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Inhibition of destruction: anticholinesterase agents

Since acetylcholine is inactivated by cholinesterases, inhibition of cholinesrerases leads to a rise in acetylcholine concentration. If this rise remains moderate, it can have beneficial effects but if is too high it causes toxic effects.

Cholinesterase inhibitors, also called anticholinesterase agents, are schematically classified, according to their intensity and duration of action and consequently of their toxicity, into reversible and irreversible inhibitors.

In human beings, inhibition of cholinesterases induces, by accumulation of acetylcholine, muscarinic and nicotinic effects. These effects are predominately central or peripheral according to whether the inhibitor penetrates or not into the brain.

Inhibition of cholinesterases of insects is a way to obtain their destruction.

Reversible inhibitors

The reversible inhibtors, which inhibit enzyme in a transitory way, as long as their concentration is sufficient, are used in therapeutics and, for the majority of them, are known for a long time.

Physostigmine or eserine

Physostigmine, also callad eserine, alkaloid obtained from calabar bean, gives primarily muscarinic effects and crosses the blood-brain barrier.

It increases the gastric and intestinal peristalsis and induces bronchoconstriction and contraction of ureters.

It increases bronchial and digestive secretions (gastric, intestinal, salivary), as well as lacrimal secretion.

Its cardiovascular action is complex but, in general, it has a muscarinic action: bradycardia and decrease of the force of cardiac contractions.

Eserine elicits miosis, spasm of accommodation, fall of intraocular pressure, hyperemia of conjunctiva and lacrymation.

Generally, it stimulates neuromuscular transmission, what results in muscle fasciculations. In addition to its indirect action by inhibition of cholinesterases, it could directly stimulate neuromuscular nicotinic receptors. It does not have an action on the uterus.

Eserine is indicated in treatment of paralytic ileus, intestinal atonicity, glaucoma, myasthenia, post-anesthetic long-lasting curarization. It was tested in the treatment of Alzheimer's disease using transdermal preparations which make possible to obtain relatively stable plasma concentrations.

The multiplicity of effects of eserine is often a disadvantage in therapeutics where only an effect is generally sought.

Neostigmine

Neostigmine, better tolerated than eserine, acts less on eye, cardiovascular system and central nervous system, but it is more active on digestive tract and bladder.

Neostigmine is used in the treatment of the postoperative atonicity (intestine, bladder), and of myasthenia in high dose combined or not with atropine.

It accelerates decurarization as an indirect antidote of competitive neuromuscular inhibitors.

Pyridostigmine

Pyridostigmine has pharmacological properties close to those of neostigmine, with perhaps a more progressive and more durable action.

It is used in the treatment of intestinal atonicity and myasthenia.

Ambenonium

Ambenonium is a long-acting inhibitor of cholinesterase, about five to six hours after oral intake, used in the treatment of myasthenia gravis.

Tacrine

Tacrine or 9 amino-1,2,3,4-tétrahydroacridine is an anticholinesterase agent which penetrates into the brain and has been used in the treatment of Alzheimer's disease. It was successively proposed as a disinfectant, as antagonist of morphine respiratory depression and finally used in the treatment of Alzheimer's disease for which it attenuates certain symptoms.

Tacrine has various adverse effects of muscarinic type but its major disadvantage is its hepatic toxicity which usually results in a rise of transaminases. A metabolite of tacrine could be responsible for this hepatic toxicity. It is not used now.

Donepezil

Donepezil is a selective and reversible inhibitor of acetylcholinesterase, having little effect on butyril-cholinesterase and penetrating well iton brain. Its half-life of plasma elimination is about 70 hours and just a once-daily intake is enough. Donepezil is indicated in the supportive care of Alzheimer's disease.

The most frequent adverse effects of the donepezil are digestive disorders (diarrhea, nausea, vomiting, abdominal pains). It can also induce dizziness and bradycardia but without hepatic toxicity, the major undesirable effect of tacrine.

Rivastigmine

Rivastigmine is a new anticholinesterase, quite well absorbed by oral route and crossing well the blood-brain barrier. It is used twice daily in the supportive care of Alzheimer's disease. It does not present hepatic toxicity.

Galantamine

Galantamine, also written galanthamine, is a product known for about fifty years. Recent studies showed that it could have an interest in the treatment of Alzheimer's disease. It is metabolized by cytochromes CYP 2d6 and CYP3A4 and interactions with drugs inhibiting these cytochromes were described.

Notice

Huperzine is an alkaloid of vegetable origin, known for many years, which inhibits cholinesterases reversibly and penetrates into the brain. It was proposed as a dietary supplement of vegetable origin intended to reduce memory disorders.

Irreversible inhibitors

Irreversible inhibitors of cholinesterases, while being fixed at enzymes by covalent bonds, inhibit them irreversibly. In fact they are mainly organophosphorus compounds which, because of their toxicity, are only exceptionally used in therapeutics.

One of the least toxic among more than 50 000 derivatives which were prepared, diisopropyle fluorophosphate or D.F.P., was tested in treatment of myasthenia, paralytic ileus and of glaucoma as an ophthalmic solution. It was at the origin of poisonings and is not released on the market any more.

The sulfur organophosphorus compound ecothiopate, was used in therapeutics in the form of an ophthalmic solution, in the treatment of glaucoma. It has very long action and its use has to be very spaced (once-daily to twice a week).

Malathion is the active product of certain preparations intended for the treatment of lice of the scalp (lice). When it is applied strictly to the hair, the scalp being intact, one does not observe general effects.

Metrifonate and dichlorvos are organophosphorus compound inhibitors of cholinesterases, having antihelminthic activity against Schistosoma mansoni and haematobium. In the body metrifonate is partly converted to dichlorvos which is considered as the active product.

Irreversible inhibitors of cholinesterases are largely used in agriculture as insecticides and some of them, because of their very great toxicity, were retained as chemical warfare agents, also called nerve gases.

  • Tétra-éthyl-pyrophosphate or T.E.P.P.
    Liquid product, of pleasant odor soluble in water where it is quickly hydrolyzed and in several organic solvents, T.E.P.P. is used as an insecticide.
  • Parathion or thiophos
    This brown, viscous yellow fluid at ordinary temperature, practically insoluble in water, soluble in ethanol, used in insecticide preparations. By itself, this product is not very toxic, but in the body, it is transformed into paraoxon, metabolite much more toxic.

Other derivatives such as formathion, diethion, malathion and diazinon are very much used as insecticides.

Generally, the substitution of the phosphorus atom by a fluorine atom or a cyanide group increases toxicity and one obtains compounds such as tabun, sarin and soman classified as nerve gas.

Anticholinesterase poisoning

The symptoms of poisoning by organophosphorus compounds depend on the conditions of poisoning and more particularly on its severity.

Between latent forms, detected by cholinesterases determination, and forms quickly fatal, there are many intermediate forms. The following symptomatology is generally observed:

  • muscarinic signs: miosis, nausea, salivation, vomiting, diarrhea, sweats, bradycardia, bronchial obstruction.
  • nicotinic signs, neuromuscular (twitchings, fasciculations, cramps, paralysis in the case of severe poisoning) and cardiac (tachycardia, rise in arterial pressure).
  • central signs :headache, drowsiness, disorientation, coma or generalized convulsions.

In severe forms where the disorders appear very quickly, death, preceded by a loss of consciousness and seizures, comes from a respiratory arrest by central inhibition and paralysis of the neuromuscular transmission phrenic nerve/diaphragm. The bronchial hypersecretion worsens moreover the respiratory failure.

Persistence of various neuropsychiatric disorders a long time after an acute poisoning or following a chronic poisoning by irreversible anticholinesterases is possible.

Treatment of poisoning by anticholinesterases consists of discontinuation of the poison, administration of atropine and possibly of pralidoxime, a cholinesterase reactivator.

  • Atropine which inhibits muscarinic effects is administered by parenteral route in doses higher than in its usual indications (1 mg possibly renewed)
  • Pralidoxime, which reactivates inhibited cholinesterases, is administered by parenteral route, generally intravenous, at renewable dose of 0,5 g in adult. It acts by detaching the phosphate group of the inhibitors from the esterasic site. It should be noticed that in animal experiments, pralidoxime in large dose can partially inhibit cholinesterases and may cause transient neuromuscular blockade. Thus, it should not be administered as an antidote in too high doses. Obidoxime is another reactivator of cholinesterases
  • Recent data show that, during severe poisonings by organophosphorus compounds, the stimulation of acetylcholine receptors by acetylcholine which accumulates induces glutamate release which makes sodium and calcium enter the cell inducing cellular damage. The use of antagonists of glutamate can thus be considered.

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Quizz : Q 29
Drugs like donepezil (Aricept*) and rivastigmine (Exelon*) act by:
increasing acetylcholine release
inhibiting cholinesterases
inhibiting monoamine oxidase
stimulating 5HT3 serotonin receptors
stimulating alpha-2 adrenergic receptors

... more quizz
33  Eserine and neostigmineact by:
112 Donepezil
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