Cholinergic physiology

The neurotransmitter acetylcholine (ACh) is found at preganglionic and postganglionic fibers in the parasympathetic system, in the preganglionic fibers in the sympathetic nervous system, and in the neuromuscular junction (nicotinic sites). Acetylcholinesterase (AChE), which is found in the synaptic cleft of the aforementioned sites, rapidly (<1 ms) hydrolyzes ACh, thereby terminating its action.

Butyrylcholinesterase, also called plasma cholinesterase or pseudocholinesterase, is synthesized by the liver, is released into the circulation (t_1/2 ∼ 23 h), and hydrolyzes biochemicals similar to ACh and, in particular, succinylcholine, mivacurium, and ester local anesthetic agents.

Anticholinesterase poisoning

Anticholinesterase drugs inhibit AChE, thereby increasing the concentration of ACh at cholinergic sites; the excess ACh results in prolonged stimulation of muscarinic and nicotinic receptors. Anesthesia providers use carbamates, anticholinesterase drugs such as neostigmine, to reverse the effects of neuromuscular blocking agents at the end of a procedure. The muscarinic side effects of neostigmine are mitigated by simultaneously infusing an anticholinergic agent, such as atropine or glycopyrrolate, with the neostigmine.

Pesticides (with the exception of sevin, a carbamate) and the chemical nerve agents are organophosphate compounds, irreversible inhibitors of AChE; once released, ACh remains at its site of action, resulting in prolonged stimulation of muscarinic and nicotinic receptors. Muscarinic signs and symptoms include salivation, lacrimation, urination, diaphoresis, gastrointestinal upset, and emesis (i.e., the mnemonic SLUDGE; or DUMBELS—diarrhea, urination, meiosis, bronchorrhea/bronchoconstriction, emesis, lacrimation, salivation). Bradycardia (or tachycardia) and hypotension are signs of severe poisoning, as are confusion and shock. Nicotinic effects occur at the neuromuscular junction; skeletal muscle initially fasciculates and then becomes weak or paralyzed because the myofibril cell membrane is unable to repolarize (Box 83-1). Severe reactions, termed cholinergic crisis, may lead to ventilatory failure and death within minutes to hours following exposure.

Anticholinergic poisoning

Inhibition of cholinergic function most often occurs because of ingestion of plants (Box 83-2) or foods that contain high concentrations of atropine or related compounds. Central anticholinergic effects are biphasic, beginning with central nervous system excitation followed by depression. Signs include fragmentary speech patterns, visual hallucinations, atypical behavior, ataxia, and fever. Peripheral anticholinergic effects include decreased saliva, sweat (further contributing to fever), and tearing. Other peripheral symptoms include loss of accommodation, blurred vision, mydriasis, tachycardia, and decreased gastrointestinal motility and urinary bladder tone. A mnemonic summarizes many central and peripheral effects of anticholinergic poisoning (Box 83-3).