CHAPTER 3-66: PHYSOSTIGMINE AND NEOSTIGMINE

INTRODUCTION

1. Pharmacology. Physostigmine and neostigmine are carbamates and reversible inhibitors of acetylcholinesterase, the enzyme that degrades acetylcholine. They increase concentrations of acetylcholine, causing stimulation of both muscarinic and nicotinic receptors. Physostigmine may also have a direct action on the acetylcholine receptor. The tertiary amine structure of physostigmine allows it to penetrate the blood-brain barrier and exert central cholinergic effects as well. Neostigmine, a quaternary ammonium compound, is unable to penetrate the CNS. Owing to cholinergic stimulation of the reticular activating system of the brainstem, physostigmine has nonspecific analeptic (arousal) effects. After parenteral administration of physostigmine, the onset of action is within 3–8 minutes and the duration of effect is usually 30–90 minutes. The average elimination half-life is 22 minutes (range 12-40). Neostigmine has a slower onset of 7–11 minutes and a longer duration of effect of 60–120 minutes.

2. Indications

   1. Physostigmine is used for the management of severe anticholinergic syndrome (agitated delirium, urinary retention, severe sinus tachycardia, or hyperthermia with absent sweating) from antimuscarinic agents (eg, benztropine, atropine, jimson weed [Datura], diphenhydramine). The typical indication is for reversal of agitated delirium in patients requiring physical and/or chemical restraints. For a discussion of anticholinergic toxicity, see Anticholinergics. Although there are anecdotal case reports of the use of physostigmine to treat delirium and coma associated with gamma-hydroxybutyrate (GHB), baclofen, and several atypical antipsychotic (olanzapine, clozapine, quetiapine) agents, its safety and efficacy are uncertain with these intoxications.

   2. Physostigmine is sometimes used diagnostically to differentiate functional psychosis from anticholinergic delirium.

   3. Neostigmine is used primarily to reverse the effect of nondepolarizing neuromuscular blocking agents.

3. Contraindications

   1. Serious tricyclic antidepressant overdose. Physostigmine may worsen cardiac conduction disturbances, cause bradyarrhythmias or asystole, and aggravate or precipitate seizures.

   2. Do not use physostigmine concurrently with depolarizing neuromuscular blockers (eg, succinylcholine).

   3. Known hypersensitivity to agent or preservative (eg, benzyl alcohol, bisulfite).

   4. Relative contraindications may include bronchospastic disease or asthma, peripheral vascular disease, intestinal and bladder blockade, parkinsonian syndrome, and cardiac conduction defects (AV block).

4. Adverse effects

   1. Bradycardia, heart block, and asystole.

   2. Seizures (particularly with rapid administration or excessive dose of physostigmine).

   3. Nausea, vomiting, hypersalivation, and diarrhea.

   4. Bronchorrhea and bronchospasm (caution required in patients with asthma).

   5. Fasciculations and muscle weakness.

   6. Use in pregnancy. FDA Category C (Introduction). Transient weakness has been noted in neonates whose mothers were treated with physostigmine for myasthenia gravis.

5. Drug or laboratory interactions

   1. May potentiate agents metabolized by the cholinesterase enzyme (eg, depolarizing neuromuscular blocking agents—succinylcholine, cocaine, esmolol), cholinesterase inhibitors (eg, organophosphate and carbamate insecticides), and other cholinergic agents (eg, pilocarpine).

   2. They may inhibit or reverse the actions of nondepolarizing neuromuscular blocking agents (eg, pancuronium, vecuronium). Neostigmine is used therapeutically for this purpose.

   3. They may have additive depressant effects on cardiac conduction in patients with cyclic antidepressant, beta-adrenergic antagonist, or calcium antagonist overdoses.

   4. Physostigmine, through its nonspecific analeptic effects, may induce arousal in patients with GHB, opioid, benzodiazepine, or sedative-hypnotic intoxication, or with ketamine- or propofol-induced sedation.

6. Dosage and method of administration. Note: The patient should be on ...