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activation of endothelial NO synthase (eNOS, NOS-3) and production of NO which diffuses to adjacent smooth muscle cells, where it stimulates the soluble guanylyl cyclase and causes relaxation (see Chapters 1 and 6). Vasodilation also may arise indirectly due to inhibition of norepinephrine (NE) release from adrenergic nerve endings by ACh. If the endothelium is damaged, as occurs under vari-ous pathophysiological conditions, the direct effect of ACh on the muscarinic receptors on vascular smooth muscle cells predominates, and the resultant mobilization of cell Ca2+causes vasoconstriction.
There is also evidence of NO-based (nitrergic) neurotransmission in peripheral blood vessels.
Cholinergic stimulation affects cardiac function both directly and by inhibiting the effects of adrenergic activation. The latter depends on the level of sympathetic drive to the heart and results in part from inhibition of cyclic AMP formation and reduction in L-type Ca2+channel activity, mediated through M2receptors. Inhibition of adrenergic stimulation of the heart also results from the capacity of M2receptors to inhibit the release of NE from sympathetic nerve endings. Cholin-ergic innervation of the ventricular myocardium is less dense, and the parasympathetic fibers ter-minate largely on specialized conduction tissue such as the Purkinje fibers but also on some ventricular myocytes, which express M2receptors.
In the SA node, each normal cardiac impulse is initiated by the spontaneous depolarization of the pacemaker cells (see Chapter 34). When a threshold is reached, an action potential is initiated and conducted through the atrial muscle fibers to the AV node and thence through the Purkinje system to the ventricular muscle. ACh slows the heart rate by decreasing the rate of spontaneous diastolic depolarization (the pacemaker current) and by increasing the repolarizing K+current at the SA node (a direct effect of bg subunits of Gi/Go); in sum, the membrane potential is more negative and attainment of the threshold potential and the succeeding events in the cardiac cycle are delayed.
In atrial muscle, ACh decreases the strength of contraction. This occurs largely indirectly, as a result of decreasing cyclic AMP and Ca2+channel activity. Direct inhibitory effects are seen at higher ACh concentrations and result from M2receptor–mediated activation of G protein–regulated K+channels. The rate of impulse conduction in the normal atrium is either unaffected or may increase in response to ACh, due to the activation of additional Na+channels, possibly in response to the ACh-induced hyperpolarization. The combination of these factors is the basis for the perpet-uation or exacerbation by vagal impulses of atrial flutter or fibrillation arising at an ectopic focus.
In contrast, primarily in the AV node and to a much lesser extent in the Purkinje conducting system, ACh slows conduction and increases the refractory period. The decrease in AV nodal conduction usually is responsible for the complete heart block that may be observed when large quantities of cholinergic agonists are administered systemically. With an increase in vagal tone, such as is pro-duced by digoxin, the increased refractory period can contribute to the reduction in the frequency with which aberrant atrial impulses are transmitted to the ventricle, and thus protect the ventricle during atrial flutter or fibrillation.
Although the effect is smaller than that observed in the atrium, ACh produces a negative inotropic effect in the ventricle. This inhibition is most apparent when there is concomitant adren-ergic stimulation or underlying sympathetic tone. ACh suppresses automaticity of Purkinje fibers and increases the threshold for ventricular fibrillation. To the extent that the ventricle receives cholinergic innervation, sympathetic and vagal nerve terminals lie in close proximity, and mus-carinic receptors are believed to exist at presynaptic as well as postsynaptic sites.
GASTROINTESTINAL AND URINARY TRACTS Although stimulation of vagal input to the gastrointestinal (GI) tract increases tone, amplitude of contraction, and secretory activity of the stomach and intestine, such responses are inconsistently seen with administered ACh. Poor perfu-sion of visceral organs and rapid hydrolysis by plasma butyrylcholinesterase limit access of sys-temically administered ACh to visceral muscarinic receptors. Parasympathetic sacral innervation causes detrusor muscle contraction, increased voiding pressure, and ureter peristalsis, but for simi-lar reasons these responses are not evident with administered ACh.
MISCELLANEOUS EFFECTS
The influence of ACh and parasympathetic innervation on various organs and tissues is discussed in detail in Chapter 6. ACh and its analogs stimulate secretion by all glands that receive parasym-pathetic innervation, including the lacrimal, tracheobronchial, salivary, and digestive glands. The effects on the respiratory system, in addition to increased tracheobronchial secretion, include bronchoconstriction and stimulation of the chemoreceptors of the carotid and aortic bodies. When instilled into the eye, muscarinic agonists produce miosis (see Chapter 63).
CHOLINOMIMETIC CHOLINE ESTERS AND NATURAL ALKALOIDS
Muscarinic cholinergic receptor agonists can be divided into two groups: (1) ACh and several syn-thetic choline esters, and (2) the naturally occurring cholinomimetic alkaloids (particularly pilocarpine, muscarine, and arecoline) and their synthetic congeners. The structures and pharmacologic properties of a congeneric series are summarized by Table 7–1 and Figure 7–1.
Methacholine (acetyl-b-methylcholine) differs from ACh chiefly in its greater duration and selectivity of action. Its action is more prolonged because the added methyl group increases its resistance to hydrolysis by cholinesterases. Carbachol and bethanechol, unsubstituted carbamoyl esters, are completely resistant to hydrolysis by cholinesterases and thus survive long enough to be distributed to areas of low blood flow. Carbachol retains substantial nicotinic activity, particularly on autonomic ganglia; both its peripheral and its ganglionic actions are probably due, in part, to the release of endogenous ACh from the terminals of cholinergic fibers.
Of the three major natural plant alkaloids, muscarine acts almost exclusively at muscarinic receptor sites, arecoline also acts at nicotinic receptors, and pilocarpine has a dominant muscarinic action but causes anomalous cardiovascular responses (the sweat glands are particularly sensitive to this drug).
Although these naturally occurring alkaloids are valuable as pharmacological tools, present clinical use is restricted largely to pilocarpine as a sialagogue and miotic agent (see Chapter 63).
Pharmacological Properties GASTROINTESTINAL TRACT
All muscarinic agonists can stimulate GI smooth muscle, increasing tone and motility; large doses will cause spasm and tenesmus. Unlike methacholine, carbachol, bethanechol, and pilocarpine stimulate the GI tract without significant cardiovascular effects.
URINARY TRACT
Choline esters and pilocarpine contract the detrusor muscle of the bladder, increase voiding pres-sure, decrease bladder capacity, and increase ureteral peristalsis. In addition, the trigone and external sphincter muscles relax. Bethanechol shows some selectivity for bladder stimulation relative to cardiovascular activity (see Table 7–1).
EXOCRINE GLANDS
Choline esters and muscarinic alkaloids stimulate secretion of glands that receive parasympa-thetic or sympaparasympa-thetic cholinergic innervation, including the lacrimal, salivary, digestive, tracheo-bronchial, and sweat glands. Pilocarpine in particular causes marked diaphoresis (2–3 L of sweat may be secreted) and markedly increases salivation. Muscarine and arecoline also are potent diaphoretic agents. Accompanying side effects may include hiccough, salivation, nausea, vomiting, weakness, and occasionally collapse. These alkaloids also stimulate the lacrimal, gastric, pan-creatic, and intestinal glands, and the mucous cells of the respiratory tract.
RESPIRATORY SYSTEM
In addition to tracheobronchial secretions, bronchial smooth muscle is stimulated by the mus-carinic agonists. Asthmatic patients respond with intense bronchoconstriction, secretions, and a reduction in vital capacity. These actions form the basis of the methacholine challenge test used to diagnose airway hyperreactivity.
Table 7–1
Some Pharmacological Properties of Choline Esters and Natural Alkaloids Muscarinic Activity
Muscarinic Susceptibility to Urinary Eye Antagonism Nicotinic
Agonist Cholinesterases Cardiovascular Gastrointestinal Bladder (Topical) by Atropine Activity
Acetylcholine +++ ++ ++ ++ + +++ ++
Methacholine + +++ ++ ++ + +++ +
Carbachol – + +++ +++ ++ + +++
Bethanechol – ± +++ +++ ++ +++ –
Muscarine – ++ +++ +++ ++ +++ –
Pilocarpine – + +++ +++ ++ +++ –
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CARDIOVASCULAR SYSTEM
Continuous intravenous infusion of methacholine elicits hypotension and bradycardia, just as ACh does but at 1/200 the dose. Muscarine, at small doses, leads to a marked fall in blood pres-sure and a slowing or temporary cessation of the heartbeat. In contrast, carbachol and bethane-chol generally cause only a transient fall in blood pressure at doses that affect the GI and urinary tracts.
EYE
Muscarinic agonists stimulate the pupillary constrictor and ciliary muscles when applied locally to the eye, causing pupil constriction and a loss of ability to accommodate to far vision.
CENTRAL NERVOUS SYSTEM
Quaternary choline esters do not cross the blood–brain barrier.
Therapeutic Uses
Acetylcholine (MIOCHOL-E) is available as an ophthalmic surgical aid for rapid production of miosis.Bethanechol chloride (URECHOLINE, others) is available in tablets and as an injection for use as a stimulant of GI smooth muscle, especially the urinary bladder. Pilocarpine hydrochloride (SALAGEN) is available as 5- or 7.5-mg oral doses for treatment of xerostomia or as ophthalmic solu-tions (PILOCAR, others) of varying strength. Methacholine chloride (PROVOCHOLINE) may be admin-istered for diagnosis of bronchial hyperreactivity. The unpredictability of absorption and intensity of response has precluded its use as a vasodilator or cardiac vagomimetic agent. Cevimeline (EVOXAC) is a newer muscarinic agonist available orally for use in treatment of xerostomia.
GASTROINTESTINAL DISORDERS
Bethanechol can be of value in certain cases of postoperative abdominal distention and in gastric atony or gastroparesis. Oral administration is preferred; the usual dosage is 10–20 mg, three or four times daily. Bethanechol is given by mouth before each main meal in cases without complete retention; when gastric retention is complete and nothing passes into the duodenum, the subcuta-neous route is necessary because of poor stomach absorption. Bethanechol has been used to advantage in certain patients with congenital megacolon and with adynamic ileus secondary to toxic states. Prokinetic agents with combined cholinergic-agonist and dopamine-antagonist activ-ity(e.g., metoclopramide) or serotonin-antagonist activity (see Chapter 37) have largely replaced bethanechol in gastroparesis and esophageal reflux disorders.
URINARY BLADDER DISORDERS
Bethanechol may be useful in treating urinary retention and inadequate emptying of the bladder when organic obstruction is absent, as in postoperative and postpartum urinary retention and in cer-tain cases of chronic hypotonic, myogenic, or neurogenic bladder. α Adrenergic antagonists are useful adjuncts in reducing outlet resistance of the internal sphincter (see Chapter 10). Bethanechol may enhance contractions of the detrusor muscle after spinal injury if the vesical reflex is intact, and some benefit has been noted in partial sensory or motor paralysis of the bladder. Catheterization thus can be avoided. For acute retention, multiple subcutaneous doses of 2.5 mg of bethanechol may be administered. The stomach should be empty when the drug is injected. In chronic cases, 10–50 mg of the drug may be given orally two to four times daily with meals to avoid nausea and vomiting.
When voluntary or spontaneous voiding begins, bethanechol is then slowly withdrawn.
XEROSTOMIA
Pilocarpine is administered orally in 5–10-mg doses given three times daily for the treatment of xerostomia that follows head and neck radiation treatments or that is associated with Sjögren’s syn-drome, an autoimmune disorder occurring primarily in women in whom secretions, particularly sali-vary and lacrimal, are compromised. Side effects typify cholinergic stimulation, with sweating being the most common complaint. Bethanechol is an oral alternative that produces less diaphoresis.
Cevimeline (EVOXAC) has activity at M3muscarinic receptors, such as those on lacrimal and salivary FIGURE 7–1 Acetylcholine and choline esters.
gland epithelia. Cevimeline has a long-lasting sialogogic action and may have fewer side effects than pilocarpine. Cevimeline also enhances lacrimal secretions in Sjögren’s syndrome.
OPHTHALMOLOGICAL
Pilocarpine is used in the treatment of glaucoma, where it is instilled into the eye usually as a 0.5–4% solution. An ocular insert (OCUSERT PILO-20) that releases 20 µg of pilocarpine per hour over 7 days also is marketed for the control of elevated intraocular pressure. Pilocarpine usually is better tolerated than are the anticholinesterases and is the standard cholinergic agent for the treatment of open-angle glaucoma. Reduction of intraocular pressure occurs within a few minutes and lasts 4–8 hours. The ophthalmic use of pilocarpine alone and in combination with other agents is discussed in Chapter 63. The miotic action of pilocarpine is useful in reversing a narrow-angle glaucoma attack and overcoming the mydriasis produced by atropine; alternated with mydriatics, pilocarpine is employed to break adhesions between the iris and the lens.
CENTRAL NERVOUS SYSTEM
Agonists that selectively stimulate postsynaptic M1receptors in the CNS without concomitantly stimulating the presynaptic M2receptors (that inhibit release of endogenous ACh) have been in clinical trial for treating the cognitive impairment associated with Alzheimer’s disease. However, lack of efficacy in improvement of cognitive function has diminished enthusiasm for this approach.
Precautions, Toxicity, and Contraindications
Muscarinic agonists are administered subcutaneously to achieve an acute response and orally to treat more chronic conditions. Should serious toxic reactions to these drugs arise, atropine sulfate (0.5–1 mg in adults) should be given subcutaneously or intravenously. Epinephrine (0.3–1 mg, subcutaneously or intramuscularly) also is of value in overcoming severe cardiovascular or bron-choconstrictor responses.
Major contraindications to the use of the muscarinic agonists are asthma, hyperthyroidism, coronary insufficiency, and acid-peptic disease. Their bronchoconstrictor action is liable to pre-cipitate an asthma attack; hyperthyroid patients may develop atrial fibrillation. Hypotension induced by these agents can severely reduce coronary blood flow, especially if it is already com-promised. Other possible undesirable effects of the cholinergic agents are flushing, sweating, abdominal cramps, belching, a sensation of tightness in the urinary bladder, difficulty in visual accommodation, headache, and salivation.
Toxicology
Poisoning from pilocarpine, muscarine, or arecoline is characterized chiefly by exaggeration of their parasympathomimetic effects. Treatment consists of the parenteral administration of atropine in doses sufficient to cross the blood–brain barrier and measures to support the respira-tory and cardiovascular systems and to counteract pulmonary edema.
MUSHROOM POISONING (MYCETISM)
Mushrooms are a rich source of toxins; mushroom poisoning has increased as the result of the popularity of hunting wild mushrooms. High concentrations of muscarine are present in various species of Inocybe and Clitocybe. The symptoms of muscarine intoxication (salivation, lacrima-tion, nausea, vomiting, headache, visual disturbances, abdominal colic, diarrhea, bronchospasm, bradycardia, hypotension, shock) develop within 30–60 minutes of ingestion. Treatment with atropine (1–2 mg intramuscularly every 30 minutes) effectively blocks these effects.
Intoxication produced by Amanita muscaria and related Amanita species arises from the neu-rologic and hallucinogenic properties of muscimol, ibotenic acid, and other isoxazole derivatives that stimulate excitatory and inhibitory amino acid receptors. Symptoms range from irritability, restlessness, ataxia, hallucinations, and delirium to drowsiness and sedation. Treatment is mainly supportive; benzodiazepines are indicated when excitation predominates; atropine often exacer-bates the delirium.
Mushrooms from Psilocybe and Panaeolus species contain psilocybin and related derivatives of tryptamine that cause short-lasting hallucinations. Gyromitra species (false morels) produce GI disorders and a delayed hepatotoxicity. The toxic substance, acetaldehyde methylformylhydra-zone, is converted in the body to reactive hydrazines. Although fatalities from liver and kidney fail-ure have been reported, they are far less frequent than with amatoxin-containing mushrooms.
The most serious form of mycetism is produced by Amanita phalloides, other Amanita species, Lepiota, and Galerina species. These species account for >90% of fatal cases. Ingestion of as little as 50 g of A. phalloides (deadly nightcap) can be fatal. The principal toxins are the amatoxins (a- and b-amanitin), a group of cyclic octapeptides that inhibit RNA polymerase II and hence
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block messenger RNA (mRNA) synthesis. This causes cell death, particularly in the GI mucosa, liver, and kidneys. Initial symptoms include diarrhea and abdominal cramps. A symptom-free period lasting up to 24 hours is followed by hepatic and renal malfunction. Death occurs in 4–7 days from renal and hepatic failure. Treatment is largely supportive; penicillin, thioctic acid, andsilibinin may be effective antidotes, but the evidence is anecdotal.
Because the toxicity and treatment strategies for mushroom poisoning depend on the species ingested, their identification is key. 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
General comments—Muscarinic receptor antagonists reduce the effects of ACh by competitively inhibiting its binding to muscarinic cholinergic receptors. In general, muscarinic antagonists cause little blockade at nicotinic receptors; however, the quaternary ammonium derivatives of atropine are generally more potent at muscarinic receptors and exhibit a greater degree of nicotinic block-ing activity, and consequently are more likely to interfere with ganglionic or neuromuscular trans-mission. At high or toxic doses, central effects of atropine and related drugs are observed, generally CNS stimulation followed by depression; since quaternary compounds penetrate the blood–brain barrier poorly, they have little or no effect on the CNS.
Parasympathetic neuroeffector junctions in different organs vary in their sensitivity to mus-carinic receptor antagonists (Table 7–2). Effects such as reduction of gastric secretions occur only at doses that produce severe undesirable effects. This hierarchy of relative sensitivities is not a con-sequence of differences in the affinity of atropine for the muscarinic receptors at these sites;
atropine lacks receptor subtype selectivity. More likely determinants include the degree to which the functions of various end organs are regulated by parasympathetic tone and the involvement of intramural neurons and reflexes. Actions of most clinically available muscarinic receptor antago-nists differ only quantitatively from those of atropine. No antagonist in the receptor-selective category, including pirenzepine, is completely selective; in fact, clinical efficacy may arise from a balance of antagonistic actions on two or more receptor subtypes.