Approximately 620 compounds have anticholinergic properties, including prescription drugs, over-the-counter medications, and plants (Table 202-1). Many of these substances possess anticholinergic activity as either a direct therapeutic effect or an adverse effect, in addition to their primary or predominant pharmacologic effect. Atropine (d,l-hyoscyamine), hyoscyamine, and scopolamine (l-hyoscine) are natural alkaloids that represent prototypical anticholinergic compounds.

Antihistamine (particularly diphenhydramine) overdose is the most common overdose that produces anticholinergic toxicity.¹ Toxicity in children may result from accidental ingestion of an anticholinergic medication, administration of hyoscyamine-containing agents to treat colic, the topical use of diphenhydramine-containing salves, and therapeutic application of a transdermal hyoscine patch.^2,3,4,5 In the elderly, therapeutic doses of one or multiple medications with anticholinergic properties may produce anticholinergic symptoms or ileus without all the signs of the anticholinergic toxidrome.^6,7 Ophthalmologic instillation of anticholinergic mydriatic agents can cause toxicity, especially in the elderly or young children; thus patients are instructed to lie down and apply 5 minutes of gentle pressure on the nasolacrimal duct when instilling these agents.⁸

Atropine is the antidote for a cholinergic syndrome produced from a nerve agent or an organophosphate insecticide.⁹ Use of high-dose atropine by someone without cholinesterase poisoning may result in anticholinergic toxicity within 1 hour. This occurred in Israel during the first Gulf War in 1991 when frightened civilians dosed themselves with atropine fearing an incoming Scud missile chemical weapon attack.

Plant poisonings may result in an anticholinergic toxidrome. In Taiwan, the anticholinergic toxidrome is most commonly associated with plant exposures.¹⁰ Belladonna alkaloid-containing plants have potent anticholinergic effects producing toxicity 1 to 4 hours after ingestion or sooner if smoked. Alkaloid plants are abused for their hallucinogenic effects.^11,12 Group anticholinergic plant poisonings are common in adolescents seeking these psychoactive hallucinogenic effects.^13,14 Inadvertent poisoning from the ingestion of belladonna-contaminated herbal teas and Chinese traditional medicines has been reported.^15,16 Ingestion of seeds and berries, sometimes due to mistaken identity, can produce anticholinergic toxicity.^17,18 Anticholinergics have been substituted for other abused psychoactive drugs and then sold to unwitting customers.¹⁹ Adulteration of commonly abused drugs, such as heroin or cocaine, with scopolamine or atropine has been observed.^20,21,22

Anticholinergic drug absorption can occur after ingestion, smoking, or ocular use. With oral ingestion, the onset of anticholinergic toxicity usually occurs within 1 to 2 hours. Because muscarinic blockade slows gastric emptying and decreases GI motility, absorption and peak clinical effects are often delayed. An example is diphenoxylate-atropine (e.g., Lomotil®), an antidiarrheal agent that may present with toxicity up to 12 hours after ingestion.

Cholinergic receptors exist as two major subtypes: muscarinic receptors and nicotinic receptors. Muscarinic receptors are found predominantly on autonomic effector cells that are innervated by postganglionic parasympathetic nerves, on some ganglia, and in the brain, particularly the hippocampus, cortex, and thalamus. Nicotinic receptors are found at peripheral autonomic ganglia, neuromuscular junctions, and also the brain. Acetylcholine is the neurotransmitter that modulates both receptor types. Five genes encode for muscarinic receptors through G protein receptor activation; four seem to be physiologically active (Table 202-2).

The structure of nicotinic receptors is complex, composed of several subunits that are encoded by multiple genes. The subunits are combined into four main families of nicotinic receptors: the muscle type, found at the neuromuscular junction; the ganglion type, found in autonomic ganglia; and two brain types, found in the CNS.

Anticholinergic drugs and plant toxins competitively inhibit or antagonize the binding of the neurotransmitter acetylcholine to muscarinic acetylcholine receptors. The term anticholinergic is technically a misnomer; a more accurate term is antimuscarinic agents, because anticholinergic agents do not antagonize the effects at nicotinic acetylcholine receptors, such as at the neuromuscular junction. Clinical manifestations from these drugs are modulated through disturbances in the CNS (central effects) and the parasympathetic nervous system (peripheral effects) (Table 202-3).