Pralidoxime belongs to a family of compounds called oximes that bind to organophosphate-inactivated acetylcholinesterase. It is used to combat poisoning by organophosphates, in conjunction with atropine.

In a normal nicotinic synaptic junction, including motor end plates and preganglionic nerve fibres, acetylcholine (ACh) is released from the presynaptic axon terminal into the synaptic cleft. The ACh then diffuses through the synaptic cleft and binds to nicotinic receptors on the postsynaptic membrane. This induces a subsequent action potential (AP) that continues through the postganglionic cell, or induces contraction in the motor end plate.

In order to prevent overstimulation or saturation of the synapse, or both, an enzyme known as acetylcholine esterase breaks down the neurotransmitter ACh. By removing the ACh, the synapse is brought to a state where it is ready for subsequent activation. Saturation of the synapse occurs when there is an excess of acetylcholine in the synaptic cleft, which inhibits further nerve transmission as the nicotinic receptors are full. Agents which inhibit acetylcholine esterase will lead to a build-up of ACh in the cleft.

Mechanism of action

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Pralidoxime binds to the organophosphate–acetylcholine esterase complex, specifically it binds to the bound nerve agent. The body readily breaks this complex down via metabolic pathways, leading to the eventual removal of the nerve agent. In addition to this, pralidoxime competitively inhibits the binding of the organophosphate, essentially protecting some of the acetylcholine esterases. It should be noted that pralidoxime is itself an inhibitor of acetylcholine esterase, and therefore can also produce the same symptoms as the toxins themselves. However, unlike organophosphates, pralidoxime binding is reversible, hence the added insult to the ACh–receptor mechanism is offset by eventual removal of the toxin.

Pralidoxime can also directly attack some forms of organophosphate toxins, sequestering them without the need for binding to an acetylcholine esterase molecule. It also achieves a similar effect reparative in muscarinic synapses, because organophosphates typically act non-specifically on all types of acetylcholine esterases. However, its use to relieve such parasympathetic symptoms is usually redundant because atropine is almost universally administered and has an overriding therapeutic effect.

Dosage

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Recommended dosages, according to online sources, seem to be:

• Adults: 30 mg/kg (Typically 1.5 - 2 g), administered either by intravenous therapy or intramuscular injection
• Children: 50 mg/kg

Interactions

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When atropine and pralidoxime are used together, the signs of atropinization (flushing, mydriasis, tachycardia, dryness of the mouth and nose) may occur earlier than might be expected when atropine is used alone. This is especially true if the total dose of atropine has been large and the administration of pralidoxime has been delayed.

The following precautions should be kept in mind in the treatment of anticholinesterase poisoning, although they do not bear directly on the use of pralidoxime: since barbiturates are potentiated by the anticholinesterases, they should be used cautiously in the treatment of convulsions; morphine, theophylline, aminophylline, succinylcholine, reserpine, and phenothiazine-type tranquilizers should be avoided in patients with organophosphate poisoning.

Contraindications

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There are no known absolute contraindications for the use of pralidoxime. Relative contraindications include known hypersensitivity to the drug and other situations in which the risk of its use clearly outweighs possible benefit.

External links

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• Chemical Bioweapons website
  
• Drugs.com
  
• DrugBank

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