Anti-cholinesterase (AchE)

Anti-cholinesterase

• Anti-cholinesterase (Anti-ChEs) are agents that inhibit the cholinesterase that is responsible for the hydrolysis of ACh. Thus, Ach is not metabolized and gets accumulated at muscarinic and nicotinic sites.
• Some ChEs have an additional direct effect on cholinergic receptors.
• Cholinesterase: it is an enzyme that catalyzes the hydrolysis of ACh into choline and acetic acid.

Reversible

Irreversible

Reversible

• Acetylcholinesterase inhibitor (anticholinesterase agents or cholinesterase inhibitors) indirectly provide a cholinergic action by preventing the degradation of Ach.
• This results in the accumulation of Ach in the synaptic cleft and leads to bind with cholinoreceptor.
• It is classified as short-acting or intermediate acting agents.

Irreversible

• A number of synthetic organophosphorus compounds have capacity to bind covalently to AchE.
• This result is a long lasting increase in Ach at site where it is released.

N.B:   Carbamate – Carbamylate is the active site of the enzyme.

• Carbamate fuse covalently with serine.
• Carbamylated (Reversible inhibitor) reacts with water slowly, and the Esteratic site is freed and ready for action, 30 min (less than the synthesis of fresh enzyme).

            Phosphate – Phosphorylate the enzyme.

• Phosphorylated (irreversible) reacts extremely slowly or not at all (takes more time then synthesis of a fresh enzyme).
• Sometimes phosphorylated enzyme loses one alkyl group and becomes resistant to hydrolysis – aging.
• Endophonium and tacrine react only at the anionic site. Short-acting organophosphates react only at the esteratic site.

Pharmacological action

• Ganglia: stimulate ganglia – muscarinic action – less prominent action.
• CVS: Muscarinic – Bradycardia and hypotension

Ganglionic action – stimulation – increases HR and BP, medullary center – stimulation followed by depression – overall unpredictable.

• Skeletal muscle: increase force of contraction in the muscle.

Reversible

Psysiostigmine

• Psysiostigmine is a nitrogenous carbamic acid ester found naturally in plants and a tertiary amine.
• It is stable carbamoylated intermediate with the enzyme and reversibly inactivated.

Action

• Stimulate muscarinic and nicotinic receptors of the NMJ.
• Duration of action 2-4 hours (intermediate acting.

Therapeutic uses

• Increases intestinal and bladder motility.
• Miosis or spasm of accommodation (ciliary muscle of the eye remains in a constant state).
• Reduce IOP (less effective than pilocarpine).
• Used as an overdose of atropine, phenothiazine, and tricyclic antidepressant.

Averse effect

• Convulsion (high dose)
• Bradycardia
• Accumulation of Ach at the skeletal NMJ results in paralysis.

Neostigmine

• Similar action to Psysiostigmine.

Action

• Neostigmine has quaternary nitrogen; it is more polar, so it is absorbed poorly from the GI tract and does not enter the CNS.
• Greater effect on skeletal muscle.
• Duration of action 30 min to 2 hours (intermediate)

Therapeutic uses

• Salivation
• Flushing decreases BP
• Nausea
• Abdominal pain
• Diarrhea
• Bronchospasm
• Does not cause CNS side effects.
• Intestine and urinary bladder obstruction, neostigmine is contraindicated.
• Should not use in case of peritonitis (inflammation of the peritoneum) or inflammation of bowel disease.

Endrophonium

• Short-acting inhibitor
• Bind reversibly to AChE, preventing the hydrolysis of Ach.
• Duration of action 10-20 min.
• Used in the diagnosis of Myasthenia gravis.

Pyridostigmine

• Used in chronic management of Myasthenia gravis.
• Duration of action 3-8 hours.
• Adverse effect similar to neostigmine.

Tacrine, Rivastigmine, Donepezil, Galantamine

• Alzheimer’s disease: deficiency of cholinergic neurons in the CNS.
• Development of AChEs as possible remedies for the loss of cognitive function.
• Tacrine: produce hepatotoxicity.
• Donepezil, Rivastigmine, Galantamine to delay the progression of Alzheimer disease.
• GI distress is primary adverse effect.

Irreversible

Echothiophate

MOA

• It is an organophosphorus that covalently binds via its phosphate group to serine-OH group at the active site of AChE and the enzyme permanently inactive and restoration of AChE activity requires the synthesis of new enzyme molecules.
• The phosphorylated enzyme slowly release one of its ethyl groups. The loss of an alkyl groups which is called aging.

Action

• Paralysis of motor function (breathing difficulties)
• Convulsion
• Miosis
• Decrease IOP (High dose of Atropine reversal)

Therapeutic uses

• Open-angle glaucoma
• Long duration, one week.