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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 at muscarinic and nicotinic receptors. Physostigmine can elicit nonspecific analeptic (arousal) effects via cholinergic stimulation of the brainstem's reticular activating system. The tertiary amine structure of physostigmine allows for entry across the blood-brain barrier. Neostigmine, a quaternary ammonium compound, cannot penetrate the CNS, and does not exert central cholinergic effects. After parenteral administration of physostigmine, onset of action is within 3-8 minutes and the duration of effect is usually 45-60 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. It is not effective for anticholinergic delirium.
  3. Contraindications
    1. Serious tricyclic antidepressant overdose with evidence of sodium channel blockade (eg, prolonged QRS interval). Although physostigmine may reverse anticholinergic effects of TCAs, it can 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 seizure disorder, bronchospastic disease or asthma, peripheral vascular disease, intestinal and bladder blockade, parkinsonian syndrome, and cardiac conduction defects (eg, 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. May inhibit or reverse the actions of nondepolarizing neuromuscular blocking agents (eg, pancuronium, vecuronium). Neostigmine is used therapeutically for this purpose.
    3. 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 a cardiac monitor in case of bradyarrhythmia.
    1. Physostigmine
      1. Adult dose. Give 0.5-1 mg IV slowly (diluted in 10 mL of D5W or normal saline) over 2-5 minutes, carefully observing for improvement or cholinergic-excess (especially bradycardia or heart block). If no effect, give additional 0.5-mg doses at 10- to 15-minute intervals up to a maximum total dose of 2 mg over the first hour (delirium reversal is usually achieved with an initial total dose less than 2 mg). If larger doses are needed, consult with a medical toxicologist.
      2. The pediatric dose is 0.01 mg/kg (not to exceed 0.5 mg) repeated as needed up to a maximum dose of 0.04 mg/kg (not to exceed a total dose of 2 mg for the first hour).
      3. Atropine should be readily available to reverse excessive muscarinic stimulation (adults: 1-4 mg; children: 1 mg).
      4. Do not administer physostigmine intramuscularly.
      5. Doses may need to be repeated every 30-60 minutes owing to the short duration of action of physostigmine.
    2. Neostigmine (parenteral). Give 0.5- to 2-mg slow IV push (children: 0.025-0.08 mg/kg per dose) and repeat as required (total dose rarely exceeds 5 mg). Premedicate with glycopyrrolate (0.2 mg/mg of neostigmine; usual adult dose: 0.2-0.6 mg; children: 0.004-0.02 mg/kg) or atropine (0.4 mg/mg of neostigmine; usual adult dose: 0.6-1.2 mg; children: 0.01-0.04 mg/kg) several minutes before or simultaneously with neostigmine to prevent muscarinic effects (bradycardia, secretions).