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Anticholinesterase Agents

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Anticholinesterase Agents

Overview

This chapter covers agents that prolong the existence of acetylcholine after it is released from cholinergic nerve terminals. These agents inhibit acetylcholinesterase, which is concentrated in synaptic regions and is responsible for the rapid catalysis of the hydrolysis of acetylcholine. Anticholinesterase agents have therapeutic utility in the treatment of glaucoma and other ophthalmologic conditions (see also Chapter 66: Ocular Pharmacology), the facilitation of gastrointestinal and bladder motility, and influencing activity at the neuromuscular junction of skeletal muscle to enhance muscle strength in myasthenia gravis. Anticholinesterase agents that cross the blood–brain barrier have shown limited efficacy in the treatment of Alzheimer's disease (see also Chapter 22: Treatment of Central Nervous System Degenerative Disorders). Antidotal therapy of the toxic effects of cholinesterase inhibitors used as insecticides and chemical warfare agents is directed to blocking the effects of excessive acetylcholine stimulation and reactivating the phosphorylated, inhibited enzyme. Modification of activity at cholinergic synapses by activation or blockade of muscarinic or nicotinic acetylcholine receptors is discussed in Chapters 7: Muscarinic Receptor Agonists and Antagonists and 9: Agents Acting at the Neuromuscular Junction and Autonomic Ganglia, respectively.




Anticholisesterase Agents: Introduction

The function of acetylcholinesterase (AChE) in terminating the action of acetylcholine (ACh) at the junctions of the various cholinergic nerve endings with their effector organs or postsynaptic sites is considered in Chapter 6: Neurotransmission: The Autonomic and Somatic Motor Nervous Systems. Drugs that inhibit AChE are called anticholinesterase (anti-ChE) agents. They cause ACh to accumulate in the vicinity of cholinergic nerve terminals and thus are potentially capable of producing effects equivalent to excessive stimulation of cholinergic receptors throughout the central and peripheral nervous systems. In view of the widespread distribution of cholinergic neurons, it is not surprising that the anti-ChE agents as a group have received extensive application as toxic agents, in the form of agricultural insecticides and potential chemical warfare 'nerve gases.' Nevertheless, several members of this class of compounds are widely used as therapeutic agents; others that cross the blood–brain barrier have been approved or are in clinical trial for the treatment of Alzheimer's disease.

Prior to World War II, only the 'reversible' anti-ChE agents were generally known, of which physostigmine is the outstanding example. Shortly before and during World War II, a new class of highly toxic chemicals, the organophosphates, was developed chiefly by Schrader, of I. G. Farbenindustrie, first as agricultural insecticides and later as potential chemical warfare agents. The extreme toxicity of these compounds was found to be due to their 'irreversible' inactivation of AChE, which resulted in long-lasting inhibitory activity. Since the pharmacological actions of both classes of anti-ChE agents are qualitatively similar, they are discussed here as a group. Interactions of anti-ChE agents with other drugs acting at peripheral autonomic synapses and the neuromuscular junction are described in Chapters 7: Muscarinic Receptor Agonists and Antagonists and 9: Agents Acting at the Neuromuscular Junction and Autonomic Ganglia.

History

Physostigmine, also called eserine, is an alkaloid obtained from the Calabar or ordeal bean, the dried ripe seed of Physostigma venenosum, Balfour, a perennial plant found in tropical West Africa. The Calabar bean, also called Esére nut, chop nut, or bean of Etu Esére, once was used by native tribes of West Africa as an 'ordeal poison' in trials for witchcraft.

The Calabar bean was brought to England in 1840 by Daniell, a British medical officer, and early investigations of its pharmacological properties were conducted by Christioson (1855), Fraser (1863), and Argyll-Robertson (1863). A pure alkaloid was isolated by Jobst and Hesse in 1864 and named physostigmine. The first therapeutic use of the drug was in 1877 by Laqueur, in the treatment of glaucoma, one of its clinical uses today. Interesting accounts of the history of physostigmine have been presented by Karczmar (1970) and Holmstedt (1972).

As a result of the basic research of Stedman (1929a,b) and associates in elucidating the chemical basis of the activity of physostigmine, others began systematic investigations of a series of substituted aromatic esters of alkyl carbamic acids. Neostigmine, a promising member of this series, was introduced into therapeutics in 1931 for its stimulant action on the intestinal tract. It was reported subsequently to be effective in the symptomatic treatment of myasthenia gravis.

It is remarkable that the first account of the synthesis of a highly potent organophosphorus anti-ChE, tetraethyl pyrophosphate (TEPP), was published by Clermont in 1854. More remarkable still is the fact that the investigator survived to report on the compound's taste; a few drops should have been lethal. Modern investigations of the organophosphorus compounds date from the 1932 publication of Lange and Krueger on the synthesis of dimethyl and diethyl phosphorofluoridates. The authors' statement that inhalation of these compounds caused a persistent choking sensation and blurred vision apparently was instrumental in leading Schrader to explore this class for insecticidal activity.

Upon synthesizing approximately 2000 compounds, Schrader (1952) defined the structural requirements for insecticidal (and, as learned subsequently, for anti-ChE) activity (see below; Gallo and Lawryk, 1991). One compound in this early series, parathion (a phosphorothioate), later became the most widely used insecticide of this class. Malathion, which currently is used extensively, also contains the thionophosphorus bond found in parathion. Prior to and during World War II, the efforts of Schrader's group were directed toward the development of chemical warfare agents. The syntheses of several compounds of much greater toxicity than parathion, such as sarin, soman, and tabun, were kept secret by the German government. Investigators in the Allied countries also followed Lange and Krueger's lead in the search for potentially toxic compounds; diisopropyl phosphorofluoridate (diisopropyl fluorophosphate; DFP), synthesized by McCombie and Saunders (1946), was studied most extensively by British and American scientists.

In the 1950s, a series of aromatic carbamates was synthesized and found to have a high degree of selective toxicity against insects and to be potent anti-ChE agents (Ecobichon, 2000).

Structure of Acetylcholinesterase

AChE exists in two general classes of molecular forms: simple homomeric oligomers of catalytic subunits (i.e., monomers, dimers, and tetramers) and heteromeric associations of catalytic subunits with structural subunits (Massoulie, 2000; Taylor et al., 2000). The homomeric forms are found as soluble species in the cell, presumably destined for export, or associated with the outer membrane of the cell through either an intrinsic hydrophobic amino acid sequence or an attached glycophospholipid. One heterologous form, largely found in neuronal synapses, is a tetramer of catalytic subunits disulfide-linked to a 20,000-dalton lipid-linked subunit. Similar to the glycophospholipid-attached form, it is found in the outer surface of the cell membrane. The other consists of tetramers of catalytic subunits, disulfide linked to each of three strands of a collagen-like structural subunit. This molecular species, whose molecular mass approaches 106 daltons, is associated with the basal lamina of junctional areas of skeletal muscle.

Molecular cloning revealed that a single gene encodes vertebrate AChEs (Schumacher et al., 1986; Taylor et al., 2000). However, multiple gene products are found; this diversity arises from alternative processing of the mRNA. The different forms differ only in their carboxyl-termini; the portion of the gene encoding the catalytic core of the enzyme is invariant. Hence, the individual AChE species can be expected to show identical substrate and inhibitor specificities.

A separate, structurally related gene encodes butyrylcholinesterase, which is synthesized in the liver and is primarily found in plasma (Lockridge et al., 1987). The cholinesterases define a superfamily of proteins whose structural motif is the hydrolase fold (Cygler et al., 1993). The family includes several esterases, other hydrolases not found in the nervous system, and, surprisingly, proteins without hydrolase activity such as thyroglobulin and members of the tactin and neuroligin families of proteins (Taylor et al., 2000).

The three-dimensional structures of AChEs show the active center to be nearly centrosymmetric to each subunit and reside at the base of a narrow gorge about 20 Å in depth (Sussman et al., 1991; Bourne et al., 1995). At the base of the gorge lie the residues of the catalytic triad: serine 203, histidine 447, and glutamate 334 (Figure 8–1). The catalytic mechanism resembles that of other hydrolases, where the serine hydroxyl group is rendered highly nucleophilic through a charge-relay system involving the carboxyl from glutamate, the imidazole on the histidine, and the hydroxyl of the serine (Figure 8–2A).

Figure 8–1. The Active Center Gorge of Mammalian Acetylcholinesterase. Bound acetylcholine is shown by the dotted structure depicting its van der Waals radii. The crystal structure of mouse cholinesterase active center is shown (Bourne et al., 1995). Included are the side chains of (a) the catalytic triad, Glu334, His447, Ser203 (hydrogen bonds are denoted by the dotted lines); (b) acyl pocket, Phe295 and Phe297; (c) choline subsite, Trp86, Glu202, and Tyr337; and (d) the peripheral site: Trp286, Tyr72, Tyr124, and Asp74. Tyrosines 337 and 449 are further removed from the active center but likely contribute to stabilization of certain ligands. The catalytic triad, choline subsite, and acyl pocket are located at the base of the gorge, while the peripheral site is at the lip of the gorge. The gorge is 18 to 20 Å deep, with its base centrosymmetric to the subunit.

Figure 8–2. Steps Involved in the Hydrolysis of Acetylcholine by Acetylcholinesterase and in the Inhibition and Reactivation of the Enzyme. The steps shown are as follows: A. Binding of substrate acetylcholine. B. Attack by the serine hydroxyl with formation of the transient tetrahedral intermediate. C. Loss of choline and formation of the acetyl enzyme. D. Deacylation of the enzyme by attack with H2O. E. Binding of the reversible inhibitor edrophonium to the active site. F. Binding of neostigmine. G. Formation of the carbamoylated enzyme. H. Hydrolysis of the carbamoylated enzyme. I. Binding of diisopropyl flurophosphate. J. Formation of the disopropyl phosphorl enzyme. K. Formation of an aged form of the monoisopropyl phosphoryl enzyme. L. Attack by pralidoxime (2-PAM) to regenerate active enzyme.

During enzymatic attack of acetylcholine, an ester with trigonal geometry, a tetrahedral intermediate between enzyme and substrate is formed (Figure 8–2B) that collapses to an acetyl enzyme conjugate with the concomitant release of choline (Figure 8–2C). The acetyl enzyme is very labile to hydrolysis, which results in the formation of acetate and active enzyme (Figure 8–2D; see Froede and Wilson, 1971; Rosenberry, 1975). AChE is one of the most efficient enzymes known and has the capacity to hydrolyze 6 x 105 ACh molecules per molecule of enzyme per minute; this yields a turnover time of 150 microseconds.

Mechanism of Action of AChE Inhibitors

The mechanisms of action of compounds that typify the three classes of anti-ChE agents also are shown in Figure 8–2E to L.

Three distinct domains on AChE constitute binding sites for inhibitory ligands and form the basis for specificity differences between AChE and butyrylcholinesterase: the acyl pocket of the active center, the choline subsite of the active center, and the peripheral anionic site (Taylor and Radić, 1994; Reiner and Radić, 2000). Reversible inhibitors such as edrophonium and tacrine bind to the choline subsite in the vicinity of tryptophan 86 and glutamate 202 (Silman and Sussman, 2000) (Figure 8–2E). Edrophonium has a brief duration of action owing to its quaternary structure and the reversibility of its binding to the AChE active center. Additional reversible inhibitors, such as donepezil, bind with higher affinity to the active center.

Other reversible inhibitors, such as propidium and the peptide toxin fasciculin, bind to the peripheral anionic site on AChE. This site resides at the lip of the gorge and is defined by tryptophan 286 and tyrosines 72 and 124 (Figure 8–1).

Drugs that have a carbamoyl ester linkage, such as physostigmine and neostigmine, are hydrolyzed by AChE, but much more slowly than is ACh. Both the quaternary amine neostigmine and the tertiary amine physostigmine exist as cations at physiological pH. By serving as alternate substrates with a similar binding orientation as acetylcholine (see Figure 8–2F, G), attack by the active center serine gives rise to the carbamoylated enzyme. The carbamoyl moiety resides in the acyl pocket outlined by phenylalanines 295 and 297. In contrast to the acetyl enzyme, methylcarbamoyl AChE and dimethylcarbamoyl AChE are far more stable (t1/2 for hydrolysis of the dimethylcarbamoyl enzyme is 15 to 30 minutes; see Figure 8–2H). Sequestration of the enzyme in its carbamoylated form thus precludes the enzyme-catalyzed hydrolysis of ACh for extended periods of time. In vivo, the duration of inhibition by the carbamoylating agents is 3 to 4 hours.

The organophosphorus inhibitors, such as diisopropyl fluorophosphate (DFP), serve as true hemisubstrates, since the resultant conjugate with the active center serine phosphorylated or phosphonylated is extremely stable (see Figure 8–2I, J, K). The organophosphorus inhibitors are tetrahedral in configuration, a configuration that resembles the transition state formed in carboxyl ester hydrolysis. Similar to the carboxyl esters, the phosphoryl oxygen binds within the oxyanion hole of the active center. If the alkyl groups in the phosphorylated enzyme are ethyl or methyl, spontaneous regeneration of active enzyme requires several hours. Secondary (as in DFP) or tertiary alkyl groups further enhance the stability of the phosphorylated enzyme, and significant regeneration of active enzyme usually is not observed. Hence, the return of AChE activity depends on synthesis of new enzyme. The stability of the phosphorylated enzyme is enhanced through 'aging,' which results from the loss of one of the alkyl groups (see Figure 8–2K; see also Aldridge, 1976).

From the foregoing account, it is apparent that the terms reversible and irreversible as applied to the carbamoyl ester and organophosphorus anti-ChE agents, respectively, reflect only quantitative differences in rates of deacylation of the acyl enzyme. Both chemical classes react covalently with the enzyme in essentially the same manner as does ACh.

Action at Effector Organs

The characteristic pharmacological effects of the anti-ChE agents are due primarily to the prevention of hydrolysis of ACh by AChE at sites of cholinergic transmission. Transmitter thus accumulates, and the response to ACh that is liberated by cholinergic impulses or that is spontaneously released from the nerve ending is enhanced. Virtually all the acute effects of moderate doses of organophosphates are attributable to this action. For example, the characteristic miosis that follows local application of DFP to the eye is not observed after chronic postganglionic denervation of the eye because there is no source from which to release endogenous ACh. The consequences of enhanced concentrations of ACh at motor end-plates are unique to these sites and are discussed below.

The tertiary amine and particularly the quaternary ammonium anti-ChE compounds all may have additional direct actions at certain cholinergic receptor sites. For example, the effects of neostigmine on the spinal cord and neuromuscular junction are based on a combination of its anti-ChE activity and direct cholinergic stimulation.

Chemistry and Structure–Activity Relationships

The structure–activity relationships of anti-ChE drugs have been reviewed extensively (see previous editions of this book). Only those agents of general therapeutic or toxicological interest are considered here.

Noncovalent Inhibitors

While drugs of this class interact by reversible and noncovalent association with the active site in AChE, they differ in their disposition in the body and their affinity for the enzyme. Edrophonium, a quaternary drug whose activity is limited to peripheral nervous system synapses, has a moderate affinity for AChE. Its volume of distribution is limited and renal elimination is rapid, accounting for its short duration of action. By contrast, tacrine and donepezil have higher affinities for AChE, are more hydrophobic, and readily cross the blood–brain barrier to inhibit AChE in the central nervous system (CNS). Their partitioning into lipid and their higher affinities for AChE account for their longer durations of action.

'Reversible' Carbamate Inhibitors

Drugs of this class that are of therapeutic interest are shown in Figure 8–3. Stedman's early studies (1929a,b) showed that the essential moiety of the physostigmine molecule was the methyl carbamate of a basically substituted simple phenol. The quaternary ammonium derivative neostigmine is a compound of greater stability and equal or greater potency. Pyridostigmine is a close congener that also is employed in the treatment of myasthenia gravis.

Figure 8–3. Representative 'Reversible' Anticholinesterase Agents Employed Clinically 

An increase in anti-ChE potency and duration of action can result from the linking of two quaternary ammonium moieties. One such example is the miotic agent demecarium, which essentially consists of two neostigmine molecules connected by a series of ten methylene groups. The second quaternary group confers additional stability to the interaction by associating with a negatively charged amino side chain, Asp74, near the lip of the gorge. Carbamoylating inhibitors with high lipid solubilities readily cross the blood–brain barrier and have longer durations of action. Such agents (rivastigmine) have been approved by the United States Food and Drug Administration (FDA) for the treatment of Alzheimer's disease (Giacobini, 2000; Corey-Bloom et al., 1998; see Chapter 22: Treatment of Central Nervous System Degenerative Disorders).

The carbamate insecticides, carbaryl (SEVIN), propoxur (BAYGON), and aldicarb (TEMIK), which are used extensively in garden products, inhibit ChE in a fashion identical with other carbamoylating inhibitors. The symptoms of poisoning closely resemble those of the organophosphates (Baron, 1991; Ecobichon, 2000). Carbaryl has a particularly low toxicity from dermal absorption. It is used topically for control of head lice in some countries. Not all carbamates in garden formulations are cholinesterase inhibitors; the dithiocarbamates are fungicidal.

Organophosphorus Compounds

The general formula for this class of cholinesterase inhibitors is presented in Table 8–1. A great variety of substituents is possible: R1 and R2 may be alkyl, alkoxy, aryloxy, amido, mercaptan, or other groups, and X, the leaving group, a conjugate base of a weak acid, is found as a halide, cyanide, thiocyanate, phenoxy, thiophenoxy, phosphate, thiocholine, or carboxylate group. For a compilation of the organophosphorus compounds and their toxicity, see Gallo and Lawryk (1991).

DFP produces virtually irreversible inactivation of AChE and other esterases by alkylphosphorylation. Its high lipid solubility, low molecular weight, and volatility facilitate inhalation, transdermal absorption, and penetration into the CNS.

The 'nerve gases'—tabun, sarin, and soman—are among the most potent synthetic toxic agents known; they are lethal to laboratory animals in submilligram doses. Insidious employment of these agents has occurred in warfare and terrorism attacks (Nozaki and Aikawa, 1995).

Because of its low volatility and stability in aqueous solution, parathion (ETILON) became widely used as an insecticide. Its acute and chronic toxicity has limited its agricultural use in the United States and other countries; potentially less hazardous compounds have replaced parathion for home and garden use. Parathion itself is inactive in inhibiting AChE in vitro; paraoxon is the active metabolite. The sulfur-for-oxygen substitution is carried out predominantly in the liver by the mixed-function oxidases. This reaction also is carried out in the insect, typically with more efficiency. Parathion probably has been responsible for more cases of accidental poisoning and death than any other organophosphorus compound. The dimethyl congener, methyl parathion, has been put on restricted use limited to nonresidential settings. Other insecticides possessing the phosphorothioate structure have been widely employed for home, garden, and agricultural use. These include diazinon (SPECTRACIDE, others) and chlorpyrifos (DURSBAN, LORSBAN). Chlorpyrifos recently has been placed under restricted use because of evidence of chronic toxicity in the newborn animal. For the same reason, diazinon was banned for indoor use in the United States in 2001 and will be phased out of all outdoor use by 2005.

Malathion (CHEMATHION MALA-SPRAY) also requires replacement of a sulfur atom with oxygen in vivo. This insecticide can be detoxified by hydrolysis of the carboxyl ester linkage by plasma carboxylesterases, and plasma carboxylesterase activity dictates species resistance to malathion. The detoxification reaction is much more rapid in mammals and birds than in insects (see Costa et al., 1987). In recent years, malathion has been employed in aerial spraying of relatively populous areas for control of citrus-orchard-destructive Mediterranean fruit flies and mosquitoes that harbor and transmit viruses harmful to human beings, such as the West Nile encephalitis virus. Evidence of acute toxicity arises only with suicide attempts or deliberate poisoning (Bardin et al., 1994). The lethal dose in mammals is about 1 g/kg. Exposure to the skin results in a small fraction (<10%) of systemic absorption. Malathion is used in the treatment of pediculosis (lice infestations; see Chapter 65: Dermatological Pharmacology).

Among the quaternary ammonium organophosphorus compounds (group E in Table 8–1), only echothiophate is useful clinically and is limited to ophthalmic administration. Being positively charged, it is not volatile and does not readily penetrate the skin.

Metrifonate is a low-molecular-weight organophosphate that is spontaneously converted to the active phosphoryl ester: dimethyl 2,2-dichlorovinyl phosphate (DDVP, dichlorvos). Both metrifonate and DDVP readily cross the blood–brain barrier to inhibit AChE in the CNS. Metrifonate originally was developed for the treatment of schistosomiasis (see Chapter 42: Drugs Used in the Chemotherapy of Helminthiasis). Its capacity to inhibit AChE in the CNS and its reported low toxicity led to its clinical trial in Alzheimer's disease (Cummings et al., 1999).

Pharmacological Properties

Generally, the pharmacological properties of anti-ChE agents can be predicted by knowing those loci where ACh is released physiologically by nerve impulses, the degree of nerve impulse activity, and the responses of the corresponding effector organs to ACh (see Chapter 6: Neurotransmission: The Autonomic and Somatic Motor Nervous Systems). The anti-ChE agents potentially can produce all the following effects: (1) stimulation of muscarinic receptor responses at autonomic effector organs; (2) stimulation, followed by depression or paralysis, of all autonomic ganglia and skeletal muscle (nicotinic actions); and (3) stimulation, with occasional subsequent depression, of cholinergic receptor sites in the CNS. Following toxic or lethal doses of anti-ChE agents, most of these effects can be noted (see below). However, with smaller doses, particularly those used therapeutically, several modifying factors are significant. In general, compounds containing a quaternary ammonium group do not penetrate cell membranes readily; hence, anti-ChE agents in this category are absorbed poorly from the gastrointestinal tract or across the skin and are excluded from the CNS by the blood–brain barrier after moderate doses. On the other hand, such compounds act preferentially at the neuromuscular junctions of skeletal muscle, exerting their action both as anti-ChE agents and as direct agonists. They have comparatively less effect at autonomic effector sites and ganglia. In contrast, the more lipid-soluble agents are well absorbed after oral administration, have ubiquitous effects at both peripheral and central cholinergic sites, and may be sequestered in lipids for long periods of time. The lipid-soluble organophosphorus agents also are well absorbed through the skin, and the volatile agents are transferred readily across the alveolar membrane (Storm et al., 2000).

The actions of anti-ChE agents on autonomic effector cells and on cortical and subcortical sites in the CNS, where the receptors are largely of the muscarinic type, are blocked by atropine. Likewise, atropine blocks some of the excitatory actions of anti-ChE agents on autonomic ganglia, since both nicotinic and muscarinic receptors are involved in ganglionic neurotransmission (see Chapter 9: Agents Acting at the Neuromuscular Junction and Autonomic Ganglia).

The sites of action of anti-ChE agents of therapeutic importance are the CNS, eye, intestine, and the neuromuscular junction of skeletal muscle; other actions are of toxicological consequence.

Eye

When applied locally to the conjunctiva, anti-ChE agents cause conjunctival hyperemia and constriction of the sphincter pupillae muscle around the pupillary margin of the iris (miosis) and the ciliary muscle (block of accommodation reflex with resultant focusing to near vision). Miosis is apparent in a few minutes and can last several hours to days. Although the pupil may be 'pinpoint' in size, it generally contracts further when exposed to light. The block of accommodation is more transient and generally disappears before termination of the miosis. Intraocular pressure, when elevated, usually falls as the result of facilitation of outflow of the aqueous humor (see Chapter 66: Ocular Pharmacology).

Gastrointestinal Tract

In human beings, neostigmine enhances gastric contractions and increases the secretion of gastric acid. After bilateral vagotomy, the effects of neostigmine on gastric motility are greatly reduced. The lower portion of the esophagus is stimulated by neostigmine; in patients with marked achalasia and dilation of the esophagus, the drug can cause a salutary increase in tone and peristalsis.

Neostigmine augments the motor activity of the small and large bowel; the colon is particularly stimulated. Atony produced by muscarinic-receptor antagonists or prior surgical intervention may be overcome, propulsive waves are increased in amplitude and frequency, and movement of intestinal contents is thus promoted. The total effect of anti-ChE agents on intestinal motility probably represents a combination of actions at the ganglion cells of Auerbach's plexus and at the smooth muscle fibers, as a result of the preservation of ACh released by the cholinergic preganglionic and postganglionic fibers, respectively.

Neuromuscular Junction

Most of the effects of potent anti-ChE drugs on skeletal muscle can be explained adequately on the basis of their inhibition of AChE at neuromuscular junctions. However, there is good evidence for an accessory direct action of neostigmine and other quaternary ammonium anti-ChE agents on skeletal muscle. For example, the intraarterial injection of neostigmine into chronically denervated muscle, or muscle in which AChE has been inactivated by prior administration of DFP, evokes an immediate contraction, whereas physostigmine does not.

Normally, a single nerve impulse in a terminal motor-axon branch liberates enough ACh to produce a localized depolarization (end-plate potential) of sufficient magnitude to initiate a propagated muscle action potential. The ACh released is rapidly hydrolyzed by AChE, such that the lifetime of free ACh within the synapse (200 microseconds) is shorter than the decay of the end-plate potential or the refractory period of the muscle. Therefore, each nerve impulse gives rise to a single wave of depolarization. After inhibition of AChE, the residence time of ACh in the synapse increases, allowing for rebinding of transmitter to multiple receptors. Successive stimulation by diffusion to neighboring receptors in the end plate results in a prolongation of the decay time of the end-plate potential. Quanta released by individual nerve impulses are no longer isolated. This action destroys the synchrony between end-plate depolarizations and the development of the action potentials. Consequently, asynchronous excitation and fibrillation of muscle fibers are observed. With sufficient inhibition of AChE, depolarization of the end-plate predominates, and blockade owing to depolarization ensues (see Chapter 9: Agents Acting at the Neuromuscular Junction and Autonomic Ganglia). When ACh persists in the synapse, it also may depolarize the axon terminal, resulting in anti-dromic firing of the motoneuron; this effect contributes to fasciculations, which involve the entire motor unit.

The anti-ChE agents will reverse the antagonism caused by competitive neuromuscular blocking agents (see Chapter 9: Agents Acting at the Neuromuscular Junction and Autonomic Ganglia). Neostigmine normally is not effective against the skeletal muscle paralysis caused by succinylcholine, since this agent also produces neuromuscular blockade by depolarization.

Actions at Other Sites

Secretory glands that are innervated by postganglionic cholinergic fibers include the bronchial, lacrimal, sweat, salivary, gastric (antral G cells and parietal cells), intestinal, and pancreatic acinar glands. Low doses of anti-ChE agents augment secretory responses to nerve stimulation, and higher doses actually produce an increase in the resting rate of secretion.

Anti-ChE agents increase contraction of smooth muscle fibers of the bronchioles and ureters, and the ureters may show increased peristaltic activity.

The cardiovascular actions of anti-ChE agents are complex, since they reflect both ganglionic and postganglionic effects of accumulated ACh on the heart and blood vessels. The predominant effect on the heart from the peripheral action of accumulated ACh is bradycardia, resulting in a fall in cardiac output. Higher doses usually cause a fall in blood pressure, often as a consequence of effects of anti-ChE agents on the medullary vasomotor centers of the CNS.

Anti-ChE agents augment vagal influences on the heart. This shortens the effective refractory period of atrial muscle fibers, and increases the refractory period and conduction time at the SA and AV nodes. At the ganglionic level, accumulating ACh initially is excitatory on nicotinic receptors, but at higher concentrations, ganglionic blockade ensues as a result of persistent depolarization of the cell membrane. The excitatory action on the parasympathetic ganglion cells would tend to reinforce the diminished cardiac output, whereas the opposite sequence would result from the action of ACh on sympathetic ganglion cells. Excitation followed by inhibition also is elicited by ACh at the medullary vasomotor and cardiac centers. All of these effects are complicated further by the hypoxemia resulting from the bronchoconstrictor and secretory actions of increased ACh on the respiratory system; hypoxemia, in turn, would reinforce both sympathetic tone and ACh-induced discharge of epinephrine from the adrenal medulla. Hence, it is not surprising that an increase in heart rate is seen with severe cholinesterase inhibitor poisoning. Hypoxemia probably is a major factor in CNS depression that appears after large doses of anti-ChE agents. The CNS-stimulant effects are antagonized by atropine, although not as completely as are the muscarinic effects at peripheral autonomic effector sites.

Absorption, Fate, and Excretion

Physostigmine is absorbed readily from the gastrointestinal tract, subcutaneous tissues, and mucous membranes. The conjunctival instillation of solutions of the drug may result in systemic effects if measures (e.g., pressure on inner canthus) are not taken to prevent absorption from the nasal mucosa. Physostigmine, administered parenterally, is largely destroyed in the body within 2 hours, mainly by hydrolytic cleavage by plasma esterases; renal excretion plays only a minor role in its elimination.

Neostigmine and pyridostigmine are absorbed poorly after oral administration, such that much larger doses are needed than by the parenteral route. Whereas the effective parenteral dose of neostigmine is 0.5 to 2 mg, the equivalent oral dose may be 15 to 30 mg or more. Neostigmine and pyridostigmine are destroyed by plasma esterases, and the quaternary alcohols and parent compounds are excreted in the urine; the half-life of these drugs is only 1 to 2 hours (Cohan et al., 1976).

Organophosphorus anti-ChE agents with the highest risk of toxicity are highly lipid-soluble liquids; many have high vapor pressures. The less volatile agents that are commonly used as agricultural insecticides (e.g., parathion, malathion) generally are dispersed as aerosols or as dusts adsorbed to an inert, finely particulate material. Consequently, the compounds are absorbed rapidly through the skin and mucous membranes following contact with moisture, by the lungs after inhalation, and by the gastrointestinal tract after ingestion (Storm et al., 2000).

Following their absorption, most organophosphorus compounds are excreted almost entirely as hydrolysis products in the urine. Plasma and liver esterases are responsible for hydrolysis to the corresponding phosphoric and phosphonic acids. However, the cytochrome P450s are responsible for converting the inactive phosphorothioates containing a phosphorus-sulfur (thiono) bond to phosphorates with a phosphorus-oxygen bond, resulting in their activation. These mixed-function oxidases also play a role in deactivation of certain organophosphorus agents.

The organophosphorus anti-ChE agents are hydrolyzed in the body by two families of enzymes known as the carboxylesterases and the paraoxonases (A-esterases). These enzymes are found in the plasma and liver and scavenge or hydrolyze a large number of organophosphorus compounds (paraoxon, DFP, TEPP, chlorpyrifos, oxon, tabun, sarin) by cleaving the phosphoester, anhydride, PF, or PCN bonds. The paraoxonases are metalloenzymes not related in structure to the cholinesterases and do not appear to form stable intermediates with organophosphates. They are associated with high-density lipoproteins and may prevent oxidation of endogenous lipids (La Du et al., 1999). A genetic polymorphism (Arg192Gln) that governs organophosphate substrate specificity has been found (Furlong et al., 2000). Wide variations in paraoxonase activity exist among animal species. Young animals are deficient in carboxylesterases and paraoxonases, and this may account for age-related toxicities seen in newborn animals and suspected to be a basis for toxicity in human beings (Padilla et al., 2000).

In addition, plasma and hepatic carboxylesterases (aliesterases) and plasma butyrylcholinesterase are inhibited irreversibly by organophosphorus compounds (Lockridge and Masson, 2000); their scavenging capacity for the organophosphates can afford partial protection against inhibition of acetylcholinesterase in the nervous system. The carboxylesterases also catalyze hydrolysis of malathion and other organophosphorus compounds that contain carboxyl-ester linkages, rendering them less active or inactive. Since carboxylesterases are inhibited by organophosphates, toxicity from exposure to two organophosphorus insecticides can be synergistic.

Toxicology

The toxicological aspects of the anti-ChE agents are of practical importance to the physician. In addition to numerous cases of accidental intoxication from the use and manufacture of organophosphorus compounds as agricultural insecticides (over 40 have been approved for use in the United States), these agents have been used frequently for homicidal and suicidal purposes, largely because of their accessibility. Organophosphorus agents account for as much as 80% of pesticide-related hospital admissions. The World Health Organization documents pesticide toxicity as a widespread global problem; most poisonings occur in developing countries (Bardin et al., 1994; Landrigan et al., 2000). Occupational exposure occurs most commonly by the dermal and pulmonary routes, while oral ingestion is most common in cases of nonoccupational poisoning.

In the United States, the Environmental Protection Agency (EPA), by virtue of revised risk assessments and the Food Quality Protection Act of 1996, has placed several organophosphate insecticides on restricted use or phase-out status in consumer products for home and garden use. A primary concern relates to children, since the developing nervous system may be particularly susceptible to certain of these agents. The Office of Pesticide Programs of the EPA provides continuous reviews of the status of organophosphate pesticides, their tolerance reassessments, and revisions of risk assessments through their web site (https://www.epa.gov/pesticides/op/). Public comment is sought prior to decisions on revisions.

Acute Intoxication

The effects of acute intoxication by anti-ChE agents are manifested by muscarinic and nicotinic signs and symptoms and, except for compounds of extremely low lipid solubility, by signs referable to the CNS. Systemic effects appear within minutes after inhalation of vapors or aerosols. In contrast, the onset of symptoms is delayed after gastrointestinal and percutaneous absorption. The duration of effects is determined largely by the properties of the compound: its lipid solubility, whether or not it must be activated to form the oxon, the stability of the organophosphorus-AChE bond, and whether or not 'aging' of the phosphorylated enzyme has occurred.

After local exposure to vapors or aerosols or after their inhalation, ocular and respiratory effects generally appear first. Ocular effects include marked miosis, ocular pain, conjunctival congestion, diminished vision, ciliary spasm, and brow ache. With acute systemic absorption, miosis may not be evident due to sympathetic discharge in response to hypotension. In addition to rhinorrhea and hyperemia of the upper respiratory tract, respiratory effects consist of 'tightness' in the chest and wheezing respiration, caused by the combination of bronchoconstriction and increased bronchial secretion. Gastrointestinal symptoms occur earliest after ingestion, and include anorexia, nausea and vomiting, abdominal cramps, and diarrhea. With percutaneous absorption of liquid, localized sweating and muscle fasciculations in the immediate vicinity are generally the earliest manifestations. Severe intoxication is manifested by extreme salivation, involuntary defecation and urination, sweating, lacrimation, penile erection, bradycardia, and hypotension.

Nicotinic actions at the neuromuscular junctions of skeletal muscle usually consist of fatigability and generalized weakness, involuntary twitchings, scattered fasciculations, and eventually severe weakness and paralysis. The most serious consequence is paralysis of the respiratory muscles.

The broad spectrum of effects on the CNS includes confusion, ataxia, slurred speech, loss of reflexes, Cheyne–Stokes respiration, generalized convulsions, coma, and central respiratory paralysis. Actions on the vasomotor and other cardiovascular centers in the medulla oblongata lead to hypotension.

The time of death after a single acute exposure may range from less than 5 minutes to nearly 24 hours, depending upon the dose, route, agent, and other factors. The cause of death primarily is respiratory failure, usually accompanied by a secondary cardiovascular component. Peripheral muscarinic and nicotinic as well as central actions all contribute to respiratory embarrassment; effects include laryngospasm, bronchoconstriction, increased tracheobronchial and salivary secretions, compromised voluntary control of the diaphragm and intercostal muscles, and central respiratory depression. Blood pressure may fall to alarmingly low levels and cardiac irregularities intervene. These effects usually result from hypoxemia; they often are reversed by assisted pulmonary ventilation.

Delayed symptoms appearing after one to four days and marked by persistent low blood cholinesterase and severe muscle weakness are termed the intermediate syndrome (Marrs, 1993; DeBleecker et al., 1992, 1995). A delayed neurotoxicity also may be evident after severe intoxication (see below).

Diagnosis and Treatment

The diagnosis of severe, acute anti-ChE intoxication is made readily from the history of exposure and the characteristic signs and symptoms. In suspected cases of milder acute or chronic intoxication, determination of the ChE activities in erythrocytes and plasma generally will establish the diagnosis (Storm et al., 2000). Although these values vary considerably in the normal population, they usually will be depressed well below the normal range before symptoms are evident.

Treatment is both specific and effective. Atropine in sufficient dosage (see below) effectively antagonizes the actions at muscarinic receptor sites, including increased tracheobronchial and salivary secretion, bronchoconstriction, bradycardia, and, to a moderate extent, peripheral ganglionic and central actions. Larger doses are required to get appreciable concentrations of atropine into the CNS. Atropine is virtually without effect against the peripheral neuromuscular compromise. The last-mentioned action of the anti-ChE agents as well as all other peripheral effects can be reversed by pralidoxime (2-PAM), a cholinesterase reactivator.

In moderate or severe intoxication with an organophosphorus anti-ChE agent, the recommended adult dose of pralidoxime is 1 to 2 g, infused intravenously within not less than 5 minutes. If weakness is not relieved or if it recurs after 20 to 60 minutes, the dose may be repeated. Early treatment is very important to assure that the oxime reaches the phosphorylated AChE while the latter still can be reactivated. Many of the alkylphosphates are extremely lipid-soluble, and if extensive partitioning into body fat has occurred, toxicity will persist and symptoms may recur after initial treatment. In some cases it has been necessary to continue treatment with atropine and pralidoxime for several weeks.

In addition, general supportive measures are important. These include (1) termination of exposure, by removal of the patient or application of a gas mask if the atmosphere remains contaminated, removal and destruction of contaminated clothing, copious washing of contaminated skin or mucous membranes with water, or gastric lavage; (2) maintenance of a patent airway, including endobronchial aspiration; (3) artificial respiration if required; (4) administration of oxygen; (5) alleviation of persistent convulsions with diazepam (5 to 10 mg, intravenously); and (6) treatment of shock (Marrs, 1993; Bardin et al., 1994).

Atropine should be given in doses sufficient to cross the blood–brain barrier. Following an initial injection of 2 to 4 mg, given intravenously if possible, otherwise intramuscularly, 2 mg should be given every 5 to 10 minutes until muscarinic symptoms disappear, if they reappear, or until signs of atropine toxicity appear. More than 200 mg may be required on the first day. A mild degree of atropine block then should be maintained for up to 48 hours or as long as symptoms are evident. Whereas the AChE reactivators can be of great benefit in the therapy of anti-ChE intoxication (see below), their use must be regarded as a supplement to the administration of atropine.

Cholinesterase Reactivators

Although the phosphorylated esteratic site of AChE undergoes hydrolytic regeneration at a slow or negligible rate, Wilson (1951) found that nucleophilic agents, such as hydroxylamine (NH2OH), hydroxamic acids (RCONH—OH), and oximes (RCH=NOH), reactivate the enzyme more rapidly than does spontaneous hydrolysis. He reasoned that selective reactivation could be achieved by a site-directed nucleophile, wherein interaction of a quaternary nitrogen with the negative subsite of the active center would place the nucleophile in close apposition to the phosphorus. This goal was achieved to a remarkable degree by Wilson and Ginsburg with pyridine-2-aldoxime methyl chloride (pralidoxime; see Figure 8–2L and below); reactivation with this compound occurs at a million times the rate of that with hydroxylamine. The oxime is oriented proximally to exert a nucleophilic attack on the phosphorus; a phosphoryloxime is formed, leaving the regenerated enzyme (Wilson, 1959).

Several bis-quaternary oximes were shown subsequently to be even more potent as reactivators for insecticide and nerve gas poisoning (see below); an example is HI-6, which is used in Europe as an antidote. The structures of pralidoxime and HI-6 are as follows:

The velocity of reactivation of phosphorylated AChE by oximes depends on their accessibility to the active center serine (Wong et al., 2000). Furthermore, certain phosphorylated AChEs can undergo a fairly rapid process of 'aging,' so that within the course of minutes or hours they become completely resistant to the reactivators. 'Aging' probably is due to the loss of one alkoxy group, leaving a much more stable monoalkyl- or monoalkoxy-phosphoryl-AChE (Fleisher and Harris, 1965; see Figure 8–2K). Organophosphorus compounds containing tertiary alkoxy groups are more prone to 'aging' than are the congeners containing the secondary or primary alkoxy groups (Aldridge, 1976). The oximes are not effective in antagonizing the toxicity of the more rapidly hydrolyzing carbamoyl ester inhibitors, and since pralidoxime itself has weak anti-ChE activity, they are not recommended for the treatment of overdosage with neostigmine or physostigmine and are contraindicated in poisoning with carbamoylating insecticides such as carbaryl.

Pharmacology, Toxicology, and Disposition

The reactivating action of oximes in vivo is most marked at the skeletal neuromuscular junction. Following a dose of an organophosphorus compound that produces total blockade of transmission, the intravenous injection of an oxime can restore the response to stimulation of the motor nerve within a few minutes. Antidotal effects are less striking at autonomic effector sites, and the quaternary ammonium group restricts entry into the CNS.

High doses of pralidoxime and related compounds can in themselves cause neuromuscular blockade and inhibition of AChE; such actions are minimal at the dose rates recommended as an antidote. If pralidoxime is injected intravenously at a rate more rapid than 500 mg per minute, it can cause mild weakness, blurred vision, diplopia, dizziness, headache, nausea, and tachycardia.

The oximes as a group are metabolized largely by the liver, and the breakdown products are excreted by the kidney.

Delayed Neurotoxicity of Organophosphorus Compounds

Certain fluorine-containing alkylorganophosphorus anti-ChE agents (e.g., DFP, mipafox) have in common with the triarylphosphates, of which triorthocresylphosphate (TOCP) is the classical example, the property of inducing delayed neurotoxicity. This syndrome first received widespread attention following the demonstration that TOCP, an adulterant of Jamaica ginger, was responsible for an outbreak of thousands of cases of paralysis that occurred in the United States during Prohibition.

The clinical picture is that of a severe polyneuropathy that begins several days after a single exposure to the toxic compound. It is manifested initially by mild sensory disturbances, ataxia, weakness, muscle fatigue and twitching, reduced tendon reflexes, and tenderness to palpation. In severe cases, the weakness may progress eventually to complete flaccid paralysis, which, over the course of weeks or months, is often succeeded by a spastic paralysis with a concomitant exaggeration of reflexes. During these phases, the muscles show marked wasting. Recovery may require several years and may be incomplete.

Because only certain triarylphosphates and fluorine-containing alkylphosphates have the greatest propensity to produce the organophosphate-induced delayed polyneuropathy (OPIDR), toxicity is not dependent upon inhibition of AChE or other cholinesterases. Evidence points to inhibition of a different esterase, termed a neurotoxic esterase, as being linked to the lesions (Johnson, 1993). The enzyme has been isolated and its gene cloned. Its substrate specificity is directed to hydrophobic esters, but its natural substrate and function are unknown (Glynn, 2000). Experimental myopathies that result in generalized necrotic lesions and changes in end-plate cytostructure also are found after long-term exposure to organophosphates (Dettbarn, 1984; DeBleeker et al., 1992).

Therapeutic Uses

Although anti-ChE agents have been recommended for the treatment of a wide variety of conditions involving the peripheral nervous system, their widespread acceptability has been established mainly in four areas: atony of the smooth muscle of the intestinal tract and urinary bladder, glaucoma, myasthenia gravis, and termination of the effects of competitive neuromuscular blocking drugs (see Chapter 9: Agents Acting at the Neuromuscular Junction and Autonomic Ganglia). Long-acting and hydrophobic cholinesterase inhibitors are the only inhibitors with efficacy, albeit limited, in the treatment of dementia symptoms of Alzheimer's disease. Physostigmine, with its shorter duration of action, is useful in the treatment of intoxication by atropine and several drugs with anticholinergic side effects (see below); it also is indicated for the treatment of Friedreich's or other inherited ataxias. Edrophonium can be used for terminating attacks of paroxysmal supraventricular tachycardia.

Available Therapeutic Agents

The compounds described here are those commonly used as anti-ChE drugs and cholinesterase reactivators in the United States. Preparations used solely for ophthalmic purposes are described in Chapter 66: Ocular Pharmacology. Conventional dosages and routes of administration are given in the discussion of therapeutic applications of these agents (see below).

Physostigmine salicylate ANTILIRIUM) is available for injection. Physostigmine sulfate ophthalmic ointment and physo-stigmine salicylate ophthalmic solution also are available. Pyridostigmine bromide is available for oral (MESTINON) or parenteral (REGONOL, MESTINON) use. Neostigmine bromide (PROSTIGMIN) is available for oral use. Neostigmine methylsulfate (PROSTIGMIN) is marketed for parenteral injection. Ambenonium chloride (MYTELASE) is available for oral use. Edrophonium chloride (TENSILON, others) is marketed for parenteral injection. Tacrine (COGNEX), donepezil (ARICEPT), rivastigmine (EXELON), and galantamine (REMINYL) have been approved for the treatment of Alzheimer's disease.

Pralidoxime chloride PROTOPAM CHLORIDE) is the only AChE reactivator currently available in the United States and can be obtained in a parenteral formulation.

Paralytic Ileus and Atony of the Urinary Bladder

In the treatment of both these conditions, neostigmine generally is the most satisfactory of the anti-ChE agents. The direct parasympathomimetic agents, discussed in Chapter 7: Muscarinic Receptor Agonists and Antagonists, are employed for the same purposes.

Neostigmine is used for the relief of abdominal distension and acute colonic pseudoobstruction from a variety of medical and surgical causes (Ponec et al., 1999). The usual subcutaneous dose of neostigmine methylsulfate for postoperative paralytic ileus is 0.5 mg, given as needed. Peristaltic activity commences 10 to 30 minutes after parenteral administration, whereas 2 to 4 hours are required after oral administration of neostigmine bromide (15 to 30 mg). A rectal tube should be inserted to facilitate expulsion of gas, and it may be necessary to assist evacuation with a small low enema. The drug should not be used when the intestine or urinary bladder is obstructed, when peritonitis is present, when the viability of the bowel is doubtful, or when bowel dysfunction is a consequence of inflammatory disease.

When neostigmine is used for the treatment of atony of the detrusor muscle of the urinary bladder, postoperative dysuria is relieved, and the time interval between operation and spontaneous urination is shortened. The drug is used in a similar dose and manner as in the management of paralytic ileus.

Glaucoma and Other Ophthalmologic Indications

Glaucoma is a disease complex characterized chiefly by an increase in intraocular pressure that, if sufficiently high and persistent, leads to damage to the optic disc at the juncture of the optic nerve and the retina; irreversible blindness can result. Of the three types of glaucoma—primary, secondary, and congenital—anti-ChE agents are of value in the management of the primary as well as of certain categories of the secondary type (e.g., aphakic glaucoma, following cataract extraction); the congenital type rarely responds to any therapy other than surgery. Primary glaucoma is subdivided into narrow-angle (acute congestive) and wide-angle (chronic simple) types, based on the configuration of the angle of the anterior chamber where reabsorption of the aqueous humor occurs.

Narrow-angle glaucoma is nearly always a medical emergency in which drugs are essential in controlling the acute attack, but the long-range management is often surgical (e.g., peripheral or complete iridectomy). Wide-angle glaucoma, on the other hand, has a gradual, insidious onset and is not generally amenable to surgical improvement; in this type, control of intraocular pressure usually is dependent upon continuous drug therapy.

Since the cholinergic agonists and cholinesterase inhibitors also block accommodation and induce myopia, these agents produce transient blurring of far vision and loss of vision at the margin when instilled in the eye. With long-term administration of the cholinergic agonists and anti-ChE agents, the compromise of vision diminishes. Nevertheless, other agents without these side effects, such as -adrenergic receptor antagonists, prostaglandin analogs, or carbonic anhydrase inhibitors, have become the primary topical therapies for open angle glaucoma (Alward, 1998; see Chapter 66: Ocular Pharmacology). Topical treatment with long-acting cholinesterase inhibitors such as echothiophate gives rise to symptoms characteristic of systemic cholinesterase inhibition. Echothiophate treatment in advanced glaucoma may be associated with the production of cataracts (Alward, 1998).

Anti-ChE agents have been employed locally in the treatment of a variety of other ophthalmologic conditions, including accommodative esotropia and myasthenia gravis confined to the extraocular and eyelid muscles. Adie (or tonic pupil) syndrome results from dysfunction of the ciliary body, perhaps because of local nerve degeneration. Low concentrations of physostigmine are reported to decrease the blurred vision and pain associated with this condition. In alternation with a mydriatic drug such as atropine, short-acting anti-ChE agents have proven useful for the breaking of adhesions between the iris and the lens or cornea. (For a complete account of the use of anti-ChE agents in ocular therapy, see Chapter 66: Ocular Pharmacology.)

Myasthenia Gravis

Myasthenia gravis is a neuromuscular disease characterized by weakness and marked fatigability of skeletal muscle (see Drachman, 1994); exacerbations and partial remissions occur frequently. Jolly (1895) noted the similarity between the symptoms of myasthenia gravis and curare poisoning in animals and suggested that physostigmine, an agent then known to antagonize curare, might be of therapeutic value. Forty years elapsed before his suggestion was given systematic trial (Walker, 1934).

The defect in myasthenia gravis is in synaptic transmission at the neuromuscular junction. When a motor nerve of a normal subject is stimulated at 25 Hz, electrical and mechanical responses are well sustained. A suitable margin of safety exists for maintenance of neuromuscular transmission. Initial responses in the myasthenic patient may be normal, but they diminish rapidly, which explains the difficulty in maintaining voluntary muscle activity for more than brief periods.

The relative importance of prejunctional and postjunctional defects in myasthenia gravis was a matter of considerable debate until Patrick and Lindstrom (1973) found that rabbits immunized with the nicotinic receptor purified from electric eels slowly developed muscular weakness and respiratory difficulties that resembled the symptoms of myasthenia gravis. The rabbits also exhibited decremental responses following repetitive nerve stimulation, enhanced sensitivity to curare, and symptomatic and electrophysiological improvement of neuromuscular transmission following administration of anti-ChE agents. Although this experimental allergic myasthenia gravis and the naturally occurring disease differ somewhat, this animal model prompted intense investigation into whether or not the natural disease represented an autoimmune response directed toward the ACh receptor. Antireceptor antibody soon was identified in patients with myasthenia gravis (Almon et al., 1974). Receptor-binding antibodies now are detectable in sera of 90% of patients with the disease, although the clinical status of the patient does not correlate precisely with the antibody titer (Drachman et al., 1982; Drachman, 1994; Lindstrom, 2000).

The picture that emerges is that myasthenia gravis is caused by an autoimmune response primarily to the ACh receptor at the postjunctional end-plate. Antibodies, which also are present in plasma, reduce the number of receptors detectable either by snake -neurotoxin-binding assays (Fambrough et al., 1973) or by electrophysiological measurements of ACh sensitivity (Drachman, 1994). The autoimmune reaction enhances receptor degradation (Drachman et al., 1982). Immune complexes along with marked ultrastructural abnormalities appear in the synaptic cleft. The latter appear to be a consequence of complement-mediated lysis of junctional folds in the end-plate. A related disease that also compromises neuromuscular transmission is Lambert–Eaton syndrome. Here, antibodies are directed against Ca2+ channels that are necessary for presynaptic release of ACh (Lang et al., 1998).

In a subset of approximately 10% of patients presenting with a myasthenic syndrome, muscle weakness has a congenital rather than an autoimmune basis. Characterization of biochemical and genetic bases of the congenital condition has shown mutations to occur in the acetylcholine receptor which affect ligand-binding and channel-opening kinetics (Engel et al., 1998). Other mutations occur as a deficiency in the form of acetylcholinesterase that contains the collagen-like tail unit (Ohno et al., 2000). As expected, following administration of anti-ChE agents (see below), subjective improvement is not seen in most congenital myasthenic patients.

Diagnosis

Although the diagnosis of autoimmune myasthenia gravis usually can be made from the history, signs, and symptoms, its differentiation from certain neurasthenic, infectious, endocrine, congenital, neoplastic, and degenerative neuromuscular diseases is challenging. However, myasthenia gravis is the only condition in which the aforementioned deficiencies can be improved dramatically by anti-ChE medication. The edrophonium test for evaluation of possible myasthenia gravis is performed by rapid intravenous injection of 2 mg of edrophonium chloride, followed 45 seconds later by an additional 8 mg if the first dose is without effect; a positive response consists of brief improvement in strength, unaccompanied by lingual fasciculation (which generally occurs in nonmyasthenic patients).

An excessive dose of an anti-ChE drug results in a cholinergic crisis. The condition is characterized by weakness resulting from generalized depolarization of the motor end-plate; other features result from overstimulation of muscarinic receptors. The weakness resulting from depolarization block may resemble myasthenic weakness, which is manifest when anti-ChE medication is insufficient. The distinction is of obvious practical importance, since the former is treated by withholding, and the latter by administering, the anti-ChE agent. When the edrophonium test is performed cautiously, limiting the dose to 2 mg and with facilities for respiratory resuscitation immediately available, a further decrease in strength indicates cholinergic crisis, while improvement signifies myasthenic weakness. Atropine sulfate, 0.4 to 0.6 mg or more intravenously, should be given immediately if a severe muscarinic reaction ensues (for complete details, see Osserman et al., 1972; Drachman, 1994). Detection of antireceptor antibodies in muscle biopsies or plasma is now widely employed to confirm the diagnosis.

Treatment

Pyridostigmine, neostigmine, and ambenonium are the standard anti-ChE drugs used in the symptomatic treatment of myasthenia gravis. All can increase the response of myasthenic muscle to repetitive nerve impulses, primarily by the preservation of endogenous ACh; with equivalent release of ACh, receptors over a greater cross-sectional area of the end-plate then presumably are exposed to concentrations of ACh that are sufficient for channel opening and production of a postsynaptic end-plate potential.

When the diagnosis of myasthenia gravis has been established, the optimal single oral dose of an anti-ChE agent can be determined empirically. Baseline recordings are made for grip strength, vital capacity, and a number of signs and symptoms that reflect the strength of various muscle groups. The patient then is given an oral dose of pyridostigmine (30 to 60 mg), neostigmine (7.5 to 15 mg), or ambenonium (2.5 to 5 mg). The improvement in muscle strength and changes in other signs and symptoms are noted at frequent intervals until there is a return to the basal state. After an hour or longer in the basal state, the drug is given again with the dose increased to one and one-half times the initial amount, and the same observations are repeated. This sequence is continued, with increasing increments of one-half the initial dose, until an optimal response is obtained.

The duration of action of these drugs is such that the interval between oral doses required to maintain a reasonably even level of strength usually is 2 to 4 hours for neostigmine, 3 to 6 hours for pyridostigmine, or 3 to 8 hours for ambenonium. However, the dose required may vary from day to day, and physical or emotional stress, intercurrent infections, and menstruation usually necessitate an increase in the frequency or size of the dose. In addition, unpredictable exacerbations and remissions of the myasthenic state may require adjustment of the dosage upward or downward. Although all patients with myasthenia gravis should be seen by a physician at regular intervals, most can be taught to modify their dosage regimens according to their changing requirements. Pyridostigmine is available in sustained-release tablets containing a total of 180 mg, of which 60 mg is released immediately and 120 mg over several hours; this preparation is of value in maintaining patients for 6- to 8-hour periods, but should be limited to use at bedtime. Muscarinic cardiovascular and gastrointestinal side effects of anti-ChE agents generally can be controlled by atropine or other anticholinergic drugs (see Chapter 7: Muscarinic Receptor Agonists and Antagonists). However, these anticholinergic drugs mask many side effects of an excessive dose of an anticholinesterase agent. In most patients, tolerance develops eventually to the muscarinic effects, so that anticholinergic medication is not necessary. A number of drugs, including curariform agents and certain antibiotics and general anesthetics, interfere with neuromuscular transmission (see Chapter 9: Agents Acting at the Neuromuscular Junction and Autonomic Ganglia); their administration to patients with myasthenia gravis is hazardous without proper adjustment of anti-ChE dosage and other appropriate precautions.

Other therapeutic measures should be considered as essential elements in the management of this disease. Controlled studies reveal that corticosteroids promote clinical improvement in a high percentage of patients. However, when treatment with steroids is continued over prolonged periods, a high incidence of side effects may result (see Chapter 60: Adrenocorticotropic Hormone; Adrenocortical Steroids and Their Synthetic Analogs; Inhibitors of the Synthesis and Actions of Adrenocortical Hormones). Gradual lowering of maintenance doses and alternate-day regimens of short-acting steroids are used to minimize side effects. Initiation of steroid treatment augments muscle weakness; however, as the patient improves with continued administration of steroids, doses of anti-ChE drugs can be reduced (Drachman, 1994). Other immunosuppressive agents such as azathioprine and cyclosporine also have been beneficial in more advanced cases.

Thymectomy should be considered in myasthenia associated with a thymoma or when the disease is not controlled adequately by anti-ChE agents and steroids. The relative risks and benefits of the surgical procedure versus anti-ChE and corticosteroid treatment require careful assessment in each case. Since the thymus contains myoid cells with nicotinic receptors (Schluep et al., 1987) and a predominance of patients have thymic abnormalities, the thymus may be responsible for the initial pathogenesis. It also is the source of autoreactive T helper cells. However, the thymus is not required for perpetuation of the condition.

In keeping with the presumed autoimmune etiology of myasthenia gravis, plasmapheresis and immune therapy have produced beneficial results in patients who have remained disabled despite thymectomy and treatment with steroids and anti-ChE agents (Drachman, 1994, 1996). Improvement in muscle strength correlates with the reduction of the titer of antibody directed against the nicotinic cholinergic receptor.

Prophylaxis in Cholinesterase Inhibitor Poisoning

Studies in experimental animals have shown that pretreatment with pyridostigmine reduces the incapacitation and mortality associated with 'nerve agent' poisoning, particularly for agents, such as soman, that show rapid aging. The first large-scale administration of pyridostigmine to human beings occurred in 1990 in anticipation of nerve-agent attack in the Persian Gulf. At an oral dose of 30 mg every 8 hours, the incidence of side effects was around 1%, but fewer than 0.1% of the subjects had responses sufficient to warrant discontinuing the drug in the setting of military action (Keeler et al., 1991). Long-term follow-up indicates that veterans of the Persian Gulf Campaign that had received pyridostigmine showed a low incidence of a neurologic syndrome, now termed the Persian Gulf War syndrome. It is characterized by impaired cognition, ataxia, confusion, myoneuropathy, adenopathy, weakness, and incontinence (Haley et al., 1997; The Iowa Persian Gulf Study Group, 1997). While pyridostigmine has been implicated by some as the causative agent, the absence of similar neuropathies in pyridostigmine-treated myasthenic patients makes it far more likely that a combination of agents, including combusted organophosphates and insect repellents in addition to pyridostigmine, contributed to this persisting syndrome. It also is difficult to distinguish residual chemical toxicity from posttraumatic stress experienced after combat action.

Intoxication by Anticholinergic Drugs

In addition to atropine and other muscarinic agents, many other drugs, such as the phenothiazines, antihistamines, and tricyclic antidepressants, have central as well as peripheral anticholinergic activity. Physostigmine is potentially useful in reversing the central anticholinergic syndrome produced by overdosage or an unusual reaction to these drugs (Nilsson, 1982). The effectiveness of physostigmine in reversing the anticholinergic effects of these agents has been clearly documented. However, other toxic effects of the tricyclic antidepressants and phenothiazines (see Chapters 19: Drugs and the Treatment of Psychiatric Disorders: Depression and Anxiety Disorders and 20: Drugs and the Treatment of Psychiatric Disorders: Psychosis and Mania), such as intraventricular conduction deficits and ventricular arrhythmias, are not reversed by physostigmine. In addition, physostigmine may precipitate seizures; hence, its usually small potential benefit must be weighed against this risk. The initial intravenous or intramuscular dose of physostigmine is 2 mg, with additional doses given as necessary. Physostigmine, a tertiary amine, crosses the blood–brain barrier, in contrast to the quaternary anti-AChE drugs. The use of anti-ChE agents to reverse the effects of competitive neuromuscular blocking agents is discussed in Chapter 9: Agents Acting at the Neuromuscular Junction and Autonomic Ganglia.

Alzheimer's Disease

A deficiency of intact cholinergic neurons, particularly those extending from subcortical areas such as the nucleus basalis of Maynert, has been observed in patients with progressive dementia of the Alzheimer's type (Markesbery, 1998). Using a rationale similar to that in other CNS degenerative diseases (see Chapter 22: Treatment of Central Nervous System Degenerative Disorders), therapy for enhancing concentrations of cholinergic neurotransmitters in the central nervous system was investigated (Mayeux and Sano, 1999). In 1993, the FDA approved tacrine (tetrahydroaminoacridine) for use in mild to moderate Alzheimer's disease, but a high incidence of hepatotoxicity and frequent liver function tests limit the efficacy of this drug. About 30% of the patients receiving low doses of tacrine within three months have alanine aminotransferase values of three times normal; upon discontinuing the drug, liver function values return to normal in 90% of the patients. Other side effects are typical of acetylcholinesterase inhibitors.

More recently, donepezil was approved for clinical use. There are efficacy data from multiple trials, most involving several hundred patients (Dooley and Lamb, 2000). At 5- and 10-mg daily oral doses, improved cognition and global clinical function were seen in the 21- to 81-week intervals studied. In long-term studies, the drug delayed symptomatic progression of the disease for periods up to 55 weeks. Side effects are largely attributable to excessive cholinergic stimulation, with nausea, diarrhea, and vomiting being most frequently reported. The drug is well tolerated in single daily doses. Usually, 5-mg doses are administered at night for 4 to 6 weeks; if this dose is well tolerated, the dose can be increased to 10 mg daily.

Rivastigmine, a long-acting carbamoylating inhibitor, recently has been approved for use in the United States and Europe. Although fewer studies have been conducted with it, the drug's efficacy, tolerability, and side effects are similar to those of donepezil (Corey-Bloom et al., 1998; Giacobini, 2000). Eptastigmine, also a carbamoylating inhibitor, was associated with adverse hematologic effects in two studies, resulting in suspension of clinical trials. Galantamine is another AChE inhibitor recently approved by the FDA for treating Alzheimer's disease. It has a side-effect profile similar to those of donepezil and rivastigmine.

Therapeutic strategies with new compounds are directed at maximizing the ratio of central to peripheral cholinesterase inhibition and the use of cholinesterase inhibitors in conjunction with selective cholinergic agonists and antagonists. Combination therapy with agents that are directed to slowing the progression of the degenerative disease also are being considered.

Chapter 9. Agents Acting at the Neuromuscular Junction and Autonomic Ganglia

Overview

The nicotinic acetylcholine receptor mediates neurotransmission at the neuromuscular junction and peripheral autonomic ganglia; in the central nervous system, it largely controls release of neurotransmitters from presynaptic sites. This chapter focuses on agonists and antagonists at the nicotinic acetylcholine receptor and their clinical utility at the neuromuscular junction or autonomic ganglia. The text begins with an overview of current structural and functional insights regarding the nicotinic acetylcholine receptor and its subtypes. A variety of neuromuscular blocking agents with varying mechanisms of blockade and pharmacokinetic properties are used to produce muscle relaxation during anesthesia (see also Chapter 14: General Anesthetics). Nicotine transiently stimulates nicotinic receptors on ganglia but is best known for its addictive properties arising from its presynaptic actions influencing neurotransmitter release in the brain (see Chapter 24: Drug Addiction and Drug Abuse). The use of ganglionic blocking agents for management of hypertension has been eclipsed by superior agents (see Chapter 33: Antihypertensive Agents and the Drug Therapy of Hypertension), although these agents are sometimes useful alternatives when other agents fail to control blood pressure in life-threatening circumstances (e.g., in the case of an acute dissecting aortic aneurysm) and in surgery where controlled hypotension is indicated.

Agents Acting at the Neuromuscular Junction and Autonomic Ganglia: Introduction

Several drugs have as their major action the interruption or mimicry of transmission of the nerve impulse at the neuromuscular junction of skeletal muscle and/or autonomic ganglia. These agents can be classified together, since they interact with a common family of receptors; these receptors are called nicotinic acetylcholine (also commonly called nicotinic cholinergic) receptors, since they are stimulated by both the neurotransmitter acetylcholine (ACh) and the alkaloid nicotine. Distinct subtypes of nicotinic receptors exist at the neuromuscular junction and the ganglia, and several pharmacological agents that act at these receptors discriminate between them. Neuromuscular blocking agents are distinguished by whether or not they cause depolarization of the motor end plate and, for this reason, are classified either as competitive (stabilizing) agents, of which curare is the classical example, or as depolarizing agents, such as succinylcholine. The competitive and depolarizing agents are used widely to achieve muscle relaxation during anesthesia. Ganglionic agents act by stimulating or blocking nicotinic receptors on the postganglionic neuron.

The Nicotinic Acetylcholine Receptor

The concept of the nicotinic acetylcholine receptor, with which ACh combines to initiate the end-plate potential (EPP) in muscle or an excitatory postsynaptic potential (EPSP) in nerve, is introduced in Chapter 6: Neurotransmission: The Autonomic and Somatic Motor Nervous Systems. Classical studies of the actions of curare and nicotine made this the prototypical pharmacological receptor over a century ago. By taking advantage of specialized structures that have evolved to mediate or block cholinergic neurotransmission, peripheral and then central nicotinic receptors have been isolated and characterized over the last 30 years. These accomplishments represent landmarks in the development of molecular pharmacology.

The electric organs from the aquatic species of Electrophorus and, especially, Torpedo provide rich sources of nicotinic receptor. The electric organ is derived embryologically from myoid tissue; however, in contrast to skeletal muscle, a significant fraction (30% to 40%) of the surface of the membrane is excitable and contains cholinergic receptors. In vertebrate skeletal muscle, motor end plates occupy 0.1% or less of the cell surface. The discovery of seemingly irreversible antagonism of neuromuscular transmission by toxins from venoms of the krait, Bungarus multicinctus (Chang and Lee, 1963), or varieties of the cobra, Naja naja, offered suitable markers for identification of the receptor. The toxins are peptides of about 7000 daltons molecular mass. The interaction of radioisotope-labeled toxins with the receptor initially was applied to an assay for identification of the isolated cholinergic receptor in vitro by Changeux and colleagues in 1970 (see Changeux and Edelstein, 1998). The toxins have extremely high affinities and slow rates of dissociation from the receptor, yet the interaction is noncovalent. In situ and in vitro their behavior resembles that expected for a high-affinity antagonist. Since cholinergic neurotransmission mediates motor activity in marine vertebrates and mammals, a large number of peptide, terpinoid, and alkaloid toxins that block the nicotinic receptors have evolved to enhance predation or protect plant and animal species from predation (Taylor et al., 2000).

Purification of the receptor from Torpedo ultimately led to the isolation of complementary DNAs (cDNAs) that encode each of the subunits. These cDNAs, in turn, have permitted the cloning of genes encoding the multiple receptor subunits from mammalian neurons and muscle (Numa et al., 1983). By simultaneously expressing the genes that encode the individual subunits in cellular systems in various permutations and by measuring binding and the electrophysiological events that result from activation by agonists, researchers have been able to correlate functional properties with details of primary structures of the receptor subtypes (Lindstrom, 2000; Karlin and Akabas, 1995; Paterson and Nordberg, 2000).

Nicotinic Receptor Structure

The nicotinic receptor of the electric organ and vertebrate skeletal muscle is a pentamer composed of four distinct subunits ( ) in the stoichiometric ratio of 2:1:1:1, respectively. In mature innervated muscle end plates, the subunit is replaced by , a closely related subunit. The individual subunits are about 40% identical in their amino acid sequences, suggesting that they arose from a common primordial gene (Numa et al., 1983).

The nicotinic receptor has become the prototype for other ligand-gated ion channels, which include the receptors for the inhibitory amino acids (gamma-aminobutyric acid and glycine) and certain serotonin (5-HT3) receptors. The family of ligand-gated ion channels are pentamers of homologous subunits, each having a molecular mass of 40,000 to 60,000 daltons. The amino-terminal 210 residues constitute virtually all of the extracellular domain. This is followed by four transmembrane-spanning domains, with the region between the third and fourth domain forming most of the cytoplasmic component (Figure 9–1).

Figure 9–1. Molecular Structure of the Nicotinic Acetylcholine Receptor. The Structure of the Receptor is Described in the Text. A. Longitudinal view with the subunit removed. The remaining subunits, two copies of , one of , and one of , are shown to surround an internal channel with an outer vestibule and its constriction located deep in the membrane bilayer region. Spans of -helices with slightly bowed structures form the perimeter of the channel and come from the M2 region of the linear sequence (see panel D). Acetylcholine binding sites, indicated by arrows, are found at the and (not visible) interfaces. Panels B and C show data on which the structure is based. Panel D presents the sequence similarities in ligand-gated ion channel receptors. B. Longitudinal view of the electron density of receptor molecules packed in a tubular membrane. Arrows indicate the synaptic surface entry to the pore and agonist site. The additional density in the cytoplasmic region below the receptor arises from an anchoring protein attached to the receptor. C. Cross-sectional view of the image reconstructed electron density taken 30 Å above the plane of the membrane. Pseudo-fivefold symmetry is evident. The arrows denote the presumed route of entry of the ligand (ACh) to the binding site shown by the star. 1 and 2 in this panel are identical in sequence; the numeric designations show that there are two copies of the -subunit in the pentamer. D. For each receptor the amino terminal region of about 210 amino acids is found in the extracellular surface. It is then followed by four hydrophobic regions that span the membrane (M1–M4), leaving the small carboxyl-terminus on the extracellular surface. The M2 region is -helical, and M2 regions from each subunit of the pentameric receptor line the internal pore of the receptor. Two disulfide loops at positions 128–142 and 192–193 are found in the -subunit of the nicotinic receptor. The 128–142 motif is conserved in the family of receptors, while the vicinal cysteines at 192 and 193 distinguish subunits from , and in the nicotinic receptor. (Adapted from Unwin, 1993, with permission.)

Each of the subunits within the nicotinic acetylcholine receptor has an extracellular and an intracellular exposure on the postsynaptic membrane. The five subunits are arranged to circumscribe an internally located channel in a fashion similar to petals on a lily (Unwin, 1993; Karlin and Akabas, 1995; Changeux and Edelstein, 1998). The receptor is an asymmetrical molecule (14 nm x 8 nm) of 250,000 daltons, with the bulk of the nonmembrane-spanning domain on the extracellular surface. In junctional areas (i.e., the motor end plate in skeletal muscle and the ventral surface of the electric organ) the receptor is present at high densities (10,000/m2) in a regular packing order. This ordering of the receptors has allowed electron microscopy image reconstruction of its molecular structure at a resolution of 10 Å or less (Unwin, 1993; Miyazawa et al., 1999; see Figure 9–1).

As is the case for other proteins where cooperativity of both binding and functional responses is evident, the binding sites are found at the subunit interfaces, but of the five interfaces, only two in muscle, and , have evolved to bind ligands. The binding of agonists, reversible competitive antagonists, and the elapid toxins is mutually exclusive and appears to involve overlapping surfaces on the receptor. Both subunits forming the subunit interface contribute to ligand specificity (Taylor et al., 2000).

Measurements of membrane conductances demonstrate that rates of ion translocation are sufficiently rapid (5 x 107 ions per second) to require ion translocation through an open channel, rather than by a rotating carrier of ions. Moreover, agonist-mediated changes in ion permeability (typically an inward movement of primarily Na+ and secondarily Ca2+) occur through a cation channel intrinsic to the receptor structure. The second transmembrane-spanning region on each of the five subunits forms the internal perimeter of the channel. The agonist-binding site is intimately coupled with an ion channel; simultaneous binding of two agonist molecules in muscle results in a rapid conformational change that opens the channel. Details on the kinetics of channel opening have evolved from electrophysiological patch–clamp techniques that enable one to distinguish the individual opening and closing events of a single receptor molecule (Sakmann, 1992).

Cloning by sequence homology enabled investigators to identify the genes encoding the nicotinic receptor for higher vertebrates, initially in muscle and then in neurons. Neuronal nicotinic receptors found in ganglia and the central nervous system (CNS) also exist as pentamers of subunits composed of one, two, or more subunits. Although only a single subunit of the type sequence (denoted as 1) is found in abundance in muscle, along with , and or , at least eight subtypes of 2 through 9) and three of the non- type (designated as 2 through 4) are found in neuronal tissues. Although not all permutations of and subunits lead to functional receptors, the diversity in subunit composition is large and exceeds the capacity of ligands to distinguish subtypes on the basis of their selectivity. Distinctive selectivities of the receptor subtypes for Na+ and Ca2+ suggest that certain subtypes may possess functions other than rapid transsynaptic signaling. Several congenital myasthenic syndromes recently have been found to arise from mutations in the muscle receptor subunits, and various manifestations of epilepsy arise from mutations of neuronal receptor subunits (Engel et al., 1998; Lindstrom, 2000).

Neuromuscular Blocking Agents

History, Sources, and Chemistry

Curare is a generic term for various South American arrow poisons. The drug has a long and romantic history. It has been used for centuries by the Indians along the Amazon and Orinoco Rivers for immobilizing and paralyzing wild animals used for food; death results from paralysis of skeletal muscles. The preparation of curare was long shrouded in mystery and was entrusted only to tribal witch doctors. Soon after the discovery of the American continent, Sir Walter Raleigh and other early explorers and botanists became interested in curare, and late in the sixteenth century samples of the native preparations were brought to Europe. Following the pioneering work of the scientist/explorer von Humboldt in 1805, the botanical sources of curare became the object of much field search. The curares from eastern Amazonia come from Strychnos species. These and other South American species of Strychnos examined contain chiefly quaternary neuromuscular blocking alkaloids, whereas the Asiatic, African, and Australian species nearly all contain tertiary, strychnine-like alkaloids.

Curare was the important tool that Claude Bernard used to demonstrate a locus of drug action at or near the nerve terminations of muscle (Bernard, 1856). The modern clinical use of curare apparently dates from 1932, when West employed highly purified fractions in patients with tetanus and spastic disorders.

Research on curare was greatly accelerated by the work of Gill (1940), who, after prolonged and intimate study of the native methods of preparing curare, brought to the United States a sufficient amount of the authentic drug to permit chemical and pharmacological investigations. The first trial of curare for promoting muscular relaxation in general anesthesia was reported by Griffith and Johnson (1942).

Details of the fascinating history of curare, its nomenclature, and the chemical identification of the curare alkaloids are presented in McIntyre, 1947, and Bovet, 1972, and previous editions of this textbook.

The essential structure of tubocurarine was established by King in 1935 (Figure 9–2). A synthetic derivative, metocurine (formerly called dimethyl tubocurarine), contains three additional methyl groups, one of which quaternizes the second nitrogen; the other two form methyl ethers at the phenolic hydroxyl groups. This compound possesses two to three times the potency of tubocurarine in human beings.

Figure 9–2. Structural Formulas of Major Neuromuscular Blocking Agents. (*The Methyl Group Is Absent in Vecuronium.) 

The most potent of all curare alkaloids are the toxiferines, obtained from Strychnos toxifera. A semisynthetic derivative, alcuronium chloride (N,N'-diallylnortoxiferinium dichloride), was in wide use clinically in Europe and elsewhere. The seeds of the trees and shrubs of the genus Erythrina, widely distributed in tropical and subtropical areas, contain erythroidines that possess curare-like activity.

Gallamine is one of a series of synthetic substitutes for curare described by Bovet and coworkers in 1949 (see review by Bovet, 1972). Early structure–activity studies led to the development of the polymethylene bis-trimethylammonium series (referred to as the methonium compounds) (Barlow and Ing, 1948; Paton and Zaimis, 1952). The most potent agent at the neuromuscular junction was found when the chain contained ten carbon atoms [decamethonium (C10), see Figure 9–2]. The member of the series containing six carbon atoms in the chain—hexamethonium (C6)—was found to be essentially devoid of neuromuscular blocking activity but is particularly effective as a ganglionic blocking agent (see below).

In 1949, the curariform action of succinylcholine was described, and its clinical application for relaxation of short duration soon followed (see Dorkins, 1982).

Classification and Chemical Properties of Neuromuscular Blocking Agents

At present, only a single depolarizing agent, succinylcholine, is in general clinical use, whereas multiple competitive or nondepolarizing agents are available (see Figure 9–2). Therapeutic selection should be based on achieving a pharmacokinetic profile consistent with the duration of the interventional procedure and minimizing cardiovascular compromise or other side effects (see Table 9–1). Two general classifications are useful, since they prove helpful in distinguishing side effects and pharmacokinetic behavior. The first relates to the duration of drug action, and these agents are categorized as intermediate-, and short-acting. The persistent blockade and difficulty in complete reversal after surgery with d-tubocurarine, metocurine, pancuronium, and doxacurium led to the development of vecuronium and atracurium, agents of intermediate duration. This was followed by the development of a short-acting agent, mivacurium. Often, the long-acting agents are the more potent, requiring the use of low concentrations. The necessity of administering these agents in low concentrations delays their onset. Rocuronium and rapacuronium are agents of intermediate duration but of rapid onset and lower potency. Their rapid onsets allow them to be used as alternatives to succinylcholine in relaxing the laryngeal and jaw muscles to facilitate tracheal intubation (Bevan, 1994; Savarese et al., 2000).

The second classification is derived from the chemical nature of the agents and includes the natural alkaloids or their congeners, the ammonio steroids, and the benzylisoquinolines (Table 9–1). The natural alkaloid, d-tubocurarine, and semisynthetic alkaloid, alcuronium, while of historical importance, seldom are used. Apart from a shorter duration of action, the newer agents exhibit greatly diminished frequency of side effects, chief of which are ganglionic blockade, block of vagal responses, and histamine release. Metocurine shows diminished histamine release and ganglionic blockade when compared with d-tubocurarine, but it is not devoid of these side effects. The prototype ammonio steroid, pancuronium, shows virtually no histamine release; however, it blocks muscarinic receptors, and this antagonism primarily is manifested in vagal blockade and tachycardia. Tachycardia is eliminated in the newer ammonio steroids: vecuronium, rocuronium, rapacuronium, and pipecuronium.

The benzylisoquinolines appear to be devoid of vagolytic and ganglionic blocking actions but still show a slight propensity for release of histamine. The unusual metabolism of the prototype compound, atracurium, and its newer congener mivacurium confers special indications for use of these compounds. For example, atracurium's disappearance from the body depends on hydrolysis of the ester moiety by plasma esterases and by a spontaneous or Hofmann degradation (cleavage of the N-alkyl portion in the benzylisoquinoline). Hence, two routes for degradation are available, both of which remain functional in renal failure. Mivacurium is extremely sensitive to cholinesterase catalysis, therein accounting for its short duration of action.

Structure–Activity Relationships

Several structural features distinguish competitive and depolarizing neuromuscular blocking agents. The competitive agents are relatively bulky, rigid molecules (e.g., tubocurarine, the toxiferines, the benzylisoquinolines, and the ammonio steroids), whereas the depolarizing agents (e.g., decamethonium, succinylcholine) generally have a more flexible structure that enables free bond rotation (see Figure 9–2; see also Bovet, 1972). While the distance between quaternary groups in the flexible depolarizing agents can vary up to the limit of the maximal bond distance (1.45 nm for decamethonium), the distance for the rigid competitive blockers is typically 1.0 ± 0.1 nm. l-Tubocurarine is considerably less potent than d-tubocurarine. While the two enantiomers have similar internitrogen distances, the d-isomer has all of the hydrophilic groups localized uniquely to one surface.

Pharmacological Properties

Skeletal Muscle

A localized paralytic action of curare was first described by Claude Bernard in the 1850s. That the site of action of d-tubocurarine and other competitive blocking agents was the motor end plate was subsequently established by modern techniques, including fluorescence and electron microscopy, microiontophoretic application of drugs, patch–clamp analysis of single channels, and intracellular recording. In brief, competitive antagonists combine with the nicotinic acetylcholine receptor at the postjunctional membrane and thereby competitively block the binding of ACh. When the drug is applied directly to the end plate of a single isolated muscle fiber, the muscle cell becomes insensitive to motor-nerve impulses and to directly applied ACh; however, the end-plate region and the remainder of the muscle fiber membrane retain their normal sensitivity to K+ depolarization, and the muscle fiber still responds to direct electrical stimulation.

To analyze the action of antagonists at the neuromuscular junction further, it is first important to consider certain details of receptor activation by acetylcholine. The steps involved in the release of ACh by the nerve action potential, the development of miniature end-plate potentials (MEPPs), their summation to form a postjunctional end-plate potential, the triggering of the muscle action potential, and contraction are described in Chapter 6: Neurotransmission: The Autonomic and Somatic Motor Nervous Systems. Biophysical experimentation has revealed that the fundamental event elicited by acetylcholine or other agonists is an 'all-or-none' opening and closing of the individual receptor channels, which gives rise to a square-wave pulse with an average open-channel conductance of 20 to 30 pS and a duration that is exponentially distributed around a time of about 1 millisecond. The duration of channel opening is far more dependent on the nature of the agonist than is the magnitude of the open-channel conductance (see Sakmann, 1992).

The influence of increasing concentrations of the competitive antagonist tubocurarine is to diminish progressively the amplitude of the postjunctional end-plate potential. The amplitude of this postjunctional potential may fall to below 70% of its initial value before it is insufficient to initiate the propagated muscle action potential; this provides a safety factor in neuromuscular transmission. Analysis of the antagonism of tubocurarine on single-channel events shows that, as expected for a competitive antagonist, it reduces the frequency of channel-opening events but does not affect the conductance or duration of opening for a single channel (Katz and Miledi, 1978). At higher concentrations, curare and other competitive antagonists will block the channel directly in a fashion that is noncompetitive with agonists and dependent on membrane potential (Colquhoun et al., 1979).

The decay time of the MEPP is of the same duration as the average lifetime of channel opening (1 to 2 milliseconds). Since the MEPPs are a consequence of the spontaneous release of one or more quanta of ACh (105 molecules), individual molecules of ACh released into the synapse have only a transient opportunity to activate the receptor and do not successively rebind to receptors to activate multiple channels before being hydrolyzed by acetylcholinesterase. The concentration of unbound ACh in the synapse from nerve-released ACh diminishes more rapidly than does the decay of the end-plate potential (or current).

If anticholinesterase (anti-ChE) drugs are present, the EPP (or end-plate current) is prolonged up to 25 to 30 milliseconds, which is indicative of the rebinding of transmitter to neighboring receptors before diffusion from the synapse. It is therefore not surprising that anti-ChE agents and tubocurarine act in opposing directions, since increasing the duration of ACh retained in the synapse should favor occupation of the receptor by transmitter and displace tubocurarine.

Simultaneous binding by two agonist molecules at the respective and subunit interfaces of the receptor is required for activation. Activation shows positive cooperativity and thus occurs over a narrow range of concentrations (Sine and Claudio, 1991; Changeux and Edelstein, 1998). Although two competitive antagonist or snake -toxin molecules can bind to each receptor molecule at the agonist sites, the binding of one molecule of antagonist to each receptor is sufficient to render it nonfunctional (see Taylor et al., 1983).

The depolarizing agents, such as succinylcholine and decamethonium, act by a different mechanism. Their initial action is to depolarize the membrane by opening channels in the same manner as ACh. However, they persist for longer durations at the neuromuscular junction, primarily because of their resistance to acetylcholinesterase. The depolarization thus is longer lasting, resulting in a brief period of repetitive excitation that may elicit transient muscle fasciculations. The initial phase is followed by block of neuromuscular transmission and flaccid paralysis. This arises because released acetylcholine binds to receptors on an already depolarized end plate. It is the change in end-plate potential elicited by the transient increases in ACh that triggers action potentials. An end plate depolarized from –80 mV to –55 mV by a depolarizing blocking agent is resistant to further depolarization by acetylcholine. In human beings, a sequence of repetitive excitation (fasciculations) followed by block of transmission and neuromuscular paralysis is elicited by depolarizing agents; however, this sequence is influenced by such factors as the anesthetic agent used concurrently, the type of muscle, and the rate of drug administration. The different characteristics of depolarization and competitive blockade are listed in Table 9–2.

In other animal species and occasionally in human beings, decamethonium and succinylcholine produce a blockade that has unique features, some of which combine those of the depolarizing and the competitive agents; Zaimis (1976) has termed this type of action a 'dual' mechanism. In such cases, the depolarizing agents produce initially the characteristic fasciculations and potentiation of the maximal twitch, followed by the rapid onset of neuromuscular block; this block is potentiated by anti-ChE agents. However, following the onset of blockade, there is a poorly sustained response to tetanic stimulation of the motor nerve, intensification of the block by tubocurarine, and usual reversal by anti-ChE agents.

The dual action of the depolarizing blocking agents also is seen in intracellular recordings of membrane potential; when agonist is applied continuously, the initial depolarization is followed by a gradual repolarization. The second phase, repolarization, resembles receptor desensitization (Katz and Thesleff, 1957).

Under clinical conditions, with increasing concentrations of succinylcholine and in time, the block may convert slowly from a depolarizing to a nondepolarizing type, termed phase I and phase II block (Durant and Katz, 1982). The pattern of neuromuscular blockade produced by depolarizing drugs in anesthetized patients appears to depend, in part, on the anesthetic; fluorinated hydrocarbons may be more apt to predispose the motor end plate to nondepolarization blockade after prolonged use of succinylcholine or decamethonium (see Zaimis, 1976; Fogdall and Miller, 1975). The characteristics of phase I and phase II block are shown in Table 9–3.

During the initial phase of application, depolarizing agents produce channel opening, which can be measured by the statistical analysis of fluctuation of muscle EPPs. The probability of channel opening associated with the binding of drug to the receptor is less with decamethonium than with ACh (Katz and Miledi, 1978). The diminished probability of channel opening would serve to classify decamethonium as a partial agonist at the end plate. Higher concentrations of decamethonium also block the channel directly and thereby interfere with ion permeability (Adams and Sakmann, 1978).

Although the observed fasciculations also may result from stimulation of the prejunctional motor-nerve terminal by the depolarizing agent, giving rise to stimulation of the motor unit in an antidromic fashion, the primary site of action of both competitive and depolarizing blocking agents is the postjunctional membrane. Presynaptic actions of the competitive agents may become significant upon repetitive, high-frequency stimulation, since prejunctional nicotinic receptors may be involved in the mobilization of ACh for release from the nerve terminal (Bowman et al., 1990; Van der Kloot and Molgo, 1994).

Many drugs and toxins block neuromuscular transmission by other mechanisms, such as interference with the synthesis or release of ACh (see Van der Kloot and Molgo, 1994; see also Chapter 6: Neurotransmission: The Autonomic and Somatic Motor Nervous Systems), but most of these agents are not employed clinically for this purpose. One exception is botulinum toxin, which has been administered locally into muscles of the orbit in the management of ocular blepharospasm and strabismus and has been used to control other muscle spasms and to facilitate facial muscle relaxation (see Chapters 6: Neurotransmission: The Autonomic and Somatic Motor Nervous Systems and Chapter 66: Ocular Pharmacology). This toxin also has been injected into the lower esophageal sphincter to treat achalasia (see Chapter 38: Prokinetic Agents, Antiemetics, and Agents Used in Irritable Bowel Syndrome). Another exception is dantrolene, which blocks release of Ca2+ from the sarcoplasmic reticulum and is used in the treatment of malignant hyperthermia (see below). The sites of action and interrelationship of several agents that serve as pharmacological tools are shown in Figure 9–3.

Figure 9–3. Sites of Action of Agents at the Neuromuscular Junction and Adjacent Structures. The anatomy of the motor end plate, shown at the left, and the sequence of events from liberation of acetylcholine (ACh) by the nerve action potential (AP) to contraction of the muscle fiber, indicated by the middle column, are described in some detail in Chapter 6: Neurotransmission: The Autonomic and Somatic Motor Nervous Systems. The modification of these processes by various agents is shown on the right; an arrow marked with an X indicates inhibition or block; an unmarked arrow indicates enhancement or activation. The insets are enlargements of the indicated structures. The highest magnification depicts the receptor in the bilayer of the postsynaptic membrane. A more detailed view of the receptor is shown in Figure 9–1.

Sequence and Characteristics of Paralysis

When an appropriate dose of a competitive blocking agent is injected intravenously in human beings, motor weakness gives way to a total flaccid paralysis. Small, rapidly moving muscles such as those of the eyes, jaw, and larynx relax before those of the limbs and trunk. Ultimately the intercostal muscles and finally the diaphragm are paralyzed, and respiration then ceases. Recovery of muscles usually occurs in the reverse order to that of their paralysis, and thus the diaphragm ordinarily is the first muscle to regain function (see Feldman and Fauvel, 1994; Savarese et al., 2000).

After a single intravenous dose of 10 to 30 mg of succinylcholine, muscle fasciculations, particularly over the chest and abdomen, occur briefly; then relaxation occurs within 1 minute, becomes maximal within 2 minutes, and disappears as a rule within 5 minutes. Transient apnea usually occurs at the time of maximal effect. Muscle relaxation of longer duration is achieved by continuous intravenous infusion. After infusion is discontinued, the effects of the drug usually disappear rapidly because of its rapid hydrolysis catalyzed by the butyrylcholinesterase of the plasma and liver. Muscle soreness may follow the administration of succinylcholine. Small prior doses of competitive blocking agents have been employed to minimize fasciculations and muscle pain caused by succinylcholine. However, this procedure is controversial, since it increases the requirement for the depolarizing drug.

During prolonged depolarization, muscle cells may lose significant quantities of K+ and gain Na+, Cl, and Ca2+. In patients in whom there has been extensive injury to soft tissues, the efflux of K+ following continued administration of succinylcholine can be life-threatening. The life-threatening complications of succinylcholine-induced hyperkalemia are discussed later in this chapter, but it is important to stress that there are many conditions for which succinylcholine administration is contraindicated or must be undertaken with great caution. The change in the nature of the blockade produced by succinylcholine (from phase I to phase II) presents an additional complication with long-term infusions.

Central Nervous System

Tubocurarine and other quaternary neuromuscular blocking agents are virtually devoid of central effects following the intravenous administration of ordinary clinical doses because of their inability to penetrate the blood–brain barrier.

The most decisive experiment performed to resolve whether or not curare significantly affects central functions in the dose range used clinically was that of Smith and associates (1947). Smith (an anesthesiologist) permitted himself to receive intravenously two and one-half times the amount of tubocurarine necessary for paralysis of all skeletal muscles. Adequate respiratory exchange was maintained by artificial respiration. At no time was there any evidence of lapse of consciousness, clouding of sensorium, analgesia, or disturbance of special senses. Despite adequate artificially controlled respiration, 'shortness of breath' was experienced, and the accumulation of unswallowed saliva in the pharynx caused the sensation of choking. The experience was decidedly unpleasant. It was concluded that tubocurarine given intravenously even in large doses has no significant central stimulant, depressant, or analgesic effects, and that its sole action in anesthesia is the peripheral paralytic effect on skeletal muscle.

Autonomic Ganglia and Muscarinic Sites

Neuromuscular blocking agents show variable potencies in producing ganglionic blockade. Just as at the motor end plate, ganglionic blockade by tubocurarine and other stabilizing drugs is reversed or antagonized by anti-ChE agents.

At the doses of tubocurarine used clinically, partial blockade probably is produced, both at autonomic ganglia and at the adrenal medulla, which results in a fall in blood pressure and tachycardia. Pancuronium and metocurine show less ganglionic blockade at common clinical doses. Atracurium, vecuronium, doxacurium, pipecuronium, mivacurium, and rocuronium are even more selective (Pollard, 1994; Savarese et al., 2000). The maintenance of cardiovascular reflex responses usually is desired during anesthesia. Pancuronium has a vagolytic action, presumably from blockade of muscarinic receptors. This leads to tachycardia.

Of the depolarizing agents, succinylcholine at doses causing neuromuscular relaxation rarely causes effects attributable to ganglionic blockade. However, cardiovascular effects are sometimes observed that are probably due to the successive stimulation of vagal ganglia (manifested by bradycardia) and of sympathetic ganglia (resulting in hypertension and tachycardia).

Histamine Release

Tubocurarine produces typical histamine-like wheals when injected intracutaneously or intraarterially in human beings, and certain clinical responses to tubocurarine (bronchospasm, hypotension, excessive bronchial and salivary secretion) appear to be caused by the release of histamine. Metocurine, succinylcholine, mivacurium, doxacurium, and atracurium also cause histamine release, but to a lesser extent unless administered rapidly. The ammonio steroids, pancuronium, vecuronium, pipecuronium, and rocuronium, have even less tendency to release histamine after intradermal or systemic injection (Basta, 1992; Watkins, 1994). Histamine release typically is a direct action of the muscle relaxant on the mast cell rather than IgE-mediated anaphylaxis (Watkins, 1994).

Actions of Neuromuscular Blocking Agents with Life-Threatening Implications

The depolarizing agents can release K+ rapidly from intracellular sites; this may be a factor in production of the prolonged apnea that has been noted in patients who receive these drugs while in electrolyte imbalance (Dripps, 1976). As indicated above, succinylcholine-induced hyperkalemia is a life-threatening complication of the drug. For example, such alterations in the distribution of K+ are of particular concern in patients with congestive heart failure who are receiving digitalis or diuretics. For the same reason, caution should be used or depolarizing blocking agents should be avoided in patients with extensive soft-tissue trauma or burns. A higher dose of a competitive blocking agent often is indicated in these patients. In addition, succinylcholine administration is contraindicated or should be given with great caution in patients with nontraumatic rhabdomyolysis, ocular lacerations, spinal cord injuries with paraplegia or quadriplegia, or with muscular dystrophies. Succinylcholine no longer is indicated for children 8 years old and younger unless emergency intubation or securing an airway is necessary. Hyperkalemia, rhabdomyolysis, and cardiac arrest have been reported. A subclinical dystrophy frequently is associated with these adverse responses (Savarese et al., 2000). Neonates also may have an enhanced sensitivity to competitive neuromuscular blocking agents.

Synergisms and Antagonisms

The interactions between the competitive and depolarizing neuromuscular blocking agents already have been considered. From a clinical viewpoint, the most important pharmacological interactions of these drugs are with certain general anesthetics, certain antibiotics, Ca2+ channel blockers, and anti-ChE compounds.

Since the anti-ChE agents neostigmine, pyridostigmine, and edrophonium preserve endogenous ACh and also act directly on the neuromuscular junction, they can be used in the treatment of overdosage with competitive blocking agents. Similarly, upon completion of the surgical procedure many anesthesiologists employ neostigmine or edrophonium to reverse and decrease the duration of competitive neuromuscular blockade. Succinylcholine should never be administered after reversal of competitive blockade with neostigmine; in this circumstance a prolonged and intense blockade often is achieved. A muscarinic antagonist (atropine or glycopyrrolate) is used concomitantly to prevent stimulation of muscarinic receptors and thereby avoid slowing of the heart rate. The anti-ChE agents, however, are synergistic with the depolarizing blocking agents, particularly in their initial phase of action. Since they will not reverse depolarizing neuromuscular blockade and, in fact, can enhance it, the distinction in the type of neuromuscular blocking agent must be clear.

Many inhalational anesthetics (e.g., halothane, isoflurane, and enflurane) exert a stabilizing effect on the postjunctional membrane and therefore act synergistically with the competitive blocking agents. Consequently, when such blocking drugs are used for muscle relaxation as adjuncts to these anesthetics, their doses should be reduced (see Fogdall and Miller, 1975).

Aminoglycoside antibiotics produce neuromuscular blockade by inhibiting ACh release from the preganglionic terminal (through competition with Ca2+) and to a lesser extent by noncompetitively blocking the receptor. The blockade is antagonized by calcium salts, but only inconsistently by anti-ChE agents (see Chapter 46: Antimicrobial Agents: The Aminoglycosides). The tetracycline antibiotics also can produce neuromuscular blockade, possibly by chelation of Ca2+. Additional antibiotics that have neuromuscular blocking action, through both presynaptic and postsynaptic actions, include polymyxin B, colistin, clindamycin, and lincomycin (see Pollard, 1994). Ca2+ channel blockers enhance neuromuscular blockade produced by both competitive and depolarizing antagonists. It is not clear whether this is a result of a diminution of Ca2+-dependent release of transmitter from the nerve ending or is a postsynaptic action. When neuromuscular blocking agents are administered to patients receiving these agents, dose adjustments should be considered; if recovery of spontaneous respiration is delayed, Ca2+ salts may facilitate recovery.

Miscellaneous drugs that may have significant interactions with either competitive or depolarizing neuromuscular blocking agents include trimethaphan, opioid analgesics, procaine, lidocaine, quinidine, phenelzine, phenytoin, propranolol, magnesium salts, corticosteroids, digitalis glycosides, chloroquine, catecholamines, and diuretics (see Zaimis, 1976; Pollard, 1994; Savarese et al., 2000).

Toxicology

The important untoward responses of the neuromuscular blocking agents include prolonged apnea, cardiovascular collapse, and those resulting from histamine release.

Failure of respiration to become adequate in the postoperative period may not always be due directly to the drug. An obstruction of the airway, decreased arterial carbon dioxide tension secondary to hyperventilation during the operative procedure, or the neuromuscular depressant effect of excessive amounts of neostigmine used to reverse the action of the competitive blocking drugs also may be implicated. Directly related factors may include alterations in body temperature; electrolyte imbalance, particularly of K+ (discussed earlier); low plasma butyrylcholinesterase levels, resulting in a reduction in the rate of destruction of succinylcholine; the presence of latent myasthenia gravis or of malignant disease such as small-cell carcinoma of the bronchus (myasthenic syndrome); reduced blood flow to skeletal muscles, causing delayed removal of the blocking drugs; and decreased elimination of the muscle relaxants secondary to reduced renal function. Great care should be taken when administering these agents to dehydrated or severely ill patients.

Malignant Hyperthermia

Malignant hyperthermia is a potentially life-threatening event triggered by the administration of certain anesthetics and neuromuscular blocking agents. The clinical features include contracture, rigidity, and heat production from skeletal muscle resulting in severe hyperthermia, accelerated muscle metabolism, metabolic acidosis, and tachycardia. Uncontrolled release of Ca2+ from the sarcoplasmic reticulum of skeletal muscle is the initiating event. Although the halogenated hydrocarbon anesthetics (halothane, isoflurane, and sevoflurane) and succinylcholine alone have been reported to precipitate the response, most of the incidents arise from the combination of depolarizing blocking agent and anesthetic. Susceptibility to malignant hyperthermia, an autosomal dominant trait, is associated with certain congenital myopathies such as central core disease. In the majority of cases, however, no clinical signs are visible in the absence of anesthetic intervention.

Determination of susceptibility is made with an in vitro contracture test (IVCT) on a fresh biopsy of skeletal muscle, where contractures in the presence of various concentrations of halothane and caffeine are measured. In over 50% of the families, a linkage is found between the IVCT phenotype and a mutation in the gene (RyR-1) encoding the skeletal muscle ryanodine receptor (RYR-1). Over 20 mutations in a region of the gene that encodes the cytoplasmic face of the receptor have been described. Other loci have been identified on the L-type Ca2+ channel (voltage-gated dihydropyridine receptor) and on other associated proteins or channel subunits. The large size of RyR-1 and the genetic heterogeneity of the condition have precluded the development of a genotypic determination for malignant hyperthermia (Hopkins, 2000; Jurkat-Rott et al., 2000).

Current treatment entails an intravenous administration of dantrolene (DANTRIUM), which blocks Ca2+ release and the metabolic sequelae. Dantrolene inhibits Ca2+ release from the sarcoplasmic reticulum of skeletal muscle by limiting the capacity of Ca2+ and calmodulin to activate RYR-1 (Fruen et al., 1997). RYR-1 and the L-type Ca2+ channel are juxtaposed to associate at a triadic junction formed between the T- tubule and sarcoplasmic reticulum. The L-type channel with its T-tubular location serves as the voltage sensor receiving the depolarizing activation signal. The intimate coupling of the two proteins at the triad, along with a host of modulatory proteins in the two organelles and the surrounding cytoplasm, regulate the release of and response to Ca2+ (Lehmann-Horn and Jurkat-Rott, 1999).

Rapid cooling, inhalation of 100% oxygen, and control of acidosis should be considered adjunct therapy in malignant hyperthermia. Declining fatality rates for malignant hyperthermia relate to anesthesiologists' awareness of the condition and the efficacy of dantrolene.

Patients with central core disease, so named because of the presence of myofibrillar cores seen upon biopsy of slow-twitch muscle fibers, show muscle weakness in infancy and delayed motor development. These individuals have a high susceptibility to malignant hyperthermia with the combination of an anesthetic and a depolarizing neuromuscular blocker. Central core disease has five allelic variants of RyR-1 in common with malignant hyperthermia. Patients with other muscle syndromes or dystonias also have an increased frequency of contracture and hyperthermia in the anesthesia setting. Succinylcholine in susceptible individuals also induces masseter muscle rigidity, which may complicate endotracheal tube insertion and airway management. This condition has been correlated with a mutation in the gene encoding the subunit of the voltage-sensitive Na+ channel (Vita et al., 1995). Masseter muscle rigidity can be an early sign of the onset of malignant hyperthermia if the anesthetic combination is continued (Hopkins, 2000).

Respiratory Paralysis

Treatment of respiratory paralysis arising from an adverse reaction or overdose of a neuromuscular blocking agent should be by positive-pressure artificial respiration with oxygen and maintenance of a patent airway until the recovery of normal respiration is assured. With the competitive blocking agents, this may be hastened by the administration of neostigmine methylsulfate (0.5 to 2 mg, intravenously) or edrophonium (10 mg, intravenously, repeated as required) (Watkins, 1994).

Interventional Strategies for Other Toxic Effects

Neostigmine antagonizes only the skeletal muscular blocking action of the competitive blocking agents effectively, and it may aggravate such side effects as hypotension or induce bronchospasm. In such circumstances, sympathomimetic amines may be given to support the blood pressure. Atropine or glycopyrrolate is administered to counteract muscarinic stimulation. Antihistamines are definitely beneficial to counteract the responses that follow the release of histamine, particularly when administered before the neuromuscular blocking agent.

Absorption, Fate, and Excretion

Quaternary ammonium neuromuscular blocking agents are very poorly and irregularly absorbed from the gastrointestinal tract. This fact was well known to the South American Indians, who ate with impunity the flesh of game killed with curare-poisoned arrows. Absorption is quite adequate from intramuscular sites. Rapid onset is achieved with intravenous administration. The more potent agents, of course, must be given in lower concentrations, and diffusional requirements slow their rate of onset.

When long-acting, competitive blocking agents, such as d-tubocurarine and pancuronium, are administered, blockade may diminish after 30 minutes owing to redistribution of the drug, yet residual blockade and plasma levels of the drug persist for longer periods. Subsequent doses show diminished redistribution. Long-acting agents may accumulate with multiple doses.

The ammonio steroids contain ester groups that are hydrolyzed in the liver. Typically, the metabolites have about one-half of the activity of the parent compound and contribute to the total relaxation profile. Ammonio steroids of intermediate duration of action, such as vecuronium, rocuronium, and rapacuronium (see Table 9–1), are more rapidly cleared by the liver than are pancuronium and pipecuronium. The more rapid offset of neuromuscular blockade with compounds of intermediate duration argues for sequential dosing of these agents, rather than administering a single dose of a long-duration neuromuscular blocking agent (Savarese et al., 2000).

Atracurium is converted to less-active metabolites by plasma esterases and spontaneous degradation. These alternative routes of metabolism are responsible for atracurium not exhibiting an increase in half-life in patients with compromised renal function. Hence, it becomes the agent of choice under these conditions (Hunter, 1994). Mivacurium shows an even greater susceptibility to butyrylcholinesterase catalysis, thus conferring to it the shortest duration among the nondepolarizing blockers.

The extremely brief duration of action of succinylcholine also is due largely to its rapid hydrolysis by the butyrylcholinesterase of liver and plasma. Among the occasional patients who exhibit prolonged apnea following the administration of succinylcholine or mivacurium, most have an atypical plasma cholinesterase or a deficiency of the enzyme, due to allelic variations (Pantuck, 1993; Primo-Parmo et al., 1996), hepatic or renal disease, or a nutritional disturbance; however, in some the enzymatic activity in plasma is normal (Whittaker, 1986).

Therapeutic Uses

The main clinical use of the neuromuscular blocking agents is as an adjuvant in surgical anesthesia to obtain relaxation of skeletal muscle, particularly of the abdominal wall, so that operative manipulations are facilitated. With muscle relaxation no longer dependent upon the depth of general anesthesia, a much lighter level of anesthesia suffices. This situation is of obvious advantage, since the risk of respiratory and cardiovascular depression is minimized. Moreover, the postanesthetic recovery period is shortened.

These considerations notwithstanding, neuromuscular blocking agents cannot be used to substitute for inadequate depth of anesthesia in the surgical planes. Otherwise, a risk of reflex responses to painful stimuli and conscious recall may occur. Muscle relaxation is also of value in various orthopedic procedures, such as the correction of dislocations and the alignment of fractures. Neuromuscular blocking agents of short duration often are used to facilitate intubation with an endotracheal tube and have been used to facilitate laryngoscopy, bronchoscopy, and esophagoscopy in combination with a general anesthetic agent.

Neuromuscular blocking agents are administered parenterally and nearly always intravenously. As potentially hazardous drugs, they should be administered to patients only by anesthesiologists and other clinicians who have had extensive training in their use and in a setting where facilities for respiratory and cardiovascular resuscitation are immediately at hand. Detailed information on dosage and monitoring the extent of muscle relaxation can be found in anesthesiology textbooks (Pollard, 1994; Savarese et al., 2000).

Measurement of Neuromuscular Blockade in Human Beings

Assessment of neuromuscular block usually is performed by stimulation of the ulnar nerve. Responses are monitored from compound action potentials or muscle tension developed in the adductor pollicis (thumb) muscle. Responses to repetitive or tetanic stimuli are most useful for evaluation of blockade of transmission, since individual measurements of twitch tension must be related to control values obtained prior to the administration of drugs. Thus, stimulus schedules such as the 'train of four' and the 'double burst' or responses to tetanic stimulation are preferred procedures (Waud and Waud, 1972; Drenck et al., 1989). Rates of onset of blockade and recovery are more rapid in the airway musculature (jaw, larynx, and diaphragm) than in the thumb. Hence, tracheal intubation can be performed before onset of complete block at the adductor pollicis, while partial recovery of function of this muscle allows sufficient recovery of respiration for extubation (Savarese et al., 2000). Differences in rates of onset of blockade, recovery from blockade, and intrinsic sensitivity between the stimulated muscle and those of the larynx, abdomen, and diaphragm should be considered.

Use to Prevent Trauma during Electroshock Therapy

Electroconvulsive therapy of psychiatric disorders occasionally is complicated by trauma to the patient; the seizures induced may cause dislocations or fractures. Inasmuch as the muscular component of the convulsion is not essential for benefit from the procedure, neuromuscular blocking agents and thiopental are employed. The combination of the blocking drug, the anesthetic agent, and postictal depression usually results in respiratory depression or temporary apnea. An endotracheal tube and oxygen always should be available. An oropharyngeal airway should be inserted as soon as the jaw muscles relax (after the seizure) and provision made to prevent aspiration of mucus and saliva. Succinylcholine or mivacurium is most often used because of the brevity of relaxation. A cuff may be applied to one extremity to prevent the effects of the drug in that limb; evidence of an effective electroshock is provided by contraction of the group of protected muscles.

Control of Muscle Spasms

Several agents, many of which have rather limited efficacy, have been used to treat spasticity involving the -motor neuron with the objective of increasing functional capacity and relieving discomfort. Some agents that act in the CNS at either higher centers or the spinal cord are considered in Chapter 22: Treatment of Central Nervous System Degenerative Disorders. These include baclofen, the benzodiazepines, and tizandine. Botulinum toxin and dantrolene act peripherally.

The anaerobic bacterium Clostridium botulinum produces a family of toxins targeted to presynaptic proteins and that block the release of acetylcholine (ACh) (see Chapter 6: Neurotransmission: The Autonomic and Somatic Motor Nervous Systems). Botulinum toxin–A (BOTOX), in blocking ACh release, produces flaccid paralysis of skeletal muscle and diminished activity of parasympathetic and sympathetic cholinergic synapses. Inhibition lasts from several weeks to 3 to 4 months, and restoration of function requires nerve sprouting. Immunoresistance may develop with continued use (Davis and Barnes, 2000).

Originally approved for the treatment of the ocular conditions of strabismus and blepharospasm and for hemifacial spasms, botulinum toxin has received wider use in the treatment of spasms and dystonias such as adductor spasmodic dysphonia, oromandibular dystonia, cervical dystonia, and spasms associated with the lower esophageal sphincter and anal fissures. Its dermatological uses include treatment of hyperhidrosis of the palms and axillae that is resistant to topical and iontophoretic remedies and removal of facial lines associated with excessive nerve stimulation and muscle activity. Treatment involves local intramuscular or intradermal injections (Boni et al., 2000).

In addition to its use in managing an acute attack of malignant hyperthermia (see above), dantrolene also has been explored in the treatment of spasticity and hyperreflexia. With its peripheral action, it causes a generalized weakness. As such, its use should be reserved to nonambulatory patients with severe spasticity. Hepatotoxicity has been reported with continued use, requiring liver function tests (Kita and Goodkin, 2000).

Ganglionic Neurotransmission

Neurotransmission in autonomic ganglia has long been recognized to be a far more complex process than that described by a single neurotransmitter–receptor system; intracellular recordings reveal at least four different changes in potential that can be elicited by stimulation of the preganglionic nerve (Eccles and Libet, 1961; Weight et al., 1979) (Figure 9–4). The primary event involves a rapid depolarization of postsynaptic sites by ACh. The receptors are nicotinic, and the pathway is sensitive to classical blocking agents such as hexamethonium and trimethaphan. Activation of this primary pathway gives rise to an initial excitatory postsynaptic potential (EPSP). This rapid depolarization is due primarily to an inward Na+ and perhaps Ca2+ current through a neuronal type of nicotinic receptor channel. Multiple nicotinic receptor subunits or their mRNAs ( 4) have been identified in ganglia with 3 and 2 being in abundance.



Figure 9–4. Representation of Autonomic Ganglion Cells and the Excitatory and Inhibitory Postsynaptic Potentials (EPSP and IPSP) Recorded from the Postganglionic Nerve Cell Body after Stimulation of the Preganglionic Nerve Fiber. The initial EPSP, if of sufficient magnitude, triggers an action potential spike, which is followed by a slow IPSP, a slow EPSP, and a late, slow EPSP. The slow IPSP and slow EPSP are not seen in all ganglia. The subsequent electrical events are thought not to trigger spikes directly but rather to increase or decrease the probability of a subsequent EPSP reaching a threshold to trigger a spike. Other interneurons, such as catecholamine-containing, small, intensely fluorescent cells, and axon terminals from sensory, afferent neurons also release transmitters and are thought to influence the slow potentials of the postganglionic neuron. A variety of cholinergic, peptidergic, adrenergic, and amino acid receptors are found on the dendrites and soma of the postganglionic neuron and the interneurons. The preganglionic terminal releases acetylcholine and peptides; the interneurons store and release catecholamines, amino acids, and peptides; and the sensory afferent nerve terminals release peptides. The initial EPSP is mediated through nicotinic (N) receptors, the slow IPSP and EPSP through M2 and M1 muscarinic receptors, and the late, slow EPSP through several types of peptidergic receptors, as detailed in the text. (After; Weight et al., 1979; Jan and Jan, 1983; Elfvin et al., 1993.)

An action potential is generated in the postganglionic neuron when the initial EPSP attains a critical amplitude. In mammalian sympathetic ganglia in vivo, it may be necessary for multiple synapses to be activated before transmission is effective. Discrete end plates with focal localization of receptors do not exist in ganglia; rather, the dendrites and nerve cell bodies contain the receptors.

Iontophoretic application of ACh to the ganglion results in a depolarization with a latency of less than 1 millisecond; this decays over a period of 10 to 50 milliseconds (Ascher et al., 1979). Measurements of single-channel conductances indicate that the characteristics of nicotinic receptor channels of the ganglia and the neuromuscular junction are quite similar.

The secondary events that follow the initial depolarization are insensitive to hexamethonium or other nicotinic antagonists. They include the slow EPSP, the late slow EPSP, and an inhibitory postsynaptic potential (IPSP). The slow EPSP is generated by ACh acting on muscarinic receptors, and it is blocked by atropine or antagonists that are selective for M1 muscarinic receptors (see Chapter 7: Muscarinic Receptor Agonists and Antagonists). The slow EPSP has a longer latency and a duration of 30 to 60 seconds. In contrast, the late slow EPSP lasts for several minutes and is initiated by the action of peptides released from presynaptic nerve endings or interneurons in specific ganglia (Dun, 1983). The peptides and ACh may be released from the same nerve ending, but the enhanced stability of the peptide in the ganglion extends its sphere of influence to postsynaptic sites beyond those in immediate proximity to the nerve ending. The slow EPSPs result from decreased K+ conductance (Weight et al., 1979). The K+ conductance has been called an M current, and it regulates the sensitivity of the cell to repetitive fast-depolarizing events (Adams et al., 1982).

Like the slow EPSP, the IPSP is unaffected by the classical nicotinic-receptor blocking agents. Substantial electrophysiological and morphological evidence has accumulated to suggest that catecholamines participate in the generation of the IPSP. Dopamine and norepinephrine cause hyperpolarization of ganglia, and both the IPSP and the catecholamine-induced hyperpolarization are blocked by -adrenergic receptor antagonists. Since the IPSP is sensitive in most systems to blockade by both atropine and -adrenergic antagonists, ACh that is released at the preganglionic terminal may act on a catecholamine-containing interneuron to stimulate the release of dopamine or norepinephrine; the catecholamine, in turn, produces hyperpolarization (an IPSP) of the ganglion cell (Eccles and Libet, 1961). At least in some ganglia, a muscarinic link in the IPSP is mediated through M2 muscarinic receptors (see Chapter 7: Muscarinic Receptor Agonists and Antagonists). Histochemical studies indicate that catecholamine-containing cells are present in ganglia. These include the dopamine- or norepinephrine-containing small, intensely fluorescent (SIF) cells and adrenergic nerve terminals. Details of the functional linkage between the SIF cells and the electrogenic mechanism of the IPSP remain to be resolved (Eränköet al., 1980).

The relative importance of the secondary pathways and even the nature of the modulating transmitters appear to differ among individual ganglia and between parasympathetic and sympathetic ganglia. A variety of peptides, including luteinizing hormone–releasing hormone, substance P, angiotensin, calcitonin gene-related peptide, vasoactive intestinal polypeptide, neuropeptide Y, and enkephalins, have been identified in ganglia by immunofluorescence. They appear localized to particular cell bodies, nerve fibers, or SIF cells; are released upon nerve stimulation; and are presumed to mediate the late slow EPSP (Dun, 1983; Elfvin et al., 1993). Other neurotransmitter substances, such as 5-hydroxytryptamine and gamma-aminobutyric acid, are known to modify ganglionic transmission. Precise details of their modulatory actions are not understood, but they appear to be most closely associated with the late slow EPSP and inhibition of the M current in various ganglia. It should be emphasized that the secondary synaptic events only modulate the initial EPSP. Conventional ganglionic blocking agents can inhibit ganglionic transmission completely; the same cannot be said for muscarinic antagonists or -adrenergic agonists (see Weight et al., 1979; Volle, 1980).

Drugs that stimulate cholinergic receptor sites on autonomic ganglia can be grouped into two major categories. The first group consists of drugs with nicotinic specificity, including nicotine itself. Their excitatory effects on ganglia are rapid in onset, are blocked by ganglionic nicotinic-receptor antagonists, and mimic the initial EPSP. The second group is composed of agents such as muscarine, McN-A-343, and methacholine. Their excitatory effects on ganglia are delayed in onset, blocked by atropine-like drugs, and mimic the slow EPSP.

Ganglionic blocking agents acting on the nicotinic receptor may be classified into two groups. The first group includes those drugs that initially stimulate the ganglia by an ACh-like action and then block them because of a persistent depolarization (e.g., nicotine); prolonged application of nicotine results in desensitization of the cholinergic receptor site and continued blockade. (See review by Volle, 1980.) The blockade of autonomic ganglia produced by the second group of blocking drugs, of which hexamethonium and trimethaphan can be regarded as prototypes, does not involve prior ganglionic stimulation or changes in ganglionic potentials. These agents impair transmission either by competing with ACh for ganglionic nicotinic receptor sites or by blocking the channel when it is open. Trimethaphan acts by competition with ACh, analogous to the mechanism of action of curare at the neuromuscular junction. Hexamethonium appears to block the channel after it opens. This action shortens the duration of current flow, since the open channel either becomes occluded or closes (Gurney and Rang, 1984). Regardless of the mechanism, the initial EPSP is blocked and ganglionic transmission is inhibited.

Ganglionic Stimulating Drugs

History

Two natural alkaloids, nicotine and lobeline, exhibit peripheral actions by stimulating autonomic ganglia. Nicotine (see Figure 9–5) was first isolated from leaves of tobacco, Nicotiana tabacum, by Posselt and Reiman in 1828, and Orfila initiated the first pharmacological studies of the alkaloid in 1843. Langley and Dickinson (1889) painted the superior cervical ganglion of rabbits with nicotine and demonstrated that its site of action was the ganglion, rather than the preganglionic or postganglionic nerve fiber. Lobeline, from Lobelia inflata, has many of the same actions as nicotine but is less potent.

Figure 9–5. Ganglionic Stimulants. 

A number of synthetic compounds also have prominent actions at ganglionic receptor sites. The actions of the 'onium' compounds, of which tetramethylammonium (TMA) is the simplest prototype, were explored in considerable detail in the last half of the nineteenth century and in the early twentieth century.

Nicotine

Nicotine is of considerable medical significance because of its toxicity, presence in tobacco, and propensity for conferring a dependence on its users. The chronic effects of nicotine and the untoward effects of the chronic use of tobacco are considered in Chapter 24: Drug Addiction and Drug Abuse.

Nicotine is one of the few natural liquid alkaloids. It is a colorless, volatile base (pKa= 8.5) that turns brown and acquires the odor of tobacco on exposure to air.

Pharmacological Actions

The complex and often unpredictable changes that occur in the body after administration of nicotine are due not only to its actions on a variety of neuroeffector and chemosensitive sites but also to the fact that the alkaloid can stimulate and desensitize receptors. The ultimate response of any one system represents the summation of stimulatory and inhibitory effects of nicotine. For example, the drug can increase heart rate by excitation of sympathetic or paralysis of parasympathetic cardiac ganglia, and it can slow heart rate by paralysis of sympathetic or stimulation of parasympathetic cardiac ganglia. In addition, the effects of the drug on the chemoreceptors of the carotid and aortic bodies and on brain centers influence heart rate, as do also the cardiovascular compensatory reflexes resulting from changes in blood pressure caused by nicotine. Finally, nicotine elicits a discharge of epinephrine from the adrenal medulla, and this hormone accelerates cardiac rate and raises blood pressure.

Peripheral Nervous System

The major action of nicotine consists initially of transient stimulation and subsequently of a more persistent depression of all autonomic ganglia. Small doses of nicotine stimulate the ganglion cells directly and may facilitate the transmission of impulses. When larger doses of the drug are applied, the initial stimulation is followed very quickly by a blockade of transmission. Whereas stimulation of the ganglion cells coincides with their depolarization, depression of transmission by adequate doses of nicotine occurs both during the depolarization and after it has subsided. Nicotine also possesses a biphasic action on the adrenal medulla; small doses evoke the discharge of catecholamines, and larger doses prevent their release in response to splanchnic nerve stimulation.

The effects of nicotine on the neuromuscular junction are similar to those on ganglia. However, with the exception of avian and denervated mammalian muscle, the stimulant phase is largely obscured by the rapidly developing paralysis. In the latter stage, nicotine also produces neuromuscular blockade by receptor desensitization.

Nicotine, like ACh, is known to stimulate a number of sensory receptors. These include mechanoreceptors that respond to stretch or pressure of the skin, mesentery, tongue, lung, and stomach; chemoreceptors of the carotid body; thermal receptors of the skin and tongue; and pain receptors. Prior administration of hexamethonium prevents the stimulation of the sensory receptors by nicotine but has little, if any, effect on the activation of the sensory receptors by physiological stimuli.

Central Nervous System

Nicotine markedly stimulates the CNS. Low doses produce weak analgesia; with higher doses, tremors leading to convulsions at toxic doses are evident. The excitation of respiration is a prominent action of nicotine; although large doses act directly on the medulla oblongata, smaller doses augment respiration reflexly by excitation of the chemoreceptors of the carotid and aortic bodies. Stimulation of the CNS with large doses is followed by depression, and death results from failure of respiration due to both central paralysis and peripheral blockade of muscles of respiration.

Nicotine induces vomiting by both central and peripheral actions. The central component of the vomiting response is due to stimulation of the emetic chemoreceptor trigger zone in the area postrema of the medulla oblongata. In addition, nicotine activates vagal and spinal afferent nerves that form the sensory input of the reflex pathways involved in the act of vomiting. Studies in isolated higher centers of the brain and spinal cord reveal that the primary sites of action of nicotine in the CNS are prejunctional, causing the release of other transmitters. Accordingly, the stimulatory and pleasure-reward actions of nicotine appear to result from release of excitatory amino acids, dopamine, and other biogenic amines from various CNS centers (MacDermott et al., 1999).

Chronic exposure to nicotine in several systems causes an increase in the density or number of nicotinic receptors (see Di Chiara et al., 2000; Stitzel et al., 2000). While the details of the mechanism are not yet understood, the response may be compensatory to the desensitization of receptor function by nicotine.

Cardiovascular System

When administered intravenously to dogs, nicotine characteristically produces an increase in heart rate and blood pressure. The latter is usually a more sustained response. In general, the cardiovascular responses to nicotine are due to stimulation of sympathetic ganglia and the adrenal medulla, together with the discharge of catecholamines from sympathetic nerve endings. Also contributing to the sympathomimetic response to nicotine is the activation of chemoreceptors of the aortic and carotid bodies, which reflexly results in vasoconstriction, tachycardia, and elevated blood pressure.

Gastrointestinal Tract

The combined activation of parasympathetic ganglia and cholinergic nerve endings by nicotine results in increased tone and motor activity of the bowel. Nausea, vomiting, and occasionally diarrhea are observed following systemic absorption of nicotine in an individual who has not been exposed to nicotine previously.

Exocrine Glands

Nicotine causes an initial stimulation of salivary and bronchial secretions that is followed by inhibition.

Absorption, Fate, and Excretion

Nicotine is readily absorbed from the respiratory tract, buccal membranes, and skin. Severe poisoning has resulted from percutaneous absorption. Being a relatively strong base, its absorption from the stomach is limited, and intestinal absorption is far more efficient. Nicotine in chewing tobacco, because it is more slowly absorbed than inhaled nicotine, has a longer duration of effect. The average cigarette contains 6 to 11 mg of nicotine and delivers about 1 to 3 mg of nicotine systemically to the smoker; bioavailability can increase as much as threefold with intensity of puffing and technique of the smoker (Henningfield, 1995; Benowitz, 1998). Nicotine is available in several dosage forms to help achieve abstinence from tobacco use. Efficacy primarily results from preventing a withdrawal or abstinence syndrome. Nicotine may be administered orally as a gum (nicotine polacrilex; NICORETTE), transdermal patch (NICODERM, HABITROL, others), a nasal spray (NICOTROL NS), and vapor inhaler (NICOTROL INHALER). The first two are most widely used, and the objective is to obtain a sustained plasma nicotine concentration lower than venous blood concentrations after smoking. Arterial blood concentrations immediately following inhalation can be as much as tenfold higher than venous concentrations. The efficacy of the above dosage forms in producing abstinence from smoking is enhanced when linked to counseling and motivational therapy (Henningfield, 1995; Fant et al., 1999; Benowitz, 1999; see also Chapter 24: Drug Addiction and Drug Abuse).

Approximately 80% to 90% of nicotine is altered in the body, mainly in the liver but also in the kidney and lung. Cotinine is the major metabolite, with nicotine-1'-N-oxide and 3-hydroxycotinine and conjugated metabolites found in lesser quantities (Benowitz, 1998). The profile of metabolites and the rate of metabolism appear to be similar in the smoker and nonsmoker. The half-life of nicotine following inhalation or parenteral administration is about 2 hours. Both nicotine and its metabolites are eliminated rapidly by the kidney. The rate of urinary excretion of nicotine is dependent upon the pH of the urine; excretion diminishes when the urine is alkaline. Nicotine also is excreted in the milk of lactating women who smoke; the milk of heavy smokers may contain 0.5 mg per liter.

Acute Nicotine Poisoning

Poisoning from nicotine may occur from accidental ingestion of nicotine-containing insecticide sprays or in children from ingestion of tobacco products. The acutely fatal dose of nicotine for an adult is probably about 60 mg of the base. Smoking tobacco usually contains 1% to 2% nicotine. Apparently, the gastric absorption of nicotine from tobacco taken by mouth is delayed because of slowed gastric emptying, so that vomiting caused by the central effect of the initially absorbed fraction may remove much of the tobacco remaining in the gastrointestinal tract.

The onset of symptoms of acute, severe nicotine poisoning is rapid; they include nausea, salivation, abdominal pain, vomiting, diarrhea, cold sweat, headache, dizziness, disturbed hearing and vision, mental confusion, and marked weakness. Faintness and prostration ensue; the blood pressure falls; breathing is difficult; the pulse is weak, rapid, and irregular; and collapse may be followed by terminal convulsions. Death may result within a few minutes from respiratory failure.

Therapy

Vomiting should be induced with syrup of ipecac or gastric lavage should be performed. Alkaline solutions should be avoided. A slurry of activated charcoal is then passed through the tube and left in the stomach. Respiratory assistance and treatment of shock may be necessary.

Other Ganglionic Stimulants

Stimulation of ganglia by tetramethylammonium (TMA) or 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP) differs from that produced by nicotine in that the initial stimulation is not followed by a dominant blocking action. DMPP is about three times more potent and slightly more ganglion-selective than nicotine. Although parasympathomimetic drugs stimulate ganglia, their effects usually are obscured by stimulation of other neuroeffector sites. McN-A-343 represents an exception to this; in certain tissues its primary action appears to occur at muscarinic M1 receptors in ganglia.

Ganglionic Blocking Drugs

The chemical diversity of compounds that block autonomic ganglia without causing prior stimulation is shown in Figure 9–6.

Figure 9–6. Ganglionic Blocking Agents. 

History and Structure–Activity Relationship

Although Marshall (1913) first described the 'nicotine paralyzing' action of tetraethylammonium (TEA) on ganglia, TEA was largely overlooked until Acheson and Moe (1946) published their definitive analyses of the effects of the ion on the cardiovascular system and autonomic ganglia. The bis-quaternary ammonium salts were developed and studied independently by Barlow and Ing (1948) and Paton and Zaimis (1952). The prototypical ganglionic blocking drug in this series, hexamethonium (C6), has a bridge of six methylene groups between the two quaternary nitrogen atoms (see Figure 9–6). It has minimal neuromuscular and muscarinic blocking activities.

Triethylsulfoniums, like the quaternary and bis-quaternary ammonium ions, possess ganglionic blocking actions. This knowledge led to the development of sulfonium ganglionic blocking agents such as trimethaphan (see Figure 9–6). Mecamylamine, a secondary amine, was introduced into therapy for hypertension in the mid-1950s.

Pharmacological Properties

Nearly all of the physiological alterations observed after the administration of ganglionic blocking agents can be anticipated with reasonable accuracy by a careful inspection of Figure 6–1 and by knowing which division of the autonomic nervous system exercises dominant control of various organs (Table 9–4). For example, blockade of sympathetic ganglia interrupts adrenergic control of arterioles and results in vasodilation, improved peripheral blood flow in some vascular beds, and a fall in blood pressure.

Generalized ganglionic blockade may result also in atony of the bladder and gastrointestinal tract, cycloplegia, xerostomia, diminished perspiration, and, by abolishing circulatory reflex pathways, postural hypotension. These changes represent the generally undesirable features of ganglionic blockade, which severely limit the therapeutic efficacy of ganglionic blocking agents.

Cardiovascular System

The importance of existing sympathetic tone in determining the degree to which blood pressure is lowered by ganglionic blockade is illustrated by the fact that blood pressure may be decreased only minimally in recumbent normotensive subjects but may fall markedly in sitting or standing subjects. Postural hypotension is a major problem in ambulatory patients receiving ganglionic blocking drugs; it is relieved to some extent by muscular activity and completely by recumbency.

Changes in cardiac rate following ganglionic blockade depend largely on existing vagal tone. In human beings, mild tachycardia usually accompanies the hypotension, a sign that indicates fairly complete ganglionic blockade. However, a decrease may occur if the heart rate is initially high.

Cardiac output often is reduced by ganglionic blocking drugs in patients with normal cardiac function as a consequence of diminished venous return resulting from venous dilation and peripheral pooling of blood. In patients with cardiac failure, ganglionic blockade frequently results in increased cardiac output due to a reduction in peripheral resistance. In hypertensive subjects, cardiac output, stroke volume, and left ventricular work are diminished.

Although total systemic vascular resistance is decreased in patients who receive ganglionic blocking agents, changes in blood flow and vascular resistance of individual vascular beds are variable. Reduction of cerebral blood flow is small unless mean systemic blood pressure falls below 50 to 60 mm Hg. Skeletal muscle blood flow is unaltered, but splanchnic and renal blood flow decrease following the administration of a ganglionic blocking agent.

Absorption, Fate, and Excretion

The absorption of quaternary ammonium and sulfonium compounds from the enteric tract is incomplete and unpredictable. This is due both to the limited ability of these ionized substances to penetrate cell membranes and to the depression of propulsive movements of the small intestine and gastric emptying. Although the absorption of mecamylamine is less erratic, a danger exists of reduced bowel activity leading to frank paralytic ileus.

After absorption, the quaternary ammonium and sulfonium blocking agents are confined primarily to the extracellular space and are excreted mostly unchanged by the kidney. Mecamylamine concentrates in the liver and kidney and is slowly excreted in an unchanged form.

Untoward Responses and Severe Reactions

Among the milder untoward responses observed are visual disturbances, dry mouth, conjunctival suffusion, urinary hesitancy, decreased potentia, subjective chilliness, moderate constipation, occasional diarrhea, abdominal discomfort, anorexia, heartburn, nausea, eructation and bitter taste, and the signs and symptoms of syncope caused by postural hypotension. More severe reactions include marked hypotension, constipation, syncope, paralytic ileus, urinary retention, and cycloplegia.

Therapeutic Uses

Of the ganglionic blocking agents that have appeared on the therapeutic scene, only mecamylamine (INVERSINE) and trimethaphan (ARFONAD) currently are utilized in the United States.

Ganglionic blocking agents have been supplanted by superior agents for the treatment of chronic hypertension (see Chapter 33: Antihypertensive Agents and the Drug Therapy of Hypertension). Alternative agents also are available for management of acute hypertensive crises (Murphy, 1995; see Chapter 33: Antihypertensive Agents and the Drug Therapy of Hypertension). A remaining use of ganglionic blockers in a hypertensive crisis is for the initial control of blood pressure in patients with acute dissecting aortic aneurysm, particularly when preexisting conditions make -adrenergic receptor antagonists a relative contraindication (Varon and Marik, 2000). Ganglionic blocking agents are well suited for this condition because they not only reduce blood pressure but also inhibit sympathetic reflexes and thereby reduce the rate of rise of pressure at the site of the tear. In such situations, trimethaphan is infused intravenously at a rate of 0.5 to 3 mg per minute with frequent monitoring of blood pressure. In the absence of symptoms or signs of renal, cerebral, or myocardial ischemia, the dose is increased until the pressure is in the low-normal range. Disappearance of pain is a sign that the dissection has stopped. A disadvantage of trimethaphan is the development of tolerance over the first 48 hours of therapy; this is in part related to fluid retention.

An additional therapeutic use of the ganglionic blocking agents is in the production of controlled hypotension; a reduction in blood pressure during surgery may be sought deliberately to minimize hemorrhage in the operative field, to reduce blood loss in various orthopedic procedures, and to facilitate surgery on blood vessels (Fukusaki et al., 1999). Trimethaphan, as an infusion, may be used as an alternative to or in combination with sodium nitroprusside, since some patients are resistant to the latter drug. Trimethaphan blunts the sympathoadrenal stimulation caused by nitroprusside and reduces the required dosage (Fahmy, 1985).

Trimethaphan can be used in the management of autonomic hyperreflexia or reflex sympathetic dystrophy. This syndrome typically is seen in patients with injuries of the upper spinal cord and results from a massive sympathetic discharge. Since normal central inhibition of the reflex is lacking in such patients, the spinal reflex is dominant.

Ganglionic Neurotransmission

Neurotransmission in autonomic ganglia has long been recognized to be a far more complex process than that described by a single neurotransmitter–receptor system; intracellular recordings reveal at least four different changes in potential that can be elicited by stimulation of the preganglionic nerve (Eccles and Libet, 1961; Weight et al., 1979) (Figure 9–4). The primary event involves a rapid depolarization of postsynaptic sites by ACh. The receptors are nicotinic, and the pathway is sensitive to classical blocking agents such as hexamethonium and trimethaphan. Activation of this primary pathway gives rise to an initial excitatory postsynaptic potential (EPSP). This rapid depolarization is due primarily to an inward Na+ and perhaps Ca2+ current through a neuronal type of nicotinic receptor channel. Multiple nicotinic receptor subunits or their mRNAs ( 4) have been identified in ganglia with 3 and 2 being in abundance.

Figure 9–4. Representation of Autonomic Ganglion Cells and the Excitatory and Inhibitory Postsynaptic Potentials (EPSP and IPSP) Recorded from the Postganglionic Nerve Cell Body after Stimulation of the Preganglionic Nerve Fiber. The initial EPSP, if of sufficient magnitude, triggers an action potential spike, which is followed by a slow IPSP, a slow EPSP, and a late, slow EPSP. The slow IPSP and slow EPSP are not seen in all ganglia. The subsequent electrical events are thought not to trigger spikes directly but rather to increase or decrease the probability of a subsequent EPSP reaching a threshold to trigger a spike. Other interneurons, such as catecholamine-containing, small, intensely fluorescent cells, and axon terminals from sensory, afferent neurons also release transmitters and are thought to influence the slow potentials of the postganglionic neuron. A variety of cholinergic, peptidergic, adrenergic, and amino acid receptors are found on the dendrites and soma of the postganglionic neuron and the interneurons. The preganglionic terminal releases acetylcholine and peptides; the interneurons store and release catecholamines, amino acids, and peptides; and the sensory afferent nerve terminals release peptides. The initial EPSP is mediated through nicotinic (N) receptors, the slow IPSP and EPSP through M2 and M1 muscarinic receptors, and the late, slow EPSP through several types of peptidergic receptors, as detailed in the text. (After; Weight et al., 1979; Jan and Jan, 1983; Elfvin et al., 1993.)

An action potential is generated in the postganglionic neuron when the initial EPSP attains a critical amplitude. In mammalian sympathetic ganglia in vivo, it may be necessary for multiple synapses to be activated before transmission is effective. Discrete end plates with focal localization of receptors do not exist in ganglia; rather, the dendrites and nerve cell bodies contain the receptors.

Iontophoretic application of ACh to the ganglion results in a depolarization with a latency of less than 1 millisecond; this decays over a period of 10 to 50 milliseconds (Ascher et al., 1979). Measurements of single-channel conductances indicate that the characteristics of nicotinic receptor channels of the ganglia and the neuromuscular junction are quite similar.

The secondary events that follow the initial depolarization are insensitive to hexamethonium or other nicotinic antagonists. They include the slow EPSP, the late slow EPSP, and an inhibitory postsynaptic potential (IPSP). The slow EPSP is generated by ACh acting on muscarinic receptors, and it is blocked by atropine or antagonists that are selective for M1 muscarinic receptors (see Chapter 7: Muscarinic Receptor Agonists and Antagonists). The slow EPSP has a longer latency and a duration of 30 to 60 seconds. In contrast, the late slow EPSP lasts for several minutes and is initiated by the action of peptides released from presynaptic nerve endings or interneurons in specific ganglia (Dun, 1983). The peptides and ACh may be released from the same nerve ending, but the enhanced stability of the peptide in the ganglion extends its sphere of influence to postsynaptic sites beyond those in immediate proximity to the nerve ending. The slow EPSPs result from decreased K+ conductance (Weight et al., 1979). The K+ conductance has been called an M current, and it regulates the sensitivity of the cell to repetitive fast-depolarizing events (Adams et al., 1982).

Like the slow EPSP, the IPSP is unaffected by the classical nicotinic-receptor blocking agents. Substantial electrophysiological and morphological evidence has accumulated to suggest that catecholamines participate in the generation of the IPSP. Dopamine and norepinephrine cause hyperpolarization of ganglia, and both the IPSP and the catecholamine-induced hyperpolarization are blocked by -adrenergic receptor antagonists. Since the IPSP is sensitive in most systems to blockade by both atropine and -adrenergic antagonists, ACh that is released at the preganglionic terminal may act on a catecholamine-containing interneuron to stimulate the release of dopamine or norepinephrine; the catecholamine, in turn, produces hyperpolarization (an IPSP) of the ganglion cell (Eccles and Libet, 1961). At least in some ganglia, a muscarinic link in the IPSP is mediated through M2 muscarinic receptors (see Chapter 7: Muscarinic Receptor Agonists and Antagonists). Histochemical studies indicate that catecholamine-containing cells are present in ganglia. These include the dopamine- or norepinephrine-containing small, intensely fluorescent (SIF) cells and adrenergic nerve terminals. Details of the functional linkage between the SIF cells and the electrogenic mechanism of the IPSP remain to be resolved (Eränköet al., 1980).

The relative importance of the secondary pathways and even the nature of the modulating transmitters appear to differ among individual ganglia and between parasympathetic and sympathetic ganglia. A variety of peptides, including luteinizing hormone–releasing hormone, substance P, angiotensin, calcitonin gene-related peptide, vasoactive intestinal polypeptide, neuropeptide Y, and enkephalins, have been identified in ganglia by immunofluorescence. They appear localized to particular cell bodies, nerve fibers, or SIF cells; are released upon nerve stimulation; and are presumed to mediate the late slow EPSP (Dun, 1983; Elfvin et al., 1993). Other neurotransmitter substances, such as 5-hydroxytryptamine and gamma-aminobutyric acid, are known to modify ganglionic transmission. Precise details of their modulatory actions are not understood, but they appear to be most closely associated with the late slow EPSP and inhibition of the M current in various ganglia. It should be emphasized that the secondary synaptic events only modulate the initial EPSP. Conventional ganglionic blocking agents can inhibit ganglionic transmission completely; the same cannot be said for muscarinic antagonists or -adrenergic agonists (see Weight et al., 1979; Volle, 1980).

Drugs that stimulate cholinergic receptor sites on autonomic ganglia can be grouped into two major categories. The first group consists of drugs with nicotinic specificity, including nicotine itself. Their excitatory effects on ganglia are rapid in onset, are blocked by ganglionic nicotinic-receptor antagonists, and mimic the initial EPSP. The second group is composed of agents such as muscarine, McN-A-343, and methacholine. Their excitatory effects on ganglia are delayed in onset, blocked by atropine-like drugs, and mimic the slow EPSP.

Ganglionic blocking agents acting on the nicotinic receptor may be classified into two groups. The first group includes those drugs that initially stimulate the ganglia by an ACh-like action and then block them because of a persistent depolarization (e.g., nicotine); prolonged application of nicotine results in desensitization of the cholinergic receptor site and continued blockade. (See review by Volle, 1980.) The blockade of autonomic ganglia produced by the second group of blocking drugs, of which hexamethonium and trimethaphan can be regarded as prototypes, does not involve prior ganglionic stimulation or changes in ganglionic potentials. These agents impair transmission either by competing with ACh for ganglionic nicotinic receptor sites or by blocking the channel when it is open. Trimethaphan acts by competition with ACh, analogous to the mechanism of action of curare at the neuromuscular junction. Hexamethonium appears to block the channel after it opens. This action shortens the duration of current flow, since the open channel either becomes occluded or closes (Gurney and Rang, 1984). Regardless of the mechanism, the initial EPSP is blocked and ganglionic transmission is inhibited.

Ganglionic Stimulating Drugs

History

Two natural alkaloids, nicotine and lobeline, exhibit peripheral actions by stimulating autonomic ganglia. Nicotine (see Figure 9–5) was first isolated from leaves of tobacco, Nicotiana tabacum, by Posselt and Reiman in 1828, and Orfila initiated the first pharmacological studies of the alkaloid in 1843. Langley and Dickinson (1889) painted the superior cervical ganglion of rabbits with nicotine and demonstrated that its site of action was the ganglion, rather than the preganglionic or postganglionic nerve fiber. Lobeline, from Lobelia inflata, has many of the same actions as nicotine but is less potent.

Figure 9–5. Ganglionic Stimulants. 

A number of synthetic compounds also have prominent actions at ganglionic receptor sites. The actions of the 'onium' compounds, of which tetramethylammonium (TMA) is the simplest prototype, were explored in considerable detail in the last half of the nineteenth century and in the early twentieth century.

Nicotine

Nicotine is of considerable medical significance because of its toxicity, presence in tobacco, and propensity for conferring a dependence on its users. The chronic effects of nicotine and the untoward effects of the chronic use of tobacco are considered in Chapter 24: Drug Addiction and Drug Abuse.

Nicotine is one of the few natural liquid alkaloids. It is a colorless, volatile base (pKa= 8.5) that turns brown and acquires the odor of tobacco on exposure to air.

Pharmacological Actions

The complex and often unpredictable changes that occur in the body after administration of nicotine are due not only to its actions on a variety of neuroeffector and chemosensitive sites but also to the fact that the alkaloid can stimulate and desensitize receptors. The ultimate response of any one system represents the summation of stimulatory and inhibitory effects of nicotine. For example, the drug can increase heart rate by excitation of sympathetic or paralysis of parasympathetic cardiac ganglia, and it can slow heart rate by paralysis of sympathetic or stimulation of parasympathetic cardiac ganglia. In addition, the effects of the drug on the chemoreceptors of the carotid and aortic bodies and on brain centers influence heart rate, as do also the cardiovascular compensatory reflexes resulting from changes in blood pressure caused by nicotine. Finally, nicotine elicits a discharge of epinephrine from the adrenal medulla, and this hormone accelerates cardiac rate and raises blood pressure.

Peripheral Nervous System

The major action of nicotine consists initially of transient stimulation and subsequently of a more persistent depression of all autonomic ganglia. Small doses of nicotine stimulate the ganglion cells directly and may facilitate the transmission of impulses. When larger doses of the drug are applied, the initial stimulation is followed very quickly by a blockade of transmission. Whereas stimulation of the ganglion cells coincides with their depolarization, depression of transmission by adequate doses of nicotine occurs both during the depolarization and after it has subsided. Nicotine also possesses a biphasic action on the adrenal medulla; small doses evoke the discharge of catecholamines, and larger doses prevent their release in response to splanchnic nerve stimulation.

The effects of nicotine on the neuromuscular junction are similar to those on ganglia. However, with the exception of avian and denervated mammalian muscle, the stimulant phase is largely obscured by the rapidly developing paralysis. In the latter stage, nicotine also produces neuromuscular blockade by receptor desensitization.

Nicotine, like ACh, is known to stimulate a number of sensory receptors. These include mechanoreceptors that respond to stretch or pressure of the skin, mesentery, tongue, lung, and stomach; chemoreceptors of the carotid body; thermal receptors of the skin and tongue; and pain receptors. Prior administration of hexamethonium prevents the stimulation of the sensory receptors by nicotine but has little, if any, effect on the activation of the sensory receptors by physiological stimuli.

Central Nervous System

Nicotine markedly stimulates the CNS. Low doses produce weak analgesia; with higher doses, tremors leading to convulsions at toxic doses are evident. The excitation of respiration is a prominent action of nicotine; although large doses act directly on the medulla oblongata, smaller doses augment respiration reflexly by excitation of the chemoreceptors of the carotid and aortic bodies. Stimulation of the CNS with large doses is followed by depression, and death results from failure of respiration due to both central paralysis and peripheral blockade of muscles of respiration.

Nicotine induces vomiting by both central and peripheral actions. The central component of the vomiting response is due to stimulation of the emetic chemoreceptor trigger zone in the area postrema of the medulla oblongata. In addition, nicotine activates vagal and spinal afferent nerves that form the sensory input of the reflex pathways involved in the act of vomiting. Studies in isolated higher centers of the brain and spinal cord reveal that the primary sites of action of nicotine in the CNS are prejunctional, causing the release of other transmitters. Accordingly, the stimulatory and pleasure-reward actions of nicotine appear to result from release of excitatory amino acids, dopamine, and other biogenic amines from various CNS centers (MacDermott et al., 1999).

Chronic exposure to nicotine in several systems causes an increase in the density or number of nicotinic receptors (see Di Chiara et al., 2000; Stitzel et al., 2000). While the details of the mechanism are not yet understood, the response may be compensatory to the desensitization of receptor function by nicotine.

Cardiovascular System

When administered intravenously to dogs, nicotine characteristically produces an increase in heart rate and blood pressure. The latter is usually a more sustained response. In general, the cardiovascular responses to nicotine are due to stimulation of sympathetic ganglia and the adrenal medulla, together with the discharge of catecholamines from sympathetic nerve endings. Also contributing to the sympathomimetic response to nicotine is the activation of chemoreceptors of the aortic and carotid bodies, which reflexly results in vasoconstriction, tachycardia, and elevated blood pressure.

Gastrointestinal Tract

The combined activation of parasympathetic ganglia and cholinergic nerve endings by nicotine results in increased tone and motor activity of the bowel. Nausea, vomiting, and occasionally diarrhea are observed following systemic absorption of nicotine in an individual who has not been exposed to nicotine previously.

Exocrine Glands

Nicotine causes an initial stimulation of salivary and bronchial secretions that is followed by inhibition.

Absorption, Fate, and Excretion

Nicotine is readily absorbed from the respiratory tract, buccal membranes, and skin. Severe poisoning has resulted from percutaneous absorption. Being a relatively strong base, its absorption from the stomach is limited, and intestinal absorption is far more efficient. Nicotine in chewing tobacco, because it is more slowly absorbed than inhaled nicotine, has a longer duration of effect. The average cigarette contains 6 to 11 mg of nicotine and delivers about 1 to 3 mg of nicotine systemically to the smoker; bioavailability can increase as much as threefold with intensity of puffing and technique of the smoker (Henningfield, 1995; Benowitz, 1998). Nicotine is available in several dosage forms to help achieve abstinence from tobacco use. Efficacy primarily results from preventing a withdrawal or abstinence syndrome. Nicotine may be administered orally as a gum (nicotine polacrilex; NICORETTE), transdermal patch (NICODERM, HABITROL, others), a nasal spray (NICOTROL NS), and vapor inhaler (NICOTROL INHALER). The first two are most widely used, and the objective is to obtain a sustained plasma nicotine concentration lower than venous blood concentrations after smoking. Arterial blood concentrations immediately following inhalation can be as much as tenfold higher than venous concentrations. The efficacy of the above dosage forms in producing abstinence from smoking is enhanced when linked to counseling and motivational therapy (Henningfield, 1995; Fant et al., 1999; Benowitz, 1999; see also Chapter 24: Drug Addiction and Drug Abuse).

Approximately 80% to 90% of nicotine is altered in the body, mainly in the liver but also in the kidney and lung. Cotinine is the major metabolite, with nicotine-1'-N-oxide and 3-hydroxycotinine and conjugated metabolites found in lesser quantities (Benowitz, 1998). The profile of metabolites and the rate of metabolism appear to be similar in the smoker and nonsmoker. The half-life of nicotine following inhalation or parenteral administration is about 2 hours. Both nicotine and its metabolites are eliminated rapidly by the kidney. The rate of urinary excretion of nicotine is dependent upon the pH of the urine; excretion diminishes when the urine is alkaline. Nicotine also is excreted in the milk of lactating women who smoke; the milk of heavy smokers may contain 0.5 mg per liter.

Acute Nicotine Poisoning

Poisoning from nicotine may occur from accidental ingestion of nicotine-containing insecticide sprays or in children from ingestion of tobacco products. The acutely fatal dose of nicotine for an adult is probably about 60 mg of the base. Smoking tobacco usually contains 1% to 2% nicotine. Apparently, the gastric absorption of nicotine from tobacco taken by mouth is delayed because of slowed gastric emptying, so that vomiting caused by the central effect of the initially absorbed fraction may remove much of the tobacco remaining in the gastrointestinal tract.

The onset of symptoms of acute, severe nicotine poisoning is rapid; they include nausea, salivation, abdominal pain, vomiting, diarrhea, cold sweat, headache, dizziness, disturbed hearing and vision, mental confusion, and marked weakness. Faintness and prostration ensue; the blood pressure falls; breathing is difficult; the pulse is weak, rapid, and irregular; and collapse may be followed by terminal convulsions. Death may result within a few minutes from respiratory failure.

Therapy

Vomiting should be induced with syrup of ipecac or gastric lavage should be performed. Alkaline solutions should be avoided. A slurry of activated charcoal is then passed through the tube and left in the stomach. Respiratory assistance and treatment of shock may be necessary.

Other Ganglionic Stimulants

Stimulation of ganglia by tetramethylammonium (TMA) or 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP) differs from that produced by nicotine in that the initial stimulation is not followed by a dominant blocking action. DMPP is about three times more potent and slightly more ganglion-selective than nicotine. Although parasympathomimetic drugs stimulate ganglia, their effects usually are obscured by stimulation of other neuroeffector sites. McN-A-343 represents an exception to this; in certain tissues its primary action appears to occur at muscarinic M1 receptors in ganglia.

Ganglionic Blocking Drugs

The chemical diversity of compounds that block autonomic ganglia without causing prior stimulation is shown in Figure 9–6.

Figure 9–6. Ganglionic Blocking Agents. 

History and Structure–Activity Relationship

Although Marshall (1913) first described the 'nicotine paralyzing' action of tetraethylammonium (TEA) on ganglia, TEA was largely overlooked until Acheson and Moe (1946) published their definitive analyses of the effects of the ion on the cardiovascular system and autonomic ganglia. The bis-quaternary ammonium salts were developed and studied independently by Barlow and Ing (1948) and Paton and Zaimis (1952). The prototypical ganglionic blocking drug in this series, hexamethonium (C6), has a bridge of six methylene groups between the two quaternary nitrogen atoms (see Figure 9–6). It has minimal neuromuscular and muscarinic blocking activities.

Triethylsulfoniums, like the quaternary and bis-quaternary ammonium ions, possess ganglionic blocking actions. This knowledge led to the development of sulfonium ganglionic blocking agents such as trimethaphan (see Figure 9–6). Mecamylamine, a secondary amine, was introduced into therapy for hypertension in the mid-1950s.

Pharmacological Properties

Nearly all of the physiological alterations observed after the administration of ganglionic blocking agents can be anticipated with reasonable accuracy by a careful inspection of Figure 6–1 and by knowing which division of the autonomic nervous system exercises dominant control of various organs (Table 9–4). For example, blockade of sympathetic ganglia interrupts adrenergic control of arterioles and results in vasodilation, improved peripheral blood flow in some vascular beds, and a fall in blood pressure.

Generalized ganglionic blockade may result also in atony of the bladder and gastrointestinal tract, cycloplegia, xerostomia, diminished perspiration, and, by abolishing circulatory reflex pathways, postural hypotension. These changes represent the generally undesirable features of ganglionic blockade, which severely limit the therapeutic efficacy of ganglionic blocking agents.

Cardiovascular System

The importance of existing sympathetic tone in determining the degree to which blood pressure is lowered by ganglionic blockade is illustrated by the fact that blood pressure may be decreased only minimally in recumbent normotensive subjects but may fall markedly in sitting or standing subjects. Postural hypotension is a major problem in ambulatory patients receiving ganglionic blocking drugs; it is relieved to some extent by muscular activity and completely by recumbency.

Changes in cardiac rate following ganglionic blockade depend largely on existing vagal tone. In human beings, mild tachycardia usually accompanies the hypotension, a sign that indicates fairly complete ganglionic blockade. However, a decrease may occur if the heart rate is initially high.

Cardiac output often is reduced by ganglionic blocking drugs in patients with normal cardiac function as a consequence of diminished venous return resulting from venous dilation and peripheral pooling of blood. In patients with cardiac failure, ganglionic blockade frequently results in increased cardiac output due to a reduction in peripheral resistance. In hypertensive subjects, cardiac output, stroke volume, and left ventricular work are diminished.

Although total systemic vascular resistance is decreased in patients who receive ganglionic blocking agents, changes in blood flow and vascular resistance of individual vascular beds are variable. Reduction of cerebral blood flow is small unless mean systemic blood pressure falls below 50 to 60 mm Hg. Skeletal muscle blood flow is unaltered, but splanchnic and renal blood flow decrease following the administration of a ganglionic blocking agent.

Absorption, Fate, and Excretion

The absorption of quaternary ammonium and sulfonium compounds from the enteric tract is incomplete and unpredictable. This is due both to the limited ability of these ionized substances to penetrate cell membranes and to the depression of propulsive movements of the small intestine and gastric emptying. Although the absorption of mecamylamine is less erratic, a danger exists of reduced bowel activity leading to frank paralytic ileus.

After absorption, the quaternary ammonium and sulfonium blocking agents are confined primarily to the extracellular space and are excreted mostly unchanged by the kidney. Mecamylamine concentrates in the liver and kidney and is slowly excreted in an unchanged form.

Untoward Responses and Severe Reactions

Among the milder untoward responses observed are visual disturbances, dry mouth, conjunctival suffusion, urinary hesitancy, decreased potentia, subjective chilliness, moderate constipation, occasional diarrhea, abdominal discomfort, anorexia, heartburn, nausea, eructation and bitter taste, and the signs and symptoms of syncope caused by postural hypotension. More severe reactions include marked hypotension, constipation, syncope, paralytic ileus, urinary retention, and cycloplegia.

Therapeutic Uses

Of the ganglionic blocking agents that have appeared on the therapeutic scene, only mecamylamine (INVERSINE) and trimethaphan (ARFONAD) currently are utilized in the United States.

Ganglionic blocking agents have been supplanted by superior agents for the treatment of chronic hypertension (see Chapter 33: Antihypertensive Agents and the Drug Therapy of Hypertension). Alternative agents also are available for management of acute hypertensive crises (Murphy, 1995; see Chapter 33: Antihypertensive Agents and the Drug Therapy of Hypertension). A remaining use of ganglionic blockers in a hypertensive crisis is for the initial control of blood pressure in patients with acute dissecting aortic aneurysm, particularly when preexisting conditions make -adrenergic receptor antagonists a relative contraindication (Varon and Marik, 2000). Ganglionic blocking agents are well suited for this condition because they not only reduce blood pressure but also inhibit sympathetic reflexes and thereby reduce the rate of rise of pressure at the site of the tear. In such situations, trimethaphan is infused intravenously at a rate of 0.5 to 3 mg per minute with frequent monitoring of blood pressure. In the absence of symptoms or signs of renal, cerebral, or myocardial ischemia, the dose is increased until the pressure is in the low-normal range. Disappearance of pain is a sign that the dissection has stopped. A disadvantage of trimethaphan is the development of tolerance over the first 48 hours of therapy; this is in part related to fluid retention.

An additional therapeutic use of the ganglionic blocking agents is in the production of controlled hypotension; a reduction in blood pressure during surgery may be sought deliberately to minimize hemorrhage in the operative field, to reduce blood loss in various orthopedic procedures, and to facilitate surgery on blood vessels (Fukusaki et al., 1999). Trimethaphan, as an infusion, may be used as an alternative to or in combination with sodium nitroprusside, since some patients are resistant to the latter drug. Trimethaphan blunts the sympathoadrenal stimulation caused by nitroprusside and reduces the required dosage (Fahmy, 1985).

Trimethaphan can be used in the management of autonomic hyperreflexia or reflex sympathetic dystrophy. This syndrome typically is seen in patients with injuries of the upper spinal cord and results from a massive sympathetic discharge. Since normal central inhibition of the reflex is lacking in such patients, the spinal reflex is dominant.

Chapter 10. Catecholamines, Sympathomimetic Drugs, and Adrenergic Receptor Antagonists

Overview

Catecholamines released by the sympathetic nervous system and adrenal medulla are involved in regulating a host of physiological functions, particularly in integrating responses to a range of stresses that would otherwise threaten homeostatic mechanisms. Norepinephrine is the major neurotransmitter in the peripheral sympathetic nervous system, whereas epinephrine is the primary hormone secreted by the adrenal medulla in mammals. Activation of the sympathetic nervous system occurs in response to diverse stimuli, including physical activity, psychological stress, blood loss, and many other normal or disease-related provocations. Because the functions mediated or modified by the sympathetic nervous system are diverse, drugs that mimic, alter, or antagonize its activity are useful in the treatment of many clinical disorders, including hypertension, cardiovascular shock, arrhythmias, asthma, and anaphylactic reactions. Some of these indications are discussed elsewhere ( see Chapters 28: Drugs Used in the Treatment of Asthma, 32: Drugs Used for the Treatment of Myocardial Ischemia, 33: Antihypertensive Agents and the Drug Therapy of Hypertension, 34: Pharmacological Treatment of Heart Failure, and 35: Antiarrhythmic Drugs).

The physiological and metabolic responses that follow stimulation of sympathetic nerves in mammals usually are mediated by the neurotransmitter norepinephrine, although cotransmitters such as peptides potentially may contribute to sympathetic effects. As part of the response to stress, the adrenal medulla also is stimulated, resulting in elevation of the concentration of epinephrine in the circulation; epinephrine functions as a hormone, acting at distant sites in the circulation. The actions of these two catecholamines are very similar at some sites but differ significantly at others. For example, both compounds stimulate the myocardium; however, epinephrine dilates blood vessels to skeletal muscle, whereas norepinephrine causes constriction of blood vessels in skin, mucosa, and kidney.

Dopamine is a third naturally occurring catecholamine. Although it is found predominantly in the basal ganglia of the central nervous system (CNS), dopaminergic nerve endings and specific receptors for this catecholamine have been identified elsewhere in the CNS and in the periphery. The role of catecholamines in the CNS is detailed in Chapter 12: Neurotransmission and the Central Nervous System and elsewhere. As might be expected, sympathomimetic amines—naturally occurring catecholamines and drugs that mimic their actions—and adrenergic receptor antagonists—drugs that block the effects of sympathetic stimulation—constitute two of the more extensively studied groups of pharmacological agents.

Many of the actions of agonists or antagonists that activate or inhibit adrenergic receptors are understandable in terms of the known physiological effects of catecholamines. Whereas endogenous catecholamines such as epinephrine are sometimes used as drugs, most of the available agonists are structural analogs of epinephrine or norepinephrine. These synthetic compounds have a variety of advantages as therapeutic agents—such as oral bioavailability, prolonged duration of action, and specificity for particular subtypes of adrenergic receptors—which serve to enhance their therapeutic actions and to diminish potential adverse effects. The structure, cellular function, and physiological effects of adrenergic agonists and antagonists are outlined in this chapter.

Catecholamines and Sympathomimetic Drugs

Most of the actions of catecholamines and sympathomimetic agents can be classified into seven broad types: (1) a peripheral excitatory action on certain types of smooth muscle, such as those in blood vessels supplying skin, kidney, and mucous membranes, and on gland cells, such as those in salivary and sweat glands; (2) a peripheral inhibitory action on certain other types of smooth muscle, such as those in the wall of the gut, in the bronchial tree, and in blood vessels supplying skeletal muscle; (3) a cardiac excitatory action, responsible for an increase in heart rate and force of contraction; (4) metabolic actions, such as an increase in rate of glycogenolysis in liver and muscle and liberation of free fatty acids from adipose tissue; (5) endocrine actions, such as modulation (increasing or decreasing) of the secretion of insulin, renin, and pituitary hormones; (6) central nervous system (CNS) actions, such as respiratory stimulation and, with some of the drugs, an increase in wakefulness and psychomotor activity and a reduction in appetite; and (7) presynaptic actions that result in either inhibition or facilitation of the release of neurotransmitters such as norepinephrine and acetylcholine; physiologically, the inhibitory action is more important than the excitatory action. Many of these actions and the receptors that mediate them are summarized in Tables 6–1 and 6–3. Not all sympathomimetic drugs show each of the above types of action to the same degree. However, many of the differences in their effects are only quantitative, and descriptions of the effects of each compound would be unnecessarily repetitive. Therefore, the pharmacological properties of these drugs as a class are described in detail for the prototypical agent, epinephrine.

Appreciation of the pharmacological properties of the drugs that are described in this chapter is critically dependent on understanding the classification, distribution, and mechanism of action of the various subtypes of adrenergic receptors ( ) (Figure 10–1). This information is presented in Chapter 6: Neurotransmission: The Autonomic and Somatic Motor Nervous Systems.

Figure 10–1. Subtypes of Adrenergic Receptors. There are three known sub-types of each of the -, and -adrenergic receptor populations. All -adrenergic receptor subtypes are coupled to stimulation of adenylyl cyclase activity; similarly, all -adrenergic receptor subtypes affect the same effector systems, i.e., inhibition of adenylyl cyclase, activation of receptor-operated K+ channels, and inhibition of voltage-sensitive Ca2+ channels. In contrast, there is evidence that different -adrenergic receptor subpopulations couple to different effector systems. indicates a site for N-glycosylation; indicates a site for thio-acylation.

History

The pressor effect of adrenal extracts was first shown by Oliver and Schäfer in 1895. The active principle was named epinephrine by Abel in 1899 and synthesized independently by Stolz and Dakin (seeHartung, 1931). The development of our knowledge of epinephrine and norepinephrine as neurohumoral transmitters is outlined in Chapter 6: Neurotransmission: The Autonomic and Somatic Motor Nervous Systems. Barger and Dale (1910) studied the pharmacological activity of a large series of synthetic amines related to epinephrine and termed their action sympathomimetic. This important study determined the basic structural requirements for activity. When it was later found that cocaine or chronic denervation of effector organs reduced the responses to ephedrine and tyramine but enhanced the effects of epinephrine, it became clear that the differences between sympathomimetic amines were not simply quantitative. It was suggested that epinephrine acted directly on the effector cell, whereas ephedrine and tyramine had an indirect effect by acting on the nerve endings. The discovery that reserpine depletes tissues of norepinephrine (Bertler et al., 1956) was followed by evidence that tyramine and certain other sympathomimetic amines do not act on tissues from animals that have been treated with reserpine; this, too, indicated that they act by releasing endogenous norepinephrine (Burn and Rand, 1958).

Chemistry and Structure-Activity Relationship of Sympathomimetic Amines

-Phenylethylamine (Table 10–1) can be viewed as the parent compound of the sympathomimetic amines, consisting of a benzene ring and an ethylamine side chain. The structure permits substitutions to be made on the aromatic ring, the - and -carbon atoms, and the terminal amino group to yield a variety of compounds with sympathomimetic activity. Norepinephrine, epinephrine, dopamine, isoproterenol, and a few other agents have hydroxyl groups substituted at positions 3 and 4 of the benzene ring. Since o-dihydroxybenzene also is known as catechol, sympathomimetic amines with these hydroxyl substitutions in the aromatic ring are termed catecholamines.

Many directly acting sympathomimetic drugs influence both and receptors, but the ratio of activities varies among drugs in a continuous spectrum from predominantly activity (phenylephrine) to predominantly activity (isoproterenol). Despite the multiplicity of the sites of action of sympathomimetic amines, several generalizations can be made (seeTable 10–1).

Separation of Aromatic Ring and Amino Group

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

Substitution on the Amino Group

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

Substitution on the Aromatic Nucleus

Maximal and activity depends on the presence of hydroxyl groups on positions 3 and 4. When one or both of these groups are absent, with no other aromatic substitution, the overall potency is reduced. Phenylephrine is thus less potent than epinephrine at both and receptors, with activity almost completely absent. Studies of the -adrenergic receptor suggest that the hydroxyl groups on serine residues 204 and 207 probably form hydrogen bonds with the catechol hydroxyl groups at positions 3 and 4, respectively (Strader et al., 1989). It also appears that aspartate 113 is a point of electrostatic interaction with the amine group on the ligand. Since the serines are in the fifth membrane-spanning region and the aspartate is in the third (seeChapter 6: Neurotransmission: The Autonomic and Somatic Motor Nervous Systems), it is likely that catecholamines bind parallel to the plane of the membrane, forming a bridge between the two membrane spans. However, models involving dopamine receptors suggest alternative possibilities (Hutchins, 1994).

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

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

Catecholamines have only a brief duration of action and are ineffective when administered orally, because they are rapidly inactivated in the intestinal mucosa and in the liver before reaching the systemic circulation (seeChapter 6: Neurotransmission: The Autonomic and Somatic Motor Nervous Systems). Compounds without one or both hydroxyl substituents are not acted upon by catechol-O-methyltransferase (COMT), and their oral effectiveness and duration of action are enhanced.

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

Substitution on the -Carbon Atom

This substitution blocks oxidation by monoamine oxidase (MAO), greatly prolonging the duration of action of noncatecholamines because their degradation depends largely on the action of MAO. The duration of action of drugs such as ephedrine or amphetamine is thus measured in hours rather than in minutes. Similarly, compounds with an -methyl substituent persist in the nerve terminal and are more likely to release norepinephrine from storage sites. Agents such as metaraminol exhibit a greater degree of indirect sympathomimetic activity.

Substitution on the Carbon

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

Optical Isomerism

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

Physiological Basis of Adrenergic Receptor Function

An important factor in the response of any cell or organ to sympathomimetic amines is the density and proportion of - and -adrenergic receptors. For example, norepinephrine has relatively little capacity to increase bronchial airflow, since the receptors in bronchial smooth muscle are largely of the subtype. In contrast, isoproterenol and epinephrine are potent bronchodilators. Cutaneous blood vessels physiologically express almost exclusively receptors; thus, norepinephrine and epinephrine cause constriction of such vessels, whereas isoproterenol has little effect. The smooth muscle of blood vessels that supply skeletal muscles has both and receptors; activation of receptors causes vasodilation, and stimulation of receptors constricts these vessels. In such vessels, the threshold concentration for activation of receptors by epinephrine is lower than that for receptors, but when both types of receptors are activated at high concentrations of epinephrine, the response to receptors predominates. Physiological concentrations of epinephrine cause primarily vasodilation.

The ultimate response of a target organ to sympathomimetic amines is dictated not only by the direct effects of the agents but also by the reflex homeostatic adjustments of the organism. One of the most striking effects of many sympathomimetic amines is a rise in arterial blood pressure caused by stimulation of vascular receptors. This stimulation elicits compensatory reflexes which are mediated by the carotid aortic baroreceptor system. As a result, sympathetic tone is diminished and vagal tone is enhanced; each of these responses leads to slowing of the heart rate. This reflex effect is of special importance for drugs that have little capacity to activate -adrenergic receptors directly. With diseases such as atherosclerosis, which may impair baroreceptor mechanisms, the effects of sympathomimetic drugs may be magnified (Chapleau et al., 1995).

Indirectly Acting Sympathomimetic Drugs

For many years, it was presumed that sympathomimetic amines produced their effects by acting directly on adrenergic receptors. However, this notion was dispelled by the finding that the effects of tyramine and many other noncatecholamines were reduced or abolished after chronic postganglionic denervation or treatment with cocaine or reserpine. Under these circumstances, the effects of exogenously administered epinephrine, and especially norepinephrine, often were enhanced. These observations led to the proposal that tyramine and related amines act indirectly, following uptake into the adrenergic nerve terminal, by displacing norepinephrine from storage sites in the synaptic vesicles or from extravesicular binding sites. Norepinephrine could then exit from the adrenergic nerve terminal and interact with receptors to produce sympathomimetic effects. The depletion of tissue stores of catecholamines that follows treatment with reserpine or degeneration of adrenergic nerve terminals would explain the lack of effect of tyramine under these conditions. In the presence of cocaine, the high-affinity neuronal transport system for catecholamines and certain congeners is inhibited, and tyramine and related amines are unable to enter the adrenergic nerve terminal. In this manner, cocaine inhibits the actions of indirectly acting sympathomimetic amines while potentiating the effects of directly acting agents that are normally removed from the synaptic cleft by this transport system (seeChapter 6: Neurotransmission: The Autonomic and Somatic Motor Nervous Systems).

In assessing the proportion of direct and indirect actions of a sympathomimetic amine, the most common experimental procedure is to compare the dose-response curves for the agent on a particular target tissue before and after treatment with reserpine (Trendelenburg, 1972). Those drugs whose actions are essentially unaltered after treatment with reserpine are classified as directly acting sympathomimetic amines (e.g., norepinephrine, phenylephrine), whereas those whose actions are abolished are termed indirectly acting (e.g., tyramine). Many agents exhibit some degree of residual sympathomimetic activity after the administration of reserpine, but higher doses of these amines are required to produce comparable effects. These are classified as mixed-acting sympathomimetic amines; that is, they have both direct and indirect actions. The proportion of direct and indirect actions can vary considerably among different tissues and species. In some cases, relatively little is known about these properties in human beings.

Since the actions of norepinephrine are more marked on and receptors than on receptors, many noncatecholamines that release norepinephrine have predominantly -receptor–mediated and cardiac effects. However, certain noncatecholamines with both direct and indirect effects on adrenergic receptors show significant activity and are used clinically for these effects. Thus, ephedrine, although dependent on release of norepinephrine for some of its effects, relieves bronchospasm by its action on receptors in bronchial muscle, an effect not seen with norepinephrine. It also must be recalled that some noncatecholamines—phenylephrine, for example—act primarily and directly on effector cells. It is therefore impossible to predict precisely the characteristic effects of noncatecholamines simply on the basis that they may provoke the release of at least some norepinephrine.

False-Transmitter Concept

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

This hypothesis, known as the false-transmitter concept, is a possible explanation for some of the effects of inhibitors of MAO. Phenylethylamines normally are synthesized in the gastrointestinal tract as a result of the action of bacterial tyrosine decarboxylase. The tyramine formed in this fashion usually is oxidatively deaminated in the gastrointestinal tract and the liver, and the amine does not reach the systemic circulation in significant concentrations. However, when a MAO inhibitor is administered, tyramine may be absorbed systemically and is transported into adrenergic nerve terminals, where its catabolism is again prevented because of the inhibition of MAO at this site; it is then -hydroxylated to octopamine and stored in the vesicles in this form. As a consequence, norepinephrine gradually is displaced, and stimulation of the nerve terminal results in the release of a relatively small amount of norepinephrine along with a fraction of octopamine. The latter amine has relatively little ability to activate either - or -adrenergic receptors. Thus, a functional impairment of sympathetic transmission parallels long-term administration of MAO inhibitors.

Despite such functional impairment, patients who have received MAO inhibitors may experience severe hypertensive crises if they ingest cheese, beer, or red wine. These and related foods, which are produced by fermentation, contain a large quantity of tyramine and, to a lesser degree, other phenylethylamines. When gastrointestinal and hepatic MAO are inhibited, the large quantity of tyramine that is ingested is absorbed rapidly and reaches the systemic circulation in high concentration. A massive and precipitous release of norepinephrine can result, with consequent hypertension that can be severe enough to cause myocardial infarction or a stroke. The properties of various MAO inhibitors (reversible or irreversible; selective or nonselective at MAO-A and MAO-B) are discussed in Chapter 19: Drugs and the Treatment of Psychiatric Disorders: Depression and Anxiety Disorders.

Endogenous Catecholamines

Epinephrine

Epinephrine (adrenaline) is a potent stimulant of both - and -adrenergic receptors, and its effects on target organs are thus complex. Most of the responses listed in Table 6–1 are seen after injection of epinephrine, although the occurrence of sweating, piloerection, and mydriasis depends on the physiological state of the subject. Particularly prominent are the actions on the heart and on vascular and other smooth muscle.

Blood Pressure

Epinephrine is one of the most potent vasopressor drugs known. If a pharmacological dose is given rapidly by an intravenous route, it evokes a characteristic effect on blood pressure, which rises rapidly to a peak that is proportional to the dose. The increase in systolic pressure is greater than the increase in diastolic pressure, so that the pulse pressure increases. As the response wanes, the mean pressure may fall below normal before returning to control levels.

The mechanism of the rise in blood pressure due to epinephrine is threefold: (1) a direct myocardial stimulation that increases the strength of ventricular contraction (positive inotropic action); (2) an increased heart rate (positive chronotropic action); and (3) vasoconstriction in many vascular beds—especially in the precapillary resistance vessels of skin, mucosa, and kidney—along with marked constriction of the veins. The pulse rate, at first accelerated, may be slowed markedly at the height of the rise of blood pressure by compensatory vagal discharge. Small doses of epinephrine (0.1 g/kg) may cause the blood pressure to fall. The depressor effect of small doses and the biphasic response to larger doses are due to greater sensitivity to epinephrine of vasodilator receptors than of constrictor receptors.

The effects are somewhat different when the drug is given by slow intravenous infusion or by subcutaneous injection. Absorption of epinephrine after subcutaneous injection is slow due to local vasoconstrictor action; the effects of doses as large as 0.5 to 1.5 mg can be duplicated by intravenous infusion at a rate of 10 to 30 g per minute. There is a moderate increase in systolic pressure due to increased cardiac contractile force and a rise in cardiac output (Figure 10–2). Peripheral resistance decreases, owing to a dominant action on receptors of vessels in skeletal muscle, where blood flow is enhanced; as a consequence, diastolic pressure usually falls. Since the mean blood pressure is not, as a rule, greatly elevated, compensatory baroreceptor reflexes do not appreciably antagonize the direct cardiac actions. Heart rate, cardiac output, stroke volume, and left ventricular work per beat are increased as a result of direct cardiac stimulation and increased venous return to the heart, which is reflected by an increase in right atrial pressure. At slightly higher rates of infusion, there may be no change or a slight rise in peripheral resistance and diastolic pressure, depending on the dose and the resultant ratio of to responses in the various vascular beds; compensatory reflexes also may come into play. The details of the effects of intravenous infusion of epinephrine, norepinephrine, and isoproterenol in human beings are compared in Table 10–2 and Figure 10–2.

Figure 10–2. Effects of Intravenous Infusion of Norepinephrine, Epinephrine, or Isoproterenol in Human Beings. (Modified from Allwood Et Al., 1963, with Permission.) 

Vascular Effects

The chief vascular action of epinephrine is exerted on the smaller arterioles and precapillary sphincters, although veins and large arteries also respond to the drug. Various vascular beds react differently, which results in a substantial redistribution of blood flow.

Injected epinephrine markedly decreases cutaneous blood flow, constricting precapillary vessels and small venules. Cutaneous vasoconstriction accounts for a marked decrease in blood flow in the hands and feet. The 'after congestion' of mucosae following the vasoconstriction from locally applied epinephrine probably is due to changes in vascular reactivity as a result of tissue hypoxia rather than to -receptor activity of the drug on mucosal vessels.

Blood flow to skeletal muscles is increased by therapeutic doses in human beings. This is due in part to a powerful -receptor vasodilator action that is only partially counterbalanced by a vasoconstrictor action on the receptors that also are present in the vascular bed. If an -adrenergic receptor antagonist is given, the vasodilation in muscle is more pronounced, the total peripheral resistance is decreased, and the mean blood pressure falls (epinephrine reversal). After the administration of a nonselective -adrenergic receptor antagonist, only vasoconstriction occurs, and the administration of epinephrine is associated with a considerable pressor effect.

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

Doses of epinephrine that have little effect on mean arterial pressure consistently increase renal vascular resistance and reduce renal blood flow by as much as 40%. All segments of the renal vascular bed contribute to the increased resistance. Since the glomerular filtration rate is only slightly and variably altered, the filtration fraction is consistently increased. Excretion of Na+, K+, and Cl is decreased; urine volume may be increased, decreased, or unchanged. Maximal tubular reabsorptive and excretory capacities are unchanged. The secretion of renin is increased as a consequence of a direct action of epinephrine on receptors in the juxtaglomerular apparatus.

Arterial and venous pulmonary pressures are raised. Although direct pulmonary vasoconstriction occurs, redistribution of blood from the systemic to the pulmonary circulation, due to constriction of the more powerful musculature in the systemic great veins, doubtless plays an important part in the increase in pulmonary pressure. Very high concentrations of epinephrine may cause pulmonary edema precipitated by elevated pulmonary capillary filtration pressure and possibly by 'leaky' capillaries.

Coronary blood flow is enhanced by epinephrine or by cardiac sympathetic stimulation under physiological conditions. The increased flow occurs even with doses that do not increase the aortic blood pressure and is the result of two factors. The first is the increased relative duration of diastole at higher heart rates (see below); this is partially offset by decreased blood flow during systole because of more forceful contraction of the surrounding myocardium and an increase in mechanical compression of the coronary vessels. The increased flow during diastole is further enhanced if aortic blood pressure is elevated by epinephrine, and, as a consequence, total coronary flow may be increased. The second factor is a metabolic dilator effect that results from the increased strength of contraction and myocardial oxygen consumption due to the direct effects of epinephrine on cardiac myocytes. This vasodilation is mediated in part by adenosine released from cardiac myocytes, which tends to override a direct vasoconstrictor effect of epinephrine that results from activation of receptors in coronary vessels.

Cardiac Effects

Epinephrine is a powerful cardiac stimulant. It acts directly on the predominant receptors of the myocardium and of the cells of the pacemaker and conducting tissues; and receptors also are present in the heart, although there are considerable species differences. Considerable recent interest has focused on the role of and receptors in the human heart, especially in heart failure. The heart rate increases, and the rhythm often is altered. Cardiac systole is shorter and more powerful, cardiac output is enhanced, and the work of the heart and its oxygen consumption are markedly increased. Cardiac efficiency (work done relative to oxygen consumption) is lessened. Direct responses to epinephrine include increases in contractile force, accelerated rate of rise of isometric tension, enhanced rate of relaxation, decreased time to peak tension, increased excitability, acceleration of the rate of spontaneous beating, and induction of automaticity in specialized regions of the heart.

In accelerating the heart, epinephrine preferentially shortens systole so that the duration of diastole usually is not reduced. Indeed, activation of receptors increases the rate of relaxation of ventricular muscle. Epinephrine speeds the heart by accelerating the slow depolarization of sinoatrial (SA) nodal cells that takes place during diastole, i.e., during phase 4 of the action potential (seeChapter 35: Antiarrhythmic Drugs). Consequently, the transmembrane potential of the pacemaker cells rises more rapidly to the threshold level at which the action potential is initiated. The amplitude of the action potential and the maximal rate of depolarization (phase 0) also are increased. A shift in the location of the pacemaker within the SA node often occurs, owing to activation of latent pacemaker cells. In Purkinje fibers, epinephrine also accelerates diastolic depolarization and may cause activation of latent pacemaker cells. These changes do not occur in atrial and ventricular muscle fibers, where epinephrine has little effect on the stable, phase 4 membrane potential after repolarization. If large doses of epinephrine are given, premature ventricular systoles occur and may herald more serious ventricular arrhythmias. This rarely is seen with conventional doses in human beings, but ventricular extrasystoles, tachycardia, or even fibrillation may be precipitated by release of endogenous epinephrine when the heart has been sensitized to this action of epinephrine by certain anesthetics or in cases of myocardial infarction. The mechanism of induction of these cardiac arrhythmias is not clear.

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

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

Epinephrine normally shortens the refractory period of the human atrioventricular (AV) node by direct effects on the heart, although doses of epinephrine that slow the heart through reflex vagal discharge may indirectly tend to prolong it. Epinephrine also decreases the grade of AV block that occurs as a result of disease, drugs, or vagal stimulation. Supraventricular arrhythmias are apt to occur from the combination of epinephrine and cholinergic stimulation. Depression of sinus rate and AV conduction by vagal discharge probably plays a part in epinephrine-induced ventricular arrhythmias, since various drugs that block the vagal effect confer some protection. The action of epinephrine in enhancing cardiac automaticity and its action in causing arrhythmias are effectively antagonized by -adrenergic receptor antagonists such as propranolol. However, receptors exist in most regions of the heart, and their activation prolongs the refractory period and strengthens myocardial contractions.

Cardiac arrhythmias have been seen in patients after inadvertent intravenous administration of conventional subcutaneous doses of epinephrine. Ventricular premature systoles can appear, which may be followed by multifocal ventricular tachycardia or ventricular fibrillation. Pulmonary edema also may occur.

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

Effects on Smooth Muscles

The effects of epinephrine on the smooth muscles of different organs and systems depend on the type of adrenergic receptor in the muscle (seeTable 6–1). The effects on vascular smooth muscle are of major physiological importance, whereas those on gastrointestinal smooth muscle are relatively minor. Gastrointestinal smooth muscle is, in general, relaxed by epinephrine. This effect is due to activation of both - and -adrenergic receptors. Intestinal tone and the frequency and amplitude of spontaneous contractions are reduced. The stomach usually is relaxed and the pyloric and ileocecal sphincters are contracted, but these effects depend on the preexisting tone of the muscle. If tone already is high, epinephrine causes relaxation; if low, contraction.

The responses of uterine muscle to epinephrine vary with species, phase of the sexual cycle, state of gestation, and dose given. Epinephrine contracts strips of pregnant or nonpregnant human uterus in vitro by interaction with receptors. The effects of epinephrine on the human uterus in situ, however, differ. During the last month of pregnancy and at parturition, epinephrine inhibits uterine tone and contractions. -Selective agonists, such as ritodrine or terbutaline, have been used to delay premature labor, although their efficacy is limited. Effects of these and other drugs on the uterus are discussed later in this chapter.

Epinephrine relaxes the detrusor muscle of the bladder as a result of activation of receptors and contracts the trigone and sphincter muscles owing to its -agonist activity. This can result in hesitancy in urination and may contribute to retention of urine in the bladder. Activation of smooth muscle contraction in the prostate promotes urinary retention.

Respiratory Effects

Epinephrine affects respiration primarily by relaxing bronchial muscle. It has a powerful bronchodilator action, most evident when bronchial muscle is contracted because of disease, as in bronchial asthma, or in response to drugs or various autacoids. In such situations, epinephrine has a striking therapeutic effect as a physiological antagonist to substances that cause bronchoconstriction.

The beneficial effects of epinephrine in asthma also may arise from inhibition of antigen-induced release of inflammatory mediators from mast cells, and to a lesser extent from diminution of bronchial secretions and congestion within the mucosa. Inhibition of mast cell secretion is mediated by -adrenergic receptors, while the effects on the mucosa are mediated by receptors; however, other drugs, such as glucocorticoids and leukotriene antagonists, have much more profound antiinflammatory effects in asthma (seeChapter 28: Drugs Used in the Treatment of Asthma).

Effects on the Central Nervous System

Because of the inability of this rather polar compound to enter the CNS, epinephrine in conventional therapeutic doses is not a powerful CNS stimulant. While the drug may cause restlessness, apprehension, headache, and tremor in many persons, these effects in part may be secondary to the effects of epinephrine on the cardiovascular system, skeletal muscles, and intermediary metabolism; that is, they may be the result of somatic manifestations of anxiety. Some other sympathomimetic drugs more readily cross the blood–brain barrier.

Metabolic Effects

Epinephrine has a number of important influences on metabolic processes. It elevates the concentrations of glucose and lactate in blood by mechanisms described in Chapter 6: Neurotransmission: The Autonomic and Somatic Motor Nervous Systems. Insulin secretion is inhibited through an interaction with receptors and is enhanced by activation of receptors; the predominant effect seen with epinephrine is inhibition. Glucagon secretion is enhanced by an action on the receptors of the cells of pancreatic islets. Epinephrine also decreases the uptake of glucose by peripheral tissues, at least in part because of its effects on the secretion of insulin, but also possibly due to direct effects on skeletal muscle. Glycosuria rarely occurs. The effect of epinephrine to stimulate glycogenolysis in most tissues and in most species involves receptors (seeChapter 6: Neurotransmission: The Autonomic and Somatic Motor Nervous Systems).

Epinephrine raises the concentration of free fatty acids in blood by stimulating receptors in adipocytes. The result is activation of triglyceride lipase, which accelerates the breakdown of triglycerides to form free fatty acids and glycerol. The calorigenic action of epinephrine (increase in metabolism) is reflected in human beings by an increase of 20% to 30% in oxygen consumption after conventional doses. This effect is mainly due to enhanced breakdown of triglycerides in brown adipose tissue, providing an increase in oxidizable substrate (seeChapter 6: Neurotransmission: The Autonomic and Somatic Motor Nervous Systems).

Miscellaneous Effects

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

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

Mydriasis is readily seen during physiological sympathetic stimulation but not when epinephrine is instilled into the conjunctival sac of normal eyes. However, epinephrine usually lowers intraocular pressure from normal levels and in wide-angle glaucoma; the mechanism of this effect is not clear, but both reduced production of aqueous humor due to vasoconstriction and enhanced outflow probably occur (seeChapter 66: Ocular Pharmacology).

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

Epinephrine promotes a fall in plasma K+ largely due to stimulation of K+ uptake into cells, particularly skeletal muscle, due to activation of receptors. This is associated with decreased renal K+ excretion. These receptors have been exploited in the management of hyperkalemic familial periodic paralysis, which is characterized by episodic flaccid paralysis, hyperkalemia, and depolarization of skeletal muscle. The -selective agonist albuterol apparently is able to ameliorate the impairment in the ability of the muscle to accumulate and retain K+.

Large or repeated doses of epinephrine or other sympathomimetic amines given to experimental animals lead to damage to arterial walls and myocardium, which is so severe as to cause the appearance of necrotic areas in the heart indistinguishable from myocardial infarcts. The mechanism of this injury is not yet clear, but - and -receptor antagonists and Ca2+ channel blockers may afford substantial protection against the damage. Similar lesions occur in many patients with pheochromocytoma or after prolonged infusions of norepinephrine.

Absorption, Fate, and Excretion

As indicated above, epinephrine is not effective after oral administration, because it is rapidly conjugated and oxidized in the gastrointestinal mucosa and liver. Absorption from subcutaneous tissues occurs relatively slowly because of local vasoconstriction and the rate may be further decreased by systemic hypotension, for example in a patient with shock. Absorption is more rapid after intramuscular injection. In emergencies, it may be necessary in some cases to administer epinephrine intravenously. When relatively concentrated solutions (1%) are nebulized and inhaled, the actions of the drug largely are restricted to the respiratory tract; however, systemic reactions such as arrhythmias may occur, particularly if larger amounts are used.

Epinephrine is rapidly inactivated in the body. The liver, which is rich in both of the enzymes responsible for destroying circulating epinephrine (COMT and MAO), is particularly important in this regard (seeFigure 6–5). Although only small amounts appear in the urine of normal persons, the urine of patients with pheochromocytoma may contain relatively large amounts of epinephrine, norepinephrine, and their metabolites.

Epinephrine is available in a variety of formulations geared for different clinical indications and routes of administration, such as by injection (usually subcutaneously but sometimes intravenously), by inhalation, or topically. Several practical points are worth noting. First, epinephrine is unstable in alkaline solution; when exposed to air or light, it turns pink from oxidation to adrenochrome and then brown from formation of polymers. Epinephrine injection is available in 1:1,000, 1:10,000, and 1:100,000 solutions. The usual adult dose given subcutaneously ranges from 0.3 mg to 0.5 mg. The intravenous route is used cautiously if an immediate and reliable effect is mandatory. If the solution is given by vein, it must be adequately diluted and injected very slowly. The dose is seldom as much as 0.25 mg, except for cardiac arrest, when larger doses may be required. Epinephrine suspensions (e.g., SUS-PHRINE) are used to slow subcutaneous absorption and must never be injected intravenously. Also, a 1% (1:100) formulation is available for administration via inhalation; every precaution must be taken not to confuse this 1:100 solution with the 1:1000 solution designed for parenteral administration, because inadvertent injection of the 1:100 solution can be fatal.

Toxicity, Adverse Effects, and Contraindications

Epinephrine may cause disturbing reactions, such as restlessness, throbbing headache, tremor, and palpitations. The effects rapidly subside with rest, quiet, recumbency, and reassurance.

More serious reactions include cerebral hemorrhage and cardiac arrhythmias. The use of large doses or the accidental, rapid intravenous injection of epinephrine may result in cerebral hemorrhage from the sharp rise in blood pressure. Ventricular arrhythmias may follow the administration of epinephrine. Angina may be induced by epinephrine in patients with coronary artery disease.

The use of epinephrine generally is contraindicated in patients who are receiving nonselective -adrenergic receptor blocking drugs, since its unopposed actions on vascular -adrenergic receptors may lead to severe hypertension and cerebral hemorrhage.

Therapeutic Uses

Epinephrine has limited clinical uses. In general, these are based on the actions of the drug on blood vessels, heart, and bronchial muscle. In the past, the most common use of epinephrine was to relieve respiratory distress due to bronchospasm; however, -selective agonists now are preferred. A major use is to provide rapid relief of hypersensitivity reactions, including anaphylaxis, to drugs and other allergens. Also, epinephrine may be used to prolong the action of local anesthetics, presumably by decreasing local blood flow. Its cardiac effects may be of use in restoring cardiac rhythm in patients with cardiac arrest due to various causes. It also is used as a topical hemostatic agent on bleeding surfaces such as in the mouth or in bleeding peptic ulcers during endoscopy of the stomach/duodenum. Systemic absorption of the drug can occur with dental application. In addition, inhalation of epinephrine may be useful in the treatment of postintubation and infectious croup. The therapeutic uses of epinephrine are discussed later in this chapter, in relation to other sympathomimetic drugs.

Norepinephrine

Norepinephrine (levarterenol, l-noradrenaline, l--[3,4- dihydroxyphenyl]--aminoethanol) is the major chemical mediator liberated by mammalian postganglionic adrenergic nerves. It differs from epinephrine only by lacking the methyl substitution in the amino group (seeTable 10–1). Norepinephrine constitutes 10% to 20% of the catecholamine content of human adrenal medulla and as much as 97% in some pheochromocytomas, which may not express the enzyme phenylethanolamine-N-methyltransferase. The history of its discovery and its role as a neurohumoral mediator are discussed in Chapter 6: Neurotransmission: The Autonomic and Somatic Motor Nervous Systems.

Pharmacological Properties

The pharmacological actions of norepinephrine and epinephrine have been extensively compared in vivo and in vitro (seeTable 10–2). Both drugs are direct agonists on effector cells, and their actions differ mainly in the ratio of their effectiveness in stimulating and receptors. They are approximately equipotent in stimulating receptors. Norepinephrine is a potent agonist at receptors and has relatively little action on receptors; however, it is somewhat less potent than epinephrine on the receptors of most organs.

Cardiovascular Effects

The cardiovascular effects of an intravenous infusion of 10 g of norepinephrine per minute in human beings are shown in Figure 10–2. Systolic and diastolic pressures and, usually, pulse pressure are increased. Cardiac output is unchanged or decreased, and total peripheral resistance is raised. Compensatory vagal reflex activity slows the heart, overcoming a direct cardioaccelerator action, and stroke volume is increased. The peripheral vascular resistance increases in most vascular beds, and blood flow is reduced to the kidneys. Norepinephrine constricts mesenteric vessels and reduces splanchnic and hepatic blood flow. Coronary flow usually is increased, probably owing both to indirectly induced coronary dilation, as with epinephrine, and to elevated blood pressure. However, patients with Prinzmetal's variant angina may be supersensitive to the -adrenergic vasoconstrictor effects of norepinephrine (seeChapter 32: Drugs Used for the Treatment of Myocardial Ischemia).

Unlike epinephrine, small doses of norepinephrine do not cause vasodilation or lower blood pressure, since the blood vessels of skeletal muscle constrict rather than dilate; -adrenergic receptor blocking agents therefore abolish the pressor effects but do not cause significant reversal, i.e., hypotension.

Other Effects

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

Absorption, Fate, and Excretion

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

Toxicity, Adverse Effects, and Precautions

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

Care must be taken that necrosis and sloughing do not occur at the site of intravenous injection owing to extravasation of the drug. The infusion should be made high in the limb, preferably through a long plastic cannula extending centrally. Impaired circulation at injection sites, with or without extravasation of norepinephrine, may be relieved by infiltrating the area with phentolamine, an -receptor antagonist. Blood pressure must be determined frequently during the infusion and particularly during adjustment of the rate of the infusion. Reduced blood flow to organs such as kidney and intestines is a constant danger with the use of norepinephrine.

Therapeutic Uses and Status

Norepinephrine (norepinephrine bitartrate, LEVOPHED) has only limited therapeutic value. The use of it and other sympathomimetic amines in shock is discussed later in this chapter. In the treatment of low blood pressure, the dose is titrated to the desired pressor response.

Dopamine

Dopamine (3,4-dihydroxyphenylethylamine) (seeTable 10–1) is the immediate metabolic precursor of norepinephrine and epinephrine; it is a central neurotransmitter particularly important in the regulation of movement (Chapters 12: Neurotransmission and the Central Nervous System, 20: Drugs and the Treatment of Psychiatric Disorders: Psychosis and Mania, and 22: Treatment of Central Nervous System Degenerative Disorders) and possesses important intrinsic pharmacological properties. Dopamine is a substrate for both MAO and COMT and thus is ineffective when administered orally. Classification of dopamine receptors is described in Chapter 22: Treatment of Central Nervous System Degenerative Disorders.

Pharmacological Properties

Cardiovascular Effects

The cardiovascular effects of dopamine are mediated by several distinct types of receptors that vary in their affinity for dopamine (Goldberg and Rajfer, 1985). At low concentrations, the primary interaction of dopamine is with vascular D1-dopaminergic receptors, especially in the renal, mesenteric, and coronary beds. By activating adenylyl cyclase and raising intracellular concentrations of cyclic AMP, D1-receptor stimulation leads to vasodilation (Missale et al., 1998). Infusion of low doses of dopamine causes an increase in glomerular filtration rate, renal blood flow, and Na+ excretion. As a consequence, dopamine has pharmacologically appropriate effects in the management of states of low cardiac output associated with compromised renal function, such as severe congestive heart failure.

At somewhat higher concentrations, dopamine exerts a positive inotropic effect on the myocardium, acting on -adrenergic receptors. Dopamine also causes the release of norepinephrine from nerve terminals, which contributes to its effects on the heart. Tachycardia is less prominent during infusion of dopamine than of isoproterenol (see below). Dopamine usually increases systolic blood pressure and pulse pressure and either has no effect on diastolic blood pressure or increases it slightly. Total peripheral resistance usually is unchanged when low or intermediate doses of dopamine are given, probably because of the ability of dopamine to reduce regional arterial resistance in some vascular beds, such as mesenteric and renal, while causing only minor increases in other vascular beds. At high concentrations, dopamine activates vascular -adrenergic receptors, leading to more general vasoconstriction.

Other Effects

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

Precautions, Adverse Reactions, and Contraindications

Before dopamine is administered to patients in shock, hypovolemia should be corrected by transfusion of whole blood, plasma, or other appropriate fluid. Untoward effects due to overdosage generally are attributable to excessive sympathomimetic activity (although this also may be the response to worsening shock). Nausea, vomiting, tachycardia, anginal pain, arrhythmias, headache, hypertension, and peripheral vasoconstriction may be encountered during an infusion of dopamine. Extravasation of large amounts of dopamine during infusion may cause ischemic necrosis and sloughing. Rarely, gangrene of the fingers or toes has followed the prolonged infusion of the drug.



Dopamine should be avoided or used at a much reduced dosage (one-tenth or less) if the patient has received a MAO inhibitor. Careful adjustment of dosage also is necessary for the patient who is taking tricyclic antidepressants, as responses may be particularly variable.

Therapeutic Uses

Dopamine (dopamine hydrochloride;INTROPIN) is used in the treatment of severe congestive failure, particularly in patients with oliguria and with low or normal peripheral vascular resistance. The drug also may improve physiological parameters in the treatment of cardiogenic and septic shock. While dopamine may acutely improve cardiac and renal function in severely ill patients with chronic heart disease or renal failure, there is relatively little evidence supporting long-term changes in clinical outcome (Marik and Iglesias, 1999). The management of shock is discussed later in this chapter.

Dopamine hydrochloride is used only intravenously. The drug is initially administered at a rate of 2 to 5 g/kg per minute; this rate may be increased gradually up to 20 to 50 g/kg per minute or more as the clinical situation dictates. During the infusion, patients require clinical assessment of myocardial function, perfusion of vital organs such as the brain, and the production of urine. Most patients should receive intensive care, with monitoring of arterial and venous pressures and the ECG. Reduction in urine flow, tachycardia, and the development of arrhythmias may be indications to slow or terminate the infusion. The duration of action of dopamine is brief, and hence the rate of administration can be used to control the intensity of effect.

Related drugs include fenoldopam and dopexamine. Fenoldopam (CORLOPAM) is a D1-receptor-selective agonist, which lowers blood pressure in severe hypertension (Elliott et al., 1990; Nichols et al., 1990). Fenoldopam does not appear to activate - or -adrenergic receptors. Intravenous infusions of fenoldopam dilate a variety of blood vessels including coronary, renal (both afferent and efferent arterioles), and mesenteric arteries (Brogden and Markham, 1997). The drug is indicated for short-term management of severe hypertension where rapid reduction of blood pressure is clinically indicated. Dopexamine (DOPACARD) is a synthetic analog related to dopamine with intrinsic activity at dopamine receptors as well as at -adrenergic receptors; it may have other effects such as inhibition of catecholamine uptake (Fitton and Benfield, 1990). It appears to have favorable hemodynamic actions in patients with severe congestive heart failure, sepsis, and shock. Dopexamine is not available in the United States.

-Adrenergic Agonists

-Adrenergic receptor agonists have been utilized in many clinical settings but now play a major role only in the treatment of bronchoconstriction in patients with asthma (reversible airway obstruction) or chronic obstructive pulmonary disease.

Epinephrine was first used as a bronchodilator at the beginning of this century, and ephedrine was introduced into western medicine in 1924, although it had been used in China for thousands of years (Chen and Schmidt, 1930). The next major advance was the development in the 1940s of isoproterenol, a -receptor-selective agonist; this provided a drug for asthma that lacked -adrenergic activity. The recent development of -selective agonists has resulted in drugs with even more valuable characteristics, including adequate oral bioavailability, lack of -adrenergic activity, and diminished likelihood of adverse cardiovascular effects.

-Adrenergic agonists may be used to stimulate the rate and force of cardiac contraction. The chronotropic effect is useful in the emergency treatment of arrhythmias such as torsades de pointes, bradycardia, or heart block (Chapter 35: Antiarrhythmic Drugs), whereas the inotropic effect is useful when it is desirable to augment myocardial contractility. The various therapeutic uses of -adrenergic agonists are discussed later in the chapter.

Isoproterenol

Isoproterenol (isopropylarterenol, isopropylnorepinephrine, isoprenaline, isopropylnoradrenaline, d,l--[3,4-dihydroxyphenyl]--isopropylaminoethanol) (seeTable 10–1) is a potent, nonselective -adrenergic agonist with very low affinity for -adrenergic receptors. Consequently, isoproterenol has powerful effects on all receptors and almost no action at receptors.

Pharmacological Actions

The major cardiovascular effects of isoproterenol (compared with epinephrine and norepinephrine) are illustrated in Figure 10–2. Intravenous infusion of isoproterenol lowers peripheral vascular resistance, primarily in skeletal muscle but also in renal and mesenteric vascular beds. Diastolic pressure falls. Systolic blood pressure may remain unchanged or rise, although mean arterial pressure typically falls. Cardiac output is increased because of the positive inotropic and chronotropic effects of the drug in the face of diminished peripheral vascular resistance. The cardiac effects of isoproterenol may lead to palpitations, sinus tachycardia, and more serious arrhythmias; large doses of isoproterenol may cause myocardial necrosis in animals.

Isoproterenol relaxes almost all varieties of smooth muscle when the tone is high, but this action is most pronounced on bronchial and gastrointestinal smooth muscle. It prevents or relieves bronchoconstriction. Its effect in asthma may be due in part to an additional action to inhibit antigen-induced release of histamine and other mediators of inflammation; this action is shared by -receptor–selective stimulants.

Absorption, Fate, and Excretion

Isoproterenol is readily absorbed when given parenterally or as an aerosol. It is metabolized primarily in the liver and other tissues by COMT. Isoproterenol is a relatively poor substrate for MAO and is not taken up by sympathetic neurons to the same extent as are epinephrine and norepinephrine. The duration of action of isoproterenol therefore may be longer than that of epinephrine, but it still is brief.

Toxicity and Adverse Effects

Palpitations, tachycardia, headache, and flushed skin are common. Cardiac ischemia and arrhythmias may occur, particularly in patients with underlying coronary artery disease.

Therapeutic Uses

Isoproterenol (isoproterenol hydrochloride;ISUPREL) may be used in emergencies to stimulate heart rate in patients with bradycardia or heart block, particularly in anticipation of inserting an artificial cardiac pacemaker or in patients with the ventricular arrhythmia torsades de pointes. In disorders such as asthma and shock, isoproterenol largely has been replaced by other sympathomimetic drugs (see below and Chapter 28: Drugs Used in the Treatment of Asthma).

Dobutamine

Dobutamine resembles dopamine structurally but possesses a bulky aromatic substituent on the amino group (seeTable 10–1). The pharmacological effects of dobutamine are due to direct interactions with - and -adrenergic receptors; its actions do not appear to be a result of release of norepinephrine from sympathetic nerve endings, nor are they exerted via dopaminergic receptors. Although dobutamine originally was thought to be a relatively selective -adrenergic agonist, it is now clear that its pharmacological effects are complex. Dobutamine possesses a center of asymmetry; the two enantiomeric forms are present in the racemic mixture that is used clinically (Ruffolo et al., 1981). The (–) isomer of dobutamine is a potent agonist at receptors and is capable of causing marked pressor responses (Ruffolo and Yaden, 1983). In contrast, (+)-dobutamine is a potent -adrenergic receptor antagonist, which can block the effects of (–)-dobutamine. The effects of these two isomers are mediated via-adrenergic receptors. The (+) isomer is about ten times more potent as a -adrenergic receptor agonist than is the (–) isomer. Both isomers appear to be full agonists.

Cardiovascular Effects

The cardiovascular effects of racemic dobutamine represent a composite of the distinct pharmacological properties of the (–) and (+) stereoisomers. Dobutamine has relatively more prominent inotropic than chronotropic effects on the heart compared to isoproterenol. The explanation for this useful selectivity is not clear. It may be due in part to the fact that peripheral resistance is relatively unchanged. Alternatively, cardiac receptors may contribute to the inotropic effect. At equivalent inotropic doses, dobutamine enhances automaticity of the sinus node to a lesser extent than does isoproterenol; however, enhancement of atrioventricular and intraventricular conduction is similar for the two drugs.

In animals, administration of dobutamine at a rate of 2.5 to 15 g/kg per minute increases cardiac contractility and cardiac output. Total peripheral resistance is not greatly affected. The relative constancy of peripheral resistance presumably reflects counterbalancing of -adrenergic receptor–mediated vasoconstriction and -receptor–mediated vasodilation (Ruffolo, 1987). The heart rate increases only modestly when the rate of administration of dobutamine is maintained at less than 20 g/kg per minute. After administration of -adrenergic blocking agents, infusion of dobutamine fails to increase cardiac output, but total peripheral resistance increases, confirming that dobutamine does have modest direct effects on receptors in the vasculature.

Adverse Effects

In some patients, blood pressure and heart rate may increase significantly during administration of dobutamine; this may require reduction of the rate of infusion. Patients with a history of hypertension may be at greater risk of developing an exaggerated pressor response. Since dobutamine facilitates atrioventricular conduction, patients with atrial fibrillation are at risk of marked increases in ventricular response rates; digoxin or other measures may be required to prevent this from occurring. Some patients may develop ventricular ectopic activity. As with any inotropic agent, dobutamine potentially may increase the size of a myocardial infarct by increasing myocardial oxygen demand. This risk must be balanced against the patient's overall clinical status. The efficacy of dobutamine over a period of more than a few days is uncertain; there is evidence for the development of tolerance (Unverferth et al., 1980).

Therapeutic Uses

Dobutamine (dobutamine hydrochloride;DOBUTREX) is indicated for the short-term treatment of cardiac decompensation that may occur after cardiac surgery or in patients with congestive heart failure or acute myocardial infarction. Dobutamine increases cardiac output and stroke volume in such patients, usually without a marked increase in heart rate. Alterations in blood pressure or peripheral resistance usually are minor, although some patients may have marked increases in blood pressure or heart rate. Clinical evidence of longer-term efficacy remains uncertain. Interestingly, an infusion of dobutamine in combination with echocardiography is useful in the noninvasive assessment of patients with coronary artery disease (Madu et al., 1994). Stressing of the heart with dobutamine may reveal cardiac abnormalities in carefully selected patients.

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

-Selective Adrenergic Agonists

Some of the major adverse effects of -adrenergic agonists in the treatment of asthma are caused by stimulation of -adrenergic receptors in the heart. Accordingly, drugs with preferential affinity for receptors compared with receptors have been developed. However, this selectivity is not absolute, and it is lost at sufficiently high concentrations of these drugs.

A second strategy that has increased the usefulness of several -selective agonists in the treatment of asthma has been structural modification that results in lower rates of metabolism and enhanced oral bioavailability (compared with catecholamines). Modifications have included placing the hydroxyl groups at positions 3 and 5 of the phenyl ring or substituting another moiety for the hydroxyl group at position 3. This has yielded drugs such as metaproterenol, terbutaline, and albuterol, which are not substrates for COMT. Bulky substituents on the amino group of catecholamines contribute to potency at -adrenergic receptors with decreased activity at -adrenergic receptors and decreased metabolism by MAO (Nelson, 1982).

A final strategy to enhance preferential activation of pulmonary receptors is the administration by inhalation of small doses of the drug in aerosol form. This approach typically leads to effective activation of receptors in the bronchi but very low systemic drug concentrations (Newhouse and Dolovich, 1986). Consequently, there is less potential to activate cardiac receptors or to stimulate receptors in skeletal muscle, which can cause tremor and thereby limit oral therapy.

Administration of -adrenergic agonists by aerosol (seeChapter 28: Drugs Used in the Treatment of Asthma) typically leads to a very rapid therapeutic response, generally within minutes, although some agonists such as salmeterol have a delayed onset of action. While subcutaneous injection also causes prompt bronchodilation, the peak effect of a drug given orally may be delayed for several hours. Aerosol therapy depends on the delivery of drug to the distal airways. This, in turn, depends on the size of the particles in the aerosol and respiratory parameters such as inspiratory flow rate, tidal volume, breath-holding time, and airway diameter (Newhouse and Dolovich, 1986). Only about 10% of an inhaled dose actually enters the lungs; much of the remainder is swallowed and ultimately may be absorbed. Successful aerosol therapy requires that each patient master the technique of drug administration. Many patients, particularly children and the elderly, do not use optimal techniques, often because of inadequate instructions (Kelly, 1985; Newhouse and Dolovich, 1986). In these patients, spacer devices may enhance the efficacy of inhalation therapy (seeChapter 28: Drugs Used in the Treatment of Asthma).

In the treatment of asthma, -adrenergic agonists are used to activate pulmonary receptors that relax bronchial smooth muscle and decrease airway resistance. Although this action appears to be a major therapeutic effect of these drugs in patients with asthma, evidence suggests that -adrenergic agonists also may suppress the release of leukotrienes and histamine from mast cells in lung tissue (Hughes et al., 1983), enhance mucociliary function, decrease microvascular permeability, and possibly inhibit phospholipase A2 (Seale, 1988). The relative importance of these actions in the treatment of human asthma remains to be determined. However, it is becoming increasingly clear that airway inflammation is directly involved in airway hyperresponsiveness (seeChapter 28: Drugs Used in the Treatment of Asthma); consequently, the use of antiinflammatory drugs such as inhaled steroids may have primary importance. The use of -adrenergic agonists for the treatment of asthma is discussed in Chapter 28: Drugs Used in the Treatment of Asthma.

Metaproterenol

Metaproterenol (called orciprenaline in Europe), along with terbutaline and fenoterol, belongs to the structural class of resorcinol bronchodilators that have hydroxyl groups at positions 3 and 5 of the phenyl ring (rather than at positions 3 and 4 as in catechols) (seeTable 10–1). Consequently, metaproterenol is resistant to methylation by COMT, and a substantial fraction (40%) is absorbed in active form after oral administration. It is excreted primarily as glucuronic acid conjugates. Metaproterenol is considered to be -selective, although it probably is less selective than albuterol or terbutaline. Effects occur within minutes of inhalation and persist for several hours. After oral administration, onset of action is slower, but effects last 3 to 4 hours. Metaproterenol (metaproterenol sulfate;ALUPENT) is used for the long-term treatment of obstructive airway diseases and for treatments of acute bronchospasm (seeChapter 28: Drugs Used in the Treatment of Asthma).

Terbutaline

Terbutaline is a -selective bronchodilator. It contains a resorcinol ring and thus is not a substrate for methylation by COMT. It is effective when taken orally, subcutaneously, or by inhalation. Effects are observed rapidly after inhalation or parenteral administration; after inhalation its action may persist for 3 to 6 hours. With oral administration, the onset of effect may be delayed for 1 to 2 hours. Terbutaline (terbutaline sulfate;BRETHINE, others) is used for the long-term treatment of obstructive airway diseases and for treatment of acute bronchospasm; furthermore, it is available for parenteral use for the emergency treatment of status asthmaticus (seeChapter 28: Drugs Used in the Treatment of Asthma).

Albuterol

Albuterol (salbutamol; VENTOLIN, PROVENTIL, others) is a selective -adrenergic agonist with pharmacological properties and therapeutic indications similar to those of terbutaline. It is administered either by inhalation or orally for the symptomatic relief of bronchospasm. When administered by inhalation, it produces significant bronchodilation within 15 minutes, and effects are demonstrable for 3 to 4 hours. The cardiovascular effects of albuterol are considerably weaker than those of isoproterenol when doses that produce comparable bronchodilatation are administered by inhalation.

Isoetharine

Isoetharine was the first drug with selectivity widely used for the treatment of airway obstruction. However, its degree of selectivity for -adrenergic receptors may not approach that of some of the other agents. Although resistant to metabolism by MAO, it is a catecholamine and thus is a good substrate for COMT (seeTable 10–1). Consequently, it is used only by inhalation for the treatment of acute episodes of bronchoconstriction.

Pirbuterol

Pirbuterol is a relatively selective agonist. It is structurally identical to albuterol except for the substitution of a pyridine ring for the benzene ring (Richards and Brogden, 1985). Pirbuterol acetate (MAXAIR) is available for inhalation therapy; dosing is typically every 4 to 6 hours.

Bitolterol

Bitolterol (bitolterol mesylate;TORNALATE) is a novel agonist in which the hydroxyl groups in the catechol moiety are protected by esterification with 4-methylbenzoate. Esterases in the lung and other tissues hydrolyze this prodrug to the active form, colterol, or terbutylnorepinephrine (seeTable 10–1). Results of animal studies have suggested that these esterases are present in higher concentration in lung than in tissues such as the heart (Nelson, 1986; Friedel and Brogden, 1988). The duration of effect of bitolterol after inhalation ranges from 3 to 6 hours.

Fenoterol

Fenoterol BEROTEC) is a -selective adrenergic receptor agonist. After inhalation, it has a prompt onset of action, and its effect typically is sustained for 4 to 6 hours. Fenoterol is not available in the United States. The possible association of fenoterol use with increased deaths from asthma in New Zealand is controversial (Pearce et al., 1995; Suissa and Ernst, 1997).

Formoterol

Formoterol FORADIL) is a long-acting -selective adrenergic receptor agonist. Significant bronchodilation occurs within minutes of inhalation of a therapeutic dose, and this action may persist for up to 12 hours (Faulds et al., 1991). Its major advantage over many other -selective agonists is this prolonged duration of action, which may be particularly advantageous in settings such as nocturnal asthma. Formoterol is not available in the United States.

Procaterol

Procaterol MASCACIN, others) is a -selective adrenergic receptor agonist. After inhalation, it has a prompt onset of action, and action is sustained for about 5 hours. Procaterol is not available in the United States.

Salmeterol

Salmeterol SEREVENT) is a -selective adrenergic receptor agonist with a prolonged duration of action, about 12 hours. However, it has a relatively slow onset of action after inhalation, so is not suitable alone for prompt relief of breakthrough attacks of bronchospasm (Lötvall and Svedmyr, 1993; Brogden and Faulds, 1991).

Ritodrine

Ritodrine is a selective -adrenergic agonist that was developed specifically for use as a uterine relaxant. Nevertheless, its pharmacological properties closely resemble those of the other agents in this group. Ritodrine is rapidly but incompletely (30%) absorbed following oral administration, and 90% of the drug is excreted in the urine as inactive conjugates; about 50% of ritodrine is excreted unchanged after intravenous administration. The pharmacokinetic properties of ritodrine are complex and incompletely defined, especially in pregnant women.

Therapeutic Uses

Ritodrine may be administered intravenously to selected patients to arrest premature labor. Ritodrine and related drugs can prolong pregnancy (King et al., 1988). However, -selective agonists may not have clinically significant benefits on perinatal mortality and may actually increase maternal morbidity (The Canadian Preterm Labor Investigators Group, 1992; Higby et al., 1993; Johnson, 1993). Given modern improvements in the care of premature babies, it is possible that existing clinical trials may not have had sufficient statistical power to demonstrate subtle, but potentially important, clinical effects. Many other drugs are used to delay labor (Bossmar, 1998; Norwitz et al., 1999). Magnesium therapy may prolong labor in preterm women. There is some evidence suggesting that indomethacin may prolong preterm labor, but a favorable risk-to-benefit ratio has not been established (Panter et al., 1999). Also, while calcium channel blockers prolong preterm labor, their long-term benefits are unclear (seeChapter 32: Drugs Used for the Treatment of Myocardial Ischemia; Carr et al., 1999).

Adverse Effects of -Selective Agonists

The major adverse effects of -adrenergic agonists occur as a result of excessive activation of -adrenergic receptors. Patients with underlying cardiovascular disease are particularly at risk for significant reactions. However, the likelihood of adverse effects can be greatly decreased in patients with lung disease by administering the drug by inhalation rather than orally or parenterally.

Skeletal muscle tremor is a relatively common adverse effect of the -selective adrenergic agonists. Tolerance generally develops to this effect; it is not clear whether tolerance reflects desensitization of the receptors of skeletal muscle or adaptation within the CNS. This adverse effect can be minimized by starting oral therapy with a low dose of drug and progressively increasing the dose as tolerance to the tremor develops. Feelings of restlessness, apprehension, and anxiety may limit therapy with these drugs, particularly after oral or parenteral treatment.

Tachycardia is a common adverse effect of systemically administered -adrenergic agonists. Stimulation of heart rate occurs primarily via receptors. It is uncertain to what extent the increase in heart rate also is due to activation of cardiac receptors or to reflex effects that stem from -receptor–mediated peripheral vasodilation. However, during a severe asthmatic attack, heart rate may actually decrease during therapy with a -adrenergic agonist, presumably because of improvement in pulmonary function with consequent reduction in endogenous cardiac sympathetic stimulation. In patients without cardiac disease, agonists rarely cause significant arrhythmias or myocardial ischemia; however, patients with underlying coronary artery disease or preexisting arrhythmias are at greater risk. The risk of adverse cardiovascular effects also is increased in patients who are receiving MAO inhibitors.

Arterial oxygen tension may fall when treatment of patients with an acute exacerbation of asthma is begun; this may be due to drug-induced pulmonary vascular dilation, which leads to increased mismatching of ventilation and perfusion. This effect usually is small and transient. Supplemental oxygen should be given if necessary. Severe pulmonary edema has been reported in women receiving ritodrine or terbutaline for premature labor.

The results of a number of epidemiologic studies have suggested a possible adverse connection between prolonged use of -adrenergic agonists and death or near-death from asthma (Suissa et al., 1994). While exact interpretation of these results is difficult, these studies have raised questions about the role of -adrenergic agonists in the treatment of chronic asthma. Tolerance to effects of -adrenergic agonists has been studied extensively, both in vitro and in vivo (seeChapter 6: Neurotransmission: The Autonomic and Somatic Motor Nervous Systems). Long-term systemic administration of -adrenergic agonists leads to downregulation of receptors in some tissues and decreased pharmacological responses. However, it appears likely that tolerance to the pulmonary effects of these drugs is not a major clinical problem for the majority of asthmatics who do not exceed recommended dosages of -adrenergic agonists over prolonged periods (Jenne, 1982; Tattersfield, 1985).

There is some evidence suggesting that regular use of -selective agonists may cause increased bronchial hyperreactivity and deterioration in disease control (Lipworth and McDevitt, 1992; Hancox et al., 1999). To what extent this potential adverse association may be even more unfavorable for very long-acting agonists or excess doses of medication is not yet known (Beasley et al., 1999). However, for patients requiring regular use of these drugs over prolonged periods, strong consideration should be given to additional or alternative therapy, such as the use of inhaled corticosteroids.

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

-Selective Adrenergic Agonists

The major clinical effects of a number of sympathomimetic drugs are due to activation of -adrenergic receptors in vascular smooth muscle. As a result, peripheral vascular resistance is increased and blood pressure is maintained or elevated. Although the clinical utility of these drugs is limited, they may be useful in the treatment of some patients with hypotension or shock. Phenylephrine and methoxamine are direct-acting vasoconstrictors and are selective activators of receptors. Mephentermine and metaraminol act both directly and indirectly; i.e., a portion of their effects is mediated through the release of endogenous norepinephrine.

Methoxamine

Methoxamine (methoxamine hydrochloride;VASOXYL;seeTable 10–1) is a relatively specific -receptor–selective adrenergic agonist; as such, it causes a dose-related increase in peripheral vascular resistance. The drug may have different intrinsic activities at receptors in different tissues (Garcia-Sainz et al., 1985). Methoxamine does not activate -adrenergic receptors, nor does it cause stimulation of the CNS. However, at high concentrations, methoxamine has some capacity to block receptors. The major cardiovascular response to the drug is a rise in blood pressure, which is associated with sinus bradycardia because of activation of vagal reflexes; the slowing of the heart rate is largely blocked by atropine. Methoxamine may be used intravenously in the treatment of hypotensive states.

Phenylephrine

Phenylephrine is an -selective agonist; it activates -adrenergic receptors only at much higher concentrations. Chemically, phenylephrine differs from epinephrine only in lacking a hydroxyl group at position 4 on the benzene ring (seeTable 10–1). The pharmacological effects of phenylephrine are similar to those of methoxamine. The drug causes marked arterial vasoconstriction during intravenous infusion. Phenylephrine (phenylephrine hydrochloride;NEOSYNEPHRINE, others) also is used as a nasal decongestant and as a mydriatic in various nasal and ophthalmic formulations (seeChapter 66: Ocular Pharmacology for ophthalmic uses).

Mephentermine

Mephentermine (seeTable 10–1) is a sympathomimetic drug that acts both directly and indirectly; it has many similarities to ephedrine (see below). After an intramuscular injection, the onset of action is prompt (within 5 to 15 minutes), and effects may last for several hours. Since the drug releases norepinephrine, cardiac contraction is enhanced, and cardiac output and systolic and diastolic pressures usually are increased. The change in heart rate is variable, depending on the degree of vagal tone. Adverse effects are related to CNS stimulation, excessive rises in blood pressure, and arrhythmias. Mephentermine (mephentermine sulfate;WYAMINE SULFATE) is used to prevent hypotension, which frequently accompanies spinal anesthesia.

Metaraminol

Metaraminol (metaraminol bitartrate;ARAMINE) (seeTable 10–1) is a sympathomimetic drug with prominent direct effects on vascular -adrenergic receptors. Metaraminol also is an indirectly acting agent that stimulates the release of norepinephrine. The drug has been used in the treatment of hypotensive states or to relieve attacks of paroxysmal atrial tachycardia, particularly those associated with hypotension (seeChapter 35: Antiarrhythmic Drugs for preferable treatments of this arrhythmia).

Midodrine

Midodrine PROAMATINE) is an orally effective, -adrenergic agonist (Fouad-Tarazi et al., 1995). It is a prodrug; its activity is due to its conversion to an active metabolite, desglymidodrine, which achieves peak concentrations about 1 hour after a dose of midodrine. The half-life of desglymidodrine is about 3 hours. Consequently, the duration of action is about 4 to 6 hours. Midodrine-induced rises in blood pressure are associated with both arterial and venous smooth muscle contraction. This is advantageous in the treatment of patients with autonomic insufficiency and postural hypotension (McClellan et al., 1998). A frequent complication in these patients is supine hypertension. This can be minimized by avoiding dosing prior to bedtime and elevating the head of the bed. Very cautious use of a short-acting antihypertensive drug at bedtime may be useful in some patients. Typical dosing, achieved by careful titration of blood pressure responses, varies between 2.5 and 10 mg three times daily, at 4-hour intervals.

-Selective Adrenergic Agonists

-Receptor-selective adrenergic agonists are used primarily for the treatment of systemic hypertension. Their efficacy as antihypertensive agents is somewhat surprising, since many blood vessels contain postsynaptic receptors that promote vasoconstriction (seeChapter 6: Neurotransmission: The Autonomic and Somatic Motor Nervous Systems). Indeed, clonidine was initially developed as a vasoconstricting nasal decongestant. Its capacity to lower blood pressure results from activation of -adrenergic receptors in the cardiovascular control centers of the CNS; such activation suppresses the outflow of sympathetic nervous system activity from the brain.

Clonidine

Clonidine, an imidazoline, was synthesized in the early 1960s and found to produce vasoconstriction that was mediated by -adrenergic receptors. During clinical testing of the drug as a topical nasal decongestant, clonidine was found to cause hypotension, sedation, and bradycardia. The structural formula of clonidine is as follows:

Pharmacological Effects

The major pharmacological effects of clonidine involve changes in blood pressure and heart rate, although the drug has a variety of other important actions. Intravenous infusion of clonidine causes an acute rise in blood pressure, apparently because of activation of postsynaptic receptors in vascular smooth muscle (Kobinger, 1978). The affinity of clonidine for these receptors is high, although the drug is a partial agonist with relatively low efficacy at these sites. The hypertensive response that follows parenteral administration of clonidine generally is not seen when the drug is given orally. However, even after intravenous administration, the transient vasoconstriction is followed by a more prolonged hypotensive response which results from decreased central outflow of impulses in the sympathetic nervous system. The exact mechanism by which clonidine lowers blood pressure is not completely understood. The effect appears to result, at least in part, from activation of receptors in the lower brainstem region. This central action has been demonstrated by infusing small amounts of the drug into the vertebral arteries or by injecting it directly into the cisterna magna.

Data obtained using [3H]clonidine as a radioligand in receptor-binding assays suggest that noradrenergic imidazoline-preferring binding sites exist in the brain. These sites, however, do not bind catecholamines and thus cannot mediate the centrally mediated hypotensive effects of norepinephrine. There is increasing evidence that these imidazoline-preferring sites may represent a new family of receptors through which clonidine and other imidazolines may elicit hypotensive effects (van Zwieten, 1999). However, the lack of an antihypertensive effect of clonidine and other imidazoline-site ligands in genetically engineered mice lacking functional 2A-adrenergic receptors affirms the importance of this receptor subtype in mediating the effects of clonidine and currently available imidazoline-site ligands, such as moxonidine and rilmenidine (MacMillan et al., 1996; Zhu et al., 1999).

Clonidine decreases discharges in sympathetic preganglionic fibers in the splanchnic nerve as well as in postganglionic fibers of cardiac nerves (Langer et al., 1980). These effects are blocked by -selective antagonists such as yohimbine. Clonidine also stimulates parasympathetic outflow, and this may contribute to the slowing of heart rate as a consequence of increased vagal tone as well as diminished sympathetic drive. In addition, some of the antihypertensive effects of clonidine may be mediated by activation of presynaptic receptors that suppress the release of norepinephrine from peripheral nerve endings. Clonidine decreases the plasma concentration of norepinephrine and reduces its excretion in the urine.

Absorption, Fate, and Excretion

Clonidine is well absorbed after oral administration, and bioavailability is nearly 100%. The peak concentration in plasma and the maximal hypotensive effect are observed 1 to 3 hours after an oral dose. The elimination half-life of the drug ranges from 6 to 24 hours, with a mean of about 12 hours (Lowenthal et al., 1988). About half of an administered dose can be recovered unchanged in the urine, and the half-life of the drug may increase with renal failure. There is good correlation between plasma concentrations of clonidine and its pharmacological effects. A transdermal delivery patch permits continuous administration of clonidine as an alternative to oral therapy. The drug is released at an approximately constant rate for a week; 3 or 4 days are required to reach steady-state concentrations in plasma. When the patch is removed, plasma concentrations remain stable for about 8 hours and then decline gradually over a period of several days; this decrease is associated with a rise in blood pressure (Langley and Heel, 1988; Lowenthal et al., 1988).

Adverse Effects

The major adverse effects of clonidine are dry mouth and sedation. These responses occur in at least 50% of patients and may require discontinuation of drug administration. However, they may diminish in intensity after several weeks of therapy. Sexual dysfunction also may occur. Marked bradycardia is observed in some patients. These and some of the other adverse effects of clonidine are frequently related to dose, and their incidence may be lower with transdermal administration of clonidine, since antihypertensive efficacy may be achieved while avoiding the relatively high peak concentrations that occur after oral administration of the drug; however, this possibility requires further evaluation (Langley and Heel, 1988). About 15% to 20% of patients develop contact dermatitis when using clonidine in the transdermal system. Withdrawal reactions follow abrupt discontinuation of long-term therapy with clonidine in some hypertensive patients (Parker and Atkinson, 1982; see also Chapter 33: Antihypertensive Agents and the Drug Therapy of Hypertension).

Therapeutic Uses

The major therapeutic use of clonidine (clonidine hydrochloride;CATAPRES) is in the treatment of hypertension (seeChapter 33: Antihypertensive Agents and the Drug Therapy of Hypertension). Clonidine also has apparent efficacy in the treatment of a range of other disorders. Stimulation of -adrenergic receptors in the gastrointestinal tract may increase absorption of sodium chloride and fluid and inhibit secretion of bicarbonate (Chang et al., 1986). This may explain why clonidine has been found to improve diarrhea in some diabetic patients with autonomic neuropathy (Fedorak et al., 1985). Clonidine also is useful in treating and preparing addicted subjects for withdrawal from narcotics (Gold et al., 1978), alcohol (Bond, 1986), and tobacco (Glassman et al., 1988) (seeChapter 24: Drug Addiction and Drug Abuse). Clonidine may help ameliorate some of the adverse sympathetic nervous activity associated with withdrawal from these agents, as well as decrease craving for the drug. The long-term benefits of clonidine in these settings and in neuropsychiatric disorders remain to be determined (Bond, 1986). Clonidine may be useful in selected patients receiving anesthesia because it may decrease the requirement for anesthetic and increase hemodynamic stability (Flacke et al., 1987; Hayashi and Maze, 1993; see also Chapter 14: General Anesthetics). Other potential benefits of clonidine and related drugs such as dexmedetomidine in anesthesia include preoperative sedation and anxiolysis, drying of secretions, and analgesia. Transdermal administration of clonidine (CATAPRES-TTS) may be useful in reducing the incidence of menopausal hot flashes (Nagamani et al., 1987).

Acute administration of clonidine has been used in the differential diagnosis of patients with hypertension and suspected pheochromocytoma. In patients with primary hypertension, plasma concentrations of norepinephrine are markedly suppressed after a single dose of clonidine; this response is not observed in many patients with pheochromocytoma (Bravo et al., 1981). The capacity of clonidine to activate postsynaptic receptors in vascular smooth muscle has been exploited in a limited number of patients whose autonomic failure is so severe that reflex sympathetic responses on standing are absent; postural hypotension is thus marked. Since the central effect of clonidine on blood pressure is unimportant in these patients, the drug can elevate blood pressure and improve the symptoms of postural hypotension (Robertson et al., 1983a).

Apraclonidine

Apraclonidine IOPIDINE) is a relatively selective -adrenergic agonist used locally to reduce intraocular pressure. While the mechanism is unclear, it may relate to reduction in formation of aqueous humor (seeChapter 66: Ocular Pharmacology).

Guanfacine

Guanfacine is a phenylacetylguanidine derivative. Its structural formula is as follows:

Guanfacine (guanfacine hydrochloride;TENEX) is an -adrenergic agonist that is more selective for receptors than is clonidine. Like clonidine, guanfacine lowers blood pressure by activation of brain stem receptors with resultant suppression of sympathetic nervous system activity (Sorkin and Heel, 1986). The drug is well absorbed after oral administration and has a large volume of distribution (4 to 6 liters/kg). About 50% of guanfacine appears unchanged in the urine; the rest is metabolized. The half-time for elimination ranges from 12 to 24 hours. Guanfacine and clonidine appear to have similar efficacy for the treatment of hypertension. The pattern of adverse effects also is similar for the two drugs, although it has been suggested that some of these effects may be milder and occur less frequently with guanfacine (Sorkin and Heel, 1986). A withdrawal syndrome may occur after the abrupt discontinuation of guanfacine, but it appears to be less frequent and milder than the syndrome that follows withdrawal of clonidine. Part of this difference may relate to the longer half-life of guanfacine.

Guanabenz

Guanabenz and guanfacine are closely related chemically and pharmacologically. The structural formula of guanabenz is as follows:

Guanabenz (guanabenz acetate;WYTENSIN) is a centrally acting agonist that decreases blood pressure by a mechanism similar to those of clonidine and guanfacine (Holmes et al., 1983). Guanabenz has a half-life of 4 to 6 hours and is extensively metabolized by the liver. Dosage adjustment may be necessary in patients with hepatic cirrhosis. The adverse effects caused by guanabenz (e.g., dry mouth and sedation) are similar to those seen with clonidine.

Methyldopa

Methyldopa -methyl-3,4-dihydroxyphenylalanine) is a centrally acting antihypertensive agent. It is metabolized to -methylnorepinephrine in the brain, and this compound is thought to activate central -adrenergic receptors and lower blood pressure in a manner similar to that of clonidine. Methyldopa is discussed in more detail in Chapter 33: Antihypertensive Agents and the Drug Therapy of Hypertension.

Tizanidine

Tizanidine ZANAFLEX) is a muscle relaxant drug used for the treatment of spasticity associated with cerebral and spinal disorders. It also is an -receptor agonist with some properties similar to those of clonidine (Wagstaff and Bryson, 1997).

Brimonidine

Brimonidine tartrate ALPHAGAN) is an -adrenergic receptor agonist administered ocularly to lower intraocular pressure in patients with ocular hypertension or open-angle glaucoma (seeChapter 66: Ocular Pharmacology).

Miscellaneous Adrenergic Agonists

Amphetamine

Amphetamine, racemic -phenylisopropylamine (seeTable 10–1), has powerful CNS stimulant actions in addition to the peripheral and actions common to indirect-acting sympathomimetic drugs. Unlike epinephrine, it is effective after oral administration and its effects last for several hours.

Cardiovascular Responses

Amphetamine given orally raises both systolic and diastolic blood pressure. Heart rate is often reflexly slowed; with large doses, cardiac arrhythmias may occur. Cardiac output is not enhanced by therapeutic doses, and cerebral blood flow does not change much. The l isomer is slightly more potent than the d isomer in its cardiovascular actions.

Other Smooth Muscles

In general, smooth muscles respond to amphetamine as they do to other sympathomimetic amines. The contractile effect on the sphincter of the urinary bladder is particularly marked, and for this reason amphetamine has been used in treating enuresis and incontinence. Pain and difficulty in micturition occasionally occur. The gastrointestinal effects of amphetamine are unpredictable. If enteric activity is pronounced, amphetamine may cause relaxation and delay the movement of intestinal contents; if the gut already is relaxed, the opposite effect may occur. The response of the human uterus varies, but there usually is an increase in tone.

Central Nervous System

Amphetamine is one of the most potent sympathomimetic amines in stimulating the CNS. It stimulates the medullary respiratory center, lessens the degree of central depression caused by various drugs, and produces other signs of stimulation of the CNS. These effects are thought to be due to cortical stimulation and possibly to stimulation of the reticular activating system. In contrast, the drug can obtund the maximal electroshock seizure discharge and prolong the ensuing period of depression. In elicitation of CNS excitatory effects, the d isomer (dextroamphetamine) is three to four times as potent as the l isomer.

The psychic effects depend on the dose and the mental state and personality of the individual. The main results of an oral dose of 10 to 30 mg include wakefulness, alertness, and a decreased sense of fatigue; elevation of mood, with increased initiative, self-confidence, and ability to concentrate; often, elation and euphoria; and increase in motor and speech activities. Performance of simple mental tasks is improved, but, although more work may be accomplished, the number of errors may increase. Physical performance—in athletes, for example—is improved, and the drug often is abused for this purpose. These effects are not invariable, and may be reversed by overdosage or repeated usage. Prolonged use or large doses are nearly always followed by depression and fatigue. Many individuals given amphetamine experience headache, palpitation, dizziness, vasomotor disturbances, agitation, confusion, dysphoria, apprehension, delirium, or fatigue (seeChapter 24: Drug Addiction and Drug Abuse).

Fatigue and Sleep

Prevention and reversal of fatigue by amphetamine have been studied extensively in the laboratory, in military field studies, and in athletics. In general, the duration of adequate performance is prolonged before fatigue appears, and the effects of fatigue are at least partly reversed. The most striking improvement appears to occur when performance has been reduced by fatigue and lack of sleep. Such improvement may be partly due to alteration of unfavorable attitudes toward the task. However, amphetamine reduces the frequency of attention lapses that impair performance after prolonged sleep deprivation and thus improves execution of tasks requiring sustained attention. The need for sleep may be postponed, but it cannot be avoided indefinitely. When the drug is discontinued after long use, the pattern of sleep may take as long as two months to return to normal.

Analgesia

Amphetamine and some other sympathomimetic amines have a small analgesic effect, but it is not sufficiently pronounced to be therapeutically useful. However, amphetamine can enhance the analgesia produced by morphine-like drugs.

Respiration

Amphetamine stimulates the respiratory center, increasing the rate and depth of respiration. In normal human beings, usual doses of the drug do not appreciably increase respiratory rate or minute volume. Nevertheless, when respiration is depressed by centrally acting drugs, amphetamine may stimulate respiration.

Depression of Appetite

Amphetamine and similar drugs have been used for the treatment of obesity, although the wisdom of this use is at best questionable. Weight loss in obese human beings treated with amphetamine is almost entirely due to reduced food intake and only in small measure to increased metabolism. The site of action is probably in the lateral hypothalamic feeding center; injection of amphetamine into this area, but not into the ventromedial satiety center, suppresses food intake. Neurochemical mechanisms of action are unclear but may involve increased release of norepinephrine and/or dopamine (Samanin and Garattini, 1993). In human beings, tolerance to the appetite suppression develops rapidly. Hence, continuous weight reduction usually is not observed in obese individuals without dietary restriction (Silverstone, 1992; Bray, 1993).

Mechanisms of Action in the CNS

Amphetamine appears to exert most or all of its effects in the CNS by releasing biogenic amines from their storage sites in nerve terminals. The alerting effect of amphetamine, its anorectic effect, and at least a component of its locomotor-stimulating action are presumably mediated by release of norepinephrine from central noradrenergic neurons. These effects can be prevented in experimental animals by treatment with -methyltyrosine, an inhibitor of tyrosine hydroxylase and, therefore, of catecholamine synthesis. Some aspects of locomotor activity and the stereotyped behavior induced by amphetamine probably are a consequence of the release of dopamine from dopaminergic nerve terminals, particularly in the neostriatum. Higher doses are required to produce these behavioral effects, and this correlates with the higher concentrations of amphetamine required to release dopamine from brain slices or synaptosomes in vitro. With still higher doses of amphetamine, disturbances of perception and overt psychotic behavior occur. These effects may be due to release of 5-hydroxytryptamine (serotonin, 5-HT) from tryptaminergic neurons and of dopamine in the mesolimbic system. In addition, amphetamine may exert direct effects on central receptors for 5-HT (seeChapter 11: 5-Hydroxytryptamine (Serotonin): Receptor Agonists and Antagonists).

Toxicity and Adverse Effects

The acute toxic effects of amphetamine usually are extensions of its therapeutic actions and, as a rule, result from overdosage. The central effects commonly include restlessness, dizziness, tremor, hyperactive reflexes, talkativeness, tenseness, irritability, weakness, insomnia, fever, and sometimes euphoria. Confusion, aggressiveness, changes in libido, anxiety, delirium, paranoid hallucinations, panic states, and suicidal or homicidal tendencies occur, especially in mentally ill patients. However, these psychotic effects can be elicited in any individual if sufficient quantities of amphetamine are ingested for a prolonged period. Fatigue and depression usually follow central stimulation. Cardiovascular effects are common and include headache, chilliness, pallor or flushing, palpitation, cardiac arrhythmias, anginal pain, hypertension or hypotension, and circulatory collapse. Excessive sweating occurs. Symptoms referable to the gastrointestinal system include dry mouth, metallic taste, anorexia, nausea, vomiting, diarrhea, and abdominal cramps. Fatal poisoning usually terminates in convulsions and coma, and cerebral hemorrhages are the main pathological findings.

The toxic dose of amphetamine varies widely. Toxic manifestations occasionally occur as an idiosyncrasy after as little as 2 mg, but are rare with doses of less than 15 mg. Severe reactions have occurred with 30 mg, yet doses of 400 to 500 mg are not uniformly fatal. Larger doses can be tolerated after chronic use of the drug.

Treatment of acute amphetamine intoxication may include acidification of the urine by administration of ammonium chloride; this enhances the rate of elimination. Sedatives may be required for the CNS symptoms. Severe hypertension may require administration of sodium nitroprusside or an -adrenergic antagonist.

Chronic intoxication with amphetamine causes symptoms similar to those of acute overdosage, but abnormal mental conditions are more common. Weight loss may be marked. A psychotic reaction with vivid hallucinations and paranoid delusions, often mistaken for schizophrenia, is the most common serious effect. Recovery usually is rapid after withdrawal of the drug, but occasionally the condition becomes chronic. In these persons, amphetamine may act as a precipitating factor hastening the onset of an incipient schizophrenia.

The abuse of amphetamine as a means of overcoming sleepiness and of increasing energy and alertness should be discouraged. The drug should be used only under medical supervision. The amphetamines are schedule II drugs under federal regulations (seeAppendix I). The additional contraindications and precautions for the use of amphetamine generally are similar to those described above for epinephrine. Its use is inadvisable in patients with anorexia, insomnia, asthenia, psychopathic personality, or a history of homicidal or suicidal tendencies.

Dependence and Tolerance

Psychological dependence often occurs when amphetamine or dextroamphetamine is used chronically, as discussed in Chapter 24: Drug Addiction and Drug Abuse. Tolerance almost invariably develops to the anorexigenic effect of amphetamines, and is often seen also in the need for increasing doses to maintain improvement of mood in psychiatric patients. Tolerance is striking in individuals who are dependent on the drug, and a daily intake of 1.7 g without apparent ill effects has been reported. Development of tolerance is not invariable, and cases of narcolepsy have been treated for years without requiring an increase in the initially effective dose.

Therapeutic Uses

Amphetamine and dextroamphetamine are used chiefly for their CNS effects. Dextroamphetamine (dextroamphetamine sulfate;DEXEDRINE), with greater CNS action and less peripheral action, generally is preferred to amphetamine; it is used in obesity, narcolepsy, and attention-deficit hyperactivity disorder. These uses are discussed later in this chapter.

Methamphetamine

Methamphetamine (methamphetamine hydrochloride;DESOXYN) is closely related chemically to amphetamine and ephedrine (seeTable 10–1). Small doses have prominent central stimulant effects without significant peripheral actions; somewhat larger doses produce a sustained rise in systolic and diastolic blood pressures, due mainly to cardiac stimulation. Cardiac output is increased, although the heart rate may be reflexly slowed. Venous constriction causes peripheral venous pressure to increase. These factors tend to increase the venous return and, therefore, the cardiac output. Pulmonary arterial pressure is raised, probably owing to increased cardiac output. Methamphetamine is a schedule II drug under federal regulations and has high potential for abuse (seeChapter 24: Drug Addiction and Drug Abuse and Appendix I). It is used principally for its central effects, which are more pronounced than those of amphetamine and are accompanied by less prominent peripheral actions. These uses are discussed below in the section of this chapter on therapeutic uses.

Methylphenidate

Methylphenidate is a piperidine derivative that is structurally related to amphetamine and has the following formula:

Methylphenidate (methylphenidate hydrochloride;RITALIN) is a mild CNS stimulant with more prominent effects on mental than on motor activities. However, large doses produce signs of generalized CNS stimulation that may lead to convulsions. Its pharmacological properties are essentially the same as those of the amphetamines. Methylphenidate also shares the abuse potential of the amphetamines. Methylphenidate is effective in the treatment of narcolepsy and attention-deficit hyperactivity disorder, as described below.

Methylphenidate is readily absorbed after oral administration and reaches peak concentrations in plasma in about 2 hours. Methylphenidate is a racemate; its more potent (+) enantiomer has a half-life of about 6 hours, and the less potent (–) enantiomer has a half-life of about 4 hours. Concentrations in the brain exceed those in plasma. The main urinary metabolite is a deesterified product, ritalinic acid, which accounts for 80% of the dose. The use of methylphenidate is contraindicated in patients with glaucoma.

Pemoline

Pemoline CYLERT) is structurally dissimilar to methylphenidate but elicits similar changes in CNS function with minimal effects on the cardiovascular system. It is employed in treating attention-deficit hyperactivity disorder and can be given once daily because of its long half-life. Clinical improvement may require treatment for 3 to 4 weeks. Its use has been associated with severe hepatic failure.

Ephedrine

Ephedrine (ephedrine sulfate) is both an - and a -adrenergic agonist; in addition, it enhances release of norepinephrine from sympathetic neurons. Ephedrine contains two asymmetrical carbon atoms (seeTable 10–1); only l-ephedrine and racemic ephedrine are used clinically.

Pharmacological Actions

Ephedrine does not contain a catechol moiety, and it is effective after oral administration. The drug stimulates heart rate and cardiac output and variably increases peripheral resistance; as a result, ephedrine usually increases blood pressure. Stimulation of the -adrenergic receptors of smooth muscle cells in the bladder base may increase the resistance to the outflow of urine. Activation of -adrenergic receptors in the lungs promotes bronchodilation. Ephedrine is a potent CNS stimulant. After oral administration, effects of the drug may persist for several hours. Ephedrine is eliminated in the urine largely as unchanged drug, with a half-life of about 3 to 6 hours.

Therapeutic Uses and Toxicity

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

Untoward effects of ephedrine include the risk of hypertension, particularly after parenteral administration or with higher than recommended oral dosing. Insomnia is a common CNS adverse effect. Tachyphylaxis may occur with repetitive dosing. Concerns have been raised about the safety of ephedrine. Usual or higher than recommended doses may cause important adverse effects in susceptible individuals and be especially of concern in patients with underlying cardiovascular disease that might be unrecognized. Of potentially greater cause for concern, large amounts of herbal preparations containing ephedrine (ma huang, Ephedra) are utilized around the world. There can be considerable variability in the content of ephedrine in these preparations, which may lead to inadvertent consumption of higher than usual does of ephedrine and its isomers.

Other Sympathomimetic Agents

Several sympathomimetic drugs are used primarily as vasoconstrictors for local application to the nasal mucous membrane or the eye. The structures of propylhexedrine (BENZEDREX), naphazoline hydrochloride (PRIVINE, NAPHCON, others), tetrahydrozoline hydrochloride (TYZINE, VISINE ORIGINAL, others), oxymetazoline hydrochloride (AFRIN, OCUCLEAR, others), and xylometazoline hydrochloride (OTRIVIN) are depicted in Table 10–1 and Figure 10–3. Ethylnorepinephrine hydrochloride (BRONKEPHRINE) (seeTable 10–1) is a -adrenergic agonist that is used as a bronchodilator. The drug also has -adrenergic agonist activity; this effect may cause local vasoconstriction and thereby reduce bronchial congestion.

Figure 10–3. Chemical Structures of Imidazoline Derivatives. 

Phenylephrine (see above), pseudoephedrine (SUDAFED, others) (a stereoisomer of ephedrine), and phenylpropanolamine (PROPAGEST, others) are the sympathomimetic drugs that have been used most commonly in oral preparations for the relief of nasal congestion. Pseudoephedrine hydrochloride is available without a prescription in a variety of solid and liquid dosage forms. Phenylpropanolamine hydrochloride shares the pharmacological properties of ephedrine and is approximately equal in potency except that it causes less CNS stimulation. The drug has been available without prescription in tablets and capsules. In addition, numerous proprietary mixtures marketed for the oral treatment of nasal and sinus congestion contain one of these sympathomimetic amines, usually in combination with an H1-histamine receptor antagonist. Also, phenylpropanolamine suppresses appetite by mechanisms possibly different from those of amphetamines (Wellman, 1992). Concern about the possibility that phenylpropanolamine increases the risk of hemorrhagic stroke in young women led the United States Food and Drug Administration (FDA) recently to consider banning the sale of the drug. The FDA has issued a public warning about the risk and has asked manufacturers of over-the-counter products containing phenylpropanolamine to stop marketing them; several manufacturers have complied with the request.

Therapeutic Uses of Sympathomimetic Drugs

The success that has attended efforts to develop therapeutic agents that can influence adrenergic receptors selectively and the variety of vital functions that are regulated by the sympathetic nervous system have resulted in a class of drugs with a large number of important therapeutic uses.

Shock

Shock is a clinical syndrome characterized by inadequate perfusion of tissues; it usually is associated with hypotension and ultimately with the failure of organ systems (Hollenberg et al., 1999). Shock is an immediately lifethreatening impairment of delivery of oxygen and nutrients to the organs of the body. Causes of shock include hypovolemia (due to dehydration or blood loss), cardiac failure (extensive myocardial infarction, severe arrhythmia, or cardiac mechanical defects such as ventricular septal defect), obstruction to cardiac output (due to pulmonary embolism, pericardial tamponade, or aortic dissection), and peripheral circulatory dysfunction (sepsis or anaphylaxis). The treatment of shock consists of specific efforts to reverse the underlying pathogenesis as well as nonspecific measures aimed at correcting hemodynamic abnormalities. Regardless of the etiology, the accompanying fall in blood pressure generally leads to marked activation of the sympathetic nervous system. This, in turn, causes peripheral vasoconstriction and an increase in the rate and force of cardiac contraction. In the initial stages of shock these mechanisms may maintain blood pressure and cerebral blood flow, although blood flow to the kidneys, skin, and other organs may be decreased, leading to impaired production of urine and metabolic acidosis (Ruffolo, 1992).

The initial therapy of shock involves basic life-support measures. It is essential to maintain blood volume, which often requires monitoring of hemodynamic parameters. Specific therapy (e.g., antibiotics for patients in septic shock) should be initiated immediately. If these measures do not lead to an adequate therapeutic response, it may be necessary to use vasoactive drugs in an effort to improve abnormalities in blood pressure and flow. This therapy is generally empirically based on response to hemodynamic measurements. Many of these pharmacological approaches, while apparently clinically reasonable, are of uncertain efficacy. Adrenergic agonists may be used in an attempt to increase myocardial contractility or to modify peripheral vascular resistance. In general terms, -adrenergic agonists increase heart rate and force of contraction, -adrenergic agonists increase peripheral vascular resistance, and dopamine promotes dilation of renal and splanchnic vascular beds, in addition to activating - and -adrenergic receptors (Breslow and Ligier, 1991).

Cardiogenic shock due to myocardial infarction has a poor prognosis; therapy is aimed at improving peripheral blood flow. Definitive therapy, such as emergency cardiac catheterization following surgical revascularization or angioplasty, may be very important. Mechanical left ventricular assist devices also may be important in maintaining cardiac output and coronary perfusion in critically ill patients. In the setting of severely impaired cardiac output, falling blood pressure leads to intense sympathetic outflow and vasoconstriction. This may further decrease cardiac output as the damaged heart pumps against a higher peripheral resistance. Medical intervention is designed to optimize cardiac filling pressure (preload), myocardial contractility, and peripheral resistance (afterload). Preload may be increased by administration of intravenous fluids or reduced with drugs such as diuretics and nitrates. A number of sympathomimetic amines have been used to increase the force of contraction of the heart. Some of these drugs have disadvantages: isoproterenol is a powerful chronotropic agent and can greatly increase myocardial oxygen demand; norepinephrine intensifies peripheral vasoconstriction; and epinephrine increases heart rate and may predispose the heart to dangerous arrhythmias. Dopamine is an effective inotropic agent that causes less increase in heart rate than does isoproterenol. It also promotes renal arterial dilation; this may be useful in preserving renal function. When given in high doses (greater than 10 to 20 g/kg per minute), dopamine activates -adrenergic receptors, causing peripheral and renal vasoconstriction. Dobutamine has complex pharmacological actions that are mediated by its stereoisomers; the clinical effects of the drug are to increase myocardial contractility with little increase in heart rate or peripheral resistance.

In some patients in shock, hypotension is so severe that vasoconstricting drugs are required to maintain a blood pressure that is adequate for perfusion of the CNS (Kulka and Tryba, 1993). -Adrenergic agonists such as norepinephrine, phenylephrine, metaraminol, mephentermine, and methoxamine have been used for this purpose. This approach may be advantageous in patients with hypotension due to failure of the sympathetic nervous system (e.g., after spinal anesthesia or injury). However, in patients with other forms of shock, such as cardiogenic shock, reflex vasoconstriction is generally intense, and -adrenergic agonists may further compromise blood flow to organs such as the kidneys and gut as well as adversely increase the work of the heart. Indeed, vasodilating drugs such as nitroprusside are more likely to improve blood flow and decrease cardiac work in such patients by decreasing afterload if a minimally adequate blood pressure can be maintained.

The hemodynamic abnormalities in septic shock are complex and are not well understood. Most patients with septic shock initially have low or barely normal peripheral vascular resistance, possibly owing to excessive effects of endogenously produced nitric oxide as well as normal or increased cardiac output. If the syndrome progresses, myocardial depression, increased peripheral resistance, and impaired tissue oxygenation occur. The primary treatment of septic shock is antibiotics. Data on the comparative value of various adrenergic agents in the treatment of septic shock are limited (Chernow and Roth, 1986). Therapy with drugs such as dopamine or dobutamine is guided by hemodynamic monitoring, with individualization of therapy depending on the patient's overall clinical condition.

Hypotension

Drugs with predominantly -adrenergic activity can be used to raise blood pressure in patients with decreased peripheral resistance in conditions such as spinal anesthesia or intoxication with antihypertensive medications. However, hypotension per se is not an indication for treatment with these agents unless there is inadequate perfusion of organs such as the brain, heart, or kidneys. Furthermore, adequate replacement of fluid or blood may be more appropriate than drug therapy for many patients with hypotension. In patients with spinal anesthesia that interrupts sympathetic activation of the heart, injections of ephedrine increase heart rate as well as peripheral vascular resistance; tachyphylaxis may occur with repetitive injections, necessitating the use of a directly acting drug.

Patients with orthostatic hypotension (excessive fall in blood pressure with standing) represent a pharmacological challenge in many cases. There are diverse causes for this disorder, including the Shy–Drager syndrome and idiopathic autonomic failure. There are several therapeutic approaches including physical maneuvers and a variety of drugs (fludrocortisone, prostaglandin synthesis inhibitors, somatostatin analogs, caffeine, vasopressin analogs, and dopamine antagonists). A number of sympathomimetic drugs have been used in treating this disorder. The ideal agents would enhance venous constriction prominently and produce relatively little arterial constriction so as to avoid supine hypertension. No such agent currently is available. Drugs used in this disorder to activate receptors include both direct and indirect-acting agents. Midodrine shows promise in treating this challenging disorder.

Hypertension

Centrally acting -adrenergic agonists such as clonidine are useful in the treatment of hypertension. Drug therapy of hypertension is discussed in Chapter 33: Antihypertensive Agents and the Drug Therapy of Hypertension.

Cardiac Arrhythmias

Cardiopulmonary resuscitation in patients with cardiac arrest due to ventricular fibrillation, electromechanical dissociation, or asystole may be facilitated by drug treatment. Epinephrine is an important therapeutic agent in patients with cardiac arrest; epinephrine and other -adrenergic agonists increase diastolic pressure and improve coronary blood flow (Raehl, 1987). -Adrenergic agonists also help to preserve cerebral blood flow during resuscitation. Cerebral blood vessels are relatively insensitive to the vasoconstricting effects of catecholamines, and perfusion pressure is increased. Consequently, during external cardiac massage, epinephrine facilitates distribution of the limited cardiac output to the cerebral and coronary circulations. Although it had been thought that the -adrenergic effects of epinephrine on the heart made ventricular fibrillation more susceptible to conversion with electrical countershock, tests in animal models have not confirmed this hypothesis (Raehl, 1987). The optimal dose of epinephrine in patients with cardiac arrest is unclear. Once a cardiac rhythm has been restored, it may be necessary to treat arrhythmias, hypotension, or shock.

In patients with paroxysmal supraventricular tachycardias, particularly those associated with mild hypotension, careful infusion of an -adrenergic agonist such as phenylephrine or methoxamine to raise blood pressure to about 160 mm Hg may end the arrhythmia by increasing vagal tone. However, this method of treatment has been replaced largely by drugs such as Ca2+ channel blockers with clinically significant effects on the AV node, -adrenergic antagonists, and adenosine, and by electrical cardioversion (seeChapter 35: Antiarrhythmic Drugs). -Adrenergic agonists such as isoproterenol may be used as adjunctive or temporizing therapy with atropine in patients with marked bradycardia who are compromised hemodynamically; if long-term therapy is required, a cardiac pacemaker usually is the treatment of choice.

Congestive Heart Failure

Sympathetic stimulation of -adrenergic receptors in the heart is a very important compensatory mechanism for maintenance of cardiac function in patients with congestive heart failure (Francis and Cohn, 1986). Evidence indicates that responses mediated by -adrenergic receptors are blunted in the failing human heart (Bristow et al., 1985). While -adrenergic agonists may increase cardiac output in acute emergency settings such as shock, long-term therapy with -adrenergic agonists as inotropic agents is not efficacious. Indeed, interest has grown in the use of -adrenergic receptor antagonists in the treatment of patients with congestive heart failure (seeChapter 34: Pharmacological Treatment of Heart Failure).

Local Vascular Effects of -Adrenergic Agonists

Epinephrine is used in many surgical procedures in the nose, throat, and larynx to shrink the mucosa and improve visualization by limiting hemorrhage. Simultaneous injection of epinephrine with local anesthetics retards the absorption of the anesthetic and increases the duration of anesthesia (seeChapter 15: Local Anesthetics). Injection of -adrenergic agonists into the penis may be useful in reversing priapism, which may complicate the use of -adrenergic antagonists in the treatment of erectile dysfunction. Both phenylephrine and oxymetazoline are efficacious vasoconstrictors when applied locally during sinus surgery (Riegle et al., 1992).

Nasal Decongestion

-Adrenergic agonists are used extensively as nasal decongestants in patients with allergic or vasomotor rhinitis and in acute rhinitis in patients with upper respiratory infections (Empey and Medder, 1981). These drugs probably decrease resistance to airflow by decreasing the volume of the nasal mucosa; this may occur by activation of -adrenergic receptors in venous capacitance vessels in nasal tissues that have erectile characteristics (Cole et al., 1983). The receptors that mediate this effect appear to be -adrenergic receptors. Interestingly, receptors may mediate contraction of arterioles that supply nutrition to the nasal mucosa (Andersson and Bende, 1984). Intense constriction of these vessels may cause structural damage of the mucosa (DeBernardis et al., 1987). A major limitation of therapy with nasal decongestants is that loss of efficacy and 'rebound' hyperemia and worsening of symptoms often occur with chronic use or when the drug is stopped. Although mechanisms are uncertain, possibilities include receptor desensitization and damage to the mucosa. Agonists that are selective for receptors may be less likely to induce mucosal damage (DeBernardis et al., 1987).

For decongestion, -adrenergic agonists may be administered either orally or topically. Oral ephedrine often causes CNS adverse effects. Pseudoephedrine is a stereoisomer of ephedrine that is less potent than ephedrine in producing tachycardia, increased blood pressure, and CNS stimulation (Empey and Medder, 1981). Sympathomimetic decongestants should be used with great caution in patients with hypertension and in men with prostatic enlargement, and they are contraindicated in patients who are taking an MAO inhibitor. A variety of compounds (see above) are available for topical use in patients with rhinitis. Topical decongestants are particularly useful in acute rhinitis because of their more selective site of action, but they are apt to be used excessively by patients, leading to rebound congestion. Oral decongestants are much less likely to cause rebound congestion but carry a greater risk of inducing adverse systemic effects. Indeed, patients with uncontrolled hypertension or ischemic heart disease generally should carefully avoid the oral consumption of over-the-counter products or herbal preparations containing sympathomimetic drugs.

Asthma

Use of adrenergic agents in the treatment of asthma is discussed in Chapter 28: Drugs Used in the Treatment of Asthma.

Allergic Reactions

Epinephrine is the drug of choice to reverse the manifestations of serious, acute hypersensitivity reactions (e.g., from a food, bee sting, or drug allergy). A subcutaneous injection of epinephrine rapidly relieves itching, hives, and swelling of lips, eyelids, and tongue. In some patients, careful intravenous infusion of epinephrine may be required to ensure prompt pharmacological effects. This treatment may be lifesaving when edema of the glottis threatens patency of the airway or when there is hypotension or shock in patients with anaphylaxis. In addition to its cardiovascular effects, epinephrine is thought to activate -adrenergic receptors that suppress the release from mast cells of mediators such as histamine or leukotrienes. Although glucocorticoids and antihistamines frequently are administered to patients with severe hypersensitivity reactions, epinephrine remains the mainstay of treatment.

Ophthalmic Uses

Application of various sympathomimetic amines for diagnostic and therapeutic ophthalmic use is discussed in Chapter 66: Ocular Pharmacology.

Narcolepsy

Narcolepsy is characterized by hypersomnia, including attacks of sleep that may occur suddenly under conditions that are not normally conducive to sleep. Some patients respond to treatment with tricyclic antidepressants or MAO inhibitors. Alternatively, CNS stimulants such as amphetamine, dextroamphetamine, or methamphetamine may be useful (Mitler et al., 1993). Modafinil (PROVIGIL), a CNS stimulant, may have benefit in narcolepsy (Fry, 1998). In the United States, it is a controlled substance (schedule IV; seeAppendix I). Its mechanism of action in narcolepsy is unclear and may not involve adrenergic receptors. Therapy with amphetamines is complicated by the risk of abuse and the likelihood of the development of tolerance. Depression, irritability, and paranoia also may occur. Amphetamines may disturb nocturnal sleep, which increases the difficulty of avoiding daytime attacks of sleep in these patients.

Weight Reduction

Obesity arises as a consequence of positive caloric balance. Optimally, weight loss is achieved by a gradual increase in energy expenditure from exercise combined with dieting to decrease the caloric intake. However, this obvious approach has a relatively low success rate. Consequently, alternative forms of treatment, including surgery or medications, have been developed in an effort to increase the likelihood of achieving and maintaining weight loss. Amphetamine was found to produce weight loss in early studies of patients with narcolepsy and was subsequently used in the treatment of obesity (Silverstone, 1986). The drug promotes weight loss by suppressing appetite rather than by increasing energy expenditure. Other anorexiant drugs include methamphetamine, dextroamphetamine, phentermine, benzphetamine, phendimetrazine, phenmetrazine, diethylpropion, mazindol, and phenylpropanolamine. In short-term (up to 20 weeks), double-blind, controlled studies, amphetamine-like drugs have been shown to be more effective than placebo in promoting weight loss; the rate of weight loss is typically increased by about 0.5 pound per week with these drugs. There is little to choose among these drugs in terms of efficacy. However, long-term weight loss has not been demonstrated unless these drugs are taken continuously (Bray, 1993). In addition, other important issues have not yet been resolved; these include the selection of patients who might be benefited by these drugs, whether the drugs should be administered continuously or intermittently, and the duration of treatment (Silverstone, 1986). Adverse effects of treatment include the potential for drug abuse and habituation, serious worsening of hypertension (although in some patients blood pressure may actually fall, presumably as a consequence of weight loss), sleep disturbances, palpitations, and dry mouth. These agents may be effective as adjuncts in the treatment of obese patients. However, available evidence does not support the isolated use of these drugs in the absence of a more comprehensive program that stresses exercise and modification of diet.

Attention-Deficit Hyperactivity Disorder (ADHD)

This syndrome, usually first evident in childhood, is characterized by excessive motor activity, difficulty in sustaining attention, and impulsiveness. Children with this disorder frequently are troubled by difficulties in school, impaired interpersonal relationships, and excitability. Academic underachievement is an important characteristic. A substantial number of children with this syndrome have characteristics that persist into adulthood, although in modified form (American Psychiatric Association, 1987). Behavioral therapy may be helpful in some patients.

Catecholamines may be involved in the control of attention at the level of the cerebral cortex. A variety of stimulant drugs have been utilized in the treatment of ADHD, and they are particularly indicated in moderate-to-severe cases. Dextroamphetamine has been demonstrated to be more effective than placebo (Klein et al., 1980); methylphenidate also is effective in children with ADHD, although information about the long-term efficacy of both drugs is limited. Treatment may start with a dose of 5 mg of methylphenidate in the morning and at lunch; the dose is increased gradually over a period of weeks depending on the response as judged by parents, teachers, and the physician. The total daily dose generally should not exceed 60 mg; because of its short duration of action, most children require two or three doses of methylphenidate each day. The timing of doses is adjusted individually in accordance with rapidity of onset of effect and duration of action. Some children may not respond, and the drug should be discontinued after one month of dosage adjustment. Methylphenidate and dextroamphetamine probably have similar efficacy in ADHD and are the preferred drugs for this disorder (Elia et al., 1999). Pemoline appears to be less effective, although it may be used once daily in some children (Klein et al., 1980). Potential adverse effects of these medications in children include insomnia, abdominal pain, anorexia, and weight loss that may be associated with suppression of growth. Minor symptoms may be transient or may respond to adjustment of dosage or administration of the drug with meals. Other drugs that have been utilized include tricyclic antidepressants, antipsychotic agents, and clonidine (Fox and Rieder, 1993). There is evidence that stimulant medications are effective in adults with similar disorders (Chiarello and Cole, 1987).

Adrenergic Receptor Antagonists

Many types of drugs interfere with the function of the sympathetic nervous system and thus have profound effects on the physiology of sympathetically innervated organs. Several of these drugs are important in clinical medicine, particularly for the treatment of cardiovascular diseases. Drugs that decrease the amount of norepinephrine released as a consequence of sympathetic nerve stimulation as well as drugs that inhibit sympathetic nervous activity by suppressing sympathetic outflow from the brain are discussed in Chapter 33: Antihypertensive Agents and the Drug Therapy of Hypertension.

The remainder of this chapter focuses on drugs termed adrenergic receptor antagonists, which inhibit the interaction of norepinephrine, epinephrine, and other sympathomimetic drugs with adrenergic receptors. Almost all of these agents are competitive antagonists in their interactions with either - or -adrenergic receptors; one exception is phenoxybenzamine, an irreversible antagonist that binds covalently to -adrenergic receptors. There are important structural differences among the various types of adrenergic receptors (see also Chapter 6: Neurotransmission: The Autonomic and Somatic Motor Nervous Systems). Since compounds have been developed that have different affinities for the various receptors, it is possible to interfere selectively with responses that result from stimulation of the sympathetic nervous system. For example, selective antagonists of -adrenergic receptors block most actions of epinephrine and norepinephrine on the heart, while having less effect on -adrenergic receptors in bronchial smooth muscle and no effect on responses mediated by - or -adrenergic receptors. Detailed knowledge of the autonomic nervous system and the sites of action of drugs that act on adrenergic receptors is essential for understanding the pharmacological properties and therapeutic uses of this important class of drugs. Additional background material is presented in Chapter 6: Neurotransmission: The Autonomic and Somatic Motor Nervous Systems. Because of their unique activity in the CNS, drugs that block dopamine receptors are considered in Chapter 20: Drugs and the Treatment of Psychiatric Disorders: Psychosis and Mania.

-Adrenergic Receptor Antagonists

-Adrenergic receptors mediate many of the important actions of endogenous catecholamines. Responses of particular clinical relevance include -receptor-mediated contraction of arterial and venous smooth muscle. -Adrenergic receptors are involved in suppressing sympathetic output, increasing vagal tone, facilitating platelet aggregation, inhibiting the release of norepinephrine and acetylcholine from nerve endings, and regulating metabolic effects. These effects include suppression of insulin secretion and inhibition of lipolysis. -Receptors also mediate contraction of some arteries and veins.

-Adrenergic receptor antagonists have a wide spectrum of pharmacological specificities and are chemically heterogeneous. Some of these drugs have markedly different affinities for and receptors. For example, prazosin is much more potent in blocking than receptors (and is termed -selective), whereas yohimbine is -selective; phentolamine has similar affinities for both of these receptor subtypes. More recently, agents that discriminate among the various subtypes of a particular receptor have become available; for example tamsulosin has higher potency at 1A than at 1B receptors.

Chemistry

The structural formulas of a number of -adrenergic antagonists are shown in Figure 10–4. These structurally diverse drugs can be divided into a number of major groups including -haloethylamine alkylating agents, imidazoline analogs, piperazinyl quinazolines, and indole derivatives.

Figure 10–4. Structural Formulas of Some -Adrenergic Receptor Antagonists. 

Pharmacological Properties

Cardiovascular System

The most important effects of -adrenergic antagonists observed clinically are on the cardiovascular system. Actions in both the CNS and the periphery are involved, and the outcome depends on the cardiovascular status of the patient at the time of drug administration and the relative selectivity of the agent for or receptors.

-Adrenergic Antagonists

Blockade of -adrenergic receptors inhibits vasoconstriction induced by endogenous catecholamines; vasodilation may occur in both arteriolar resistance vessels and veins. The result is a fall in blood pressure because of decreased peripheral resistance. The magnitude of such effects depends on the activity of the sympathetic nervous system at the time the antagonist is administered and thus is less in supine than in upright subjects and is particularly marked if there is hypovolemia. For most -adrenergic antagonists, the fall in blood pressure is opposed by baroreceptor reflexes that cause increases in heart rate and cardiac output, as well as fluid retention. These reflexes are exaggerated if the antagonist also blocks receptors on peripheral sympathetic nerve endings, leading to enhanced release of norepinephrine and increased stimulation of postsynaptic receptors in the heart and on juxtaglomerular cells (Langer, 1981; Starke et al., 1989; see also Chapter 6: Neurotransmission: The Autonomic and Somatic Motor Nervous Systems). Although stimulation of -adrenergic receptors in the heart may cause an increased force of contraction, the importance of blockade at this site in human beings is uncertain.

Blockade of -adrenergic receptors also inhibits vasoconstriction and the increase in blood pressure produced by the administration of a sympathomimetic amine. The pattern of effects depends on the adrenergic agonist that is administered: pressor responses to phenylephrine can be completely suppressed; those to norepinephrine are only incompletely blocked because of residual stimulation of cardiac receptors; and pressor responses to epinephrine may be transformed to vasodepressor effects (epinephrine 'reversal') because of residual stimulation of receptors in the vasculature with resultant vasodilation.

-Adrenergic Antagonists

-Adrenergic receptors have an important role in regulation of the activity of the sympathetic nervous system, both peripherally and centrally. As mentioned above, activation of presynaptic receptors inhibits the release of norepinephrine from peripheral sympathetic nerve endings. Activation of receptors in the pontomedullary region of the CNS inhibits sympathetic nervous system activity and leads to a fall in blood pressure; these receptors are a site of action of drugs such as clonidine. Blockade of -adrenergic receptors with selective antagonists such as yohimbine can thus increase sympathetic outflow and potentiate the release of norepinephrine from nerve endings, leading to activation of and receptors in the heart and peripheral vasculature with a consequent rise in blood pressure (Goldberg and Robertson, 1983). Antagonists that also block receptors give rise to similar effects on sympathetic outflow and release of norepinephrine, but the net increase in blood pressure is prevented by inhibition of vasoconstriction.

Although certain vascular beds contain -adrenergic receptors that promote contraction of smooth muscle, it is thought that these receptors are preferentially stimulated by circulating catecholamines, whereas receptors are activated by norepinephrine released from sympathetic nerve fibers (Davey, 1987; van Zwieten, 1988). In other vascular beds, receptors promote vasodilation by stimulating the release of endothelium-derived relaxing factor (nitric oxide). The physiological role of vascular -adrenergic receptors in the regulation of blood flow within various vascular beds is uncertain (Cubeddu, 1988). -Adrenergic receptors contribute to smooth muscle contraction in human saphenous vein, whereas receptors are more prominent in dorsal hand veins (Haefeli et al., 1993; Gavin et al., 1997). The effects of -adrenergic antagonists on the cardiovascular system are dominated by actions in the CNS and on sympathetic nerve endings.

Other Actions of -Adrenergic Antagonists

- Adrenergic antagonists can block receptors that mediate contraction of nonvascular smooth muscle. For example, contraction of the trigone and sphincter muscles in the base of the urinary bladder and in the prostate may be inhibited by -receptor antagonists, leading to decreased resistance to urinary outflow. Recent evidence suggests that 1A receptors are important in mediating catecholamine-induced prostate smooth muscle contraction (Ruffolo and Hieble, 1999). Although receptors may promote contraction of bronchial smooth muscle, the importance of this effect is minimal. Catecholamines increase the output of glucose from the liver; in human beings, this effect is mediated predominantly by -adrenergic receptors, although receptors may contribute (Rosen et al., 1983). -Adrenergic receptors of the 2A subtype facilitate platelet aggregation; the effect of blockade of platelet receptors in vivo is not clear. Activation of receptors in the pancreatic islets greatly suppresses insulin secretion; blockade of pancreatic receptors may facilitate insulin release (Kashiwagi et al., 1986).

Phenoxybenzamine and Related Haloalkylamines

Phenoxybenzamine is a haloalkylamine that blocks - and -adrenergic receptors irreversibly. Although phenoxybenzamine may have slight selectivity for receptors, it is not clear whether or not this has any significance in human beings.

Chemistry

The haloalkylamine adrenergic blocking drugs are closely related chemically to the nitrogen mustards; as in the latter, the tertiary amine cyclizes with the loss of chlorine to form a reactive ethyleniminium or aziridinium ion (seeChapter 52: Antineoplastic Agents). The molecular configuration directly responsible for blockade is probably a highly reactive carbonium ion formed upon cleavage of the three-membered ring. It is presumed that the arylalkyl amine moiety of the molecule is responsible for the relative specificity of action of these agents, since the reactive intermediate probably reacts with sulfhydryl, amino, and carboxyl groups in many proteins. Because of these chemical reactions, phenoxybenzamine is covalently conjugated with -adrenergic receptors. Consequently, receptor blockade is irreversible, and restoration of cellular responsiveness to -adrenergic agonists probably requires the synthesis of new receptors.

Pharmacological Properties

The major effects of phenoxybenzamine result from blockade of -adrenergic receptors in smooth muscle. Phenoxybenzamine causes a progressive decrease in peripheral resistance and an increase in cardiac output that is due, in part, to reflex sympathetic nerve stimulation. Tachycardia may be accentuated by enhanced release of norepinephrine (because of blockade) and decreased inactivation of the amine because of inhibition of neuronal and extraneuronal uptake mechanisms (see below; see also Chapter 6: Neurotransmission: The Autonomic and Somatic Motor Nervous Systems). Pressor responses to exogenously administered catecholamines are impaired. Indeed, hypotensive responses to epinephrine occur because of unopposed -adrenergic receptor–mediated vasodilation. Although phenoxybenzamine has relatively little effect on supine blood pressure in normotensive subjects, there is a marked fall in blood pressure on standing because of antagonism of compensatory vasoconstriction. In addition, the ability to respond to hypovolemia and anesthetic-induced vasodilation is impaired.

Phenoxybenzamine inhibits the uptake of catecholamines into both adrenergic nerve terminals and extraneuronal tissues. In addition to blockade of -adrenergic receptors, substituted -haloalkylamines irreversibly inhibit responses to 5-HT, histamine, and acetylcholine. However, somewhat higher doses of phenoxybenzamine are required to produce these effects than to produce blockade of -adrenergic receptors. The general pharmacology of the haloalkylamines has been reviewed by Nickerson and Hollenberg (1967) and Furchgott (1972); also, more detailed discussion can be found in earlier editions of this textbook.

The pharmacokinetic properties of phenoxybenzamine are not well understood. The half-life of phenoxybenzamine is probably less than 24 hours. However, since the drug inactivates -adrenergic receptors irreversibly, the duration of its effect is dependent not only on the presence of the drug but also on the rate of synthesis of -adrenergic receptors. Many days may be required before the number of functional -adrenergic receptors on the surface of target cells returns to normal (Hamilton et al., 1982). Blunted maximal responses to catecholamines may not be as persistent, since there are so-called spare receptors in vascular smooth muscle (Hamilton et al., 1983).

Therapeutic Uses

A major use of phenoxybenzamine (phenoxybenzamine hydrochloride;DIBENZYLINE) is in the treatment of pheochromocytoma. Pheochromocytomas are tumors of the adrenal medulla and sympathetic neurons that secrete enormous quantities of catecholamines into the circulation. The usual result is hypertension, which may be episodic and severe. The vast majority of pheochromocytomas are treated surgically; however, phenoxybenzamine is frequently used to treat the patient in preparation for surgery. The drug controls episodes of severe hypertension and minimizes other adverse effects of catecholamines, such as contraction of plasma volume and injury of the myocardium. A conservative approach is to initiate treatment with phenoxybenzamine (at a dosage of 10 mg twice daily) 1 to 3 weeks before the operation. The dose is increased every other day until the desired effect on blood pressure is achieved. Therapy may be limited by postural hypotension; nasal stuffiness is another frequent adverse effect. The usual total daily dose of phenoxybenzamine in patients with pheochromocytoma is 40 to 120 mg given in two or three divided portions. Some physicians do not use phenoxylenzamine preoperatively in patients with pheochromocytoma (Boutros et al., 1990). Prolonged treatment with phenoxybenzamine may be necessary in patients with inoperable or malignant pheochromocytoma. In some patients, particularly those with malignant disease, administration of metyrosine may be a useful adjuvant (Brogden et al., 1981; Perry et al., 1990). Metyrosine is a competitive inhibitor of tyrosine hydroxylase, the rate-limiting enzyme in the synthesis of catecholamines (seeChapter 6: Neurotransmission: The Autonomic and Somatic Motor Nervous Systems). -Adrenergic receptor antagonists also are used to treat pheochromocytoma, but only after the administration of an -receptor antagonist (see below).

Phenoxybenzamine was the first -receptor antagonist used in the medical therapy of benign prostatic hyperplasia (BPH); blockade of receptors in smooth muscle of the prostate and bladder base may decrease both obstructive symptoms and the need to urinate at night (Caine et al., 1981). However, terazosin and related drugs are safer and preferable -adrenergic antagonists for this disorder (see below). Phenoxybenzamine has been used to control the manifestations of autonomic hyperreflexia in patients with spinal cord transection (Braddom and Rocco, 1991).

Toxicity and Adverse Effects

The major adverse effect of phenoxybenzamine is postural hypotension. This is often accompanied by reflex tachycardia and other arrhythmias. Hypotension can be particularly severe in hypovolemic patients or under conditions that promote vasodilation (administration of vasodilator drugs, exercise, ingestion of alcohol or large quantities of food). Reversible inhibition of ejaculation and aspermia after orgasm may occur because of impaired smooth muscle contraction in the vas deferens and ejaculatory ducts. Phenoxybenzamine has mutagenic activity in the Ames test, and repeated administration of this drug to experimental animals causes peritoneal sarcomas and lung tumors (IARC, 1980). The clinical significance of these findings is not known.



Phentolamine and Tolazoline

Phentolamine, an imidazoline, is a competitive -adrenergic antagonist that has similar affinities for and receptors. Its effects on the cardiovascular system are very similar to those of phenoxybenzamine. Phentolamine also can block receptors for 5-HT, and it causes release of histamine from mast cells. In addition, phentolamine has been found to block K+ channels (McPherson, 1993). Tolazoline is a related but somewhat less potent compound. Tolazoline and phentolamine stimulate gastrointestinal smooth muscle, an effect that is antagonized by atropine, and they also enhance gastric acid secretion. Tolazoline stimulates secretion by salivary, lacrimal, and sweat glands as well.

The pharmacokinetic properties of phentolamine are not known, although the drug is extensively metabolized. Tolazoline is well absorbed after oral administration and is excreted in the urine.

Therapeutic Uses

Phentolamine (phentolamine mesylate;REGITINE) can be used in the short term to control hypertension in patients with pheochromocytoma. Rapid infusions of phentolamine may cause severe hypotension, and the drug should be administered cautiously. Phentolamine also may be useful to relieve pseudoobstruction of the bowel in patients with pheochromocytoma; this condition may result from the inhibitory effects of catecholamines on intestinal smooth muscle. Phentolamine has been used locally to prevent dermal necrosis after the inadvertent extravasation of an -adrenergic agonist. The drug also may be useful for the treatment of hypertensive crises that follow the abrupt withdrawal of clonidine or that may result from the ingestion of tyramine-containing foods during the use of nonselective inhibitors of monoamine oxidase. Although excessive activation of -adrenergic receptors is important in the development of severe hypertension in these settings, there is little information about the safety and efficacy of phentolamine compared with those of other antihypertensive agents in the treatment of such patients. Direct intracavernous injection of phentolamine (in combination with papaverine) has been proposed as a treatment for male sexual dysfunction (Sidi, 1988; Zentgraf et al., 1988). The long-term efficacy of this treatment is not known. Intracavernous injection of phentolamine may cause orthostatic hypotension and priapism; pharmacological reversal of drug-induced erections can be achieved with an -adrenergic agonist such as phenylephrine. Repetitive intrapenile injections may cause fibrotic reactions (Sidi, 1988). Interestingly, there is preliminary evidence suggesting that buccally or orally administered phentolamine may have efficacy in some men with sexual dysfunction (Zorgniotti, 1994; Becker et al., 1998).

Tolazoline (tolazoline hydrochloride;PRISCOLINE) has been used in the treatment of persistent pulmonary hypertension of the newborn and as an aid in visualizing distal peripheral vessels during arteriography (Gouyon and Francoise, 1992; Wilms et al., 1993). The use of tolazoline in the newborn may be replaced by the use of prostaglandins or nitric oxide (Gouyon and Francoise, 1992).

Toxicity and Adverse Effects

Hypotension is the major adverse effect of phentolamine. In addition, reflex cardiac stimulation may cause alarming tachycardia, cardiac arrhythmias, and ischemic cardiac events, including myocardial infarction. Gastrointestinal stimulation may result in abdominal pain, nausea, and exacerbation of peptic ulcer. Phentolamine should be used with particular caution in patients with coronary artery disease or a history of peptic ulcer.

Prazosin and Related Drugs

Prazosin, the prototype of a family of agents that contain a piperazinyl quinazoline nucleus, is a very potent and selective -adrenergic antagonist. Its affinity for receptors is about 1000-fold greater than that for receptors. Prazosin has similar potencies at 1A 1B, and 1D receptor subtypes. Interestingly, the drug also is a relatively potent inhibitor of cyclic nucleotide phosphodiesterases, and it was originally synthesized for this purpose (Hess, 1975). The pharmacological properties of prazosin have been characterized extensively, and the drug is used frequently for the treatment of hypertension (seeChapter 33: Antihypertensive Agents and the Drug Therapy of Hypertension).

Pharmacological Properties

Prazosin

The major effects of prazosin are a result of its blockade of -adrenergic receptors in arterioles and veins. This leads to a fall in peripheral vascular resistance and in venous return to the heart. Administration of prazosin usually does not increase heart rate, a response that occurs frequently with other vasodilating drugs. Since prazosin has little or no -receptor–blocking effect at concentrations achieved clinically, it probably does not promote the release of norepinephrine from sympathetic nerve endings in the heart. In addition, prazosin decreases cardiac preload and thus has little tendency to increase cardiac output and rate, in contrast to vasodilators such as hydralazine that have minimal dilatory effects on veins. Although the combination of reduced preload and selective -receptor blockade might be sufficient to account for the relative absence of reflex tachycardia, prazosin also may act in the CNS to suppress sympathetic outflow (seeCubeddu, 1988). Prazosin appears to depress baroreflex function in hypertensive patients (Sasso and O'Connor, 1982). Prazosin and related drugs in this class tend to have small but favorable effects on serum lipids in human beings, decreasing low-density lipoproteins (LDL) and triglycerides while increasing concentrations of high-density lipoproteins (HDL). The clinical significance of these changes is not known. Prazosin and related drugs may have effects on cell growth unrelated to antagonism of receptors (Yang et al., 1997; Hu et al., 1998).

Prazosin (prazosin hydrochloride;MINIPRESS) is well absorbed after oral administration, and bioavailability is about 50% to 70%. Peak concentrations of prazosin in plasma are generally reached 1 to 3 hours after an oral dose. The drug is tightly bound to plasma proteins (primarily -acid glycoprotein), and only 5% of the drug is free in the circulation; diseases that modify the concentration of this protein (e.g., inflammatory processes) may change the free fraction (Rubin and Blaschke, 1980). Prazosin is extensively metabolized in the liver, and little unchanged drug is excreted by the kidneys. The plasma half-life is approximately 2 to 3 hours (this may be prolonged to 6 to 8 hours in congestive heart failure). The duration of action of the drug is typically 7 to 10 hours in the treatment of hypertension.

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

Terazosin

Terazosin (terazosin hydrochloride;HYTRIN) is a close structural analog of prazosin (Kyncl, 1993; Wilde et al., 1993). It is less potent than prazosin but retains high specificity for receptors; terazosin does not discriminate among 1A 1B, and 1D receptors. The major distinction between the two drugs is in their pharmacokinetic properties. Terazosin is more soluble in water than is prazosin, and its bioavailability is high (>90%) (Cubeddu, 1988; Frishman et al., 1988); this may facilitate titration of dosage. The half-time of elimination of terazosin is approximately 12 hours, and its duration of action usually extends beyond 18 hours. Consequently, the drug may be taken once daily to treat hypertension and BPH in most patients. Terazosin has been found more effective that finasteride in treatment of BPH (Lepor et al., 1996). Only about 10% of terazosin is excreted unchanged in the urine. An initial first dose of 1 mg is recommended. Doses are titrated upward depending on the therapeutic response. Doses of 10 mg/day may be required for maximal effect in BPH.

Doxazosin

Doxazosin CARDURA) is another structural analog of prazosin. It, too, is a highly selective antagonist at -adrenergic receptors, although nonselective among -receptor subtypes, but it differs in its pharmacokinetic profile (Babamoto and Hirokawa, 1992). The half-life of doxazosin is approximately 20 hours, and its duration of action may extend to 36 hours (Cubeddu, 1988). The bioavailability and extent of metabolism of doxazosin and prazosin are similar. Most doxazosin metabolites are eliminated in the feces. The hemodynamic effects of doxazosin appear to be similar to those of prazosin. Doxazosin should be given initially as a one-mg dose in the treatment of hypertension or BPH. The role of doxazosin in the monotherapy of hypertension recently has been questioned by the results of a clinical trial. A slow-release formulation of doxazosin is under investigation; preliminary evidence suggests that this might ease dose titration (Os and Stokke, 1999).

Alfuzosin

Alfuzosin is a quinozoline-based -receptor antagonist with similar affinity at all of the -receptor subtypes (Foglar et al., 1995; Kenny et al., 1996). It has been used extensively in treating BPH. Its bioavailability is about 64%; it has a half-life of 3 to 5 hours. Alfuzosin is not currently available in the United States.

Tamsulosin

Tamsulosin FLOMAX), a benzenesulfonamide, is an receptor antagonist with some selectivity for 1A (and 1D) receptor subtypes compared to 1B receptor subtype (Kenny et al., 1996). This selectivity may favor blockade of 1A receptors in prostate compared to 1B receptors, which are important in vascular smooth muscle. Tamsulosin is efficacious in the treatment of BPH with little effect on blood pressure (Wilde and McTavish, 1996; Beduschi et al., 1998). Tamsulosin is well absorbed and has a half-life of 5 to 10 hours. It is extensively metabolized by the cytochrome P450 system. Tamsulosin may be administered at a 0.4-mg starting dose; a dose of 0.8 mg ultimately will be more efficacious in some patients. Abnormal ejaculation is an adverse effect of tamsulosin.

Adverse Effects

A major potential adverse effect of prazosin and its congeners is the so-called first-dose phenomenon; marked postural hypotension and syncope are sometimes seen 30 to 90 minutes after a patient takes an initial dose. Occasionally, syncopal episodes also have occurred with a rapid increase in dosage or with the addition of a second antihypertensive drug to the regimen of a patient who is already taking a large dose of prazosin. The mechanisms responsible for such exaggerated hypotensive responses or for the development of tolerance to these effects are not clear. An action in the CNS to reduce sympathetic outflow may contribute (see above). The risk of the first-dose phenomenon is minimized by limiting the initial dose to 1 mg at bedtime, by increasing the dosage slowly, and by introducing additional antihypertensive drugs cautiously. Since orthostatic hypotension may be a problem during long-term treatment with prazosin or its congeners, it is essential to check standing as well as recumbent blood pressure. Nonspecific adverse effects such as headache, 'dizziness,' and asthenia do not often limit treatment with prazosin. The nonspecific complaint of 'dizziness' is generally not due to orthostatic hypotension. Although not extensively documented, the adverse effects of the structural analogs of prazosin appear to be similar to those of the parent compound. For tamsulosin, at a dose of 0.4 mg daily, effects on blood pressure are not expected, although impaired ejaculation may occur.

Therapeutic Uses

Prazosin and its congeners have been used successfully in the treatment of primary systemic hypertension (seeChapter 33: Antihypertensive Agents and the Drug Therapy of Hypertension). The most important distinction among these drugs relates to their duration of action and thus the required dosing interval. Considerable recent interest has focused on the use of -adrenergic antagonists in the treatment of hypertension in view of the tendency of these drugs to improve rather than worsen lipid profiles and glucose-insulin metabolism in patients with hypertension who are at risk for atherosclerotic disease (Grimm, 1991). Also, catecholamines are powerful stimulators of vascular smooth muscle hypertrophy, acting via receptors (Majesky et al., 1990; Okazaki et al., 1994). To what extent these effects of antagonists have clinical significance in diminishing risk of atherosclerosis is not known.

Congestive Heart Failure

-Adrenergic antagonists have been used in the treatment of congestive heart failure, as have other vasodilating drugs. The short-term effects of prazosin in these patients are due to dilation of both arteries and veins, resulting in a reduction of preload and afterload, which increases cardiac output and reduces pulmonary congestion (Colucci, 1982). In contrast to results obtained with inhibitors of angiotensin converting enzyme or a combination of hydralazine and an organic nitrate, prazosin has not been found to prolong life in patients with congestive heart failure (Cohn et al., 1986).

Benign Prostatic Hyperplasia

-Adrenergic receptors in the trigone muscle of the bladder and urethra contribute to the resistance to outflow of urine. Prazosin reduces this resistance in some patients with impaired bladder emptying caused by prostatic obstruction or parasympathetic decentralization from spinal injury (Kirby et al., 1987; Andersson, 1988). The efficacy and importance of -adrenergic-receptor antagonists in the medical treatment of benign prostatic hyperplasia have been demonstrated in multiple controlled clinical trials. Transurethral resection of the prostate has been the accepted surgical treatment for symptoms of urinary obstruction in men with BPH; however, there are some serious potential complications, and improvement may not be permanent. Other, less invasive procedures also are available. Medical therapy has utilized -adrenergic antagonists for many years. Finasteride, a drug that inhibits conversion of testosterone to dihydrotestosterone (seeChapter 59: Androgens), and can reduce prostate volume in some patients, has been approved for this indication. However, its overall efficacy appears less than that observed with receptor antagonists (Lepor et al., 1996). -Selective adrenergic antagonists have efficacy in benign prostatic hyperplasia owing to relaxation of smooth muscle in the bladder neck, prostate capsule, and prostatic urethra. These drugs rapidly improve urinary flow, whereas the actions of finasteride are typically delayed for months. Phenoxybenzamine was the first adrenergic antagonist used extensively for benign prostatic hyperplasia; however, the relative lack of extensive safety information about this drug has led to its replacement by newer, reversible antagonists for this indication. Prazosin, terazosin, doxazosin, tamsulosin, and alfuzosin have been studied extensively and used widely in patients with benign prostatic hyperplasia (Cooper et al., 1999). With the exception on tamsulosin, the comparative efficacies of each of these drugs, especially in comparison with relative adverse effects such as postural hypotension, appear similar, although direct comparisons are limited. Tamsulosin at the recommended dose of 0.4 mg daily is less likely to cause orthostatic hypotension than are the other drugs; its relative efficacy in BPH requires further study. Animal models have some utility in comparing potencies of adrenergic antagonists but may not adequately reflect the human prostate or predict clinical efficacy (Breslin et al., 1993). The nature of the subtype(s) of receptors contributing to contraction in human prostate is unclear. However, there is growing evidence that the predominant -receptor subtype expressed in the prostate is the 1A receptor (Price et al., 1993; Faure et al., 1994; Forray et al., 1994). Indeed, studies of receptor binding and smooth muscle contraction in the human prostate also suggest the importance of the cloned 1A receptor (Forray et al., 1994). Developments in this area will provide the basis for the selection of -adrenergic antagonists with specificity for the relevant subtype of receptor in human prostate. However, the possibility remains that some of the symptoms of BPH are due to receptors in other sites, such as bladder, spinal cord, or brain.

Other Disorders

Although anecdotal evidence suggested that prazosin might be useful in the treatment of patients with variant angina (Prinzmetal's angina) due to coronary vasospasm, several small controlled trials have failed to demonstrate a clear benefit (Robertson et al., 1983b; Winniford et al., 1983). Some studies have indicated that prazosin can decrease the incidence of digital vasospasm in patients with Raynaud's disease; however, its relative efficacy as compared with other vasodilators (e.g., Ca2+ channel blockers) is not known (Surwit et al., 1984; Wollersheim et al., 1986). Prazosin may have some benefit in patients with other vasospastic disorders (Spittell and Spittell, 1992). Prazosin decreases ventricular arrhythmias induced by coronary artery ligation or reperfusion in laboratory animals; the therapeutic potential for this use in human beings is not known (Davey, 1986). Prazosin also might be useful for the treatment of patients with mitral or aortic valvular insufficiency, presumably because of reduction of afterload; additional data are needed (Jebavy et al., 1983; Stanaszek et al., 1983).

Ergot Alkaloids

The ergot alkaloids were the first adrenergic blocking agents to be discovered, and most aspects of their general pharmacology were disclosed in the classic studies of Dale (1906). Ergot alkaloids exhibit a complex variety of pharmacological properties. To varying degrees, these agents act as partial agonists or antagonists at -adrenergic, 5-HT, and dopamine receptors.

Chemistry

Details of the chemistry of the ergot alkaloids are presented in Chapter 11: 5-Hydroxytryptamine (Serotonin): Receptor Agonists and Antagonists. In general, compounds of the ergonovine type, which lack a peptide side chain, have no adrenergic blocking activity. Of the natural ergot preparations, 'ergotoxine' has the greatest -adrenergic blocking potency. It is a mixture of three alkaloids—ergocornine, ergocristine, and ergocryptine. Dihydrogenation of the lysergic acid nucleus increases -adrenergic blocking activity and decreases, but does not eliminate, the ability to stimulate smooth muscle by an action on tryptaminergic receptors.

Pharmacological Properties

Both the natural and the dihydrogenated peptide alkaloids produce -adrenergic blockade. This is relatively persistent for a competitive antagonist, but it is of much shorter duration than that produced by phenoxybenzamine. These drugs also are effective antagonists of 5-HT. Although the hydrogenated ergot alkaloids are among the most potent -adrenergic blocking agents known, a plethora of adverse effects prevents the administration of doses that could produce more than minimal blockade in human beings.

The most important effects of the ergot alkaloids are due to actions on the CNS and direct stimulation of smooth muscle. The latter occurs in many different organs (seeChapter 11: 5-Hydroxytryptamine (Serotonin): Receptor Agonists and Antagonists), and even dihydroergotoxine (ergoloid mesylate) has been observed to produce spastic contractions of the intestine.

The peptide ergot alkaloids can reverse the pressor response to epinephrine to a depressor action. However, all the natural ergot alkaloids cause a significant rise in blood pressure as a result of peripheral vasoconstriction, which is more pronounced in postcapillary than in precapillary vessels. Although hydrogenation reduces this action, dihydroergotamine still is an effective vasoconstrictor; a residual constrictor action of dihydroergotoxine also is demonstrable. Ergotamine, ergonovine, and other ergot alkaloids can produce coronary vasoconstriction, often with associated ischemic changes and anginal pain in patients with coronary artery disease. The ergot alkaloids usually induce bradycardia even when the blood pressure is not increased. This is predominantly due to increased vagal activity, but a central reduction in sympathetic tone and direct myocardial depression also may be involved.

Toxicity and Adverse Effects

The dose of dihydroergotoxine in human beings is limited by the occurrence of nausea and vomiting. Prolonged or excessive administration of any of the natural peptide ergot alkaloids can cause vascular insufficiency, including myocardial ischemia and gangrene of the extremities due to marked arterial constriction (Galer et al., 1991). This is particularly likely to occur in the presence of preexisting vascular pathological processes. In severe cases, prompt vasodilation is essential. There have been no comparative studies on the treatment of this sporadic condition, but a directly acting drug such as nitroprusside appears to be most effective (Carliner et al., 1974). Toxic effects of the ergot alkaloids are described in more detail in Chapter 11: 5-Hydroxytryptamine (Serotonin): Receptor Agonists and Antagonists.

Therapeutic Uses

The primary uses of ergot alkaloids are to stimulate contraction of the uterus postpartum and to relieve the pain of migraine (Mitchell and Elbourne, 1993; Saxena and De Deyn, 1992; seeChapter 11: 5-Hydroxytryptamine (Serotonin): Receptor Agonists and Antagonists). However, newer alternatives, such as sumatriptan and other 5-HT1-receptor agonists, may have better efficacy and safety in migraine (Dechant and Clissold, 1992; see also Chapter 11: 5-Hydroxytryptamine (Serotonin): Receptor Agonists and Antagonists). Ergonovine and methylergonovine are useful in preventing and treating postpartum hemorrhage due to uterine atonia, probably by stimulating uterine contraction, which compresses bleeding blood vessels. Synthetic preparations of the posterior pituitary hormone oxytocin also are used to enhance uterine contractions (seeChapter 56: Pituitary Hormones and Their Hypothalamic Releasing Factors); this may have the benefit not only of preventing or treating uterine hemorrhage but also of inducing or augmenting labor. Dinoprostone (prostaglandin E2) also inhibits postpartum bleeding and may be efficacious if there is an inadequate response to ergot alkaloids or oxytocin (Winkler and Rath, 1999). Ergot alkaloids have been used clinically in many settings: diagnostically to stimulate coronary artery contraction; as putative cognition enhancers (Wadworth and Chrisp, 1992); and in the management of orthostatic hypotension (Stumpf and Mitrzyk, 1994). The effect of bromocriptine on the secretion of prolactin is described in Chapter 56: Pituitary Hormones and Their Hypothalamic Releasing Factors.

Additional -Adrenergic Antagonists

Indoramin

Indoramin is a selective, competitive -receptor antagonist that has been used for the treatment of hypertension. Competitive antagonism of histamine H1 and 5-HT receptors also is evident (Cubeddu, 1988). As an -selective antagonist, indoramin lowers blood pressure with minimal tachycardia. The drug also decreases the incidence of attacks of Raynaud's phenomenon (Holmes and Sorkin, 1986).

The bioavailability of indoramin is generally less than 30% (with considerable variability), and it undergoes extensive first-pass metabolism (Holmes and Sorkin, 1986; Pierce, 1990). Little unchanged drug is excreted in the urine, and some of the metabolites may be biologically active. The elimination half-life is about 5 hours. Some of the adverse effects of indoramin include sedation, dry mouth, and failure of ejaculation. Although indoramin is an effective antihypertensive agent, it has complex pharmacokinetics and lacks a well-defined place in current therapy. Indoramin currently is not available in the United States.

Labetalol

Labetalol, a potent -adrenergic receptor antagonist, competitively blocks receptors as well (see below).

Ketanserin

Although developed as a 5-HT-receptor antagonist, ketanserin also blocks -adrenergic receptors. Ketanserin is discussed in Chapter 11: 5-Hydroxytryptamine (Serotonin): Receptor Agonists and Antagonists.

Urapidil

Urapidil is a novel, selective -adrenergic antagonist that has a chemical structure distinct from those of prazosin and related compounds. Blockade of peripheral receptors appears to be primarily responsible for the hypotension produced by urapidil, although it has actions in the CNS as well (Cubeddu, 1988; van Zwieten, 1988). The drug is extensively metabolized and has a half-life of 3 hours. The role of urapidil in the treatment of hypertension remains to be determined. Urapidil is not currently available for clinical use in the United States.

Bunazosin

Bunazosin is an -selective antagonist of the quinazoline class of compounds. Bunazosin has been shown to lower blood pressure in patients with hypertension (Harder and Thurmann, 1994). Bunazosin is not currently available in the United States.

Yohimbine

Yohimbine YOCON) is a competitive antagonist that is selective for -adrenergic receptors. The compound is an indolealkylamine alkaloid and is found in the bark of the tree Pausinystalia yohimbe and in Rauwolfia root; its structure resembles that of reserpine. Yohimbine readily enters the CNS, where it acts to increase blood pressure and heart rate; it also enhances motor activity and produces tremors. These actions are opposite to those of clonidine, an agonist (seeGoldberg and Robertson, 1983; Grossman et al., 1993). Yohimbine also is an antagonist of 5-HT. In the past, it has been used extensively to treat male sexual dysfunction. Although efficacy was never clearly demonstrated, there is renewed interest in the use of yohimbine in the treatment of male sexual dysfunction. The drug enhances sexual activity in male rats (Clark et al., 1984), and it may benefit some patients with psychogenic erectile dysfunction (Reid et al., 1987). However, the efficacies of sildenafil and apomorphine have been much more conclusively demonstrated in oral treatment of erectile dysfunction. Several small studies suggest that yohimbine also may be useful for diabetic neuropathy and in the treatment of postural hypotension.

Neuroleptic Agents

Natural and synthetic compounds of several other chemical classes developed primarily because they are antagonists of D2dopamine receptors also exhibit -adrenergic blocking activity. Chlorpromazine, haloperidol, and other neuroleptic drugs of the phenothiazine and butyrophenone types produce significant -receptor blockade in both laboratory animals and human beings.

-Adrenergic Receptor Antagonists

-Adrenergic receptor antagonists ( blockers) have received enormous clinical attention because of their efficacy in the treatment of hypertension, ischemic heart disease, congestive heart failure, and certain arrhythmias.

History

Ahlquist's hypothesis that the effects of catecholamines were mediated by activation of distinct - and -adrenergic receptors provided the initial impetus for the synthesis and pharmacological evaluation of -adrenergic blocking agents (seeChapter 6: Neurotransmission: The Autonomic and Somatic Motor Nervous Systems). The first such selective agent was dichloroisoproterenol (Powell and Slater, 1958). However, this compound is a partial agonist, and this property was thought to preclude its safe clinical use. Sir James Black and his colleagues initiated a program in the late 1950s to develop additional agents of this type. Although the usefulness of their first antagonist, pronethalol, was limited by the production of thymic tumors in mice, propranolol soon followed (Black and Stephenson, 1962; Black and Prichard, 1973). Propranolol is a competitive -adrenergic receptor antagonist and remains the prototype to which other -adrenergic antagonists are compared. Subsequent efforts to generate additional antagonists have resulted in compounds that can be distinguished by the following properties: relative affinity for and receptors, intrinsic sympathomimetic activity, blockade of -adrenergic receptors, differences in lipid solubility, capacity to induce vasodilation, and general pharmacokinetic properties. Some of these distinguishing characteristics have clinical significance, and they help guide the appropriate choice of a -adrenergic antagonist for an individual patient.

Propranolol has equal affinity for and receptors; thus, it is a nonselective -adrenergic antagonist. Agents such as metoprolol and atenolol have somewhat greater affinity for than for receptors; these are examples of selective antagonists, even though the selectivity is not absolute. Propranolol is a pure antagonist, and it has no capacity to activate -adrenergic receptors. Several blockers (e.g., pindolol and acebutolol) activate receptors partially in the absence of catecholamines; however, the intrinsic activities of these drugs are less than that of a full agonist such as isoproterenol. These partial agonists are said to have intrinsic sympathomimetic activity. Substantial sympathomimetic activity would be counterproductive to the response desired from a -adrenergic antagonist; however, slight residual activity may, for example, prevent profound bradycardia or negative inotropy in a resting heart. The potential clinical advantage of this property, however, is unclear and may be a disadvantage in the context of secondary prevention of myocardial infarction (see below). In addition, other -receptor antagonists have been found to have the property of so-called inverse agonism (seeChapter 2: Pharmacodynamics: Mechanisms of Drug Action and the Relationship Between Drug Concentration and Effect). These drugs can decrease basal activation of -receptor signaling by shifting the equilibrium of spontaneously active receptors toward the inactive state (Chidiac et al., 1994). The clinical significance of this property is unknown. Although most -adrenergic antagonists do not block -adrenergic receptors, labetalol and carvedilol are examples of agents that block both and receptors. Celiprolol is an example of a drug that is a -selective antagonist and a -selective agonist and that promotes vasodilation.

Chemistry

The structural formulas of some -adrenergic antagonists in general use are shown in Figure 10–5. The structural similarities between agonists and antagonists that act on receptors are closer than those between -receptor agonists and antagonists. Substitution of an isopropyl group or other bulky substituent on the amino nitrogen favors interaction with -adrenergic receptors. There is a rather wide tolerance for the nature of the aromatic moiety in the nonselective -receptor antagonists; however, the structural tolerance for -selective antagonists is far more constrained. The -adrenergic receptor, as shown in Figure 10–1 and discussed in Chapter 6: Neurotransmission: The Autonomic and Somatic Motor Nervous Systems, is a member of the G protein–coupled receptor family with seven membrane-spanning domains.

Figure 10–5. Structural Formulas of Some -Adrenergic Receptor Antagonists. 

Pharmacological Properties

As in the case of -adrenergic blocking agents, the pharmacological properties of -adrenergic antagonists can be explained largely from knowledge of the responses elicited by the receptors in the various tissues and the activity of the sympathetic nerves that innervate these tissues (seeTable 6–1). For example, -receptor blockade has relatively little effect on the normal heart of an individual at rest but has profound effects when sympathetic control of the heart is dominant, as during exercise or stress.

Cardiovascular System

The major therapeutic effects of -adrenergic antagonists are on the cardiovascular system. It is important to distinguish these effects in normal subjects from those in subjects with cardiovascular disease such as hypertension or myocardial ischemia.

Since catecholamines have positive chronotropic and inotropic actions, -adrenergic antagonists slow the heart rate and decrease myocardial contractility. When tonic stimulation of receptors is low, this effect is correspondingly modest. However, when the sympathetic nervous system is activated, as during exercise or stress, -adrenergic antagonists attenuate the expected rise in heart rate. Short-term administration of -adrenergic antagonists such as propranolol decreases cardiac output; peripheral resistance increases in proportion to maintain blood pressure as a result of blockade of vascular receptors and compensatory reflexes, such as increased sympathetic nervous system activity, leading to activation of vascular -adrenergic receptors. However, with long-term use of -adrenergic antagonists, total peripheral resistance returns to initial values (Mimran and Ducailar, 1988) or decreases in patients with hypertension (Man in't Veld et al., 1988). With -receptor antagonists that also are -receptor antagonists, such as labetalol and carvedilol, cardiac output is maintained with a greater fall in peripheral resistance.

-Adrenergic receptor antagonists have significant effects on cardiac rhythm and automaticity. Although it had been thought that these effects were due exclusively to blockade of receptors, -adrenergic receptors likely also are involved in regulating heart rate in human beings (Brodde, 1988). -Adrenergic antagonists reduce sinus rate, decrease the spontaneous rate of depolarization of ectopic pacemakers, slow conduction in the atria and in the AV node, and increase the functional refractory period of the AV node.

Although high concentrations of many blockers produce quinidine-like effects ('membrane-stabilizing activity'), it is doubtful that this is significant at usual doses of these agents. However, this effect may be important when there is overdosage. Interestingly, there is some evidence suggesting that d-propranolol may suppress ventricular arrhythmias independently of -receptor blockade (Murray et al., 1990).

The cardiovascular effects of -adrenergic antagonists are most evident during dynamic exercise. In the presence of -receptor blockade, the exercise-induced increases in heart rate and myocardial contractility are attenuated. However, the exercise-induced increase in cardiac output is less affected because of an increase in stroke volume (Shephard, 1982; Tesch, 1985; Van Baak, 1988). The effects of -adrenergic antagonists on exercise are somewhat analogous to the changes that occur with normal aging. In healthy elderly persons, catecholamine-induced increases in heart rate are smaller than in younger individuals; however, the increase in cardiac output in older people may be preserved because of an increase in stroke volume during exercise. Blockers tend to decrease work capacity, as assessed by their effects on intense short-term or more prolonged steady-state exertion (Kaiser et al., 1986). Exercise performance may be impaired to a lesser extent by -selective agents than by nonselective antagonists (Tesch, 1985). Blockade of receptors tends to blunt the increase in blood flow to active skeletal muscle during submaximal exercise (Van Baak, 1988). Blockade of receptors also may attenuate catecholamine-induced activation of glucose metabolism and lipolysis.

Coronary arterial blood flow increases during exercise or stress to meet the metabolic demands of the heart. By increasing heart rate, contractility, and systolic pressure, catecholamines increase myocardial oxygen demand. However, in patients with coronary artery disease, fixed narrowing of these vessels attenuates the expected increase in flow, leading to myocardial ischemia. -Adrenergic antagonists decrease the effects of catecholamines on the determinants of myocardial oxygen consumption. However, these agents may tend to increase the requirement for oxygen by increasing end-diastolic pressure and systolic ejection period. Usually, the net effect is to improve the relationship between cardiac oxygen supply and demand; exercise tolerance generally is improved in patients with angina, whose capacity to exercise is limited by the development of chest pain (seeChapter 32: Drugs Used for the Treatment of Myocardial Ischemia).

Activity As Antihypertensive Agents

-Adrenergic antagonists generally do not cause a reduction in blood pressure in patients with normal blood pressure. However, these drugs do lower blood pressure in patients with hypertension. Despite their widespread use, the mechanisms responsible for this important clinical effect are not well understood. The release of renin from the juxtaglomerular apparatus is stimulated by the sympathetic nervous system, and this effect is blocked by -adrenergic antagonists (seeChapter 31: Renin and Angiotensin). However, the relationship between this phenomenon and the fall in blood pressure is not clear. Some investigators have found that the antihypertensive effect of propranolol is most marked in patients with elevated concentrations of plasma renin, as compared with patients with low or normal concentrations of renin. However, -receptor antagonists are effective even in patients with low plasma renin, and pindolol is an effective antihypertensive agent that has little or no effect on plasma renin activity (Frishman, 1983).

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

As indicated above, some -adrenergic receptor antagonists have additional effects that may contribute to their ability to lower blood pressure. Three properties of some -receptor antagonists have been suggested to contribute to peripheral vasodilation: -adrenergic receptor blockade; -adrenergic receptor agonism; and mechanism(s) independent of adrenergic receptors. For example, drugs such as labetalol and carvedilol, which block -adrenergic receptors directly, decrease peripheral resistance. Celiprolol appears to be a partial -receptor agonist and additionally to have nonadrenergic-receptor–mediated vasodilating properties, which contribute to decreasing peripheral resistance (Shanks, 1991; Milne and Buckley, 1991). The clinical significance in human beings of some of these relatively subtle differences in pharmacological properties is unclear (Fitzgerald, 1991). Particular interest has focused on patients with congestive heart failure or peripheral arterial occlusive disease.

Propranolol and other nonselective -adrenergic antagonists inhibit the vasodilation caused by isoproterenol and augment the pressor response to epinephrine. This is particularly significant in patients with a pheochromocytoma, in whom -adrenergic antagonists should be used only after adequate -adrenergic blockade has been established. This avoids uncompensated -receptor-mediated vasoconstriction caused by epinephrine secreted from the tumor.

Pulmonary System

Nonselective -adrenergic antagonists such as propranolol block -adrenergic receptors in bronchial smooth muscle. This usually has little effect on pulmonary function in normal individuals. However, in patients with asthma or chronic obstructive pulmonary disease, such blockade can lead to life-threatening bronchoconstriction. Although -selective antagonists or antagonists with intrinsic sympathomimetic activity are less likely than propranolol to increase airway resistance in patients with asthma, these drugs should be used only with great caution, if at all, in patients with bronchospastic diseases. Drugs such as celiprolol, with -receptor selectivity and -receptor partial agonism, are of potential promise, although clinical experience is limited (Pujet et al., 1992).

Metabolic Effects

-Adrenergic antagonists modify the metabolism of carbohydrates and lipids. Catecholamines promote glycogenolysis and mobilize glucose in response to hypoglycemia. Nonselective blockers may adversely affect recovery from hypoglycemia in insulin-dependent diabetics. -Adrenergic antagonists should be used with great caution in patients with labile diabetes and frequent hypoglycemic reactions. If such a drug is strongly indicated, a -selective compound is preferable, since these drugs are less likely to delay recovery from hypoglycemia. All blockers mask the tachycardia that is typically seen with hypoglycemia, denying the patient an important warning sign. Although insulin secretion is enhanced by -adrenergic agonists, blockade only rarely impairs insulin release.

-Adrenergic receptors mediate activation of hormone sensitive lipase in fat cells, leading to the release of free fatty acids into the circulation. The potential role of receptors in mediating this response in human beings is discussed in Chapter 6: Neurotransmission: The Autonomic and Somatic Motor Nervous Systems. This increased flux of fatty acids is an important energy source for exercising muscle. -Adrenergic antagonists can attenuate the release of free fatty acids from adipose tissue. Nonetheless, in some patients, nonselective blockers modestly elevate plasma concentrations of triglycerides and decrease those of high-density lipoproteins. Concentrations of LDLs usually do not change (Miller, 1987). Although the significance of these changes is not known, there is concern that they may be undesirable effects, particularly in patients with hypertension (Reaven and Hoffman, 1987; Rabkin, 1993). -Selective antagonists and those with intrinsic sympathomimetic activity may cause less of an effect on lipid metabolism than do nonselective antagonists. The mechanism of these effects is not clear.

-Adrenergic agonists decrease the plasma concentration of K+ by promoting the uptake of the ion, predominantly into skeletal muscle. At rest, an infusion of epinephrine causes a decrease in the plasma concentration of K+ (Brown et al., 1983). The marked increase in the concentration of epinephrine that occurs with stress (such as myocardial infarction) may cause hypokalemia, which could predispose to cardiac arrhythmias (Struthers and Reid, 1984). The hypokalemic effect of epinephrine is blocked by an experimental antagonist, ICI 118551, which has a high affinity for - and -adrenergic receptors (Brown et al., 1983; Emorine et al., 1989). Exercise causes an increase in the efflux of K+ from skeletal muscle. Catecholamines tend to buffer the rise in K+ by increasing its influx into muscle. -blocking agents negate this buffering effect (Brown, 1985).

Other Effects

-Adrenergic antagonists block catecholamine-induced tremor. They also block inhibition of mast-cell degranulation by catecholamines (seeChapter 25: Histamine, Bradykinin, and Their Antagonists).

Non-Subtype-Selective -Adrenergic Antagonists

Propranolol

In view of the extensive experience with propranolol (propranolol hydrochloride;INDERAL), it is useful as a prototype (seeTable 10–3). Propranolol interacts with and receptors with equal affinity, lacks intrinsic sympathomimetic activity, and does not block -adrenergic receptors.

Absorption, Fate, and Excretion

Propranolol is highly lipophilic and is almost completely absorbed after oral administration. However, much of the drug is metabolized by the liver during its first passage through the portal circulation; on average, only about 25% reaches the systemic circulation. In addition, there is great interindividual variation in the presystemic clearance of propranolol by the liver; this contributes to enormous variability in plasma concentrations (approximately 20-fold) after oral administration of the drug and contributes to the wide range of doses in terms of clinical efficacy. In other words, a clinical disadvantage of propranolol is that multiple, increasing steps in drug dose may be required over time. The degree of hepatic extraction of propranolol declines as the dose is increased. The bioavailability of propranolol may be increased by the concomitant ingestion of food and during long-term administration of the drug.

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

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

A sustained-release formulation of propranolol (INDERAL LA) has been developed to maintain therapeutic concentrations of propranolol in plasma throughout a 24-hour period (Nace and Wood, 1987). Suppression of exercise-induced tachycardia is maintained throughout the dosing interval, and patient compliance may be improved.

Therapeutic Uses

For the treatment of hypertension and angina, the initial oral dose of propranolol is generally 40 to 80 mg per day. The dose may then be titrated upward until the optimal response is obtained. For the treatment of angina, the dose may be increased at intervals of less than one week, as indicated clinically. In hypertension, the full blood-pressure response may not develop for several weeks. Typically, doses are less than 320 mg per day. If propranolol is taken twice daily for hypertension, blood pressure should be measured just prior to a dose to ensure that the duration of effect is sufficiently prolonged. Adequacy of -adrenergic blockade can be assessed by measuring suppression of exercise-induced tachycardia. Propranolol may be administered intravenously for the management of life-threatening arrhythmias or to patients under anesthesia. Under these circumstances, the usual dose is 1 to 3 mg, administered slowly (less than 1 mg per minute) with careful and frequent monitoring of blood pressure, ECG, and cardiac function. If an adequate response is not obtained, a second dose may be given after several minutes. If bradycardia is excessive, atropine should be administered to increase heart rate. Change to oral therapy should be initiated as soon as possible.

Nadolol

Nadolol CORGARD) is a long-acting antagonist with equal affinity for - and -adrenergic receptors. It is devoid of both membrane-stabilizing and intrinsic sympathomimetic activity. A distinguishing characteristic of nadolol is its relatively long half-life.

Absorption, Fate, and Excretion

Nadolol is very soluble in water and is incompletely absorbed from the gut; its bioavailability is about 35% (Frishman, 1981). Interindividual variability is less than with propranolol. The low solubility of nadolol in fat may result in lower concentrations of the drug in the brain as compared with more lipid-soluble -adrenergic antagonists. Although it frequently has been suggested that the incidence of CNS adverse effects is lower with hydrophilic -adrenergic antagonists, data from controlled trials to support this contention are limited. Nadolol is not extensively metabolized and is largely excreted intact in the urine. The half-life of the drug in plasma is approximately 20 hours; consequently, it generally is administered once daily. Nadolol may accumulate in patients with renal failure, and dosage should be reduced in such individuals.

Timolol

Timolol (timolol maleate;BLOCADREN) is a potent, non-subtype-selective -adrenergic antagonist. It has no intrinsic sympathomimetic activity and no membrane-stabilizing activity.

Absorption, Fate, and Excretion

Timolol is well absorbed from the gastrointestinal tract and is subject to moderate first-pass metabolism. It is metabolized extensively by the liver, and only a small amount of unchanged drug appears in the urine. The half-life in plasma is about 4 hours. Interestingly, the ocular formulation of timolol (TIMOPTIC), used for the treatment of glaucoma, may be extensively absorbed systemically (seeChapter 66: Ocular Pharmacology); adverse effects can occur in susceptible patients, such as those with asthma or congestive heart failure.

Pindolol

Pindolol VISKEN) is a non-subtype-selective -adrenergic antagonist with intrinsic sympathomimetic activity. It has low membrane-stabilizing activity and is moderately soluble in lipid.

Although only limited data are available, blockers with slight partial agonist activity may produce smaller reductions in resting heart rate and blood pressure. Hence, such drugs may be preferred as antihypertensive agents in individuals with diminished cardiac reserve or a propensity for bradycardia. Nonetheless, the clinical significance of partial agonism has not been substantially demonstrated in controlled trials but may be of importance in individual patients (Fitzgerald, 1993). Agents like pindolol do block exercise-induced increases in heart rate and cardiac output.

Absorption, Fate, and Excretion

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

Labetalol

Labetalol (labetalol hydrochloride;NORMODYNE, TRANDATE) is representative of a class of drugs that act as competitive antagonists at both - and -adrenergic receptors. Labetalol has two optical centers, and the formulation used clinically contains equal amounts of the four diastereomers (Gold et al., 1982). The pharmacological properties of the drug are complex, because each isomer displays different relative activities. The properties of the mixture include selective blockade of -adrenergic receptors (as compared with the subtype), blockade of and receptors, partial agonist activity at receptors, and inhibition of neuronal uptake of norepinephrine (cocaine-like effect) (seeChapter 6: Neurotransmission: The Autonomic and Somatic Motor Nervous Systems). The potency of the mixture for -adrenergic blockade is fivefold to tenfold that for -adrenergic blockade.

The pharmacological effects of labetalol have become clearer since the four isomers were separated and tested individually. The R,R isomer is about four times more potent as a -adrenergic antagonist than is racemic labetalol, and it accounts for much of the -blockade produced by the mixture of isomers, although it is no longer in development as a separate drug (dilevalol). As an antagonist, this isomer is less than 20% as potent as the racemic mixture (Sybertz et al., 1981; Gold et al., 1982). The R,S isomer is almost devoid of both - and -adrenergic blocking effects. The S,R isomer has almost no -adrenergic-blocking activity, yet is about five times more potent as an blocker than is racemic labetalol. The S,S isomer is devoid of -blocking activity and has a potency similar to that of racemic labetalol as an -receptor antagonist (Gold et al., 1982). The R,R isomer has some intrinsic sympathomimetic activity at receptors; this may contribute to vasodilation (Baum et al., 1981). Labetalol also may have some direct vasodilating capacity.

The actions of labetalol on both - and -adrenergic receptors contribute to the fall in blood pressure observed in patients with hypertension. -Receptor blockade leads to relaxation of arterial smooth muscle and vasodilation, particularly in the upright position. The blockade also contributes to a fall in blood pressure, in part by blocking reflex sympathetic stimulation of the heart. In addition, the intrinsic sympathomimetic activity of labetalol at receptors may contribute to vasodilation.

Labetalol is available in oral form for therapy of chronic hypertension and as an intravenous formulation for use in hypertensive emergencies. Labetalol has been associated with hepatic injury in a limited number of patients (Clark et al., 1990).

Absorption, Fate, and Excretion

Although labetalol is completely absorbed from the gut, there is extensive first-pass clearance; bioavailability is only about 20% to 40% and is highly variable (McNeil and Louis, 1984). Bioavailability may be increased by food intake. The drug is rapidly and extensively metabolized in the liver by oxidative biotransformation and glucuronidation; very little unchanged drug is found in the urine. The rate of metabolism of labetalol is sensitive to changes in hepatic blood flow. The elimination half-life of the drug is about 8 hours. The half-life of the R,R isomer of labetalol (dilevalol) is about 15 hours. Labetalol provides an interesting and challenging example of pharmacokinetic-pharmacodynamic modeling applied to a drug that is a racemic mixture of isomers with different kinetics and pharmacological actions (Donnelly and Macphee, 1991).

Carvedilol

Carvedilol COREG) is a non-subtype-selective -receptor antagonist that also is an antagonist of receptors (McTavish et al., 1993; Dunn et al., 1997; Frishman, 1998). Interestingly, carvedilol also has antioxidant activity (Yue et al., 1995; Tadolini and Franconi, 1998). The clinical significance of this action, especially in patients with congestive heart failure, is not clear.

Absorption, Fate, and Excretion

Carvedilol has a bioavailability of about 25% to 35% because of extensive first-pass metabolism. Carvedilol is eliminated by hepatic metabolism and has a terminal half-life of 7 to 10 hours, but most of the drug is eliminated with a half-life of about 2 hours.

Therapeutic Uses

In the treatment of hypertension, the usual starting dose is 6.25 mg twice daily; if an adequate therapeutic response is not achieved, the dose may be increased progressively over time, typically to a maximum of 25 mg twice daily. In the treatment of congestive heart failure, dosing is much more cautious due to possibility of acutely worsening heart failure. Dosing often starts at 3.125 mg twice per day with cautious increases over time.

-Selective Adrenergic Antagonists

Metoprolol

Metoprolol (metoprolol tartrate;LOPRESSOR) is a - selective adrenergic antagonist that is devoid of intrinsic sympathomimetic activity.

Absorption, Fate, and Excretion

Metoprolol is almost completely absorbed after oral administration, but bioavailability is relatively low (about 40%) because of first-pass metabolism. Plasma concentrations of the drug vary widely (up to 17-fold), perhaps because of genetically determined differences in the rate of metabolism (Benfield et al., 1986). Metoprolol is extensively metabolized by the hepatic monooxygenase system, and only 10% of the administered drug is recovered unchanged in the urine. The half-life of metoprolol is 3 to 4 hours. An extended-release formulation (TOPROL XL) is available for once-daily administration (Plosker and Clissold, 1992).

Therapeutic Uses

For the treatment of hypertension, the usual initial dose is 100 mg per day. The drug is sometimes effective when given once daily, although it is frequently used in two divided doses. Dosage may be increased at weekly intervals until optimal reduction of blood pressure is achieved. If the drug is taken only once daily, it is important to confirm that blood pressure is controlled for the entire 24-hour period. Metoprolol is generally used in two divided doses for the treatment of stable angina. Conventional dosage forms of metoprolol have been extensively established for indications in hypertension and ischemic heart disease. The extended-release formulation, which provides relatively constant rates of drug delivery over 24-hour periods, may be given once daily. For the initial treatment of patients with acute myocardial infarction, an intravenous formulation of metoprolol tartrate is available. Oral dosing is initiated as soon as the clinical situation permits. Metoprolol generally is contraindicated for the treatment of acute myocardial infarction in patients with heart rates of less than 45 beats per minute, heart block greater than first degree (PR interval greater than or equal to 0.24 second), systolic blood pressure less than 100 mm Hg, or moderate-to-severe heart failure.

Atenolol

Atenolol TENORMIN) is a -selective antagonist that is devoid of intrinsic sympathomimetic activity (Wadworth et al., 1991). Atenolol is very hydrophilic and appears to penetrate the brain only to a limited extent. Its half-life is somewhat longer than that of metoprolol.

Absorption, Fate, and Excretion

Atenolol is incompletely absorbed (about 50%), but most of the absorbed dose reaches the systemic circulation. There is relatively little interindividual variation in the plasma concentrations of atenolol; peak concentrations in different patients vary over only a fourfold range (Cruickshank, 1980). The drug is excreted largely unchanged in the urine, and the elimination half-life is about 5 to 8 hours. The drug accumulates in patients with renal failure, and dosage should be adjusted for patients whose creatinine clearance is less than 35 ml/minute.

Therapeutic Uses

The initial dose of atenolol for the treatment of hypertension usually is 50 mg per day, given once daily. If an adequate therapeutic response is not evident within several weeks, the daily dose may be increased to 100 mg; higher doses are unlikely to provide any greater antihypertensive effect. Atenolol has been shown to be efficacious, in combination with a diuretic, in elderly patients with isolated systolic hypertension.

Esmolol

Esmolol (esmolol hydrochloride;BREVIBLOC) is a - selective antagonist with a very short duration of action. It has little if any intrinsic sympathomimetic activity, and it lacks membrane-stabilizing actions. Esmolol is administered intravenously and is used when blockade of short duration is desired or in critically ill patients in whom adverse effects of bradycardia, heart failure, or hypotension may necessitate rapid withdrawal of the drug.

Absorption, Fate, and Excretion

Esmolol has a half-life of about 8 minutes and an apparent volume of distribution of approximately 2 liters/kg. The drug contains an ester linkage, and it is hydrolyzed rapidly by esterases in erythrocytes. The half-life of the carboxylic acid metabolite of esmolol is far longer (4 hours), and it accumulates during prolonged infusion of esmolol (seeBenfield and Sorkin, 1987). However, this metabolite has very low potency as a -adrenergic antagonist (1/500 of the potency of esmolol; Reynolds et al., 1986); it is excreted in the urine.

The onset and cessation of -adrenergic blockade with esmolol are rapid; peak hemodynamic effects occur within 6 to 10 minutes of administration of a loading dose, and there is substantial attenuation of blockade within 20 minutes of stopping an infusion. Esmolol may have striking hypotensive effects in normal subjects, although the mechanism of this effect is unclear (Reilly et al., 1985).

Since esmolol is used in urgent settings where immediate onset of -adrenergic receptor blockade is warranted, a partial loading dose typically is administered, followed by a continuous infusion of the drug. If an adequate therapeutic effect is not observed within 5 minutes, the same loading dose is repeated, followed by a maintenance infusion at a higher rate. This process, including progressively greater infusion rates, may need to be repeated until the desired end point (e.g., lowered heart rate or blood pressure) is approached.

Acebutolol

Acebutolol (acebutolol hydrochloride;SECTRAL) is a selective -adrenergic antagonist with some intrinsic sympathomimetic activity.

Absorption, Fate, and Excretion

Acebutolol is well absorbed, but it is extensively metabolized to an active metabolite, diacetolol, which accounts for most of the drug's activity (Singh et al., 1985). The elimination half-life of acebutolol is typically about 3 hours, but the half-life of diacetolol is 8 to 12 hours; it is excreted in the urine.

Therapeutic Uses

The initial dose of acebutolol in hypertension is usually 400 mg per day; it may be given as a single dose, but two divided doses may be required for adequate control of blood pressure. Optimal responses usually occur with doses of 400 to 800 mg per day (range 200 to 1200 mg). For treatment of ventricular arrhythmias, the drug should be given twice daily.

Other -Adrenergic Antagonists

A plethora of other -adrenergic antagonists also have been synthesized and evaluated to varying extents. Bopindolol (SANDONORM, others; not available in the United States), carteolol (CARTROL, OCUPRESS), oxprenolol, and penbutolol (LEVATOL) are non-subtype-selective blockers with intrinsic sympathomimetic activity. Medroxalol and bucindolol are nonselective -adrenergic blockers with -receptor-blocking activity (Rosendorff, 1993). Levobunolol (BETAGAN LIQUIFILM, others) and metipranolol (OPTIPRANOLOL) are non-subtype-selective antagonists used as topical agents in the treatment of glaucoma (Brooks and Gillies, 1992). Bisoprolol (ZEBETA) and nebivolol are -selective antagonists without partial agonist activity (Jamin et al., 1994; Van de Water et al., 1988). Betaxolol (BETOPTIC), a -selective antagonist, is available as an ophthalmic preparation for glaucoma and an oral formulation for systemic hypertension. Betaxolol may be less likely to induce bronchospasm than are the ophthalmic preparations of the nonselective blockers timolol and levobunolol. Similarly, there have been suggestions that ocular administration of carteolol may be less likely than timolol to have systemic effects, possibly because of its intrinsic sympathomimetic activity; cautious monitoring is required, nonetheless (Chrisp and Sorkin, 1992). Celiprolol (SELECTOR) is a -selective adrenergic receptor antagonist with mild -selective agonism as well as additional weak vasodilator properties of uncertain mechanism (Milne and Buckely, 1991). Sotalol (BETAPACE) is a nonselective antagonist that is devoid of membrane-stabilizing actions. However, it has antiarrhythmic actions independent of its ability to block -adrenergic receptors (Fitton and Sorkin, 1993; seeChapter 35: Antiarrhythmic Drugs). Propafenone (RYTHMOL) is a Na+-channel blocking drug that also is a -adrenergic receptor antagonist (Bryson et al., 1993).

Adverse Effects and Precautions

The most common adverse effects of -adrenergic antagonists arise as pharmacological consequences of blockade of receptors; serious adverse effects unrelated to -receptor blockade are rare.

Cardiovascular System

-Adrenergic antagonists may induce congestive heart failure in susceptible patients, since the sympathetic nervous system provides critical support for cardiac performance in many individuals with impaired myocardial function. Thus, -adrenergic blockade may cause or exacerbate heart failure in patients with compensated heart failure, acute myocardial infarction, or cardiomegaly. It is not known whether -adrenergic antagonists that possess intrinsic sympathomimetic activity or peripheral vasodilating properties are safer in these settings. Nonetheless, there now is convincing evidence that chronic administration of -adrenergic antagonists is efficacious in prolonging life in the therapy of heart failure in selected patients (see below; see alsoChapter 34: Pharmacological Treatment of Heart Failure).

Bradycardia is a normal response to -adrenergic blockade; however, in patients with partial or complete atrioventricular conduction defects, -adrenergic antagonists may cause life-threatening bradyarrhythmias. Particular caution is indicated in patients who are taking other drugs, such as verapamil or various antiarrhythmic agents, which may impair sinus-node function or AV conduction.

Some patients complain of cold extremities while taking -adrenergic antagonists. Symptoms of peripheral vascular disease may worsen, although this is uncommon (Lepäntalo, 1985), or Raynaud's phenomenon may develop. The risk of worsening intermittent claudication is probably very small with this class of drugs, and the clinical benefits of -adrenergic antagonists in patients with peripheral vascular disease and coexisting coronary artery disease may be very important.

Abrupt discontinuation of -adrenergic antagonists after long-term treatment can exacerbate angina and may increase the risk of sudden death. The underlying mechanism is unclear, but it is well established that there is enhanced sensitivity to -adrenergic agonists in patients who have undergone long-term treatment with certain -adrenergic antagonists after the blocker is withdrawn abruptly. For example, chronotropic responses to isoproterenol are blunted in patients who are receiving -adrenergic antagonists; however, abrupt discontinuation of propranolol leads to greater-than-normal sensitivity to isoproterenol. This increased sensitivity is evident several days after stopping propranolol and may persist for at least one week (Nattel et al., 1979). Such enhanced sensitivity can be attenuated by tapering the dose of the blocker for several weeks before discontinuation (Rangno et al., 1982). Supersensitivity to isoproterenol also has been observed after abrupt discontinuation of metoprolol, but not of pindolol (Rangno and Langlois, 1982). The concentration of -adrenergic receptors on circulating lymphocytes is increased in subjects who have received propranolol for long periods; pindolol has the opposite effect (Hedberg et al., 1986). Optimal strategies for discontinuation of blockers are not known, but it is prudent to decrease the dose gradually and to restrict exercise during this period.

Pulmonary Function

A major adverse effect of -adrenergic antagonists is caused by blockade of receptors in bronchial smooth muscle. These receptors are particularly important for promoting bronchodilation in patients with bronchospastic disease, and blockers may cause a life-threatening increase in airway resistance in such patients. Drugs with selectivity for receptors or those with intrinsic sympathomimetic activity at receptors may be somewhat less likely to induce bronchospasm. Since the selectivity of current blockers for -adrenergic receptors is modest, these drugs should be avoided if at all possible in patients with asthma. However, in some patients with chronic obstructive pulmonary disease, the potential advantage of using -receptor antagonists after myocardial infarction may outweigh the risk of worsening pulmonary function (Gottlieb et al., 1998).

Central Nervous System

The adverse effects of -adrenergic antagonists that are referable to the CNS may include fatigue, sleep disturbances (including insomnia and nightmares), and depression. The previously ascribed association between these drugs and depression (Thiessen et al., 1990) may not be substantiated by more recent clinical studies (Gerstman et al., 1996; Ried et al., 1998). Interest has focused on the relationship between the incidence of the adverse effects of -adrenergic-receptor antagonists and their lipophilicity; however, no clear correlation has emerged (Drayer, 1987; Gengo et al., 1987).

Metabolism

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

Miscellaneous

The incidence of sexual dysfunction in men with hypertension who are treated with -adrenergic antagonists is not clearly defined. Although experience with the use of -adrenergic antagonists in pregnancy is increasing, information about the safety of these drugs during pregnancy is still limited (seeWiderhorn et al., 1987).

Overdosage

The manifestations of poisoning with -adrenergic antagonists depend on the pharmacological properties of the ingested drug, particularly its selectivity, intrinsic sympathomimetic activity, and membrane-stabilizing properties (seeFrishman et al., 1984). Hypotension, bradycardia, prolonged AV conduction times, and widened QRS complexes are common manifestations of overdosage. Seizures and/or depression may occur. Hypoglycemia is rare, and bronchospasm is uncommon in the absence of pulmonary disease. Significant bradycardia should be treated initially with atropine, but a cardiac pacemaker often is required. Large doses of isoproterenol or an -adrenergic agonist may be necessary to treat hypotension. Glucagon has positive chronotropic and inotropic effects on the heart that are independent of interactions with -adrenergic receptors, and the drug has been useful in some patients.

Drug Interactions

Both pharmacokinetic and pharmacodynamic interactions have been noted between -adrenergic- blocking agents and other drugs. Aluminum salts, cholestyramine, and colestipol may decrease the absorption of blockers. Drugs such as phenytoin, rifampin, and phenobarbital, as well as smoking, induce hepatic biotransformation enzymes and may decrease plasma concentrations of -adrenergic antagonists that are metabolized extensively (e.g., propranolol). Cimetidine and hydralazine may increase the bioavailability of agents such as propranolol and metoprolol by affecting hepatic blood flow. -Adrenergic antagonists can impair the clearance of lidocaine.

Other drug interactions have pharmacodynamic explanations. For example, -adrenergic antagonists and Ca2+ channel blockers have additive effects on the cardiac conducting system. Additive effects on blood pressure between blockers and other antihypertensive agents often are sought. However, the antihypertensive effects of -adrenergic antagonists can be opposed by indomethacin and other nonsteroidal antiinflammatory drugs (seeChapter 27: Analgesic-Antipyretic and Antiinflammatory Agents and Drugs Employed in the Treatment of Gout).

Therapeutic Uses

Cardiovascular Diseases

-Adrenergic antagonists are used extensively in the treatment of hypertension (seeChapter 33: Antihypertensive Agents and the Drug Therapy of Hypertension), angina and acute coronary syndromes (seeChapter 32: Drugs Used for the Treatment of Myocardial Ischemia), and congestive heart failure (seeChapter 34: Pharmacological Treatment of Heart Failure). These drugs also are used frequently in the treatment of supraventricular and ventricular arrhythmias (seeChapter 35: Antiarrhythmic Drugs).

Myocardial Infarction

A great deal of interest has focused on the use of -adrenergic antagonists in the treatment of acute myocardial infarction and in the prevention of recurrences for those who have survived an initial attack. Numerous trials have shown that -adrenergic antagonists administered during the early phases of acute myocardial infarction and continued long-term may decrease mortality by about 25% (Freemantle et al., 1999). The precise mechanism is not known, but the favorable effects of -adrenergic antagonists may stem from decreased myocardial oxygen demand, redistribution of myocardial blood flow, and antiarrhythmic actions. There is likely much less benefit if -receptor antagonists are administered for only a short time. In studies of secondary prevention, the most extensive, favorable clinical trial data are available for propranolol, metoprolol, and timolol. In spite of these benefits, many patients with myocardial infarction do not receive a -receptor antagonist.

Congestive Heart Failure

It is a common clinical observation that acute administration of -adrenergic antagonists can worsen markedly or even precipitate congestive heart failure in compensated patients with multiple forms of heart disease, such as ischemic or congestive cardiomyopathy. Consequently, the hypothesis that -adrenergic antagonists might be efficacious in the long-term treatment of heart failure originally seemed counterintuitive to many physicians. Nonetheless, after the completion of a number of well-designed, randomized control clinical trials, it is clear that some of these drugs are beneficial in patients with mild to moderate heart failure (Packer, 1998; Krum, 1999; and Teerlink and Massie, 1999; see alsoChapter 34: Pharmacological Treatment of Heart Failure). From the point of view of the history of therapeutic advances in the treatment of congestive heart failure, it is interesting to note how a drug class has moved from being completely contraindicated to being almost the standard of modern care in many settings.

Alterations in cardiac responsiveness to catecholamines have been found in heart failure. A consistent observation is that sympathetic nervous system activity is increased in patients with congestive heart failure (Bristow, 1993). Infusions of -adrenergic agonists have been found toxic to the heart in several animal models. Also, overexpression of -adrenergic receptors in mice leads to a dilated cardiomyopathy (Engelhardt et al., 1999). A number of changes in -adrenergic receptor signaling occur in the myocardium from patients with heart failure as well as in a variety of animal models (Post et al., 1999). Decreased numbers and functioning of -adrenergic receptors consistently have been found in heart failure, leading to attenuation of -adrenergic receptor–mediated stimulation of positive inotropic responses in the failing heart. These changes may be due in part to increased expression of -adrenergic receptor kinase-1 (ARK-1, GRK2) (Lefkowitz et al., 2000; see also Chapter 6: Neurotransmission: The Autonomic and Somatic Motor Nervous Systems).

It is of potential interest that -receptor expression is relatively maintained in these settings of heart failure. While both and receptors activate adenylyl cyclase via Gs, there is evidence suggesting that -adrenergic receptors also stimulate Gi; this capacity to activate Gi may attenuate contractile responses to activation of receptors as well as lead to activation of other effector pathways downstream of Gi (Lefkowitz et al., 2000). Overexpression of receptors in mouse heart may be associated with increased cardiac force without the development of cardiomyopathy (Liggett et al., 2000).

The mechanism(s) utilized by -adrenergic receptor antagonists in decreasing mortality in patients with congestive heart failure is unclear. Perhaps this is not surprising, given that the mechanism by which this class of drugs lowers blood pressure in patients with hypertension, in spite of years of investigation, remains elusive (seeChapter 33: Antihypertensive Agents and the Drug Therapy of Hypertension). At the moment there are several hypotheses, all of which require further experimental testing. This is much more than an academic undertaking; a deeper understanding of involved pathways could lead to selection of the most appropriate available drugs as well as the development of novel compounds with especially desirable properties. The potential differences between - and -receptor function in heart failure is one example of the complexity of adrenergic pharmacology of this syndrome.

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

Studies involving numerous patients have demonstrated that certain -receptor antagonists may improve myocardial function and prolong life in patients with mild to moderate congestive heart failure. Data from randomized trials are available for several drugs in this class. It is important to emphasize that beneficial effects in congestive heart failure may not be true of all -receptor antagonists. Extensive favorable experience is available for metoprolol. The -subtype selective receptor antagonist bisoprolol also has been demonstrated to prolong life in patients with moderate heart failure (Teerlink and Massie, 1999). Carvedilol has favorable effects in patients with congestive heart failure. Bucindolol likely improves cardiac function in patients with heart failure; the results of a study [Beta-blocker Estimation of Survival Trial (BEST)] of its potential effects on mortality are not yet available.

Because of the real possibility of acutely worsening cardiac function in patients with congestive heart failure, particular caution and the involvement of an experienced physician are required in initiating therapy with a -receptor antagonist in these patients. As might be anticipated, starting with very low doses of drug and advancing doses slowly over time, depending on each patient's response, are critical for the safe use of these drugs in patients with congestive heart failure.

Other Cardiovascular Diseases

-Adrenergic antagonists, particularly propranolol, are used in the treatment of hypertrophic obstructive cardiomyopathy. Propranolol is useful for relieving angina, palpitations, and syncope in patients with this disorder. Efficacy probably is related to partial relief of the pressure gradient along the outflow tract. blockers also may attenuate catecholamine-induced cardiomyopathy in pheochromocytoma (Rosenbaum et al., 1987).

-Adrenergic antagonists are used to treat arrhythmias in patients with mitral valve prolapse and to combat arrhythmias in patients with pheochromocytoma (see alsoChapter 35: Antiarrhythmic Drugs). However, it is very important to initiate treatment with an -receptor antagonist before a -receptor antagonist is administered. Otherwise, hypertension may be exacerbated because of the loss of -receptor–mediated vasodilation.

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

Other Uses

Many of the signs and symptoms of hyperthyroidism are reminiscent of the manifestations of increased sympathetic nervous system activity. Indeed, excess thyroid hormone increases the expression of -adrenergic receptors in some types of cells. -Adrenergic antagonists control many of the cardiovascular signs and symptoms of hyperthyroidism and are useful adjuvants to more definitive therapy (Geffner and Hershman, 1992). In addition, propranolol inhibits the peripheral conversion of thyroxine to triiodothyronine, an effect that may be independent of -receptor blockade. However, caution is advised in treating patients with cardiac enlargement, since the use of -adrenergic blockers may precipitate congestive heart failure (seeChapter 57: Thyroid and Antithyroid Drugs for further discussion of the treatment of hyperthyroidism).

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

Propranolol and other blockers are effective in controlling acute panic symptoms in individuals who are required to perform in public or in other anxiety-provoking situations (Lader, 1988). Thus, public speakers may be calmed by the prophylactic administration of the drug, and the performance of musicians may be improved (Brantigan et al., 1982). Tachycardia, muscle tremors, and other evidence of increased sympathetic activity are reduced. Propranolol also may be useful in the treatment of essential tremor.

-Adrenergic antagonists decrease intraocular pressure, probably by decreasing the rate of production of aqueous humor by the ciliary body. The use of topically administered blockers for the treatment of glaucoma is discussed in Chapter 66: Ocular Pharmacology. Topically administered blockers usually are well tolerated; however, they are systemically absorbed, which can lead to adverse cardiovascular and pulmonary effects in susceptible patients. The agents therefore should be used with great caution in glaucoma patients at risk for adverse systemic effects of -receptor antagonists. Use of a -receptor–selective drug, such as betaxolol, may be preferable in these cases.

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

Selection of a -Adrenergic Antagonist

The various -adrenergic antagonists that are used for the treatment of hypertension and angina appear to have similar efficacies. Selection of the most appropriate drug for an individual patient should be based on pharmacokinetic and pharmacodynamic differences among the drugs, cost, and whether or not there are associated medical problems. For some diseases (e.g., myocardial infarction, migraine, cirrhosis with varices, congestive heart failure), it should not be assumed that all members of this class of drugs are interchangeable; the appropriate drug should be selected from those that have documented efficacy for the disease. -Selective antagonists are preferable in patients with bronchospasm, diabetes, peripheral vascular disease, or Raynaud's phenomenon. Although no clinical advantage of -adrenergic antagonists with intrinsic sympathomimetic activity has been established clearly, such drugs might be preferable in patients with bradycardia. In addition, -adrenergic antagonists that dilate the peripheral vasculature, via -adrenergic blockade, selective -receptor partial agonism, or some other mechanism, may be potentially advantageous in patients with hypertension, occlusive peripheral arterial disease or congestive heart failure.






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