Physostigmine was first used as an antidote in 1864 to counteract severe atropine poisoning.33 Today its role is primarily in the treatment of antimuscarinic poisoning. More than 600 xenobiotics respond to physostigmine.12 Anticholinergics fall into the categories of antimuscarinic (atropine, scopolamine, propantheline, benztropine, trihexyphenidyl), neuromuscular blockers (curare), and ganglionic blockers (trimethaphan). Other xenobiotics (antihistamines, antipsychotics, and antidepressants) have antimuscarinic properties that are not their primary therapeutic actions and are often considered adverse drug effects.
The clinical use of physostigmine has varied over time.42 Owing to its ability to cause CNS arousal, physostigmine was used in the 1970s to reverse the CNS effects of a large number of antimuscarinics and used inappropriately to treat toxicity from nonantimuscarinics.18,31,32,34,38 The success with regard to antimuscarinics is directly related to the inhibition of cholinesterase. The effects of physostigmine on nonantimuscarinic xenobiotics such as the benzodiazepines, opioids,28,39,51 and GHB4,48 result from either the direct action of acetylcholine on the reticular activating system or interdependence of central neurotransmitters.34 Few serious adverse effects are reported.50 However, asystole followed administration of physostigmine in two patients with tricyclic antidepressant (TCA) overdose.35 This occurrence led to the realization that toxicity from TCA is complex and consists of more than just antimuscarinic effects.35 Cyclic antidepressant induced sodium channel blockade causes myocardial depression, QRS interval prolongation, and ventricular dysrhythmias. Physostigmine augments vagal effects, thus contributing to decreased cardiac output and cardiac conduction defects. An extensive review of the literature concluded that the safety of physostigmine use for seizures or cardiotoxicity in the setting of cyclic antidepressant toxicity was difficult to predict and thus not recommended.45 A reevaluation must conclude that the risks of physostigmine use for xenobiotics that are not primarily antimuscarinic often outweigh any benefit.
This analysis is certainly true with regard to GHB (Chap. 83) as well.48 GHB is often used with other xenobiotics, and its effects are highly variable.55 Recovery from GHB typically occurs spontaneously within several hours (16 minutes to 6 hours).7,8,14,29,48,49 Three patients in whom a presumptive diagnosis of GHB toxicity was made were treated with physostigmine.7 The three patients had an improved mental status within 5 to 15 minutes. One of these patients relapsed and then fully awakened 40 minutes later. This patient was incontinent of feces, an adverse effect likely caused by the physostigmine.7 All three of the patients were arousable before physostigmine use. Although anesthetic study of GHB in the 1970s is the rationale for current use, it is illogical in the care of those who illicitly use GHB.20
However, in cases of antimuscarinic overdose, physostigmine use clearly is beneficial. A study of 52 patients showed that whereas physostigmine controlled agitation and reversed delirium in 96% and 87% of patients, respectively,6 benzodiazepines controlled agitation in 24% of patients but were ineffective in reversing delirium. A shorter time to recovery after agitation was observed in those treated with physostigmine. No significant differences between these groups with regard to side effects or length of stay were noted.6
Indications for physostigmine use include the presence of peripheral or central antimuscarinic manifestations without evidence of significant QRS or QT prolongation. Peripheral manifestations include dry mucosa, dry skin, flushed face, mydriasis, hyperthermia, decreased bowel sounds, urinary retention, and tachycardia. Central manifestations include agitation, delirium, hallucinations, seizures, and coma.16,30 The peripheral and central findings usually occur simultaneously. In the early phases of overdose, peripheral manifestations typically precede central manifestations, although the central manifestations often are more remarkable.1,5,9,13,15,22,41,44 The central findings may persist longer than the peripheral findings, particularly when a patient is recovering from an overdose of an antimuscarinic xenobiotic.