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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.
Pharmacological Properties: The Prototypical Alkaloids Atropine
disorientation, hallucinations, or delirium (see discussion of atropine poisoning, below). With still larger doses, stimulation is followed by depression, leading to circulatory collapse and respiratory failure after a period of paralysis and coma.
Scopolamine in therapeutic doses normally causes CNS depression manifested as drowsiness, amnesia, fatigue, and dreamless sleep, with a reduction in rapid eye movement (REM) sleep.
Scopolamine also causes euphoria and is therefore subject to some abuse. Scopolamine is effective in preventing motion sickness.
The belladonna alkaloids and related muscarinic receptor antagonists have long been used in parkinsonism. These agents can be effective adjuncts to treatment with levodopa (see Chapter 20).
Muscarinic receptor antagonists also are used to treat the extrapyramidal symptoms that commonly occur as side effects of conventional antipsychotic drug therapy (see Chapter 18). Certain antipsy-chotic drugs are relatively potent muscarinic receptor antagonists, and these cause fewer extrapyra-midal side effects.
GANGLIA AND AUTONOMIC NERVES Cholinergic neurotransmission in autonomic gan-glia is mediated primarily by activation of nicotinic ACh receptors (see Chapters 6 and 9). ACh and other cholinergic agonists also cause the generation of slow excitatory postsynaptic potentials (EPSPs) that are mediated by ganglionic M1receptors. This response is particularly sensitive to blockade by pirenzepine. The extent to which the slow EPSPs can alter impulse transmission through the different sympathetic and parasympathetic ganglia is difficult to assess, but the effects of pirenzepine on responses of end organs suggest a physiological modulatory function for the ganglionic M1receptor.
Pirenzepine inhibits gastric acid secretion at doses that have little effect on salivation or heart rate. Since the muscarinic receptors on the parietal cells do not appear to have a high affinity for pirenzepine, the M1receptor responsible for alterations in gastric acid secretion may be localized in intramural ganglia. Blockade of ganglionic muscarinic receptors (rather than those at the neu-roeffector junction) apparently underlies the capacity of pirenzepine to inhibit relaxation of the lower esophageal sphincter. Likewise, blockade of parasympathetic ganglia may contribute to the response to muscarinic antagonists in lung and heart.
Presynaptic muscarinic receptors on terminals of sympathetic and parasympathetic neurons generally inhibit transmitter release; thus, blockade of these presynaptic receptors will augment transmitter release. Nonselective muscarinic blocking agents may thus augment ACh release, par-tially counteracting their effective postsynaptic receptor blockade. Since muscarinic receptor antag-onists can alter autonomic activity at the ganglion and postganglionic neuron, the ultimate response of end organs to blockade of muscarinic receptors is difficult to predict. Thus, while direct blockade at neuroeffector sites predictably reverses the usual effects of the parasympathetic nervous system, concomitant inhibition of ganglionic or presynaptic receptors may produce paradoxical responses.
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 63). Thus, they dilate the pupil (mydriasis) and paralyze accommodation (cycloplegia). Locally applied atropine and scopolamine produce ocular effects of considerable duration; accommodation and pupillary reflexes may not fully recover for 7–12 days; thus, other muscarinic antagonists with shorter durations of action are preferred as mydriatics (see Chapter 63). Muscarinic receptor antagonists administered systemically have little effect on intraocular pressure except in patients predisposed to narrow-angle glaucoma, in whom the pressure may occasionally rise dangerously.
CARDIOVASCULAR SYSTEM
Heart Although the dominant response to atropine is tachycardia, the heart rate often decreases slightly (4–8 beats/min) transiently with average clinical doses (0.4–0.6 mg). The slow-ing is usually absent after rapid intravenous injection. Larger doses of atropine cause progressively increasing tachycardia by blocking vagal effects on M2receptors on the SA node. Resting heart rate increased by 35–40 beats/min 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.
With low doses of scopolamine (0.1–0.2 mg), the cardiac slowing is greater than with atropine.
With higher doses, a transient cardioacceleration may be observed.
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Adequate doses of atropine can abolish many types of reflex vagal cardiac slowing or asystole—
for example, from inhalation of irritant vapors, stimulation of the carotid sinus, pressure on the eye-balls, 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 influence on the heart by atropine also may facilitate AV conduction.
Circulation Atropine, alone, has little effect on blood pressure, an expected result since most vessels lack cholinergic innervation. However, in clinical doses, atropine completely counteracts the peripheral vasodilation and sharp fall in blood pressure caused by choline esters. Atropine in toxic, and occasionally therapeutic, doses can dilate cutaneous blood vessels, especially those in the blush area (atropine flush).
RESPIRATORY TRACT Belladonna alkaloids inhibit secretions of the nose, mouth, phar-ynx, and bronchi, and thus dry the mucous membranes of the respiratory tract. Reduction of mucous secretion and mucociliary clearance resulting in mucus plugs are undesirable side effects of atropine in patients with airway disease. Inhibition by atropine of bronchoconstriction caused by histamine, bradykinin, and the eicosanoids presumably reflects the participation of parasympathetic efferents in the bronchial reflexes elicited by these agents. The ability to block the indirect bron-choconstrictive effects of these mediators that are released during attacks of asthma forms the basis for the use of anticholinergic agents, along with b-adrenergic receptor agonists, in the treatment of asthma (see Chapter 27).
GASTROINTESTINAL TRACT Atropine can completely abolish the effects of ACh (and other parasympathomimetic drugs) on the motility and secretions of the GI tract, but can only incompletely inhibit the effects of vagal impulses. This difference is particularly striking in the effects of atropine on gut motility. Preganglionic vagal fibers that innervate the GI tract synapse not only with postganglionic cholinergic fibers, but also with a network of noncholinergic intramural neurons. These neurons of the enteric plexus release numerous neurotransmitters and neuromodu-lators (e.g., 5-HT, DA, myriad peptides) whose actions atropine does not block and which can effect changes in motility. Similarly, while vagal activity modulates gastrin-elicited histamine release and gastric acid secretion, the actions of gastrin can occur independently of vagal tone. Histamine H2receptor antagonists and proton pump inhibitors have replaced nonselective muscarinic antago-nists as inhibitors of acid secretion (see Chapter 36).
Secretions
Salivary secretion, mediated through M3receptors, is particularly sensitive to inhibition by mus-carinic receptor antagonists, which can completely abolish the copious, watery, parasympathetically induced secretion. The mouth becomes dry, and swallowing and talking may become difficult. Gas-tric secretions during the cephalic and fasting phases are reduced markedly by muscarinic antago-nists; the intestinal phase of gastric secretion is only partially inhibited. Atropine also reduces the cytoprotective secretions (HCO3–, mucus) of the superficial epithelial cells (see Figure 36–1).
Motility
The parasympathetic nerves enhance both tone and motility and relax sphincters, thereby favoring intestinal transit. Muscarinic antagonists produce prolonged inhibitory effects on the motor activity of the GI tract; relatively large doses are needed to produce such inhibition. The complex myenteric nerv-ous system can regulate motility independently of parasympathetic control, however (see Chapter 6).
OTHER SMOOTH MUSCLES 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, but at doses of atropine that inhibit salivation and lacrimation and cause blurring of vision (Table 7–2). Control of blad-der contraction is complex, involving mainly M2receptors at multiple sites and also M3receptors that can mediate detrusor muscle contraction.
Biliary Tract
Atropine exerts a mild antispasmodic action on the gallbladder and bile ducts, an effect that usu-ally is insufficient to overcome or prevent the marked spasm and increase in biliary duct pressure induced by opioids, for which nitrites (see Chapter 31) are more effective.
SWEAT GLANDS AND TEMPERATURE
Small doses of atropine or scopolamine inhibit the activity of sweat glands innervated by sympa-thetic cholinergic fibers, making the skin hot and dry. After large doses or at high environmental temperatures, sweating may be sufficiently depressed to raise the body temperature.