myasthenic crisis (weakness due to inadequate anticholinesterase treatment or severe disease) from a cholinergic crisis (weakness caused by over-treatment with an anticholinesterase). Myasthenic weakness is substantially improved by edrophonium whereas cholinergic weakness is aggravated but the effect is transient; the action of 3 mg i.v. is lost in 5 minutes.

Carbaryl (carbaril) is another reversible carbamoy-lating anticholinesterase that closely resembles physostigmine in its actions. It is widely used as a garden insecticide and, clinically, to kill head and body lice. Sensitive insects lack cholinesterase-rich erythrocytes and succumb to the accumulation of acetylcholine in the synaptic junctions of their nervous system. Effective and safe use in humans is possible because we possess cholinesterase, and absorption of carbaryl is very limited after topical application. The anticholinesterase malathion is effective against scabies, head and crab lice.

A more recent use of anticholinesterase drugs has been to improve cognitive function in patients with Alzheimer's disease, where both the degree of dementia and amyloid plaque density correlate with the impairment of brain cholinergic function. Donepezil and rivastigmine7 are licensed in the UK for this indication. Both are orally active and cross the blood-brain barrier readily (see p. 408).

Anticholinesterase poisoning

The anticholinesterases used in therapeutics are generally of the carbamate type that reversibly inactivate cholinesterase only for a few hours. This contrasts markedly with the very long-lived inhibition caused by inhibitors of the organophosphate (OP) type. In practice, the inhibition is so long that clinical recovery from organophosphate exposure is usually dependent on synthesis of new enzyme. This process may take weeks to complete although clinical recovery is usually evident in days. Cases of acute poisoning are usually met outside therapeutic practice, e.g. after agricultural, industrial or transport accidents. Substances of this type have also been developed and used in war, especially the

7 Report. Drug and Therapeutics Bulletin 1998 38:15-16.

three G agents, GA (tabun), GB (sarin) and GD (soman). Although called nerve 'gas', they are actually volatile liquids, which facilitates their use.8 Where there is known risk of exposure, prior use of pyridostigmine, which occupies cholinesterases reversibly for a few hours (the lesser evil), competitively protects them from access by the irreversible warfare agent (the greater evil); soldiers expecting attack have been provided with preloaded syringes (of the same design as the Epipen for delivering adrenaline) as antidote therapy (see below). Organophosphate agents are absorbed through the skin, the gastrointestinal tract and by inhalation. Diagnosis depends on observing a substantial part of the list of actions below.

Typical features of acute poisoning involve the gastrointestinal tract (salivation, vomiting, abdominal cramps, diarrhoea, involuntary defaecation), the respiratory system (bronchorrhoea, bronchocon-striction, cough, wheezing, dyspnoea), the cardiovascular system (bradycardia), the genitourinary system (involuntary micturition), the skin (sweating), the skeletal system (muscle weakness, twitching) and the nervous system (miosis, anxiety, headache, convulsions, respiratory failure). Death is due to a combination of the actions in the central nervous system, to paralysis of the respiratory muscles by peripheral depolarising neuromuscular block, and to excessive bronchial secretions and constriction causing respiratory failure. At autopsy, ileal intussusceptions are commonly found.

Quite frequently, and typically 1-4 days after resolution of symptoms of acute exposure, the intermediate syndrome may develop, characterised by a proximal flaccid limb paralysis which may reflect muscle necrosis. Even later, after a gap of 2-4 weeks, some exposed persons exhibit the delayed polyneuropathy, with sensory and motor impairment usually of the lower limbs. Claims of chronic effects (subtle cognitive defects, peripheral neuropathy) following recurrent, low-dose exposure, as with organophosphate used as sheep dip, continues to be the subject of investigation but, as yet, no conclusive proof.

8 In recent times, there have been major instances of use against populations by both military and terrorist bodies (in the field and in an underground transport system).

Treatment. Since the most common circumstance of accidental poisoning is exposure to pesticide spray or spillage, contaminated clothing should be removed and the skin washed. Gastric lavage is needed if any of the substance has been ingested. Attendants should take care to ensure that they themselves do not become contaminated.

• Atropine is the mainstay of treatment; 2 mg is given i.m. or i.v. as soon as possible and repeated every 15-60 min until dryness of the mouth and a heart rate in excess of 70 beats per minute indicate that its effect is adequate. A poisoned patient may require 100 mg or more for a single episode. Atropine antagonises the muscarinic parasympathomimetic effects of the poison, i.e. due to the accumulated acetylcholine stimulating postganglionic nerve endings (excessive secretion and vasodilatation), but has no effect on the neuromuscular block, which is nicotinic.

• Mechanical ventilation may therefore be needed to assist the respiratory muscles; special attention to the airway is vital because of bronchial constriction and excessive secretion.

• Diazepam may be needed for convulsions.

• Atropine eyedrops may relieve the headache caused by miosis.

• Enzyme reactivation. The organophosphate (OP) pesticides inactivate cholinesterase by irreversibly phosphorylating the active centre of the enzyme. Substances that reactivate the enzyme hasten the destruction of the accumulated acetylcholine and, unlike atropine, they have both antinicotinic and antimuscarinic effects. The principal agent is pralidoxime, 1 g of which should be given 4-hourly i.m. or (diluted) by slow i.v. infusion, as indicated by the patient's condition; its efficacy is greatest if administered within 12 hours of poisoning then falls of steadily as the phosphorylated enzyme is further stabilised by 'aging'. If significant reactivation occurs, muscle power improves within 30 min.

Poisoning with reversible anticholinesterases is appropriately treated by atropine and the necessary general support; it lasts only hours.

In poisoning with irreversible agents, erythrocyte or plasma cholinesterase content should be measured if possible, both for diagnosis and to determine when a poisoned worker may return to the task (should he or she be willing to do so). Return should not be allowed until the cholin-esterase exceeds 70% of normal, which may take several weeks. Recovery from the intermediate syndrome and delayed polyneuropathy is slow and is dependent on muscle and nerve regeneration.

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