Can Physostigmine Cause Muscle Twitches?
Yes, physostigmine can cause muscle twitches and fasciculations through its mechanism as an acetylcholinesterase inhibitor, leading to acetylcholine accumulation at nicotinic receptors in the neuromuscular junction. 1
Mechanism of Action
Physostigmine is a tertiary reversible cholinesterase inhibitor that crosses the blood-brain barrier and inhibits acetylcholinesterase, causing acetylcholine to accumulate in the synaptic cleft. 1 This excess acetylcholine overstimulates nicotinic receptors at the neuromuscular junction, which directly produces fasciculations (muscle twitches). 2, 1
The same mechanism applies to other acetylcholinesterase inhibitors like neostigmine, pyridostigmine, and edrophonium—all can cause fasciculations through nicotinic receptor overstimulation. 1 Organophosphate pesticides and chemical nerve agents (like sarin) bind even more permanently to acetylcholinesterase, producing weakness, fasciculations, and paralysis due to unopposed acetylcholine action. 3
Clinical Evidence and Safety Profile
In a comprehensive 10-year retrospective review of 191 patients who received physostigmine, the drug demonstrated a good safety profile with 95.3% of patients experiencing no documented adverse effects. 4 However, when adverse effects did occur, they were primarily cholinergic in nature.
The FDA drug label explicitly warns that if excessive symptoms of salivation, emesis, urination, and defecation occur, physostigmine should be terminated. 5 The label also cautions that rapid intravenous administration can cause bradycardia, hypersalivation leading to respiratory difficulties, and possible convulsions. 5 An overdose can cause a cholinergic crisis. 5
Distinguishing True Fasciculations from Tremor
It's important to distinguish true fasciculations from muscle tremor caused by other medications. Acetylcholinesterase inhibitors like physostigmine cause fasciculations through spontaneous depolarization of motor units at the neuromuscular junction. 1 This differs mechanistically from the rhythmic muscle tremor produced by sympathomimetic agents (like theophylline, salbutamol, or terbutaline), which work through beta-adrenergic receptor activation and increased intracellular calcium cycling. 1
Clinical Context and Appropriate Use
Physostigmine is primarily used as an antidote to reverse anticholinergic delirium, where it has demonstrated 96% effectiveness in controlling agitation and 87% effectiveness in reversing delirium. 6 In this context, the muscle twitches represent a predictable cholinergic side effect rather than a therapeutic failure.
The key clinical pitfall is administering physostigmine too rapidly or in excessive doses, which increases the risk of cholinergic side effects including fasciculations. 5 The FDA recommends intravenous administration at a slow, controlled rate of no more than 1 mg per minute. 5
Contraindications Related to Muscle Effects
Physostigmine should be avoided in patients with QRS prolongation on EKG, and caution should be used in patients with coronary artery disease or overdoses involving QRS-prolonging medications. 7 While seizures occurred in 0.61% of patients in one large review, all were self-limited or treated successfully with benzodiazepines without neurological sequelae. 7