A variety of pharmaceuticals and naturally occurring products can produce an anticholinergic syndrome (Table 121.1). Many drugs with anticholinergic effects may be classified in a manner that does not identify this activity (e.g., histamine-1 [H₁]–blockers, gastrointestinal and genitourinary tract antispasmodics, cough and cold preparations, over-the-counter sleep aids, and anticholinergic plants). For some, anticholinergic effects are desirable (e.g., atropine to treat bradycardia induces mydriasis and inhibits secretions). For others, the anticholinergic effects are an undesirable side effect (e.g., antihistamines, antipsychotics, and tricyclic antidepressants).

Pharmaceuticals and plants with anticholinergic action may be intentionally abused for mind-altering effects; especially common is the use of Datura stramonium (jimsonweed) [3]. Anticholinergic toxicity has occurred by a number of routes other than ingestion, including inhalation of nebulized medication [4], inhalation of pyrolysis products (e.g., the smoking of plant parts) [3], transdermal use, and ocular instillation.

Anticholinergic agents antagonize the effects of the endogenous neurotransmitter acetylcholine (ACh). Receptors for ACh are widely distributed in the body, including the central nervous system and the sympathetic and parasympathetic ganglia, postganglionic parasympathetic terminals, and motor end plates of the peripheral nervous system.

ACh receptors are divided into two types, muscarinic and nicotinic, based on their ability to bind muscarine or nicotine. This division has a functional significance as well, best described in the peripheral nervous system, where muscarinic receptors predominate in the parasympathetic terminals and nicotinic receptors in autonomic ganglia and motor end plates. Most drugs have predominant effects on one of the two main ACh receptors, but at high doses, there may be some crossover effect. For example, nicotine primarily stimulates nicotinic receptors. Stimulation produces tachycardia, hypertension, muscle fasciculations, and receptor fatigue, with consequent paralysis at high doses. Nicotinic antagonists, such as the nondepolarizing muscle relaxants (e.g., pancuronium), block the action of ACh at the motor end plate and produce skeletal muscle paralysis. Excessive muscarinic receptor stimulation (e.g., organophosphate poisoning) leads to the cholinergic toxidrome (see Chapters 128 and 141). Agents that block muscarinic receptors may cause anticholinergic toxicity, the focus of this chapter.

Many drugs with anticholinergic properties undergo extensive hepatic metabolism into active and inactive metabolites. A number of these drugs may have half-lives greater than 12 to 24 hours (e.g., tricyclic antidepressants). More important may be the persistence of muscarinic receptor binding. In the intensive care unit (ICU), many patients emerge from coma into a delirious state. Reversal by physostigmine suggests persistence anticholinergic delirium rather than ICU psychosis [2].

Anticholinergic effects have been classically described by the mnemonic “Blind as a bat, Hot as Hades, Dry as a bone, Red as a beet, and Mad as a hatter” in reference to the consequences of ciliary muscle paralysis, hyperthermia, anhydrosis, vasodilation, and delirium, respectively. The toxidrome has been subdivided into the peripheral anticholinergic syndrome and the central anticholinergic syndrome (Table 121.2). The former
is due to quaternary amines (e.g., glycopyrrolate), which are charged molecules that poorly penetrate the blood–brain barrier, whereas the latter is due to tertiary amines (e.g., atropine), which are uncharged and reach the central nervous system. The most serious anticholinergic manifestations include agitated delirium, hyperthermia, and seizures. Patients may present with primarily peripheral signs and symptoms, primarily central ones, or both. In addition, central symptoms may persist longer than the peripheral manifestations.