6: Adrenergic Agonists

CHAPTER 6 Adrenergic Agonists

YAPING. TU, MICHAEL T. PIASCIK, PETER W. ABEL

The endogenous catecholamines norepinephrine, epinephrine, and dopamine compose an important class of neurotransmitters and hormones. By activating adrenergic receptors, these biochemicals mediate numerous functions in the periphery and in the central nervous system (CNS). These and other adrenergic agonists represent an important group of drugs with a broad spectrum of actions. Adrenergic agents are also referred to as sympathomimetic drugs because they mimic the effects caused by stimulation of the sympathetic nervous system. There are several therapeutic uses for these compounds: as vasoconstrictors in local anesthetic solutions and for hemostasis; as decongestants in ophthalmic and nasal preparations; as vasopressor agents to maintain blood pressure in some types of shock; and as bronchodilators for asthmatic attacks and for allergic reactions, including anaphylaxis. Centrally acting adrenergic agonists are used to treat essential hypertension, narcolepsy, and attention-deficit/hyperactivity disorder.

HISTORY

The first recorded study of an adrenergic agent resulted in the isolation in 1887 of ephedrine from the herb ma huang, which had been grown and used in China for centuries. At the same time, investigators were making extracts of all the organs of the body in an attempt to discover new hormones. Studies by Oliver and Schafer in the early 1890s showed a potent vasopressor substance in extracts of the adrenal gland. The active agent, epinephrine, was soon isolated by Abel, prepared commercially, and marketed in the United States under the trade name of Adrenalin(e). By 1905, it had been synthesized and was being incorporated with local anesthetics. In that year, an account was published of the results of mixing procaine with epinephrine to obtain dental anesthesia.3 1887 also witnessed the synthesis of amphetamine, which was first marketed in the 1930s and became widely abused by the mid 1950s. The addictive nature of amphetamine was soon realized and led to its designation in 1970 as a drug of high abuse potential. Concerns in more recent years regarding the potential adverse cardiovascular effects of various sympathomimetic drugs have prompted the U.S. Food and Drug Administration to regulate increasingly their use as appetite suppressants, nasal decongestants, and cold remedies. In 2004, ma huang was banned for sale as a dietary supplement.

CLASSIFICATION OF ADRENERGIC DRUGS AND RECEPTORS

Since the identification of norepinephrine as the neurotransmitter at adrenergic neuroeffector junctions, and of epinephrine and norepinephrine as the two adrenergic agents released by the adrenal medulla, numerous agonists with adrenergic activity have been developed. Direct-acting adrenergic agonists are agonists that directly bind to adrenergic receptors and activate the receptors to produce their effects. Indirect-acting agonists act by increasing the amount of norepinephrine available to stimulate adrenergic receptors. Although indirect-acting agonists may act through many different mechanisms, their most common action is to cause the release of the neurotransmitter norepinephrine from sympathetic nerve terminals. Mixed-acting adrenergic agonists have direct and indirect mechanisms of action. One common feature of all these drugs is that their effects are mediated through activation of adrenergic receptors.

Adrenergic receptors have been classified into three major types: α1-adrenergic, α2-adrenergic, and β-adrenergic receptors. In recent years, numerous receptor subtypes (α1A, α1B, α1D; α2A, α2B, α2C; β1, β2, β3) have been discovered by molecular cloning and pharmacologic techniques.4,20,36,43 Several dopamine receptors have also been identified (D1, D2, D3, D4, D5).15,45 These receptor subtypes are distinguished by differences in their amino acid sequences, as determined from gene-cloning experiments,4,45 and by their affinity for subtype-selective drugs. Many adrenergic agonists activate more than one of the major adrenergic receptor types. In contrast, some agonists selectively activate α receptors, others activate β receptors, and some are selective for an individual adrenergic receptor subtype (e.g., β1 or β2). Similarly, as discussed in Chapter 7, there are antagonists for the various adrenergic receptors, some of which are receptor type or subtype selective, and some of which are nonselective. The development of receptor-selective agonists and antagonists remains an active area of research.33,37,40,43

Although most adrenergic agonists have prominent peripheral actions that form the basis for their therapeutic applications, some of these drugs have important actions in the CNS. Adrenergic drugs such as amphetamine and ephedrine are capable of causing stimulation of adrenergic receptors in the CNS. Several drugs have been developed, including the antihypertensive agent clonidine, that have their principal action on CNS α2 receptors, whose stimulation results in a decrease in sympathetic outflow from the brain.

CHEMISTRY AND STRUCTURE-ACTIVITY RELATIONSHIPS

The chemical structures of the three endogenous adrenergic amines—dopamine, norepinephrine, and epinephrine—are illustrated in Figure 6-1. These compounds are synthesized sequentially in adrenergic nerve terminals and adrenal chromaffin cells (see Chapter 5). These three agents, all derived from tyrosine, are also referred to as catecholamines because they are catechol derivatives of phenylethylamine.

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FIGURE 6-1 Chemical structures of three naturally occurring adrenergic agonists.

Table 6-1 lists some adrenergic agonists currently in use and illustrates certain major alterations in biologic activity that occur with structural modifications. The following conclusions about the relationship between structure and activity can be drawn:

1. Direct-acting agonists (agonists that bind to adrenergic receptors) generally require a hydroxyl group at positions 3 and 4 of the aromatic ring plus a hydroxyl group on the β-carbon atom of the side chain for maximal stimulation of α and β receptors. The two hydroxyl groups on the ring are believed to form hydrogen bonds with serine residues in the fifth membrane-spanning region of the receptor.46
2. Indirect-acting agonists (agonists that cause release of norepinephrine) have no β-hydroxyl group and either no or one hydroxyl group on the ring. Agents devoid of hydroxyl substitutions can penetrate the blood-brain barrier better and exert prominent CNS effects.
3. Mixed-acting agonists (agonists having both actions already described) generally have a β-hydroxyl group and a single ring hydroxyl group.
4. Dopamine, which lacks the β-carbon hydroxyl moiety present in other endogenous catecholamines, stimulates dopamine receptors in addition to α1 and β1 receptors. Low concentrations of systemically administered dopamine selectively stimulate D1 receptors.
5. Slight modifications in chemical structure can confer significant differences in pharmacodynamics. Therapeutic agents can be designed to provide specific responses by selective action on receptor subtypes.33 Other structural modifications yield differences in pharmacokinetics. Methyl substitution on the α carbon yields orally active compounds able to resist enzymatic destruction by monoamine oxidase (MAO) in the stomach and small intestine.
6. As the alkyl substitution on the nitrogen is increased in molecular weight, a shift in drug affinity toward the β2-adrenergic receptor is observed. The affinity of norepinephrine, with no alkyl substitution, is much greater for α-adrenergic receptors than for β2-adrenergic receptors; the affinity of epinephrine, with a methyl group, is similar for α-adrenergic and β2-adrenergic receptors; and the affinity of isoproterenol, with an isopropyl group, is much greater for β2 receptors than for α receptors. All three drugs have significant β1-adrenergic receptor effects. Changes in the position of ring hydroxyl groups (to the 3 and 5 positions, or a single hydroxyl group in the 4 position) lead to compounds (e.g., terbutaline and ritodrine) with selective affinity for the β2-adrenergic receptor.
7. Besides structural modifications, many of the compounds listed exist as optical isomers. Substitutions on either the α-carbon or β-carbon atom of the phenylethylamine nucleus produce stereoisomeric pairs. Levorotatory substitution on the β carbon enhances adrenergic receptor effects. Dextrorotatory substitution on the α carbon increases CNS stimulant activity (e.g., d-amphetamine).

TABLE 6-1 Structure-Activity Relationships of Selected Adrenergic Agonists

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The catecholamine nucleus is extremely sensitive to oxidation. This chemical reaction results in the formation of a quinone, adrenochrome, which accounts for inactivation and color changes that may occur in solutions of catecholamines, such as in dental anesthetic cartridges. A sulfite salt (e.g., sodium metabisulfite) is incorporated in such solutions as an antioxidant to prevent catecholamine degradation.

PHARMACOLOGIC EFFECTS

The pharmacology of the adrenergic agonists is complicated by the diversity of the drugs in this group. They differ in mode of action (direct, indirect, or mixed), receptor selectivity, and relative predominance of peripheral and CNS effects. Predicting the pharmacologic activity of any adrenergic agonist is possible by knowing whether it is direct acting or indirect acting, and what receptors it affects. The density of the receptor population in a particular organ or organ system also influences the effectiveness of adrenergic agonists. A smooth muscle with a high density of α-adrenergic receptors would be strongly contracted by a drug that is efficacious in activating α-adrenergic receptors, but another smooth muscle, expressing few or no α receptors, would be minimally or not at all affected by the same agonist. Table 6-2 summarizes the relative receptor preferences of several adrenergic drugs.

TABLE 6-2 Receptor Selectivity of Adrenergic Receptor Agonists

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Of the many adrenergic agonists that have been isolated or synthesized and are used clinically, only a few are considered in detail here. The following discussion begins with agents that are endogenous transmitters or hormones, capable of interacting with α and β receptors, and then focuses successively on other direct-acting agonists that are more selective in receptor preference. This discussion concludes with indirect-acting and mixed-acting drugs that cause the release of norepinephrine as their primary mode of action. Where appropriate, additional drugs are mentioned in the sections on therapeutic applications and adverse effects.

Endogenous Catecholamines: Norepinephrine and Epinephrine

Vascular effects

The net effect of systemic administration of norepinephrine or epinephrine on the cardiovascular system depends on various factors, including the route and rate of administration, the dose given, and the presence or absence of interacting drugs. When injected locally, norepinephrine and epinephrine cause contraction of vascular smooth muscle and vasoconstriction in the surrounding tissues by stimulating α-adrenergic receptors. Systemic effects on the vasculature occurring after absorption of these catecholamines into the circulation depend on the plasma concentrations achieved and on the drugs’ actions at α-adrenergic and β-adrenergic receptors. With plasma concentrations attained by an intravenous infusion of 0.2 µg/kg/min or more, the response to norepinephrine reflects stimulation of α receptors causing increased systolic and diastolic blood pressures, with a reflex bradycardia caused by activation of the baroreceptor reflex. The bradycardia occurs despite the direct stimulation of cardiac β1 receptors by norepinephrine, which tends to increase heart rate.

Although the same infusion of epinephrine stimulates α-adrenergic and β2-adrenergic receptors in the vasculature, the more robust α receptor–mediated vasoconstrictor response masks the vasodilatory effect of β2 receptor stimulation, and the net result is usually vasoconstriction, similar to that of norepinephrine. However, at low plasma concentrations, as achieved by an intravenous administration of 0.1 µg/kg/min or less, the effect of epinephrine on α-adrenergic receptors is less, allowing the β2 receptor vasodilator response to become manifest. Under these conditions, mean arterial blood pressure may decrease, and the direct stimulant effect of epinephrine on the myocardium (tachycardia) is observed. This effect is not shared by norepinephrine because it does not stimulate β2 receptors.

Figure 6-2 shows the typical cardiovascular responses to the intravenous bolus injection of these catecholamines. The qualitatively different effects of high versus low doses of epinephrine on blood pressure and heart rate described earlier are apparent as the initially high concentration of drug declines over the course of several minutes into the low dose range.

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FIGURE 6-2 Schematic representation of the effects of three catecholamines on heart rate and arterial blood pressure in the dog. The drugs were administered intravenously by bolus injection at a dose of 1 µg/kg. Note the biphasic effect of epinephrine. Initially, the drug resembles norepinephrine by causing an increase in blood pressure and reduction in heart rate. As the concentration of epinephrine falls into the physiologic range, however, β-adrenergic receptor activation predominates. Diastolic pressure decreases, and direct cardiac effects are unmasked. The decreased heart rates seen with norepinephrine and at the beginning of the epinephrine response are produced indirectly by the baroreceptor reflex. The drug effects shown here last for approximately 5 minutes.

Cardiac effects

Norepinephrine and epinephrine stimulate β1-adrenergic receptors located in cardiac muscle, pacemaker, and conducting tissues of the heart; β2 receptors, also located in these tissues but in smaller numbers, contribute to the cardiac effects of epinephrine. Not only is the strength of contraction increased by β receptor stimulation (positive inotropic effect), but also the rate of force development and subsequent relaxation is accentuated, resulting in a shorter systolic interval. The spread of the excitatory action potential through the conductile tissues is also increased (positive dromotropic action). Pacemaker cells increase their firing rate (positive chronotropic effect), and automaticity is enhanced in normally quiescent muscle (latent pacemaker cells are activated).

All the effects described are effectively antagonized by β receptor blockade. Simulation of α1-adrenergic receptors has been shown to enhance myocardial contraction and to prolong the refractory period, however, and has been implicated in certain ventricular arrhythmias occurring during general anesthesia.41

Stimulation of β-adrenergic receptors increases the work of the heart, which elevates cardiac oxygen consumption. Overall, cardiac efficiency (cardiac work done relative to oxygen consumption) is diminished. The delivery of oxygen to the heart by the coronary arteries is variably affected by the relative amounts of α and β receptor activation produced by each adrenergic agonist (see Table 6-2) and by metabolic regulators of local blood flow.

Effects on nonvascular smooth muscle

The effect of adrenergic agonists on smooth muscle in the organs of the thoracic and abdominal cavities is usually relaxation. The gastrointestinal tract shows decreased motility from activation of β2-adrenergic receptors on smooth muscle, causing relaxation, and α2-adrenergic receptors located on excitatory parasympathetic nerves that inhibit acetylcholine release. The sphincters are constricted through α1 receptor stimulation. A similar situation exists for the urinary bladder. The sphincter and trigone muscles contract as a result of α1 receptor stimulation, whereas the detrusor muscle is relaxed by β2 receptor stimulation, causing urinary retention. The response of the uterus varies with the species, the stage of the estrous cycle, and pregnancy. Generally, α1-adrenergic receptor activation leads to contraction, whereas β2 receptor activation leads to relaxation. In either case, these effects require doses of epinephrine or norepinephrine that result in significant cardiovascular stimulation and are too evanescent to be useful therapeutically.

Bronchodilation is another example of smooth muscle relaxation that is of major therapeutic importance. The β2-adrenergic receptors of the bronchioles are stimulated by epinephrine. Although epinephrine is a drug of choice to counteract bronchospasm associated with hypotension, as in anaphylactic shock, β2 receptor–selective drugs such as albuterol produce bronchodilation with less concomitant β1 receptor stimulation of the heart and are preferred in asthmatic patients.

Epinephrine and norepinephrine stimulate α1 receptors to cause the splenic capsule to contract, although in humans this does not seem to play an important role in increasing the hematocrit. The pilomotor muscles of the skin contract to cause piloerection, and the radial muscle of the iris contracts to cause mydriasis in response to norepinephrine and epinephrine activation of α1 receptors.

Effects on salivary glands

Epinephrine and norepinephrine affect secretion by salivary glands through activation of adrenergic receptors on secretory cells and by stimulation of vascular adrenergic receptors that alter blood flow to the glands. Secretory cells of the major salivary glands contain α1-adrenergic, β1-adrenergic, and some β2-adrenergic receptors. The principal adrenergic receptor linked to protein secretion is the β1 receptor, although α1 receptors also play a secretory role, and some evidence supports a role for β2 receptors, at least in some species. The primary effect of α1 receptor stimulation on secretory cells resembles qualitatively that of muscarinic receptor stimulation because water and electrolyte secretion is stimulated. Salivary glands also contain myoepithelial cells, in which α1 receptor stimulation causes contraction around secretory acinar units, contributing to secretion. Stimulation of β receptors causes a more protein-rich (e.g., amylase) secretion. Overall, the predominant characteristic of epinephrine and norepinephrine stimulation of the salivary glands is a modest secretion with a high concentration of protein.

Metabolic responses

Metabolic responses to β2-adrenergic and β1-adrenergic receptor stimulation lead to a transitory increase in circulating blood glucose as a result of liver glycogenolysis and increased glucagon secretion.1 An α2 receptor–mediated inhibition of insulin secretion contributes to the hyperglycemia caused by epinephrine. Stimulation of β1 and β3 receptors is involved in the hydrolysis of triglycerides, causing an increase in triglyceride lipase activity and subsequently in the concentration of circulating free fatty acids. The specific receptors that mediate metabolic effects vary among species.

Central nervous system effects

Although the catecholamines are extensively involved in neurotransmission in the CNS, peripherally administered catecholamines gain little access to the CNS because hydroxyl groups on the aromatic ring deter passage across the blood-brain barrier. Intravenous injection of epinephrine produces a variety of apparently central effects, however, including feelings of anxiety, jitteriness, and apprehension. Most, if not all, of these effects are thought to be indirect, resulting from sensory input to the brain from the periphery. Centrally mediated reflex respiratory apnea is induced by drugs that cause an increase in blood pressure.

Dopamine

Although dopamine is primarily a CNS neurotransmitter, it also has effects in the periphery, where dopamine receptors have been identified in various tissues. Molecular cloning studies have revealed at least five subtypes of the dopamine receptor (D1 to D5). Although the D1 receptor subtype is thought to cause peripheral vasodilation, other dopamine receptor subtypes may also contribute to the various peripheral effects of dopamine. Peripheral dopamine-containing neurons have been found in autonomic ganglia in the form of small, intensely fluorescent cells and in kidney glomeruli. Evidence suggests that dopamine neurons help regulate sympathetic nervous system transmission, promote gastrointestinal relaxation, and cause vasodilation in some vascular beds.

Cardiovascular effects

Dopamine interacts with various receptor types to influence vascular function, and is used therapeutically for maintaining renal function in cases of shock associated with compromised cardiac output. Although “low-dose” dopamine has now been used in this manner for more than 30 years, there is currently a growing body of evidence suggesting that this use for dopamine should be abandoned. Early data using indirect clearance measurements of blood flow suggested that dopamine stimulates vascular D1 receptors to dilate selectively the renal, celiac, hepatic, and mesenteric vasculatures, and that increases in glomerular filtration rate and Na+ excretion occur in conjunction with increased renal blood flow.16 With moderate doses, dopamine was thought to act at myocardial β1-adrenergic receptors to increase contractile force. Critics of low-dose dopamine have suggested that this increase in cardiac index, rather than dilation of the renal vasculature, is the primary reason for any observed increases in renal blood flow with low-dose dopamine,44 and that the potential for harm outweighs the benefits.30 At higher doses, dopamine also stimulates α1-adrenergic receptors, which produces vasoconstriction. As with all catecholamines, excessive doses of dopamine can cause tachycardia and generate arrhythmias. In addition to stimulating α1 and β1 receptors directly, dopamine in moderate to high doses causes the release of norepinephrine from sympathetic nerve terminals.

Fenoldopam, a pharmacologic congener of dopamine, selectively activates D1 receptors at therapeutic doses. It decreases mean blood pressure, increases renal blood flow, and causes diuresis and natriuresis. It is used intravenously for acute treatment of severe hypertension (see Chapter 28).

Other effects

Dopamine is involved with the sensory division of the autonomic nervous system. The high concentration of dopamine in the glomus cells of the carotid body and the effects of hypoxia on these cells suggest that dopamine is an inhibitory transmitter that modulates the frequency of discharge of the sensory fibers from that structure.19 It is theorized that, by this mechanism, dopamine may affect cardiovascular and respiratory responses.

Dopamine itself does not penetrate the blood-brain barrier. Levodopa, which is converted into dopamine, does enter the CNS, however, and is used to treat Parkinson’s disease (see Chapter 15). Approximately 95% of an oral dose of levodopa is normally decarboxylated in the periphery to dopamine,8 leading to significant peripheral side effects attributable to dopamine. Dopamine can also produce nausea and vomiting as a result of excitation of the medullary chemoreceptor trigger zone, which lies outside the blood-brain barrier.

Another physiologic role for dopamine is modulation of the release of several anterior pituitary hormones. Dopamine acts as a prolactin release–inhibiting hormone by binding to D2 receptors on the lactotrope cells of the anterior pituitary. Although dopamine itself is limited therapeutically by its inability to penetrate the blood-brain barrier, bromocriptine and other dopamine receptor agonists that are sufficiently lipid soluble to enter the CNS have been used successfully in the treatment of female infertility and other health problems resulting from hyperprolactinemia. Bromocriptine has also proved effective in controlling excessive secretion of growth hormone associated with pituitary adenomas. This last therapeutic application is surprising because dopamine is a stimulant of growth hormone release in the normal pituitary.

α-Adrenergic Receptor Agonists

The group of drugs classified as α-adrenergic receptor agonists is growing increasingly diverse. These drugs stimulate α-adrenergic receptors, but have low affinity for β-adrenergic receptors. Phenylephrine and methoxamine differ from epinephrine and norepinephrine by being selective agonists at α1-adrenergic receptors. Their primary pharmacologic effect is to cause contraction of vascular smooth muscle, resulting in an increase in systolic and diastolic blood pressures and reflex bradycardia. They are often administered either intranasally or systemically for temporary relief from nasal congestion. Because these drugs increase blood pressure, safety is always a concern. The α-adrenergic receptor agonist phenylpropanolamine was widely used in over-the-counter cold remedies until research studies showed that it increased the risk of hemorrhagic stroke in women,25 which led the U.S. Food and Drug Administration (FDA) to mandate its removal from these medications. Other agonists with actions similar to phenylephrine and methoxamine include metaraminol, although it is a mixed-acting agonist (discussed later) because it releases catecholamines in addition to directly stimulating α1-adrenergic receptors. Midodrine is a newer synthetic drug that selectively activates α1-adrenergic receptors. It also causes vasoconstriction, and is used to treat postural hypotension caused by impaired autonomic nervous system function.

The α2-adrenergic receptor agonists clonidine, guanabenz, guanfacine, and methyldopa (Figure 6-3) effectively enter into the CNS and stimulate α2-adrenergic receptors in the brain. They are, in varying degrees, selective agonists at α2 receptors. Methyldopa, an α-methyl derivative of dopa (dihydroxyphenylalanine, an important intermediate in the synthesis of norepinephrine), enters into the nerve terminal and is converted into the α2 receptor–selective agonist α-methylnorepinephrine by the same synthetic process that converts dopa into norepinephrine. Although α-methylnorepinephrine is present in neuronal storage vesicles in peripheral sympathetic nerves, this metabolite of methyldopa is nearly equipotent to norepinephrine as a vasoconstrictor in humans. This agent has been developed as the drug levonordefrin, which is used as a vasoconstrictor in local anesthetic solutions. Clonidine was first used as a nasal decongestant, but it was soon found to decrease blood pressure. An imidazoline derivative, clonidine is a selective α2-adrenergic receptor agonist with relatively weak peripheral effects. Guanabenz and guanfacine are guanidine derivatives that, similar to clonidine, also selectively activate α2-adrenergic receptors.

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FIGURE 6-3 Structural formulas of some centrally acting α2-adrenergic receptor agonists.

These centrally acting agonists are thought to exert their antihypertensive effect by acting on α2 receptors in the nucleus tractus solitarius of the brainstem, leading to a decrease in sympathetic outflow. This proposed mechanism of action is supported by experiments involving the stereotaxic administration of α2 receptor agonists into the nucleus tractus solitarius followed by inhibition of drug effects by α receptor antagonists injected into the cerebrospinal fluid. Blocking the conversion of methyldopa to α-methylnorepinephrine prevents the antihypertensive action of this drug.

The administration of these centrally acting drugs in humans results in moderate decreases in mean arterial blood pressure. This effect usually occurs without increases in heart rate because a decrease in CNS sympathetic outflow tends to reduce venous return, heart rate, and cardiac output. Guanfacine decreases peripheral vascular resistance without affecting cardiac output.18 Intravenous administration of these drugs may increase blood pressure acutely as a result of stimulation of peripheral vasoconstrictor α2 receptors. This effect is not usually seen with oral administration.

Serendipity has played a role in the use of clonidine to treat the withdrawal symptoms of opioid addiction.29 Clonidine, when given to addicts undergoing withdrawal, blocks the nausea, vomiting, sweating, diarrhea, and other symptoms of excessive autonomic discharge (see Chapter 51). Evidence indicates that either systemic or intracerebral injection of opioids inhibits neuronal activity in the locus ceruleus of the dorsolateral pons. When the opioids are withdrawn, certain neurons are thought to be disinhibited and to release excessive norepinephrine, which gives rise to the symptoms of withdrawal. Clonidine, by stimulating presynaptic α2 receptors on these same neurons, />

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Related posts:

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  2. 26: Antianginal Drugs
  3. 27: Diuretic Drugs
  4. 45: Antiplaque and Antigingivitis Agents
  5. 10: Drugs Affecting Nicotinic Receptors
  6. 28: Antihypertensive Drugs

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Jan 5, 2015 | Posted by in General Dentistry | Comments Off on 6: Adrenergic Agonists

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