145 - Anticholinergics

peripheral (autonomic and somatic) nervous systems. In the autonomic (sympathetic and parasympathetic) nervous system, acetylcholine is released from all preganglionic neurons, as well as from postganglionic parasympathetic neurons. Degradation of acetylcholine by the enzyme acetylcholinesterase occurs in the synapse between the presynaptic and postsynaptic membranes. There are two types of postsynaptic acetylcholine receptors: nicotinic and muscarinic. Nicotinic acetylcholine receptors are ion channels that open in response to stimulation. Found throughout the central nervous system (CNS) (most abundantly in the spinal cord), they are the postsynaptic receptors in the preganglionic sympathetic and parasympathetic neurons. Additionally, these receptors are found in the somatic nervous system at postganglionic skeletal neuromuscular junctions that mediate muscle contraction, as well as in postganglionic neurons of the adrenal medulla, which are subsequently responsible for the release of epinephrine and norepinephrine. Muscarinic acetylcholine receptors are linked to G proteins to execute their postreceptor effects. They are found primarily in the CNS (most abundantly in the brain). They are also present at effector organs innervated by postganglionic parasympathetic neurons. Stimulation of these end-organs, either pharmacologically or through enhanced neuronal output, results in miosis, lacrimation, salivation, bronchospasm, bronchorrhea, bradydysrhythmia, urination, and increased gastrointestinal motility (Table 145.1). Finally, muscarinic receptors are located in sweat glands innervated by postsynaptic sympathetic neurons and cause diaphoresis when stimulated. Muscarinic acetylcholine receptor antagonists competitively inhibit muscarinic acetylcholine receptors. These agents cause the classic anticholinergic poisoning syndrome, which perhaps may be more appropriately designated the antimuscarinic poisoning syndrome because nicotinic acetylcholine receptors are not affected. Muscarinic receptors in different organs are not equally sensitive to antimuscarinic agents. Tricyclic antidepressants are a unique subset of antimuscarinic agents that deserve special attention. Their antidepressant effect is achieved pharmacologically through blockade of the reuptake of norepinephrine, dopamine, and serotonin in the CNS. Additionally, tricyclic antidepressants interact with other channels and receptors and cause considerably more profound clinical toxicity in overdose than occurs with most other agents that exhibit anticholinergic effects. Adverse effects of a tricyclic antidepressant overdose include competitive inhibition at both central and peripheral muscarinic acetylcholine receptors (antimuscarinic poisoning syndrome); histamine receptor antagonism (sedation); sodium channel blockade in the myocardium (widening of the QRS complex • Antimuscarinic poisoning syndrome is a more appropriate description than anticholinergic overdose because only the muscarinic receptors, not the nicotinic acetylcholine receptors, are involved. In this chapter the term anticholinergic will be used for consistency and is specifically meant to indicate antimuscarinic. • Anticholinergic agents antagonize the neurotransmitter acetylcholine at both central and peripheral muscarinic acetylcholine receptors, which leads to altered mental status, mydriasis, tachycardia, urinary retention, ileus, and dry, flushed skin. • The diagnosis of anticholinergic syndrome is largely clinical and should include physical examination, fingerstick serum glucose measurement, and an electrocardiogram. • Anticholinergic syndrome is a key clinical finding leading to the diagnosis of poisoning by tricyclic antidepressants (a subset of antimuscarinic agents). • Basic treatment involves supportive care of the vital signs, activated charcoal, benzodiazepines for agitation, sodium bicarbonate for a QRS complex longer than 100 msec or wide-complex tachycardia, and physostigmine for consequential central and peripheral anticholinergic (antimuscarinic) manifestations, if appropriate. KEY POINTS