Antiacetylcholinesterase drugs

Neurotoxic venom effects can appear within a very short time following bites of numerous elapid species, several viper and other species.

The currently available antivenoms are not very effective with regard to their neurotoxin-neutralising activity.

For that reason alternative treatments that act in a timely and efficacious manner are required. Low molecular weight chemical inhibitors of neurotoxic PLA₂ such as the selective sPLA2 inhibitor Varespladib have shown some promising activity against pre-synaptic snake neurotoxins and developments must be closely followed-up.

Endotracheal intubation and artificial respiration are reliable methods that are successful even if they need to be continued for days or even weeks.

Acetylcholinesterase inhibitors can be used in certain situations at least as adjunctive therapy. Their efficacy depends on the location of activity of the neurotoxins of a snake species and has been proven in clinical studies for some snake species, in particular for those species with postsynaptically active venoms (e.g. Naja philippinensis).

"Anticholinesterase drugs may produce a rapid, useful improvement in neuromuscular transmission in patients envenomed by some species of Asian and African cobras, death adders (Acanthophis species), some coral snakes (Micrurus species) and kraits" (Warrell 2023, citing Watt et al. 1986).

Tensilon test and treatment with acetylcholinesterase inhibitors

Warrell (2023), Watt et al. (1986)

Guidelines for the Management of Snakebites, WHO Regional Office SE Asia

Diagnostic and treatment steps	Procedure	Comments
Baseline observations and measurements	Assessment: Signs of improved neuromuscular transmission. Ptosis may disappear and ventilator capacity (peak flow, FEV-1 or maximum expiratory pressure) may improve.	The baseline observations and measurements are made against which to assess the effectiveness of the cholinesterase inhibitors.
Tensilon test	Atropine sulphate i.v.: 0.6 mg (adults), 50 µg/kg BW (children) to block muscarinic effects. followed by Tensilon (edrophonium) i.v.: 10 mg (adults), 0.25 mg/kg BW (children); caution is required in children below 12 years _______ Alternatively: Neostigmine bromide or methylsulphate (Prostigmin®) by intramuscular injection, 0.02 mg/kg for adults, 0.04 mg/kg for children may be used. _______ Alternatively: The ‘ice test’. An ice-filled plastic glove is applied to the closed lid of one eye for 2 minutes. If this improves the ptosis on that side compared to the other, effectiveness of anticholinesterase may be inferred.	Indication: Some species of Asian and African cobras, death adders (Acanthophis species), some coral snakes (Micrurus species) and kraits" (Warrell 2023, citing Watt et al. 1986) or in the absence of evidence that points towards one of the culprits above, all patients with neurological signs of envenoming can be given a trial. However, this should not delay antivenom treatment or endotracheal intubation. Patients must be observed closely as they may deteriorate while the trial of anticholinesterase is being carried out.
Observation	Observation of signs of improved neuromuscular transmission. Ptosis may disappearand ventilator capacity (peak flow, FEV-1 or maximum expiratory pressure) may improve. 10-20 minutes (Tensilon, edrophonium) 30-60 minutes (neostigmine)	Assessment against the baseline observations and measurements.
Patients with a convincingly positive response
Long-acting anticholinesterase inhibitors	Maintainance on neostigmine methylsulphate, 0.5–2.5 mg every 1–3 hours up to 10 mg/24 hours maximum for adults or 0.01–0.04 mg/kg every 2–4 hours for children, by intramuscular, intravenous or subcutaneous injection. _______ Alternatively: Neostigmine methylsulphate continuous i.v. infusion (Perfusor) 25(–50–100) µg/kg BW/h. _______ To block muscarinic effects: Atropine sulphate s.c. 15 µg/kg BW 4-hourly. _______ Adult patients able to swallow tablets may be maintained on atropine 0.6 mg twice each day, neostigmine 15 mg four times daily or pyridostigmine 60 mg four times daily.	Indication: Improvement of neurological signs of envenoming under the Tensilon (edrophonium) test or altrenative tests (see above). Dose adjustment: Titration according to the effect. Adverse reactions: Among other reactions, acetylcholinesterase inhibitors may cause cramping abdominal pain, which can be controlled with atropine. An overdose of acetylcholinesterase inhibitors can lead to a cholinergic crisis with progressive muscle weakness and respiratory paralysis.