Goodman and Gilman Manual of Pharmacology and Therapeutics
Muscarinic Receptor Agonists and Antagonists
ACETYLCHOLINE AND ITS MUSCARINIC RECEPTOR TARGET
Muscarinic acetylcholine receptors in the peripheral nervous system occur primarily on autonomic effector cells innervated by postganglionic parasympathetic nerves. Muscarinic receptors are also present in autonomic ganglia and on some cells (e.g., vascular endothelial cells) that, paradoxically, receive little or no cholinergic innervation. Within the CNS, the hippocampus, cortex, and thalamus have high densities of muscarinic receptors. Acetylcholine (ACh), the naturally occurring neurotransmitter for these receptors, has virtually no systemic therapeutic applications because its actions are diffuse, and its hydrolysis, catalyzed by both acetylcholinesterase (AChE) and plasma butyrylcholinesterase, is rapid. Muscarinic agonists mimic the effects of ACh at these sites and are longer-acting congeners of ACh or natural alkaloids.
Cholinergic synapses are found at:
• Autonomic effector sites innervated by postganglionic parasympathetic nerves (or, in the sweat glands, by postganglionic sympathetic nerves)
• Sympathetic and parasympathetic ganglia and the adrenal medulla, innervated by preganglionic autonomic nerves
• Motor end plates on skeletal muscle, innervated by somatic motor nerves
• Certain synapses in the CNS, where ACh can have either pre- or postsynaptic actions
The actions of ACh and related drugs at autonomic effector sites are termed muscarinic, based on the observation that the alkaloid muscarine acts selectively at those sites and produces the same qualitative effects as ACh (see Table 8–1). Muscarinic receptors are present in autonomic ganglia and the adrenal medulla but primarily function to modulate the nicotinic actions of ACh at these sites (see Chapter 11). In the CNS, muscarinic receptors are widely distributed and mediate many important responses. The actions of ACh and its congeners at muscarinic receptors can be blocked competitively by atropine.
PROPERTIES AND SUBTYPES OF MUSCARINIC RECEPTORS
Muscarinic receptors comprise 5 distinct gene products, designated as M1 through M5 (see Table 8–3). Muscarinic receptors are GPCRs that in turn couple to various cellular effectors. Selectivity is not absolute but, in general, stimulation of M1, M3, and M5 receptors activates the Gq-PLC-IP3/DAG-Ca2+ pathway, resulting in a variety of Ca2+-mediated responses. By contrast, M2 and M4 muscarinic receptors couple to the pertussis toxin–sensitive G proteins, Gi and Go, to inhibit adenylyl cyclase and regulate specific ion channels.
The 5 muscarinic receptor subtypes are widely distributed in both the CNS and peripheral tissues; most cells express at least 2 subtypes (see Table 8–3). The M2 receptor is the predominant subtype in the cholinergic control of the heart, whereas the M3 receptor is the predominant subtype in the cholinergic control of smooth muscle, secretory glands, and the eye. The M1 receptor has an important role in the modulation of nicotinic cholinergic transmission in ganglia.
PHARMACOLOGICAL EFFECTS OF ACETYLCHOLINE
CARDIOVASCULAR SYSTEM. ACh has 4 primary effects on the cardiovascular system:
• Decrease heart rate (negative chronotropic effect)
• Decrease the conduction velocity in the atrioventricular (AV) node (negative dromotropic effect)
• Decrease in the force of cardiac contraction (negative inotropic effect)
The negative inotropic effect is less significant in the ventricles than in the atria. Some of these responses can be obscured by baroreceptor and other reflexes that dampen the direct responses to ACh. Although ACh rarely is given systemically, its cardiac actions are important because the cardiac effects of cardiac glycosides, anti-arrhythmic agents, and many other drugs are at least partly due to changes in parasympathetic (vagal) stimulation of the heart; in addition, afferent stimulation of the viscera during surgical interventions can reflexly increase the vagal stimulation of the heart.
The intravenous injection of a small dose of ACh produces a transient fall in blood pressure owing to generalized vasodilation (mediated by vascular endothelial NO), which is usually accompanied by reflex tachycardia. A considerably larger dose is required to see direct effects of ACh on the heart, such as eliciting bradycardia or AV nodal conduction block. The generalized vasodilation produced by exogenously administered ACh is due to the stimulation of muscarinic receptors, primarily of the M3 subtype, located on vascular endothelial cells despite the apparent lack of cholinergic innervation. Occupation of the receptors by agonist activates the Gq-PLC-IP3 pathway, leading to Ca2+-calmodulin–dependent activation of endothelial NO synthase and production of NO, which diffuses to adjacent vascular smooth muscle cells and causes them to relax (see Chapters 3 and 8). If the endothelium is damaged, as occurs under various pathophysiological conditions, ACh acts predominantly on M3receptors located on vascular smooth muscle cells, causing vasoconstriction.
ACh affects cardiac function directly and also indirectly through inhibition of the adrenergic stimulation of the heart. Cardiac effects of ACh are mediated primarily by M2 muscarinic receptors, which couple to Gi/Go. The direct effects include:
• Increase in the ACh-activated K+ current (IK-ACh) due to activation of K-ACh channels
• Decrease in the L-type Ca2+ current (ICa-L) due to inhibition of L-type Ca2+ channels
• Decrease in the cardiac pacemaker current (If) due to inhibition of HCN (pacemaker) channels
The indirect effects include:
• Gi-mediated decrease in cyclic AMP, which opposes and counteracts the β1 receptor/Gs–mediated increase in cyclic AMP
• Inhibition of the release of NE from sympathetic nerve terminals
The inhibition of NE release is mediated by presynaptic M2 and M3 receptors, which are stimulated by ACh released from adjacent parasympathetic postganglionic nerve terminals. Presynaptic M2 receptors also inhibit ACh release from parasympathetic postganglionic nerve terminals in the human heart.
ACh slows the heart rate primarily by decreasing the rate of spontaneous depolarization of the SA node (see Chapter 29); attainment of the threshold potential and the succeeding events in the cardiac cycle are therefore delayed. In the atria, ACh causes hyperpolarization and a decreased action potential duration by increasing IK-ACh. ACh also inhibits cyclic AMP formation and NE release, decreasing atrial contractility. The rate of impulse conduction is either unaffected or may increase in response to ACh; the increase probably is due to the activation of additional Na+ channels in response to ACh-induced hyperpolarization. In contrast, in the AV node (which has Ca2+ channel-dependent action potentials; see Chapter 29), ACh slows conduction and increases the refractory period by inhibiting ICa-L; the decrement in AV conduction is responsible for the complete heart block that may be observed when large quantities of cholinergic agonists are administered systemically.
Cholinergic (vagal) innervation of the His-Purkinje system and ventricular myocardium is sparse and the effects of ACh are smaller than those observed in the atria and nodal tissues. In the ventricles, ACh, whether released by vagal stimulation or applied directly, has a small negative inotropic effect; this inhibition is most apparent when there is concomitant adrenergic stimulation or underlying sympathetic tone. Automaticity of Purkinje fibers is suppressed, and the threshold for ventricular fibrillation is increased.
RESPIRATORY TRACT. The parasympathetic nervous system plays a major role in regulating bronchomotor tone. The effects of ACh on the respiratory system include not only bronchoconstriction but also increased tracheobronchial secretion and stimulation of the chemoreceptors of the carotid and aortic bodies. These effects are mediated primarily by M3muscarinic receptors.
URINARY TRACT. Parasympathetic sacral innervation causes detrusor muscle contraction, increased voiding pressure, and ureteral peristalsis. M2 receptors appear most prevalent in the bladder; M3 receptor mediates detrusor muscle contraction.
GI TRACT. Stimulation of vagal input to the GI tract increases tone, amplitude of contractions, and secretory activity of the stomach and intestine. The muscarinic receptors of the M2subtype are most prevalent, but M3 muscarinic receptors are primarily responsible for mediating the cholinergic control of GI motility.
SECRETORY AND OCULAR EFFECTS. ACh stimulates secretion from glands that receive parasympathetic or sympathetic cholinergic innervation, including the lacrimal, nasopharyngeal, salivary, and sweat glands. These effects are mediated primarily by M3 muscarinic receptors; M1 receptors also contribute significantly to the cholinergic stimulation of salivary secretion. When instilled into the eye, ACh produces miosis by contracting the pupillary sphincter muscle and accommodation for near vision by contracting the ciliary muscle (see Chapter 64); both effects are mediated primarily by M3 muscarinic receptors.
CNS EFFECTS. All 5 muscarinic receptor subtypes are found in the brain, and studies suggest that muscarinic receptor-regulated pathways may have an important role in cognitive function, motor control, appetite regulation, nociception, and other processes. Elevation of ACh with AChE inhibitors is used in treating some of the cognitive symptoms of Alzheimer disease (see Table 22–2).
MUSCARINIC RECEPTOR AGONISTS
Muscarinic cholinergic receptor agonists can be divided into 2 groups:
• Choline esters, including ACh and several synthetic esters
• Naturally occurring cholinomimetic alkaloids (particularly pilocarpine, muscarine, and arecoline) and their synthetic congeners
Of several hundred synthetic choline derivatives investigated, only methacholine, carbachol, and bethanechol have had clinical applications, along with a few natural alkaloids (Figure 9–1; Table 9–1).
Figure 9–1 Structural formulas of acetylcholine, choline esters, and natural alkaloids that stimulate muscarinic receptors.
Some Pharmacological Properties of Choline Esters and Natural Alkaloids
Methacholine (acetyl-β-methylcholine), the β-methyl analog of ACh, is a synthetic choline ester that differs from ACh chiefly in its greater duration of action (the added methyl group increases its resistance to hydrolysis by cholinesterases) and its predominantly muscarinic selectivity. Carbachol and bethanechol are unsubstituted carbamoyl esters that are completely resistant to hydrolysis by cholinesterases; their t1/2 are thus sufficiently long that they become distributed to areas of low blood flow. Carbachol retains substantial nicotinic activity, particularly on autonomic ganglia. Bethanechol has mainly muscarinic actions, with prominent effects on motility of the GI tract and urinary bladder. The major natural alkaloid muscarinic agonists are muscarine, pilocarpine, and arecoline. Muscarine acts almost exclusively at muscarinic receptor sites and is of toxicological significance (see below). Pilocarpine has a dominant muscarinic action but is a partial rather than a full agonist; the sweat glands are particularly sensitive to pilocarpine. Arecoline acts at nicotinic receptors. Although these naturally occurring alkaloids are of great value as pharmacological tools, present clinical use is restricted largely to the employment of pilocarpine as a sialagogue and miotic agent (see Chapter 64).
ABSORPTION, DISTRIBUTION, AND ELIMINATION. Muscarine and the choline esters are quaternary amines (see Figure 9–1), hence they are poorly absorbed following oral administration and have a limited ability to cross the blood-brain barrier. The choline esters are short-acting agents due to rapid elimination by the kidneys. Muscarine can still, however, be toxic when ingested and can even have CNS effects. Pilocarpine and arecoline, being tertiary amines, are readily absorbed and can cross the blood-brain barrier. Pilocarpine clearance is decreased in patients with hepatic impairment. The natural alkaloids are primarily eliminated by the kidneys; excretion of the tertiary amines can be accelerated by acidification of the urine.
THERAPEUTIC USES OF MUSCARINIC RECEPTOR AGONISTS
Muscarinic agonists are currently used in the treatment of urinary bladder disorders and xerostomia and in the diagnosis of bronchial hyper-reactivity. They are also used in ophthalmology as miotic agents and for the treatment of glaucoma. There is growing interest in the role of muscarinic receptors in cognition and the potential utility of M1 agonists in treating the cognitive impairment associated with Alzheimer disease.
ACETYLCHOLINE. ACh (MIOCHOL-E) is used topically for the induction of miosis during ophthalmologic surgery; it is instilled into the eye as a 1% solution (see Chapter 64).
METHACHOLINE. Methacholine (PROVOCHOLINE) is administered by inhalation for the diagnosis of bronchial airway hyperreactivity in patients who do not have clinically apparent asthma. Contraindications to methacholine testing include severe airflow limitation, recent myocardial infarction or stroke, uncontrolled hypertension, or pregnancy. The response to methacholine also may be exaggerated or prolonged in patients taking β adrenergic receptor antagonists. Methacholine is available as a powder that is diluted with 0.9% NaCl and administered via a nebulizer.
BETHANECHOL. Bethanechol (URECHOLINE, others) primarily affects the urinary and GI tracts. In the urinary tract, bethanechol has utility in treating urinary retention and inadequate emptying of the bladder as in postoperative urinary retention. When used chronically, 10-50 mg of the drug is given orally 3 to 4 times daily, administered on an empty stomach (i.e., 1 h before or 2 h after a meal) to minimize nausea and vomiting. In the GI tract, bethanechol stimulates peristalsis, increases motility, and increases resting lower esophageal sphincter pressure. Bethanechol formerly was used to treat postoperative abdominal distention, gastric atony, gastroparesis, adynamic ileus, and gastroesophageal reflux; more efficacious therapies for these disorders are now available (see Chapters 45 and 46).
CARBACHOL. Carbachol (MIOSTAT, ISOPTO CARBACHOL, others) is used topically in ophthalmology for the treatment of glaucoma and the induction of miosis during surgery; it is instilled into the eye as a 0.01-3% solution (see Chapter 64).
PILOCARPINE. Pilocarpine hydrochloride (SALAGEN, others) is used for the treatment of xerostomia that follows head and neck radiation treatments or that is associated with Sjögren syndrome, an autoimmune disorder occurring primarily in women in whom secretions, particularly salivary and lacrimal, are compromised. Side effects typify cholinergic stimulation. The usual dose is 5-10 mg 3 times daily; the dose should be lowered in patients with hepatic impairment. Pilocarpine (ISOPTO CARPINE, others) is used topically in ophthalmology for the treatment of glaucoma and as a miotic agent; it is instilled in the eye as a 0.5-6% solution and also can be delivered via an ocular insert (see Chapter 64).
CEVIMELINE. Cevimeline (EVOXAC), a quinuclidine derivative of ACh, is a muscarinic agonist with a high affinity for M3 muscarinic receptors on lacrimal and salivary gland epithelia. Cevimeline has a long-lasting sialogogic action and may have fewer side effects than pilocarpine. The usual dose is 30 mg 3 times daily.
CONTRAINDICATIONS, PRECAUTIONS, AND ADVERSE EFFECTS
Contraindications to the use of muscarinic agonists include asthma, chronic obstructive pulmonary disease, urinary or GI tract obstruction, acid-peptic disease, cardiovascular disease, hypotension, and hyperthyroidism (muscarinic agonists may precipitate atrial fibrillation in hyperthyroid patients). Common adverse effects include diaphoresis; diarrhea, abdominal cramps, nausea/vomiting, and other GI side effects; a sensation of tightness in the urinary bladder; difficulty in visual accommodation; and hypotension. The adverse effects are of limited concern with topical administration for ophthalmic use.
Poisoning from the ingestion of plants containing pilocarpine, muscarine, or arecoline is characterized chiefly by exaggeration of their various parasympathomimetic effects and resembles that produced by consumption of mushrooms of the genus Inocybe. Treatment consists of the parenteral administration of atropine in doses sufficient to cross the blood-brain barrier and measures to support the respiratory and cardiovascular systems.
MUSHROOM POISONING (MYCETISM). High concentrations of muscarine are present in various species of Inocybe and Clitocybe. The symptoms of intoxication attributable to muscarine develop within 30-60 min of ingestion; they include salivation, lacrimation, nausea, vomiting, headache, visual disturbances, abdominal colic, diarrhea, bronchospasm, bradycardia, hypotension, and shock. Treatment with atropine (1-2 mg intramuscularly every 30 min) effectively blocks these effects.
Other mushroom species produce toxins unrelated to ACh. Intoxication by Amanita species arises from the neurologic and hallucinogenic properties of muscimol (a GABAA agonist), ibotenic acid, and other isoxazole derivatives that stimulate excitatory and inhibitory amino acid receptors. Mushrooms from Psilocybe and Panaeolus species contain hallucinogens [psilocybin (a 5HT2A pro-agonist) and related derivatives of tryptamine]. Gyromitra species (false morels) produce GI disorders and a delayed hepatotoxicity. The most serious mycetism is produced by Amanita phalloides, other Amanitaspecies, Lepiota, and Galerina species. These species account for > 90% of all fatal cases. Ingestion of as little as 50 g of A. phalloides (deadly nightcap) can be fatal. The principal toxins are the amatoxins (α- and β-amanitin), a group of cyclic octapeptides that inhibit RNA polymerase II and thereby block mRNA synthesis. Initial symptoms, which often are unnoticed or when present are due to other toxins, include diarrhea and abdominal cramps. A symptom-free period lasting up to 24 h is followed by hepatic and renal malfunction. Death occurs in 4-7 days from renal and hepatic failure. Treatment is largely supportive.
Because the severity of toxicity and treatment strategies for mushroom poisoning depend on the species ingested, seek their identification. Regional poison control centers in the U.S. maintain up-to-date information on the incidence of poisoning in the region and treatment procedures.
MUSCARINIC RECEPTOR ANTAGONISTS
Muscarinic antagonists prevent the effects of ACh by blocking its binding to muscarinic receptors on effector cells. In general, muscarinic antagonists cause little blockade of nicotinic receptors. However, the quaternary ammonium antagonists generally exhibit a greater degree of nicotinic blocking activity and therefore are more likely to interfere with ganglionic or neuromuscular transmission. An important consideration in the therapeutic use of muscarinic antagonists is the fact that physiological functions in different organs vary in their sensitivity to muscarinic receptor blockade (Table 9–2).
Effects of Atropine in Relation to Dose
The muscarinic receptor antagonists include:
• The naturally occurring alkaloids, atropine and scopolamine
• Semisynthetic derivatives of these alkaloids, which primarily differ from the parent compounds in their disposition in the body or their duration of action
• Synthetic derivatives, some of which show selectivity for subtypes of muscarinic receptors
Noteworthy agents among the latter 2 categories are homatropine and tropicamide, which have a shorter duration of action than atropine, and methscopolamine, ipratropium, and tiotropium, which are quaternized and do not cross the blood-brain barrier or readily cross membranes. The synthetic derivatives possessing some degree of receptor selectivity include pirenzepine, which shows selectivity for M1receptors; and darifenacin and solifenacin, which show selectivity for M3 receptors.
Small doses of atropine depress salivary and bronchial secretion and sweating. Much larger doses are required to inhibit gastric motility and secretion, which are associated with unwanted side effects. This hierarchy of relative sensitivities is not a consequence of differences in the affinity of atropine for the muscarinic receptors at these sites; atropine lacks selectivity toward different muscarinic receptor subtypes. More likely determinants include the degree to which the functions of various end organs are regulated by parasympathetic tone, the “spareness” of receptors and signaling mechanisms, the involvement of intramural neurons and reflexes.
Most clinically available muscarinic antagonists are nonselective and their actions differ little from those of atropine. No subtype-selective antagonist, including pirenzepine, is completely selective. In fact, the clinical efficacy of some agents may arise from a balance of antagonistic actions on 2 or more receptor subtypes. Atropine and related compounds compete with ACh and other muscarinic agonists for a common binding site on the muscarinic receptor. Because antagonism by atropine is competitive, it can be overcome if the concentration of ACh at muscarinic receptors of the effector organ is increased sufficiently.
PHARMACOLOGICAL EFFECTS OF MUSCARINIC ANTAGONISTS
The pharmacological effects of atropine provide a good background for understanding the therapeutic uses of the various muscarinic antagonists. The effects of other muscarinic antagonists will be mentioned only when they differ significantly from those of atropine. Table 9–2 summarizes the major pharmacological effects of increasing doses of atropine.
Heart. Although the dominant response is tachycardia, the heart rate often decreases transiently with average clinical doses (0.4-0.6 mg). The slowing is modest (4-8 beats per minute) and is usually absent after rapid intravenous injection. Larger doses of atropine cause progressive tachycardia by blocking M2 receptors on the SA nodal pacemaker cells, thereby antagonizing parasympathetic (vagal) tone to the heart. The resting heart rate is increased by ~35-40 beats per minute in young men given 2 mg of atropine intramuscularly. The maximal heart rate (e.g., in response to exercise) is not altered by atropine. The influence of atropine is most noticeable in healthy young adults, in whom vagal tone is considerable. In infancy and old age, even large doses of atropine may fail to accelerate the heart. Atropine often produces cardiac arrhythmias, but without significant cardiovascular symptoms.
Atropine can abolish many types of reflex vagal cardiac slowing or asystole, such as from inhalation of irritant vapors, stimulation of the carotid sinus, pressure on the eyeballs, peritoneal stimulation, or injection of contrast dye during cardiac catheterization. Atropine also prevents or abruptly abolishes bradycardia or asystole caused by choline esters, acetylcholinesterase inhibitors, or other parasympathomimetic drugs, as well as cardiac arrest from electrical stimulation of the vagus. The removal of vagal tone to the heart by atropine also may facilitate AV conduction.
Circulation. Atropine, alone, has little effect on blood pressure, since most vessels lack significant cholinergic innervation. However, in clinical doses, atropine completely counteracts the peripheral vasodilation and sharp fall in blood pressure caused by choline esters. In toxic and occasionally in therapeutic doses, atropine can dilate cutaneous blood vessels, especially those in the blush area (atropine flush). This may be a compensatory reaction permitting the radiation of heat to offset the atropine-induced rise in temperature that can accompany inhibition of sweating.
RESPIRATORY SYSTEM. Atropine inhibits the secretions of the nose, mouth, pharynx, and bronchi, and thus dries the mucous membranes of the respiratory tract. Atropine can inhibit the bronchoconstriction caused by histamine, bradykinin, and the eicosanoids, which presumably reflects the participation of reflex parasympathetic (vagal) activity in the bronchoconstriction elicited by these agents. The ability to block the indirect bronchoconstrictive effects of these mediators forms the basis for the use of muscarinic receptor antagonists, along with β adrenergic receptor agonists, in the treatment of asthma and COPD (see Chapter 36).
EYE. Muscarinic receptor antagonists block the cholinergic responses of the pupillary sphincter muscle of the iris and the ciliary muscle controlling lens curvature (see Chapter 64). Thus, they dilate the pupil (mydriasis) and paralyze accommodation (cycloplegia). Locally applied atropine produces ocular effects of considerable duration; accommodation and pupillary reflexes may not fully recover for 7-12 days. Other muscarinic receptor antagonists with shorter durations of action are therefore preferred as mydriatics in ophthalmologic practice (see Chapter 64). Muscarinic receptor antagonists administered systemically have little effect on intraocular pressure except in patients predisposed to angle-closure glaucoma, in whom the pressure may occasionally rise dangerously.
GI TRACT. Muscarinic receptor antagonists are used as antispasmodic agents for GI disorders and in the treatment of peptic ulcer disease. Although atropine can completely abolish the effects of ACh (and other parasympathomimetic drugs) on GI motility and secretion, it inhibits only incompletely the GI responses to vagal stimulation. This difference can be attributed to the fact that preganglionic vagal fibers innervating the GI tract synapse not only with postganglionic cholinergic fibers, but also with a network of noncholinergic intramural neurons. In addition, vagal stimulation of gastrin secretion is mediated by gastrin-releasing peptide (GRP), not ACh. The gastric parietal cell secretes acid in response to at least 3 agonists: gastrin, histamine, and ACh; furthermore, stimulation of muscarinic receptors on enterochromaffin-like cells will cause histamine release. Atropine inhibits the component of acid secretion that results from muscarinic stimulation of enterochromaffin cells and parietal cells (see Figure 45–1).
Secretions. Salivary secretion is particularly sensitive to inhibition by muscarinic receptor antagonists, which can completely abolish the copious, watery secretion induced by parasympathetic stimulation. The mouth becomes dry, and swallowing and talking may become difficult. Gastric secretion during the cephalic and fasting phases is also reduced markedly by muscarinic receptor antagonists. In contrast, the intestinal phase of gastric secretion is only partially inhibited. Although muscarinic antagonists can reduce gastric secretion, the doses required also affect salivary secretion, ocular accommodation, micturition, and GI motility (see Table 9–2). Thus, histamine H2 receptor antagonists and proton pump inhibitors have replaced muscarinic antagonists as inhibitors of acid secretion (see Chapter 45).
Motility. The parasympathetic nerves enhance both tone and motility and relax sphincters, thereby favoring the passage of gastrointestinal contents. Muscarinic antagonists produce prolonged inhibitory effects on the motor activity of the stomach, duodenum, jejunum, ileum, and colon, characterized by a reduction in tone, amplitude and frequency of peristaltic contractions. Relatively large doses are needed to produce such inhibition. This probably can be explained by the ability of the enteric nervous system to regulate motility independently of parasympathetic control (see Chapter 8 and Figure 46–1).
OTHER SMOOTH MUSCLE
Urinary Tract. Muscarinic antagonists decrease the normal tone and amplitude of contractions of the ureter and bladder, and often eliminate drug-induced enhancement of ureteral tone. However, this inhibition cannot be achieved in the absence of inhibition of salivation and lacrimation and blurring of vision (see Table 9–2).
Biliary Tract. Atropine exerts a mild antispasmodic action on the gallbladder and bile ducts in humans. However, this effect usually is not sufficient to overcome or prevent the marked spasm and increase in biliary duct pressure induced by opioids, for which nitrates (see Chapter 27) are more effective.
SWEAT GLANDS AND TEMPERATURE. Small doses of atropine inhibit the activity of sweat glands innervated by sympathetic cholinergic fibers, and the skin becomes hot and dry. Sweating may be depressed enough to raise the body temperature, but only notably so after large doses or at high environmental temperatures.
CNS. Atropine has minimal effects on the CNS at therapeutic doses, although mild stimulation of the parasympathetic medullary centers may occur. With toxic doses of atropine, central excitation becomes more prominent, leading to restlessness, irritability, disorientation, hallucinations, or delirium. With still larger doses, stimulation is followed by depression, leading to circulatory collapse and respiratory failure after a period of paralysis and coma. In contrast to atropine, scopolamine has prominent central effects at low therapeutic doses; atropine therefore is preferred over scopolamine for many purposes. The basis for this difference is probably the greater permeation of scopolamine across the blood-brain barrier. Specifically, scopolamine in therapeutic doses normally causes CNS depression manifest as drowsiness, amnesia, fatigue, and dreamless sleep, with a reduction in REM sleep. Scopolamine is effective in preventing motion sickness.
Muscarinic receptor antagonists have long been used in the treatment of Parkinson disease. These agents can be effective adjuncts to treatment with levodopa (see Chapter 22). Muscarinic receptor antagonists also are used to treat the extrapyramidal symptoms that commonly occur as side effects of conventional antipsychotic drug therapy (see Chapter 16). Certain antipsychotic drugs are relatively potent muscarinic receptor antagonists and, perhaps for this reason, cause fewer extrapyramidal side effects.
IPRATROPIUM AND TIOTROPIUM. The quaternary ammonium compounds ipratropium and tiotropium are used exclusively for their effects on the respiratory tract. When inhaled, their action is confined almost completely to the mouth and airways. Dry mouth is the only frequently reported side effect, as the absorption of these drugs from the lungs or the GI tract is very inefficient. Ipratropium appears to block all subtypes of muscarinic receptors and accordingly also antagonizes the inhibition of ACh release by presynaptic M2 receptors on parasympathetic postganglionic nerve terminals in the lung; the resulting increase in ACh release may counteract its blockade of M3 receptor-mediated bronchoconstriction. In contrast, tiotropium shows some selectivity for M1 and M3 receptors; its lower affinity for M2 receptors minimizes its presynaptic effect to enhance ACh release.
ABSORPTION, DISTRIBUTION, AND ELIMINATION. The belladonna alkaloids and the tertiary synthetic and semisynthetic derivatives are absorbed rapidly from the GI tract. They also enter the circulation when applied locally to the mucosal surfaces of the body. Absorption from intact skin is limited, although efficient absorption does occur in the postauricular region for some agents, allowing delivery by transdermal patch. Systemic absorption of inhaled or orally ingested quaternary muscarinic receptor antagonists is limited even from the conjunctiva of the eye. Quaternary agents do not cross the blood-brain barrier. Atropine has a t1/2 of ~4 h; hepatic metabolism accounts for the elimination of about half of a dose; the remainder is excreted unchanged in the urine.
Ipratropium is administered as an aerosol or solution for inhalation whereas tiotropium is administered as a dry powder. As with most drugs administered by inhalation, ~90% of the dose is swallowed. Most of the swallowed drug appears in the feces. Maximal responses develop over 30-90 min, with tiotropium having the slower onset. The effects of ipratropium last for 4-6 h, while tiotropium’s effects persist for 24 h.
THERAPEUTIC USES OF MUSCARINIC RECEPTOR ANTAGONISTS
Muscarinic receptor antagonists have been used in the treatment of a wide variety of clinical conditions, predominantly to inhibit effects of parasympathetic activity in the respiratory tract, urinary tract, GI tract, eye, and heart. Their CNS effects have resulted in their use in the treatment of Parkinson disease, the management of extrapyramidal side effects of antipsychotic drugs, and the prevention of motion sickness.
RESPIRATORY TRACT. Ipratropium (ATROVENT, others) and tiotropium (SPIRIVA) are important agents in the treatment of chronic obstructive pulmonary disease. These agents often are used with inhaled long-acting β2 adrenergic receptor agonists. Ipratropium is administered 4 times daily via a metered-dose inhaler or nebulizer; tiotropium is administered once daily via a dry powder inhaler (see Chapter 36). Ipratropium also is used in nasal inhalers for the treatment of the rhinorrhea associated with the common cold or with allergic or nonallergic perennial rhinitis.
GENITOURINARY TRACT. Overactive urinary bladder can be successfully treated with muscarinic receptor antagonists. Muscarinic antagonists can be used to treat enuresis in children, particularly when a progressive increase in bladder capacity is the objective, and to reduce urinary frequency and increase bladder capacity in spastic paraplegia. The muscarinic receptor antagonists indicated for overactive bladder are oxybutynin (DITROPAN, others), tolterodine (DETROL), trospium chloride (SANCTURA), darifenacin (ENABLEX), solifenacin (VESICARE), and fesoterodine (TOVIAZ); available preparations and dosages are summarized in Table 9–3. The most important adverse reactions are consequences of muscarinic receptor blockade and include xerostomia, blurred vision, and GI side effects such as constipation and dyspepsia. CNS-related antimuscarinic effects, including drowsiness, dizziness, and confusion, can occur and are particularly problematic in elderly patients.
Muscarinic Receptor Antagonists Used in the Treatment of Overactive Urinary Bladder
GI TRACT. Although muscarinic receptor antagonists can reduce gastric motility and the secretion of gastric acid, antisecretory doses produce pronounced side effects (see Table 9–2). As a consequence, patient compliance in the long-term management of symptoms of acid-peptic disease with these drugs is poor. Pirenzepine, a tricyclic drug similar in structure to imipramine, has selectivity for M1 over M2and M3 receptors. However, pirenzepine’s affinities for M1 and M4 receptors are comparable, so it does not possess total M1 selectivity. Telenzepine, an analog of pirenzepine, has higher potency and similar selectivity for M1 muscarinic receptors. Both drugs are used in the treatment of acid-peptic disease in Europe, Japan, and Canada, but not currently in the U.S. At therapeutic doses of pirenzepine, the incidence of xerostomia, blurred vision, and central muscarinic disturbances is relatively low. Central effects are not seen because of the drug’s limited penetration into the CNS. H2 receptor antagonists and proton pump inhibitors generally are the current drugs of choice to reduce gastric acid secretion (see Chapter 45).
The belladonna alkaloids (atropine, hyoscyamine sulfate [ANASPAZ, others], and scopolamine) alone or in combination with sedatives (phenobarbital [DONNATAL, others]) or anti-anxiety agents (chlordiazepoxide [LIBRAX]) have been used in a variety of conditions known to involve irritable bowel and increased tone (spasticity) or motility of the GI. Glycopyrrolate (ROBINUL, others), a muscarinic antagonist structurally unrelated to the belladonna alkaloids, also is used to reduce GI tone and motility; as a quaternary amine, it is less likely to cause adverse CNS effects. The belladonna alkaloids and synthetic substitutes are very effective in reducing excessive salivation, such as drug-induced salivation and that associated with heavy-metal poisoning and Parkinson disease. A subtherapeutic dose of atropine is included with diphenoxylate in antidiarrheal LOMOTIL to discourage overuse.
Dicyclomine hydrochloride (BENTYL, others) is a weak muscarinic receptor antagonist that also has nonspecific direct spasmolytic effects on smooth muscle of the GI tract. It is occasionally used in the treatment of diarrhea-predominant irritable bowel syndrome.
EYE. Effects limited to the eye are obtained by topical administration of muscarinic receptor antagonists to produce mydriasis and cycloplegia. Cycloplegia is not attainable without mydriasis and requires higher concentrations or more prolonged application of a given agent. Homatropine hydrobromide (ISOPTO HOMATROPINE, others), a semisynthetic derivative of atropine, cyclopentolate hydrochloride (CYCLOGYL, others), and tropicamide (MYDRIACYL, others) are agents used in ophthalmological practice. These agents are preferred to topical atropine or scopolamine because of their shorter duration of action (see Chapter 64).
CARDIOVASCULAR SYSTEM. The cardiovascular effects of muscarinic receptor antagonists are of limited clinical utility. Atropine may be considered in the initial treatment of patients with acute myocardial infarction in whom excessive vagal tone causes sinus bradycardia or AV nodal block. Dosing must be judicious; doses that are too low can cause a paradoxical bradycardia (described earlier), while excessive doses will cause tachycardia that may extend the infarct by increasing the demand for oxygen. Atropine may reduce the degree of AV block when increased vagal tone is a major factor in the conduction defect, such as the second-degree AV block that can be produced by digitalis.
CNS. Scopolamine is the most effective prophylactic agent for short (4-6 h) exposures to severe motion, and probably for exposures of up to several days. All agents used to combat motion sickness should be given prophylactically. A transdermal preparation of scopolamine (TRANSDERM SCOP), used for the prevention of motion sickness, is applied to the postauricular mastoid region, an area where transdermal absorption of the drug is especially efficient, resulting in the delivery of ~0.5 mg of scopolamine over 72 h. Dry mouth is common, drowsiness is not infrequent, and blurred vision occurs in some individuals. Mydriasis and cycloplegia can occur. Rare but severe psychotic episodes have been reported. Centrally acting muscarinic antagonists are efficacious in preventing extrapyramidal side effects such as dystonias or parkinsonian symptoms in patients treated with antipsychotic drugs (see Chapter 16). The muscarinic antagonists used for Parkinson disease and drug-induced extrapyramidal symptoms include benztropine mesylate (COGENTIN, others), trihexyphenidyl hydrochloride (ARTANE, others), and biperiden; all are tertiary amines that readily gain access to the CNS.
USES IN ANESTHESIA. Atropine commonly is given to block responses to vagal reflexes induced by surgical manipulation of visceral organs. Atropine or glycopyrrolate is used with neostigmine to block its parasympathomimetic effects when the latter agent is used to reverse skeletal muscle relaxation after surgery (see Chapter 11). Serious cardiac arrhythmias have occasionally occurred.
ANTICHOLINESTERASE POISONING. The use of atropine in large doses for the treatment of poisoning by anticholinesterase organophosphorus insecticides is discussed in Chapter 10. Atropine also may be used to antagonize the parasympathomimetic effects of pyridostigmine or other anticholinesterases administered in the treatment of myasthenia gravis. It is most useful early in therapy, before tolerance to muscarinic side effects of anticholinesterases have developed.
OTHER THERAPEUTIC USES OF MUSCARINIC ANTAGONISTS. Methscopolamine bromide (PAMINE) is a quaternary ammonium derivative of scopolamine is primarily used in combination products for the temporary relief of symptoms of allergic rhinitis, sinusitis, and the common cold.
CONTRAINDICATIONS AND ADVERSE EFFECTS
Most contraindications, precautions, and adverse effects of muscarinic antagonists are predictable consequences of muscarinic receptor blockade: xerostomia, constipation, blurred vision, dyspepsia, and cognitive impairment. Important contraindications to the use of muscarinic antagonists include urinary tract obstruction, GI obstruction, and uncontrolled (or susceptibility to attacks of) angle-closure glaucoma.
TOXICOLOGY OF DRUGS WITH ANTIMUSCARINIC PROPERTIES
The deliberate or accidental ingestion of natural belladonna alkaloids is a major cause of poisonings. Many histamine H1 receptor antagonists, phenothiazines, and tricyclic antidepressants also block muscarinic receptors and, in sufficient dosage, produce syndromes that include features of atropine intoxication.
Among the tricyclic antidepressants, protriptyline and amitriptyline are the most potent muscarinic receptor antagonists, with an affinity for the receptor that is ~ one-tenth of that reported for atropine. Since these drugs are administered in therapeutic doses considerably higher than the effective dose of atropine, antimuscarinic effects are often observed clinically (see Chapter 15) and overdose with suicidal intent is a danger in the population using antidepressants. Fortunately, most of the newer antidepressants and SSRIs have more limited anticholinergic properties. The newer antipsychotic drugs, classified as “atypical” and characterized by their low propensity for inducing extrapyramidal side effects, also include agents that are potent muscarinic receptor antagonists (e.g., clozapine and olanzapine). A paradoxical side effect of clozapine is increased salivation and drooling, possibly the result of partial agonist properties of this drug.
Infants and young children are especially susceptible to the toxic effects of muscarinic antagonists. Indeed, cases of intoxication in children have resulted from conjunctival instillation for ophthalmic refraction and other ocular effects. Systemic absorption occurs either from the nasal mucosa after the drug has traversed the nasolacrimal duct or from the GI tract if the drug is swallowed. Poisoning with diphenoxylate-atropine (LOMOTIL, others), used to treat diarrhea, has been extensively reported in the pediatric literature. Transdermal preparations of scopolamine used for motion sickness have been noted to cause toxic psychoses, especially in children and in the elderly. Jimson weed contains a variety of belladonna alkaloids; serious intoxication can result from ingestion and smoking of the plant.
Table 9–2 shows the oral doses of atropine causing undesirable responses or symptoms of overdosage. These symptoms are predictable results of blockade of parasympathetic innervation. In cases of full-blown atropine poisoning, the syndrome may last 48 h or longer. Intravenous injection of the anticholinesterase agent physostigmine may be used for confirmation. Depression and circulatory collapse are evident only in cases of severe intoxication; the blood pressure declines, convulsions may ensue, respiration becomes inadequate, and death due to respiratory failure may follow. If marked excitement is present and more specific treatment is not available, a benzodiazepine is the most suitable agent for sedation and for control of convulsions. Phenothiazines or agents with antimuscarinic activity should not be used, because their antimuscarinic action is likely to intensify toxicity. Support of respiration and control of hyperthermia may be necessary.