The muscarinic receptor antagonists include: 1) the naturally occurring alkaloids, atropine and scopolamine; 2) semisynthetic derivatives of these alkaloids, which primarily differ from the parent compounds in their disposition in the body or their duration of action; and 3) synthetic derivatives, some of which show selectivity for subtypes of muscarinic receptors. Noteworthy agents among the latter two 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 M1 receptors; and darifenacin and solifenacin, which show selectivity for M3 receptors.
Muscarinic antagonists prevent the effects of ACh by blocking its binding to muscarinic receptors on effector cells at parasympathetic (and sympathetic cholinergic) neuroeffector junctions, in peripheral ganglia, and in the CNS. 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.
While many effects of muscarinic antagonists can be predicted from an understanding of the physiological responses mediated by muscarinic receptors at parasympathetic (and sympathetic cholinergic) neuroeffector junctions, paradoxical responses are sometimes seen. For example, presynaptic muscarinic receptors of variable subtype are present on postganglionic parasympathetic nerve terminals. Since blockade of presynaptic receptors generally augments neurotransmitter release, the presynaptic effects of muscarinic antagonists may counteract their postsynaptic receptor blockade. Blockade of the modulatory muscarinic receptors in peripheral ganglia represents an additional mechanism for paradoxical responses.
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). Small doses of atropine depress salivary and bronchial secretion and sweating. With larger doses, the pupil dilates, accommodation of the lens to near vision is inhibited, and vagal effects on the heart are blocked so that the heart rate increases. Larger doses antagonize parasympathetic control of the urinary bladder and GI tract, thereby inhibiting micturition and decreasing intestinal tone and motility. Still larger doses are required to inhibit gastric motility and particularly secretion. Thus, doses of atropine and most related muscarinic antagonists that depress gastric secretion also almost invariably affect salivary secretion, ocular accommodation, micturition, and GI motility. This hierarchy of relative sensitivities is not a consequence of differences in the affinity of atropine for the muscarinic receptors at these sites because 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, and the presence of other regulatory mechanisms.
Most clinically available muscarinic antagonists are nonselective and their actions differ little from those of atropine, the prototype of the group. No subtype-selective antagonist, including pirenzepine, is completely selective (i.e., can be used to define a single receptor subtype relative to all other receptor subtypes). In fact, the clinical efficacy of some agents may arise from a balance of antagonistic actions on two or more receptor subtypes.
History. The naturally occurring muscarinic receptor antagonists atropine and scopolamine are alkaloids of the belladonna (Solanaceae) plants. Preparations of belladonna were known to the ancient Hindus and have long been used by physicians. During the time of the Roman Empire and in the Middle Ages, the deadly nightshade shrub was frequently used to produce an obscure and often prolonged poisoning, prompting Linnaeus to name the shrub Atropa belladonna, after Atropos, the oldest of the three Fates, who cuts the thread of life. The name belladonna derives from the alleged use of this preparation by Italian women to dilate their pupils; modern-day fashion models are known to use this same device for visual appeal. Atropine (d,l-hyoscyamine) also is found in Datura stramonium (Jamestown or jimson weed). Scopolamine (l-hyoscine) is found chiefly in Hyoscyamus niger(henbane). In India, the root and leaves of jimson weed were burned and the smoke inhaled to treat asthma. British colonists observed this ritual and introduced the belladonna alkaloids into western medicine in the early 1800s.
Accurate study of the actions of belladonna dates from the isolation of atropine in pure form by Mein in 1831. Bezold and Bloebaum (1867) showed that atropine blocked the cardiac effects of vagal stimulation, and Heidenhain (1872) found that it prevented salivary secretion produced by stimulation of the chorda tympani. Many semisynthetic congeners of the belladonna alkaloids and a large number of synthetic muscarinic receptor antagonists have been prepared, primarily with the objective of altering GI or bladder activity without causing dry mouth or pupillary dilation.
Chemistry. Atropine and scopolamine are esters formed by combination of an aromatic acid, tropic acid, and complex organic bases, either tropine (tropanol) or scopine. Scopine differs from tropine only in having an oxygen bridge between the carbon atoms designated as 6 and 7 (Figure 9–2). Homatropine is a semisynthetic compound produced by combining the base tropine with mandelic acid. The corresponding quaternary ammonium derivatives, modified by the addition of a second methyl group to the nitrogen, are methylatropine nitrate, methscopolamine bromide, and homatropine methylbromide. Ipratropium and tiotropium also are quaternary tropine analogs esterified with synthetic aromatic acids. A similar agent, oxitropium bromide, an N-ethyl-substituted, quaternary derivative of scopolamine, is available in Europe.
Structure-Activity Relationships. An intact ester of tropine and tropic acid is essential for antimuscarinic action, since neither the free acid nor the basic alcohol exhibits significant antimuscarinic activity. The presence of a free OH group in the acyl portion of the ester also is important for activity. When given parenterally, quaternary ammonium derivatives of atropine and scopolamine are generally more potent than their parent compounds in both muscarinic and ganglionic (nicotinic) blocking activities. The quaternary derivatives, when given orally, are poorly and unreliably absorbed.
Both tropic and mandelic acids have an enantiomeric center (boldface red C in the formulas in Figure 9–2). Scopolamine is l-hyoscine and is much more active than d-hyoscine. Atropine is racemized during extraction and consists of d,l-hyoscyamine, but antimuscarinic activity is almost wholly due to the naturally occurring l isomer. Synthetic derivatives show a wide range of structures that spatially replicate the aromatic acid and the bridged nitrogen of the tropine.
Mechanism of Action. Atropine and related compounds compete with ACh and other muscarinic agonists for a common binding site on the muscarinic receptor. Since antagonism by atropine is competitive, it can be overcome if the concentration of ACh at muscarinic receptors of the effector organ is increased sufficiently. Muscarinic receptor antagonists inhibit responses to postganglionic cholinergic nerve stimulation less effectively than they inhibit responses to injected choline esters. The difference may be explained by the fact that release of ACh by cholinergic nerve terminals occurs in close proximity to the receptors, resulting in very high concentrations of the transmitter at the receptors.
Structural formulas of the belladonna alkaloids and semisynthetic and synthetic analogs. The red C identifies an asymmetric carbon atom.
Pharmacological Effects of Muscarinic Antagonists
The pharmacological effects of atropine, the prototypical muscarinic antagonist, 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. The major pharmacological effects of increasing doses of atropine, summarized in Table 9–2, offer a general guide to the problems associated with administration of this class of agents.
Heart. The main effect of atropine on the heart is to alter the rate. Although the dominant response is tachycardia, the heart rate often decreases transiently with average clinical doses (0.4-0.6 mg; Table 9–2). The slowing is modest (4-8 beats per minute) and is usually absent after rapid intravenous injection. There are no accompanying changes in blood pressure or cardiac output. This unexpected effect has been attributed to the block of presynaptic M1 muscarinic receptors on parasympathetic postganglionic nerve terminals in the SA node, which normally inhibit ACh release (Wellstein and Pitschner, 1988).
Table 9-2Effects of Atropine in Relation to Dose ||Download (.pdf) Table 9-2 Effects of Atropine in Relation to Dose
|DOSE (mg) ||EFFECTS |
|0.5 ||Slight cardiac slowing; some dryness of mouth; inhibition of sweating |
|1 ||Definite dryness of mouth; thirst; acceleration of heart, sometimes preceded by slowing; mild dilation of pupils |
|2 ||Rapid heart rate; palpitation; marked dryness of mouth; dilated pupils; some blurring of near vision |
|5 ||Above symptoms marked; difficulty in speaking and swallowing; restlessness and fatigue; headache; dry, hot skin; ?difficulty in micturition; reduced ?intestinal peristalsis |
|≥10 ||Above symptoms more marked; pulse rapid and weak; iris practically obliterated; vision very blurred; skin flushed, hot, dry, and scarlet; ataxia, restlessness, and excitement; hallucinations and delirium; coma |
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. Atropine shortens the functional refractory period of the AV node and can increase ventricular rate in patients who have atrial fibrillation or flutter. In certain cases of second-degree AV block (e.g., Wenckebach AV block), in which vagal activity is an etiological factor (as with digitalis toxicity), atropine may lessen the degree of block. In some patients with complete AV block, the idioventricular rate may be accelerated by atropine; in others it is stabilized. Atropine may improve the clinical condition of patients with inferior or posterior wall myocardial infarction by relieving severe sinus or nodal bradycardia or AV block.
Circulation. Atropine, in clinical doses, completely counteracts the peripheral vasodilation and sharp fall in blood pressure caused by choline esters. In contrast, when given alone, its effect on blood vessels and blood pressure is neither striking nor constant. This result is expected because most vascular beds lack significant cholinergic innervation. 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. Although atropine can cause some bronchodilation and decrease in tracheobronchial secretion in normal individuals by blocking parasympathetic (vagal) tone to the lungs, its effects on the respiratory system are most significant in patients with respiratory disease. 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 (Chapter 36). Muscarinic antagonists also have an important role in the treatment of chronic obstructive pulmonary disease (Chapter 36).
Atropine inhibits the secretions of the nose, mouth, pharynx, and bronchi, and thus dries the mucous membranes of the respiratory tract. This action is especially marked if secretion is excessive and formed the basis for the use of atropine and other muscarinic antagonists to prevent irritating inhalational anesthetics such as diethyl ether from increasing bronchial secretion. While the newer inhalational anesthetics are less irritating, muscarinic antagonists are similarly used to decrease the rhinorrhea associated with the common cold or with allergic and nonallergic rhinitis. Reduction of mucous secretion and mucociliary clearance can, however, result in mucus plugs, a potentially undesirable side effect of muscarinic antagonists in patients with airway disease.
Eye. Muscarinic receptor antagonists block the cholinergic responses of the pupillary sphincter muscle of the iris and the ciliary muscle controlling lens curvature (Chapter 64). Thus, they dilate the pupil (mydriasis) and paralyze accommodation (cycloplegia). The wide pupillary dilation results in photophobia; the lens is fixed for far vision, near objects are blurred, and objects may appear smaller than they are. The normal pupillary reflex constriction to light or upon convergence of the eyes is abolished. These effects can occur after either local or systemic administration of the alkaloids.
However, conventional systemic doses of atropine (0.6 mg) have little ocular effect, in contrast to equal doses of scopolamine, which cause evident mydriasis and loss of accommodation. 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 (Chapter 64). Pilocarpine and choline esters (e.g., carbachol) in sufficient concentrations can reverse the ocular effects of atropine.
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. The rise in pressure occurs when the anterior chamber is narrow and the iris obstructs outflow of aqueous humor into the trabeculae. Muscarinic antagonists may precipitate a first attack in unrecognized cases of this relatively rare condition. In patients with open-angle glaucoma, an acute rise in pressure is unusual. Atropine-like drugs generally can be used safely in this latter condition, particularly if the glaucoma is being treated appropriately.
GI Tract. Knowledge of the actions of muscarinic receptor agonists on the stomach and intestine led to the use of muscarinic receptor antagonists 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 gastrointestinal responses to vagal stimulation. This difference, which is particularly striking in the effects of atropine on gut motility, 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. These neurons, which form the plexuses of the enteric nervous system, utilize numerous neurotransmitters or neuromodulators including serotonin (5-HT), dopamine, and peptides, the effects of which are not blocked by atropine. Another reason that atropine only incompletely inhibits the GI responses to vagal activity is that vagal stimulation of gastrin secretion is mediated by gastrin-releasing peptide (GRP), not ACh. The parietal cell secretes acid in response to at least three agonists: gastrin, histamine, and acetylcholine; furthermore, stimulation of muscarinic receptors on enterochromaffin-like cells will cause histamine release. Atropine will inhibit the component of acid secretion that results from muscarinic stimulation of enterochromafin cells (histamine secretors) and parietal cells (acid secretors).
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. The concentration of acid is not necessarily lowered because secretion of HCO3–as well as that of H+ is blocked. The gastric cells that secrete mucin and proteolytic enzymes are more directly under vagal influence than are the acid-secreting cells, and atropine decreases their secretory function. Although muscarinic antagonists can reduce gastric secretion, the doses required also affect salivary secretion, ocular accommodation, micturition, and GI motility (Table 9–2). Thus, histamine H2 receptor antagonists and, more recently, proton pump inhibitors have replaced muscarinic antagonists as inhibitors of acid secretion (Chapter 45).
In contrast to most muscarinic receptor antagonists, pirenzepine, which shows some selectivity for M1 receptors, inhibits gastric acid secretion at doses that have little effect on salivation or heart rate. Since the muscarinic receptors on the parietal cells are primarily M3 receptors and do not appear to have a high affinity for pirenzepine, the M1 receptor responsible for alterations in gastric acid secretion is postulated to be localized in intramural ganglia (Eglen et al., 1996). Blockade of ganglionic muscarinic receptors (rather than those at the neuroeffector junction) may underlie the ability of pirenzepine to inhibit the relaxation of the lower esophageal sphincter. The physiology and pharmacology here are complex: Pirenzepine reportedly inhibits carbachol-stimulated acid secretion in KO mice lacking M1 receptors (Aihara et al., 2005).
Motility. The parasympathetic nerves enhance both tone and motility and relax sphincters, thereby favoring the passage of gastrointestinal contents. Both in normal subjects and in patients with gastrointestinal disease, muscarinic antagonists produce prolonged inhibitory effects on the motor activity of the stomach, duodenum, jejunum, ileum, and colon, characterized by a reduction in tone and in 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; parasympathetic nerves serve only to modulate the effects of the enteric nervous system (Chapter 8).
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 (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. The nitrates (Chapter 27) are more effective than atropine in this respect.
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.
Central Nervous System 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 (see the discussion of atropine poisoning later in the chapter). 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 rapid eye movement (REM) sleep. It also causes euphoria and can therefore be subject to abuse. The depressant and amnesic effects formerly were sought when scopolamine was used as an adjunct to anesthetic agents or for preanesthetic medication. However, in the presence of severe pain, the same doses of scopolamine can occasionally cause excitement, restlessness, hallucinations, or delirium. These excitatory effects resemble those of toxic doses of atropine. Scopolamine also is effective in preventing motion sickness, probably by blocking neural pathways from the vestibular apparatus in the inner ear to the emetic center in the brainstem.
Muscarinic receptor antagonists have long been used in the treatment of Parkinson disease. These agents can be effective adjuncts to treatment with levodopa (Chapter 22). Muscarinic receptor antagonists also are used to treat the extrapyramidal symptoms that commonly occur as side effects of conventional antipsychotic drug therapy (Chapter 16). Certain antipsychotic drugs are relatively potent muscarinic receptor antagonists (Richelson, 1999; Roth et al., 2004) 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. The degree of bronchodilation achieved by these agents is thought to reflect the level of basal parasympathetic tone, supplemented by reflex activation of cholinergic pathways brought about by various stimuli. In normal individuals, inhalation of the drugs can provide virtually complete protection against the bronchoconstriction produced by the subsequent inhalation of such irritants as sulfur dioxide, ozone, or cigarette smoke. However, patients with atopic asthma or patients with demonstrable bronchial hyperresponsiveness are less well protected. Although these drugs cause a marked reduction in sensitivity to methacholine in asthmatic subjects, more modest inhibition of responses to challenge with histamine, bradykinin, or PGF2α is achieved, and little protection is afforded against the bronchoconstriction induced by 5-HT or leukotrienes. A therapeutically important property of ipratropium and tiotropium is their minimal inhibitory effect on mucociliary clearance relative to atropine. Hence, the choice of these agents for use in patients with airway disease minimizes the increased accumulation of lower airway secretions encountered with atropine.
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 (Barnes, 2004; Disse et al., 1999)
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 (e.g., scopolamine, allowing delivery by transdermal patch). Systemic absorption of inhaled or orally ingested quaternary muscarinic receptor antagonists is limited. The quaternary ammonium derivatives of the belladonna alkaloids also penetrate the conjunctiva of the eye less readily, and central effects are lacking because the quaternary agents do not cross the blood-brain barrier. Atropine has a t1/2 of ~4 hours; 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. After inhalation, maximal responses usually develop over 30-90 minutes, with tiotropium having the slower onset. The effects of ipratropium last for 4-6 hours, while tiotropium's effects persist for 24 hours so that the drug is amenable to once-daily dosing (Barnes and Hansel, 2004).
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. The major limitation in the use of the nonselective drugs is often failure to obtain desired therapeutic responses without concomitant side effects. While the latter usually are not serious, they can be sufficiently disturbing to decrease patient compliance, particularly during long-term administration. To date, selectivity has mainly been achieved by local administration, e.g., by pulmonary inhalation or instillation in the eye, since few available muscarinic antagonists show absolute selectivity. The development of allosteric modulators that recognize sites unique to particular receptor subtypes is currently considered an important approach to the development of selective drugs for the treatment of specific clinical conditions (Conn et al., 2009b).
Respiratory Tract. Ipratropium (atrovent, others) and tiotropium (spiriva) are important agents in the treatment of chronic obstructive pulmonary disease; they are less effective in most asthmatic patients (Barnes, 2004; Barnes and Hansel, 2004; Gross, 2004). These agents often are used with inhaled long-acting β2 adrenergic receptor agonists, although there is little evidence of true synergism. Ipratropium is administered four times daily via a metered-dose inhaler or nebulizer; tiotropium is administered once daily via a dry powder inhaler. The therapeutic uses of ipratropium and tiotropium are discussed further in Chapter 36.
Ipratropium also is FDA-approved for use in nasal inhalers for the treatment of the rhinorrhea associated with the common cold or with allergic or nonallergic perennial rhinitis. Although the ability of muscarinic antagonists to reduce nasopharyngeal secretions may provide some symptomatic relief, such therapy does not affect the natural course of the condition. It is probable that the contribution of first-generation antihistamines employed in nonprescription cold medications is due primarily to their antimuscarinic properties, except in conditions with an allergic basis (Chapter 32). The uncomplicated common cold will generally last 2 weeks if treated and 14 days if untreated; cold medications may, however, ameliorate some of the symptoms.
Genitourinary Tract. Overactive urinary bladder can be successfully treated with muscarinic receptor antagonists. These agents can lower intravesicular pressure, increase capacity, and reduce the frequency of contractions by antagonizing parasympathetic control of the bladder; they also may alter bladder sensation during filling (Chapple et al., 2005). 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 (Chapple, 2000; Goessl et al., 2000).
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. Although some comparison trials have demonstrated small but statistically significant differences in efficacy between agents (Chapple et al., 2005), whether these efficacy differences are clinically significant is uncertain. 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. CNS effects appear to be less likely with trospium, a quaternary amine, and with darifenacin and solifenacin; the latter agents are relatively selective for M3 receptors and therefore have minimal effects on M1 receptors in the CNS, which appear to play an important role in memory and cognition (Kay et al., 2006). Adverse effects can limit the tolerability of these drugs with continued use, and patient acceptance declines. Xerostomia is the most common reason for discontinuation.
Oxybutynin, the oldest of the antimuscarinics currently used to treat overactive bladder disorders, is associated with a high incidence of antimuscarinic side effects, particularly xerostomia. In an attempt to increase patient acceptance, oxybutynin is marketed as a transdermal system (oxytrol) that is associated with a lower incidence of side effects than the oral immediate- or extended-release formulations; a topical gel formulation of oxybutynin (gelnique) also appears to offer a more favorable side effect profile. Because of the extensive metabolism of oral oxybutynin by enteric and hepatic CYP3A4, higher doses are used in oral than transdermal administration; the dose may need to be reduced in patients taking drugs that inhibit CYP3A4.
Tolterodine shows selectivity for the urinary bladder in animal models and in clinical studies, resulting in greater patient acceptance; however, studies on isolated receptors do not reveal a unique subtype selectivity (Abrams et al., 1998, 1999; Chapple, 2000). Inhibition of a particular complement of receptors in the bladder may give rise to synergism and clinical efficacy. Tolterodine is metabolized by CYP2D6 to 5-hydroxymethyltolterodine. Since this metabolite possesses similar activity to the parent drug, variations in CYP2D6 levels do not affect the net antimuscarinic activity or duration of action of the drug. However, in patients who poorly metabolize tolterodine via CYP2D6, the CYP3A4 pathway becomes important in tolterodine elimination. Because it is often difficult to assess which patients will be poor metabolizers, tolterodine doses may need to be reduced in patients taking drugs that inhibit CYP3A4 (dosage adjustments generally are not necessary in patients taking drugs that inhibit CYP2D6). Patients with significant renal or hepatic impairment also should receive lower doses of the drug. Fesoterodine, a new agent, is a prodrug that is rapidly hydrolyzed to the active metabolite of tolterodine.
Trospium, a quaternary amine, is as effective as oxybutynin with better tolerability. Trospium is the only antimuscarinic used for overactive bladder that is eliminated primarily by the kidneys; 60% of the absorbed trospium dose is excreted unchanged in the urine, and dosage adjustment is necessary for patients with impaired renal function.
Solifenacin is relatively selective for muscarinic receptors of the M3 subtype, giving it a favorable efficacy:side effect ratio (Chapple et al., 2004). Solifenacin is significantly metabolized by CYP3A4; thus, patients taking drugs that inhibit CYP3A4 should receive lower doses.
Like solifenacin, darifenacin is relatively selective for M3 receptors. It is metabolized by CYP2D6 and CYP3A4; as with tolterodine, the latter pathway becomes more important in patients who poorly metabolize the drug by CYP2D6. Darifenacin doses may need to be reduced in patients taking drugs that inhibit either of these CYPs.
Flavoxate hydrochloride, a drug with direct spasmolytic actions on smooth muscle, especially of the urinary tract, is used for the relief of dysuria, urgency, nocturia, and other urinary symptoms associated with genitourinary disorders (e.g., cystitis, prostatitis, urethritis). Flavoxate also has weak antihistaminic, local anesthetic, analgesic, and, at high doses, antimuscarinic effects.
Table 9-3Muscarinic Receptor Antagonists Used in the Treatment of Overactive Urinary Bladder ||Download (.pdf) Table 9-3 Muscarinic Receptor Antagonists Used in the Treatment of Overactive Urinary Bladder
|NONPROPRIETARY NAME ||TRADE NAME ||t1/2 (HOURS) ||PREPARATIONSa ||DAILY DOSE (ADULT) |
|Oxybutynin ||ditropan, others ||2-5 ||IR ||10-20 mgb |
| ||oxytrol || ||ER ||5-30 mgb |
| ||gelnique || ||Transdermal patch ||3.9 mg |
| || || ||Topical gel ||100 mg |
|Tolterodine ||DETROL ||2-9.6c ||IR ||2-4 mgb,d |
| || ||6.9-18c ||ER ||4 mgb,d |
|Trospium chloride ||sanctura ||20 ||IR ||20-40 mge |
| || ||35 ||ER ||60 mge |
|Solifenacin ||vesicare ||55 ||IR ||5-10 mgb |
|Darifenacin ||enablex ||13-19 ||ER ||7.5-15 mgf |
|Fesoterodine ||toviaz ||7 ||ER ||4-8 mg |
GI Tract. Muscarinic receptor antagonists were once widely used for the management of peptic ulcer. Although they can reduce gastric motility and the secretion of gastric acid, antisecretory doses produce pronounced side effects, such as xerostomia, loss of visual accommodation, photophobia, and difficulty in urination (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 M2 and M3 receptors (Caulfield, 1993; Caulfield and Birdsall, 1998). 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.
Most studies indicate that pirenzepine (100-150 mg per day) produces about the same rate of healing of duodenal and gastric ulcers as the H2 receptor antagonists cimetidine or ranitidine; it also may be effective in preventing the recurrence of ulcers (Carmine and Brogden, 1985; Tryba and Cook, 1997). Side effects necessitate drug withdrawal in <1% of patients. Studies in human subjects have shown pirenzepine to be more potent in inhibiting gastric acid secretion produced by neural stimuli than by muscarinic agonists, supporting the postulated localization of M1 receptors at ganglionic sites. Nevertheless, H2 receptor antagonists and proton pump inhibitors generally are considered to be the current drugs of choice to reduce gastric acid secretion (Chapter 45).
Myriad conditions known or supposed to involve increased tone (spasticity) or motility of the GI tract are treated with belladonna alkaloids (e.g., atropine, hyoscyamine sulfate [anaspaz, others], and scopolamine) alone or in combination with sedatives (e.g., phenobarbital [donnatal, others]) or antianxiety agents (e.g., chlordiazepoxide [librax]). The belladonna alkaloids and their synthetic substitutes can reduce tone and motility when administered in maximally tolerated doses, and they might be expected to be efficacious in conditions simply involving excessive smooth muscle contraction, a point that is often in doubt. M3-selective antagonists might achieve more selectivity but are unlikely to be better tolerated, as M3 receptors also have an important role in the control of salivation, bronchial secretion and contraction, and bladder motility. Glycopyrrolate (robinul, others), a muscarinic antagonist that is structurally unrelated to the belladonna alkaloids, also is used to reduce GI tone and motility; being a quaternary amine, it is less likely to cause adverse CNS effects than atropine, scopolamine, and other tertiary amines. Alternative agents for treatment of increased GI motility and its associated symptoms are discussed in Chapter 46.
Diarrhea associated with irritation of the lower bowel, such as mild dysenteries and diverticulitis, may respond to atropine-like drugs, an effect that likely involves actions on ion transport as well as motility. However, more severe conditions such as Salmonella dysentery, ulcerative colitis, and Crohn's disease respond little if at all to muscarinic antagonists. 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.
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. Mydriasis often is necessary for thorough examination of the retina and optic disc and in the therapy of iridocyclitis and keratitis. The belladonna mydriatics may be alternated with miotics for breaking or preventing the development of adhesions between the iris and the lens. Complete cycloplegia may be necessary in the treatment of iridocyclitis and choroiditis and for accurate measurement of refractive errors.
Homatropine hydrobromide (isopto homatropine, others), a semisynthetic derivative of atropine (Figure 9–2), 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. Additional information on the ophthalmological properties and preparations of these and other drugs is provided in Chapter 64.
Cardiovascular System. The cardiovascular effects of muscarinic receptor antagonists are of limited clinical utility. Generally, these agents are used only in coronary care units for short-term interventions or in surgical settings.
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. Sinus bradycardia is the most common arrhythmia seen during acute myocardial infarction of the inferior or posterior wall. Atropine may prevent further clinical deterioration in cases of high vagal tone or AV block by restoring heart rate to a level sufficient to maintain adequate hemodynamic status and to eliminate 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 occasionally is useful in reducing the severe bradycardia and syncope associated with a hyperactive carotid sinus reflex. It has little effect on most ventricular rhythms. In some patients, atropine may eliminate premature ventricular contractions associated with a very slow atrial rate. It also 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. Selective M2 receptor antagonists would be of potential utility in blocking ACh-mediated bradycardia or AV block; however, none is currently available for clinical use.
Central Nervous System. The belladonna alkaloids were among the first drugs to be used in the prevention of motion sickness. Scopolamine is the most effective prophylactic agent for short (4-6 hour) exposures to severe motion, and probably for exposures of up to several days. All agents used to combat motion sickness should be given prophylactically; they are much less effective after severe nausea or vomiting has developed. A transdermal preparation of scopolamine (transderm scop) has been shown to be highly effective when used prophylactically for the prevention of motion sickness. The drug, incorporated into a multilayered adhesive unit, 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 hours.
Xerostomia is common, drowsiness is not infrequent, and blurred vision occurs in some individuals. Mydriasis and cycloplegia can occur by inadvertent transfer of the drug to the eye from the fingers after handling the patch. Rare but severe psychotic episodes have been reported. As noted earlier, the preoperative use of scopolamine to produce tranquilization and amnesia is no longer recommended. Given alone in the presence of pain or severe anxiety, scopolamine may induce outbursts of uncontrolled behavior.
For many years, the belladonna alkaloids and subsequently synthetic substitutes were the only agents helpful in the treatment of Parkinson disease. Levodopa combined with carbidopa (sinemet) and dopamine receptor agonists are currently the most important treatments for Parkinson disease, but alternative or concurrent therapy with muscarinic receptor antagonists may be required in some patients (Chapter 22). Centrally acting muscarinic antagonists are efficacious in preventing extrapyramidal side effects such as dystonias or parkinsonian symptoms in patients treated with antipsychotic drugs (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.
Current evidence based on studies using muscarinic receptor knockout mice, subtype-selective drugs, and early-stage clinical trials suggest that selective blockade of specific muscarinic receptor subtypes in the CNS may have important therapeutic applications. For example, selective M1 and M4 muscarinic antagonists may be efficacious for the treatment of Parkinson disease with fewer side effects than nonselective muscarinic antagonists, while selective M3 antagonists may be useful in the treatment of obesity and associated metabolic abnormalities (Wess et al., 2007).
Uses in Anesthesia. The use of anesthetics that are relatively non-irritating to the bronchi has virtually eliminated the need for prophylactic use of muscarinic receptor antagonists. 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 (Chapter 11). Serious cardiac arrhythmias have occasionally occurred, perhaps because of the initial bradycardia produced by atropine combined with the cholinomimetic effects of neostigmine.
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 does not interfere with the salutary effects at the skeletal neuromuscular junction. 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 and therefore lacks the central actions of scopolamine. Although formerly used to treat peptic ulcer disease, at present it is primarily used in certain combination products for the temporary relief of symptoms of allergic rhinitis, sinusitis, and the common cold.
Homatropine methylbromide, the methyl derivative of homatropine, is less potent than atropine in antimuscarinic activity but four times more potent as a ganglionic blocking agent. Formerly used for the treatment of irritable bowel syndrome and peptic ulcer disease, at present it is primarily used with hydrocodone as an antitussive combination (hycodan, others).
Contraindications and Adverse Effects
Most contraindications, precautions, and adverse effects 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. Muscarinic receptor antagonists also are contraindicated (or should be used with extreme caution) in patients with benign prostatic hyperplasia. These adverse effects and contraindications generally are of more limited concern with muscarinic antagonists that are administered by inhalation or used topically in ophthalmology.
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 (Chapter 15). In addition, overdose with suicidal intent is a danger in the population using antidepressants. Fortunately, most of the newer antidepressants and selective serotonin reuptake inhibitors have more limited anticholinergic properties (Cusack et al., 1994).
Like the tricyclic antidepressants, many of the older antipsychotic drugs have antimuscarinic effects. These effects are most likely to be observed with the less potent drugs, e.g., chlorpromazine and thioridazine, which must be given in higher doses. 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. In particular, clozapine binds to human brain muscarinic receptors with high affinity (10 nM, compared to 1-2 nM for atropine); olanzapine also is a potent muscarinic receptor antagonist (Richelson, 1999; Roth et al., 2004). Accordingly, xerostomia is a prominent side effect of these drugs. A paradoxical side effect of clozapine is increased salivation and drooling, possibly the result of partial agonist properties of this drug (Richelson, 1999).
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. Serious intoxication may occur in children who ingest berries or seeds containing belladonna alkaloids. Poisoning from ingestion and smoking of jimson weed is seen with some frequency today.
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 hours or longer. Intravenous injection of the anticholinesterase agent physostigmine may be used for confirmation. If physostigmine does not elicit the expected salivation, sweating, bradycardia, and intestinal hyperactivity, intoxication with atropine or a related agent is almost certain. 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 after a period of paralysis and coma.
Measures to limit intestinal absorption should be initiated without delay if the poison has been taken orally. For symptomatic treatment, slow intravenous injection of physostigmine rapidly abolishes the delirium and coma caused by large doses of atropine, but carries some risk of overdose in mild atropine intoxication. Since physostigmine is metabolized rapidly, the patient may again lapse into coma within 1-2 hours, and repeated doses may be needed (Chapter 10). 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. Ice bags and alcohol sponges help to reduce fever, especially in children.