A third approach to protection against excessive acetylcholinesterase inhibition is pretreatment with intermediate-acting enzyme inhibitors that transiently occupy the active site to prevent binding of the much longer-acting organophosphate inhibitor. This prophylaxis can be achieved with pyridostigmine but is reserved for situations in which possibly lethal poisoning is anticipated, eg, chemical warfare (see Chapter 7). Simultaneous use of atropine is required to control muscarinic excess.
The use of biological scavengers has emerged as an adjunct to oximes in the reactivation of acetylcholinesterase inactivated by organophosphates. Human acetylcholinesterase, acting catalytically, increased the effectiveness of PAM in reactivating the enzyme. Butyrylcholinesterase can achieve the same effect, but it acts stoichiometrically, and thus large amounts of this bioscavenger are required. (Another use for butyrylcholinesterase is in the treatment of cocaine toxicity because butyrylcholinesterase displays cocaine hydrolase activity. The catalytic efficiency of human butyrylcholinesterase against cocaine has been increased by mutation of the enzyme such that it can prevent the effect of a lethal dose of cocaine in experimental animals.)
Mushroom poisoning has traditionally been divided into rapid-onset and delayed-onset types. The rapid-onset type is usually apparent within 30 minutes to 2 hours after ingestion of the mushrooms and can be caused by a variety of toxins. Some of these produce simple upset stomach; others can have disulfiram-like effects; some cause hallucinations; and a few mushrooms (eg, Inocybe species) can produce signs of muscarinic excess: nausea, vomiting, diarrhea, urinary urgency, sweating, salivation, and sometimes bronchoconstriction. Parenteral atropine, 1–2 mg, is effective treatment in such intoxications. Despite its name, Amanita muscaria contains not only muscarine (the alkaloid was named after the mushroom), but also numerous other alkaloids, including antimuscarinic agents, and ingestion of A muscaria often causes signs of atropine poisoning, not muscarine excess.
Delayed-onset mushroom poisoning, usually caused by Amanita phalloides, Amanita virosa, Galerina autumnalis, or Galerina marginata, manifests its first symptoms 6–12 hours after ingestion. Although the initial symptoms usually include nausea and vomiting, the major toxicity involves hepatic and renal cellular injury by amatoxins that inhibit RNA polymerase. Atropine is of no value in this form of mushroom poisoning (see Chapter 58).
H. Other Applications
Hyperhidrosis (excessive sweating) is sometimes reduced by antimuscarinic agents. However, relief is incomplete at best, probably because apocrine rather than eccrine glands are usually involved.
Treatment with atropine or its congeners directed at one organ system almost always induces undesirable effects in other organ systems. Thus, mydriasis and cycloplegia are adverse effects when an antimuscarinic agent is used to reduce gastrointestinal secretion or motility, even though they are therapeutic effects when the drug is used in ophthalmology.
At higher concentrations, atropine causes block of all parasympathetic functions. However, atropine is a remarkably safe drug in adults. Atropine poisoning has occurred as a result of attempted suicide, but most cases are due to attempts to induce hallucinations. Poisoned individuals manifest dry mouth, mydriasis, tachycardia, hot and flushed skin, agitation, and delirium for as long as 1 week. Body temperature is frequently elevated. These effects are memorialized in the adage, “dry as a bone, blind as a bat, red as a beet, mad as a hatter.”