Physostigmine Is a Reversible Centrally Acting Acetylcholinesterase Inhibitor
PHYSOSTIGMINE
.
Introduction
Physostigmine is a reversible centrally acting acetylcholinesterase inhibitor.
In toxicology it can be used to treat the delirium of anticholinergic agents in those patients in whom benzodiazepines have not adequately controlled symptoms.
History
Physostigmine is a natural alkaloid of the Physostigma venenosum (or Calabar), a leguminous plant native to tropical Africa. The Calabar bean contains toxic alkaloids, which include, physostigmine.
Physostigmine was first described by the Scottish physician Sir Robert Christison in 1846.
It was first synthesized in 1935 by Percy Lavon Julian and Josef Pikl.
Chemistry
Physostigmine is a carbamate with a tertiary amine structure.
Classification
Reversible acetylcholinesterase inhibitors can be classified thus:
1. Short acting:
● Edrophonium
2. Long acting:
Do not readily cross BBB:
● Neostigmine
● Pyridostigmine
Readily cross BBB:
● Physostigmine
● Tacrine
Preparation
Physostigmine as:
Ampoules:
● 1 mg in 2 ml ampoules.
Mechanism of Action
Physostigmine is a reversible centrally acting acetylcholinesterase inhibitor.
Its action will elevate levels of acetylcholine and so overcome the post-synaptic muscarinic receptor blockade produced by anticholinergic agents.
Pharmacodynamics
The duration of action of physostigmine is relatively short at around 2 hours.
Repeat doses may not be required however, following initial reversal of delirium.
Pharmacokinetics
Absorption:
● Physostigmine is very poorly absorbed after oral administration, so must be given IV.
Distribution:
● Physostigmine crosses the blood-brain barrier, hence is able to reverse central CNS anticholinergic effects.
Metabolism and elimination:
● It is rapidly metabolized by cholinesterase
● It has an elimination half-life of approximately 20 minutes.
Indications
Treatment of the delirium of anticholinergic agents in those patients in whom benzodiazepines have not adequately controlled symptoms.
Contra-indications / Precautions
These include
1. Bradyarrhythmias
2. Conduction delays
● Including intraventricular conduction delays (QRS > 100 msecs).
3. Bronchospasm
4. It may prolong the effect of succinylcholine and reduce the action of non-depolarizing neuromuscular blocking agents.
Adverse Reactions
Excessive dosing will lead to cholinergic symptoms.
1. Bradycardia.
2. Seizures.
3. Nausea, vomiting diarrhea
3. Bronchospasm/ bronchorrhoea.
Dosing
All patients must be managed in a monitored resus cube.
● Give physostigmine 0.5 - 1.0 mg IV over 5 minutes.
The paediatric dose is 0.02 mg/kg to a maximum of 0.5 mg IV
The above dose can be repeated every 10 minutes until the desired clinical effect has been achieved, (i.e resolution of delirium).
It is rare for a total dose of more than 4 mg to be required.
Although the duration of action of physostigmine is relatively short (about 2 hours) repeat dosing is often not required after the initial reversal of the delirium,
Should excessive cholinergic symptoms occur such as severe bradycardia, atropine in carefully titrated doses can be used to reverse its effects.
References
1. Anticholinergic syndrome in L Murray et al. Toxicology Handbook 3rd ed 2015
2. Physostigmine in L Murray et al. Toxicology Handbook 3rd ed 2015.