes a net be demonstrated by administration of atropine, a choli- increase in total peripheral resistance. Increased sympa- noreceptor antagonist. Atropine abolishes the com- thetic tone increases neural release of norepinephrine pensatory vagal reﬂexes. Under conditions of vagal and its interaction both with -adrenoceptors on car- blockade, the direct cardiac stimulatory effects of nor- diac cells and with -adrenoceptors on vascular smooth epinephrine are unmasked. There is marked tachycar- muscle cells. As a consequence, the systolic and diastolic dia, an increase in stroke volume, and as a consequence, blood pressures are elevated. It follows that the mean a marked increase in cardiac output (Fig. 10.4). arterial blood pressure must also be increased. Epinephrine Norepinephrine A small dose of epinephrine causes a fall in mean Norepinephrine, administered to a normotensive and diastolic pressure with little or no effect on systolic adult either subcutaneously or by slow intravenous in- pressure. This is due to the net decrease in total periph- jection, constricts most blood vessels. Venules as well as eral resistance that results from the predominance of arterioles are constricted. As a consequence, there is a vasodilation in the skeletal muscle vascular bed. The in- net increase in the total peripheral resistance. travenous infusion or subcutaneous administration of The effects of norepinephrine on cardiac function epinephrine in the range of doses used in humans gen- are complex because of the dynamic interaction of the erally increases the systolic pressure, but the diastolic direct effects of norepinephrine on the heart and the pressure is decreased. Therefore, the mean pressure initiation of powerful cardiac reﬂexes. The baroreceptor may decrease, remain unchanged, or increase slightly, reﬂexes are discussed in detail in Chapter 9. depending on the balance between the rise in systolic Important considerations are as follows: (1) The di- and fall in diastolic blood pressures (Fig. 10.4). rect effect of norepinephrine on the heart is stimulatory. The cardiac effects of epinephrine are due to its ac- (2) The reﬂex initiated is inhibitory, that is, opposite to tion on -adrenoceptors in the heart. The rate and con- the direct effect. (3) The reﬂex varies with the level of tractile force of the heart are increased; consequently, sympathetic and parasympathetic activity just before cardiac output is markedly increased. Because total pe- the initiation of the reﬂex. (4) The distribution of sym- ripheral resistance is decreased, the increase in cardiac pathetic and parasympathetic nerves is not uniform in output is largely responsible for the increase in systolic the heart. pressure. Since epinephrine causes little change in the 102 II DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM Norepinephrine Epinephrine Isoproterenol Dopamine Pulse rate 100 (min) 50 Blood pressure 180 (mm Hg) 150 120 90 60 10 g/min 0.5 mg/min 10 g/min 10 g/min Peripheral resistance 0 15 0 15 0 15 0 15 Time (min) FIGURE 10.4 Cardiovascular effects of infusion of norepinephrine, epinephrine, isoproterenol, and dopamine in humans. Infusions were made intravenously during the time indicated by the broken lines. Heart rate is given in beats per minute, blood pressure in millimeters of mercury, and peripheral resistance in arterial blood pressure. (Reprinted with permission from Allwood MJ, Cobbald AF, and Ginsburg J. Peripheral vascular effects of noradrenaline, isopropyl-noradrenaline, and dopamine. Br Med Bull 19:132, 1963. Reproduced by permission of the Medical Department, The British Council. mean arterial blood pressure, reﬂex slowing of the heart messenger system. This system plays an important role is usually not seen in humans. in the regulation of blood pressure and vascular tone. Vascular endothelium also plays an important role in Isoproterenol maintaining vascular tone.The endothelium can modulate Slow intravenous infusion of therapeutic doses of both vasodilation and vasoconstriction through its ability isoproterenol in humans produces a marked decrease in to locally synthesize and release vasodilators such as nitric total peripheral resistance, owing to the predominance oxide, endothelium-derived hyperpolarizing factor, and of vasodilation in skeletal muscle vascular beds. As a PGI2, and vasoconstrictors such as endothelin, which in consequence, diastolic and mean blood pressures fall turn directly affect vascular smooth muscle activity. (Fig. 10.4). The depressor action of isoproterenol is more Stimulation of 2-adrenoceptors located on the endothe- pronounced than that of epinephrine because isopro- lial cells in certain vascular beds (such as the coronary ar- terenol causes no vasoconstriction, whereas epinephrine tery) results in the release of nitric oxide and vasodilation. does in some vascular beds. Systolic blood pressure may In any blood vessel, the ﬁnal integrated response to remain unchanged or may increase. When an increase in either neuronally released norepinephrine or to circu- systolic blood pressure is seen, it is due to the marked in- lating epinephrine probably depends on the relative crease in cardiac output produced by isoproterenol. participation of at least four populations of -adreno- Isoproterenol usually increases the heart rate and ceptors: postjunctional 1- and 2-adrenoceptors medi- stroke volume more than does epinephrine. This is ate constriction of vascular smooth muscle, while pre- partly due to its ability to decrease mean blood pres- junctional and endothelial 2-adrenoceptors mediate sure, which then reﬂexively diminishes vagal activity, vasodilation. An understanding of the vessel vascular and partly to its action on the heart. response to adrenomimetic drugs also must include the effects of drugs on adventitial innervation, smooth mus- cle, and other vascular factors that may be present. Effects on Vascular Smooth Muscle Postjunctional 1-adrenoceptors are always found in Effects on Nonvascular Smooth Muscle veins, arteries, and arterioles. Activation of these recep- tors results in the entry of extracellular calcium through In general, the responses to administered catechol- receptor-operated channels and in the release of intra- amines are similar to those seen after sympathetic nerve cellularly stored calcium; this is brought about through stimulation and depend on the type of adrenoceptor in the participation of the inositol triphosphate second- the muscle. 10 Adrenomimetic Drugs 103 Bronchial smooth muscle is relaxed by epinephrine bolic processes. Most of these are mediated through an and isoproterenol through their interaction with 2- interaction with -adrenoceptors. Norepinephrine is adrenoceptors. Epinephrine and isoproterenol are po- usually effective only in large doses. Epinephrine and tent bronchodilators, while norepinephrine has a rela- isoproterenol in therapeutic doses increase oxygen con- tively weak action in this regard (see Chapter 39). sumption by 20 to 30%. Endogenous epinephrine se- Smooth muscle of the gastrointestinal tract is gener- creted by the adrenal medulla in response to stress such ally relaxed by catecholamines, but this may depend on as exercise increases blood levels of glucose, lactic acid, the existing state of muscle tone. Usually motility of the and free fatty acids. gut is reduced by catecholamines while the gastroin- Epinephrine, the most potent stimulant of hepatic testinal sphincters are contracted. Catecholamines ap- glycogenolysis, gives rise to glucose, which readily en- pear to produce relaxation of the gut through an action ters the circulation; isoproterenol produces relatively on 2-adrenoceptors on ganglionic cells. Activation of weak hyperglycemia. Administration of both - and these receptors reduces acetylcholine release from -adrenoceptor blocking agents is necessary for com- cholinergic neurons. Catecholamines also may produce plete antagonism of glycogenolysis in this tissue. gastrointestinal relaxation through an action on 2- Isoproterenol is the most potent stimulant of skele- adrenoceptors on smooth muscle cells. Contraction of tal muscle glycogenolysis, followed by epinephrine the sphincters occurs through an action on 1-adreno- and norepinephrine. 2-Adrenoceptors mediate muscle ceptors. These effects are quite transient in humans and glycogenolysis. Stimulation of skeletal muscle glyco- therefore have no therapeutic value. genolysis will raise blood lactic acid levels rather than The radial (dilator) muscle of the iris contains - blood glucose levels because skeletal muscle lacks the adrenoceptors. Epinephrine and norepinephrine cause enzyme glucose-6-phosphatase, which catalyzes the dilation of the pupil (mydriasis) by contracting the dila- conversion of glucose-6-phosphate to glucose. tor muscle. The release of free fatty acids from adipose tissue Uterine muscle contains both - and -adrenocep- (lipolysis) is mediated through 3-adrenoceptors. Iso- tors, which mediate contraction and relaxation, respec- proterenol is the most potent agonist, followed by epi- tively. The response of the human uterus to cate- nephrine and norepinephrine. cholamines is variable and depends on the endocrine balance of the individual at the time of amine adminis- tration (see Chapter 62). During the last stage of preg- Potassium Homeostasis nancy and during parturition, epinephrine inhibits the The catecholamines can play an important role in the uterine muscle, as does isoproterenol; norepinephrine short-term regulation of plasma potassium levels. contracts the uterus. Stimulation of hepatic -adrenoceptors will result in the The detrusor muscle (which contains 2-adrenocep- release of potassium from the liver. In contrast, stimula- tors) in the body of the urinary bladder is relaxed by tion of 2-adrenoceptors, particularly in skeletal muscle, epinephrine and isoproterenol. On the other hand, the will lead to the uptake of potassium into this tissue. The trigone and sphincter (which contain 1-receptors) are 2-adrenoceptors are linked to the enzyme Na , K contracted by norepinephrine and epinephrine; this ac- adenosine triphosphatase (ATPase). Excessive stimula- tion inhibits the voiding of urine. tion of these 2-adrenoceptors may produce hy- pokalemia, which in turn can be a cause of cardiac ar- Central Nervous System Effects rhythmias. Epinephrine, in therapeutic doses, mildly stimulates the CNS. The most noticeable features of this stimulation PHARMACOLOGICAL ACTIONS are apprehension, restlessness, and increased respira- OF DOPAMINE tion. In therapeutic doses both isoproterenol and nor- epinephrine also have minor CNS stimulant properties. Dopamine is a naturally occurring catecholamine; it is Since these compounds do not easily cross the blood- the immediate biochemical precursor of the norepi- brain barrier, the mechanism of their stimulatory effects nephrine found in adrenergic neurons and the adrenal is not clear. It is likely that the stimulating effects are medulla. It is also a neurotransmitter in the CNS, where primarily, if not entirely, due to actions in the periphery it is released from dopaminergic neurons to act on spe- that alter the neural input to the CNS. ciﬁc dopamine receptors (see Chapter 31). Dopamine is a unique adrenomimetic drug in that it exerts its cardiovascular actions by (1) releasing norepi- Metabolic Effects nephrine from adrenergic neurons, (2) interacting with The catecholamines, primarily epinephrine and isopro- -and 1-adrenoceptors, and (3) interacting with spe- terenol, exert a number of important effects on meta- ciﬁc dopamine receptors. 104 II DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM The cardiovascular response to dopamine in hu- useful in the therapy of urticaria, angioneurotic edema, mans depends on the concentration infused. Low rates and serum sickness. of dopamine infusion can produce vasodilation in the Epinephrine also has been used to lower intraocular renal, mesenteric, coronary, and intercerebral vascular pressure in open-angle glaucoma. Its use promotes an beds with little effect on other blood vessels or on the increase in the outﬂow of aqueous humor. Because epi- heart. The vasodilation produced by dopamine is not nephrine administration will decrease the ﬁltration an- antagonized by the -adrenoceptor blocking agent pro- gle formed by the cornea and the iris, its use is con- pranolol but is antagonized by haloperidol and other traindicated in angle-closure glaucoma; under these dopamine receptor–blocking agents. conditions the outﬂow of aqueous humor via the ﬁltra- Dopamine can exert pronounced cardiovascular tion angle and into the venous system is hindered, and and renal effects through the activation of both D1- and intraocular pressure may rise abruptly. D2-receptor subtypes. Stimulation of the D1-receptor, The vasoconstrictor actions of epinephrine and nor- which is present on blood vessels and certain other pe- epinephrine have been used to prolong the action of lo- ripheral sites, will result in vasodilation, natriuresis, and cal anesthetics by reducing local blood ﬂow in the re- diuresis. D2-receptors are found on ganglia, on sympa- gion of the injection. Epinephrine has been used as a thetic nerve terminals, on the adrenal cortex, and within topical hemostatic agent for the control of local hemor- the cardiovascular centers of the CNS; their activation rhage. Norepinephrine is infused intravenously to com- produces hypotension, bradycardia, and regional va- bat systemic hypotension during spinal anesthesia or sodilation (e.g., renal vasodilation). The kidney appears other hypotensive conditions in which peripheral resist- to be a particularly rich source for endogenous ance is low, but it is not used to combat the hypotension dopamine in the periphery. due to most types of shock. In shock, marked sympa- The infusion of moderately higher concentrations of thetic activity is already present, and perfusion of or- dopamine increases the rate and contractile force of the gans, such as the kidneys, may be jeopardized by norepi- heart and augments the cardiac output. This action is nephrine administration. mediated by 1-adrenoceptors and norepinephrine re- Dopamine is used in the treatment of shock owing lease and is antagonized by propranolol. In contrast to to inadequate cardiac output (cardiogenic shock), isoproterenol, which has a marked effect on both the which may be due to myocardial infarction or conges- rate and the contractile force of the heart, dopamine has tive heart failure. It is also used in the treatment of a greater effect on the force than on cardiac rate. The septic shock, since renal circulation is frequently com- advantage of this greater inotropic than chronotropic promised in this condition. An advantage of using effect of dopamine is that it produces a smaller increase dopamine in the treatment of shock is that its in- in oxygen demand by the heart than does isoproterenol. otropic action increases cardiac output while dilating Systolic blood pressure is increased by dopamine, renal blood vessels and thereby increasing renal blood whereas diastolic pressure is usually not changed signif- flow. icantly. Total peripheral resistance is decreased because of the vasodilator effect of dopamine (Fig. 10.4). At still higher concentrations, dopamine causes Adverse Effects -adrenoceptor-mediated vasoconstriction in most vas- Because they increase the force of the heartbeat, all cular beds and stimulates the heart. Total peripheral re- three catecholamines may produce an excessively rapid sistance may be increased. If the concentration of heart rate. Palpitations produced by epinephrine and dopamine reaching the tissue is high enough, vasocon- isoproterenol are accompanied by tachycardia, whereas striction of the renal and mesenteric beds also occurs. those produced by norepinephrine usually are accom- The vasoconstrictive action of dopamine is antagonized panied by bradycardia owing to reﬂex slowing of the by -adrenoceptor blocking agents such as phentol- heart. Headache and tremor are also common. amine. Epinephrine is especially likely to produce anxiety, fear, and nervousness. The greatest hazards of accidental overdosage with epinephrine and norepinephrine are cardiac arrhyth- CLINICAL USES OF CATECHOLAMINES mias, excessive hypertension, and acute pulmonary The clinical uses of catecholamines are based on their edema. Large doses of isoproterenol can produce such actions on bronchial smooth muscle, blood vessels, and excessive cardiac stimulation, combined with a decrease the heart. Epinephrine is also useful for the treatment in diastolic blood pressure, that coronary insufﬁciency of allergic reactions that are due to liberation of hista- may result. It also may cause arrhythmias and ventricu- mine in the body, because it produces certain physio- lar ﬁbrillation. Tissue sloughing and necrosis due to se- logical effects opposite to those produced by histamine. vere local ischemia may follow extravasation of norepi- It is the primary treatment for anaphylactic shock and is nephrine at its injection site. 10 Adrenomimetic Drugs 105 OTHER ADRENOMIMETIC AGENTS damage has occurred from injudicious use of the nasal spray. It is also employed in ophthalmology as a mydri- A number of adrenomimetic amines are not cate- atic agent. Phenylephrine, however, should not be given cholamines. Some of these are directly acting amines to patients with closed-angle glaucoma before iridec- that must interact with adrenoceptors to produce a re- tomy, since further increases in intraocular pressure sponse in effector tissues. Some directly acting com- may result. In dentistry, phenylephrine is used to pro- pounds, such as phenylephrine and methoxamine, acti- long the effectiveness of a local anesthetic. vate -adrenoceptors almost exclusively, whereas others, like albuterol and terbutaline, are nearly pure - Dobutamine adrenoceptor agonists. Drugs that exert their pharma- cological actions by releasing norepinephrine from its Dobutamine (Dobutrex), in contrast to dopamine, does neuronal stores (indirectly acting) produce effects that not produce a signiﬁcant proportion of its cardiac effects are similar to those of norepinephrine. They tend to ex- through the release of norepinephrine from adrenergic ert strong -adrenoceptor activity, but 1-adrenoceptor nerves; dobutamine acts directly on 1-adrenoceptors in activity typical of norepinephrine, such as myocardial the heart. Dobutamine exerts a greater effect on the stimulation, also occurs. contractile force of the heart relative to its effect on the Some of the indirectly acting adrenomimetic amines heart rate than does dopamine. Dobutamine increases are used primarily for their vasoconstrictive properties. the oxygen demands on the heart to a lesser extent than They are applied locally to the nasal mucosa or to the does dopamine. Like dopamine, although at higher eye. Other amines are used as bronchodilators, while doses, it produces vasodilation of renal and mesenteric still others are used exclusively for their ability to stim- blood vessels. Dobutamine may be more useful than ulate the CNS. Many noncatecholamine adrenomimetic dopamine in the treatment of cardiogenic shock. amines resist enzymatic destruction, have prolonged ac- tions, and are orally effective. The indirectly acting Terbutaline and Albuterol drugs are effective only when given in large doses, and they often produce tachyphylaxis. Terbutaline and albuterol are relatively selective 2- adrenoceptor agonists. Both have a longer duration of action than isoproterenol because they are not metabo- Directly Acting Adrenomimetic Drugs lized by COMT. Like isoproterenol, they are not me- Phenylephrine, Metaraminol, and Methoxamine tabolized by MAO and are not transported into adren- ergic neurons. Terbutaline and albuterol are effectively These drugs are directly acting adrenomimetic amines administered either orally or subcutaneously. Because that exert their effects primarily through an action on of their selectivity for 2-adrenoceptors, they produce -adrenoceptors. Consequently, these agents have little less cardiac stimulation than does isoproterenol but are or no direct action on the heart. All three drugs increase not completely without effects on the heart. both systolic and diastolic blood pressures through their Therapeutically, terbutaline and albuterol are used vasoconstrictor action. The pressor response is accom- to treat bronchial asthma and bronchospasm associated panied by reﬂex bradycardia, no change in the contrac- with bronchitis and emphysema (see Chapter 39). tile force of the heart, and little change in cardiac out- Side effects include nervousness, tremor, tachycar- put. They do not precipitate cardiac arrhythmias and do dia, palpitations, headache, nausea, vomiting, and sweat- not stimulate the CNS. ing. The frequency of appearance of these adverse ef- Phenylephrine is not a substrate for COMT, while fects is minimized, however, when the drugs are given metaraminol and methoxamine are not metabolized by by inhalation. either COMT or MAO. Consequently, their duration of action is considerably longer than that of norepineph- Indirectly Acting Adrenomimetic Drugs rine. Following intravenous injection, pressor responses Ephedrine to phenylephrine may persist for 20 minutes, while pres- sor responses to metaraminol and methoxamine may Ephedrine is a naturally occurring alkaloid that can cross last for more than 60 minutes. the blood-brain barrier and thus exert a strong CNS-stim- The clinical uses of these drugs are associated with ulating effect in addition to its peripheral actions. The lat- their potent vasoconstrictor action. They are used to re- ter effects are primarily due to its indirect actions and de- store or maintain blood pressure during spinal anesthe- pend largely on the release of norepinephrine. However, sia and certain other hypotensive states. The reﬂex ephedrine may cause some direct receptor stimulation, bradycardia induced by their rapid intravenous injec- particularly in its bronchodilating effects. Because it re- tion has been used to terminate attacks of paroxysmal sists metabolism by both COMT and MAO, its duration atrial tachycardia. Phenylephrine is commonly used as a of action is longer than that of norepinephrine. As is the nasal decongestant, although occasional nasal mucosal case with all indirectly acting adrenomimetic amines, 106 II DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM ephedrine is much less potent than norepinephrine; in insomnia, nervousness, nausea, vomiting, and emotional addition, tachyphylaxis develops to its peripheral actions. disturbances may develop. Ephedrine should not be Unlike epinephrine or norepinephrine, however, ephe- used in patients with cardiac disease, hypertension, or drine is effective when administered orally. hyperthyroidism. Pharmacological Actions Amphetamine Ephedrine increases systolic and diastolic blood Amphetamine is an indirectly acting adrenomimetic pressure; heart rate is generally not increased. amine that depends for its action on the release of nor- Contractile force of the heart and cardiac output are epinephrine from noradrenergic nerves. Its pharmaco- both increased. Ephedrine produces bronchial smooth logical effects are similar to those of ephedrine; how- muscle relaxation of prolonged duration when adminis- ever, its CNS stimulant activity is somewhat greater. tered orally. Aside from pupillary dilation, ephedrine Both systolic and diastolic blood pressures are increased has little effect on the eye. by oral dosing with amphetamine. The heart rate is fre- quently slowed reﬂexively. Cardiac output may remain Clinical Uses unchanged in the low- and moderate-dose range. Ephedrine is useful in relieving bronchoconstriction The therapeutic uses of amphetamine are based on and mucosal congestion associated with bronchial its ability to stimulate the CNS. The D-isomer (dex- asthma, asthmatic bronchitis, chronic bronchitis, and troamphetamine) is three to four times as potent as the bronchial spasms. It is often used prophylactically to L-isomer in producing CNS effects. It has been used in prevent asthmatic attacks and is used as a nasal decon- the treatment of obesity because of its anorexic effect, gestant, as a mydriatic, and in certain allergic disorders. although tolerance to this effect develops rapidly. It Although its bronchodilator action is weaker than that prevents or overcomes fatigue and has been used as a of isoproterenol, its oral effectiveness and prolonged CNS stimulant. Amphetamine is no longer recom- duration of action make it valuable in the treatment of mended for these uses because of its potential for abuse. these conditions. Because of their oral effectiveness and Amphetamine is useful in certain cases of narcolepsy or greater bronchiolar selectivity, terbutaline and albuterol minimal brain dysfunction. are replacing ephedrine for bronchodilation. Further discussion of amphetamine can be found in Chapters 29 and 35. Adverse Effects Symptoms of overdose are related primarily to car- diac and CNS effects. Tachycardia, premature systoles, Study Questions 1. Selective 2-agonists, such as terbutaline (C) Decreases peripheral resistance through stimu- (A) Have shorter durations of action than cate- lation of 1-receptors on the vascular smooth mus- cholamines when taken orally cle cells. (B) Have stronger cardiac stimulant effects than (D) Decreases peripheral resistance through 2- epinephrine adrenoceptor stimulation predominantly in skeletal (C ) Can be taken orally because these agents are muscle vascular beds. not degraded by COMT 4. The pressor response to amphetamine is (D) Are deﬁnitely no better than methylxanthines (A) Decreased in the presence of a monoamine ox- for asthmatic patients who are hypertensive. idase (MAO) inhibitor. 2. Which drug does not induce mydriasis? (B) Potentiated by a reuptake inhibitor, such as co- (A) Phenylephrine caine (B) Cocaine (C) Associated with marked tolerance (tachyphy- (C) Phentolamine laxis) (D) Norepinephrine (D) Potentiated by pretreatment with reserpine (E) Ephedrine 5. When phenylephrine is administered by slow infu- 3. Epinephrine given in small therapeutic doses sion of the therapeutic dose, which is the most likely (A) Increases systolic blood pressure through 2 re- effect illustrated in the following table: increase (↑); ceptor stimulation in the left ventricle decrease (↓); no change (0)? (B) Decreases heart rate reﬂexively. 10 Adrenomimetic Drugs 107 Heart Rate Effect Blood Pressure (total peripheral resistance) Reﬂex (via baroreceptor) Direct Reﬂex and Direct (A) ↑ ↓ ↑ ↑ or ↓ (B) ↑ ↓ 0 ↓ (C) ↓ ↑ ↑ ↑ or ↓ ANSWERS 1. C. Structural modiﬁcation by placing the hydroxy 5. B. Phenylephrine is an 1-selective agonist. It groups at positions 3 and 5 of the phenyl ring has causes an increase in peripheral vascular resistance. resulted in compounds that are not substrates for The major cardiovascular response to this drug is a COMT, resulting in lower rates of metabolism and rise in blood pressure associated with reﬂex brady- enhanced oral bioavailability compared to cate- cardia. The slowing of the heart rate is blocked by cholamines. atropine. 2. C. -Adrenoceptors mediate contraction of the ra- dial muscle of the iris. The shortening of the radial SUPPLEMENTAL READING muscle cells opens the pupil. Phentolamine blocks Burnstock G and Grifﬁth SG. Nonadrenergic -adrenoceptors, allowing parasympathetic nerves Innervation of Blood Vessels. Boca Raton, FL: innervating the sphincter muscle to take over. This CRC, 1988. leads to a less opposed contraction of the sphincter Gootman PM (ed.). Developmental Neurobiology of muscle induced by transmitter acetylcholine and a the Autonomic Nervous System. Clifton, NJ: constriction of the pupil or miosis. Humana, 1986. 3. D. A small dose of epinephrine (0.1 g/kg) given Insel PA and Feldman RD. -Adrenergic Receptors in by intravenous route may cause the blood pressure Health and Disease. Boca Raton, FL: CRC, 1994. to fall, decreasing peripheral resistance. The depres- Lee TJF. Endothelial messengers and cerebral vascular sor effect of small doses is due to greater sensitivity tone regulation. In: Olesen J and Edvinsson L to epinephrine of vasodilator 2-adrenoceptors than (eds.). Headache Pathogenesis: Monoamines, of constrictor -adrenoceptors and a dominant ac- Neuropeptides, Purines, and Nitric Oxide. tion on 2-adrenoceptors of vessels in skeletal mus- Philadelphia: Lippincott-Raven, 1997:61–72. cle. Consequently, diastolic blood pressure usually Limbird E (ed.). The Alpha-2 Adrenergic Receptors. falls. The mean blood pressure in general, however, Clifton, NJ: Humana, 1988. is not greatly elevated. The compensatory barore- Missale C et al. Dopamine receptors: From structure to ceptor reﬂexes do not appreciably antagonize the function. Physiol Rev 1998;78:189–225. direct cardiac actions. Moncada SR, Palmer MJ, and Higgs EA. Nitric oxide: 4. C. Amphetamine is an indirectly acting adreno- Physiology, pathophysiology, and pharmacology. mimetic amine that depends on the release of nor- Pharmacol Rev 1991;43:109–142. epinephrine from noradrenergic nerves for its ac- Patel TB et al. Molecular biological approaches to un- tion. Thus, its effect depends on neuronal uptake ravel adenylyl cyclase signaling and function. Gene (blocked by cocaine) to displace norepinephrine 2001;16:13–25. from the vesicles and the availability of norepineph- Post SR, Hammond HR, and Insel PA. Beta-adrenergic rine (depleted by reserpine). The substitution on the receptors and receptor signaling in heart failure. -carbon atom blocks oxidation by monoamine oxi- Annu Rev Pharmacol Toxicol 1999;39:343–360. dase. With no substitution on its benzene ring, am- phetamine resists metabolism by COMT. 108 II DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM Case Study Help for the Heart T . L. is a highly successful scientist who spends long hours in the laboratory and is constantly in demand as a speaker and reviewer for scientiﬁc ANSWER: Dobutamine injection would provide particular beneﬁt in meeting the therapeutic needs of this patient. Dobutamine augments ventricular papers and grants. He has a family history of contractility and thus enhances cardiac output, cardiovascular disease, having lost both his father especially stroke volume, in patients with depressed and grandfather before either reached age 60. He cardiac function. It does this by stimulating has recently noticed decreased energy, especially -adrenoceptors in the heart while producing during exercise, and had symptoms (difﬁculty in relatively little increase in chronotropic activity or breathing, chest pain) that took him to the any signiﬁcant elevation in systemic blood pressure emergency department. The examining physician since it lacks -adrenoceptor stimulating effects. thought the best treatment would be short-term Thus, in contrast to a nonselective -adrenoceptor therapy with a directly acting inotropic agent, stimulant such as isoproterenol, which increases especially one that would not markedly increase an cardiac output primarily by increasing heart rate, already elevated heart rate. Based on a knowledge dobutamine’s actions increase cardiac output of the distribution of cardiovascular autonomic without being accompanied by either a marked receptors, which of the following agents— increase in heart rate or a signiﬁcant increase in epinephrine, norepinephrine, amphetamine, or systemic vascular resistance. dobutamine—would be a logical choice to use in this initial short-term treatment?