Cholinesterase inhibitors mechanisms

Bajgar, J. (1985). Intoxication with organophosphoras cholinesterase inhibitors. Mechanism of action, diagnosis and treatment. In Novinky v medicine News in Medicine), Vol. 34, pp. 7-40. Avicenum, Prague. (In Czech)... 

The mechanism of OPIDN is poorly understood, but, since all organophosphate esters that produce OPIDN are either direct cholinesterase inhibitors or are metabolically converted to cholinesterase inhibitors, inhibition of an esterase of some kind has generally been thought to be involved (Baron 1981). Certain... 

Anticholinesterase agents of all classes can initiate antidromic firing of action potentials in motor neurons, possibly due to an activation of prejunctional ACh receptors that are activated by the elevated synaptic ACh. Quaternary ammonium inhibitors can also act as agonists at these receptors. The initiation of antidromic firing may be a mechanism by which cholinesterase inhibitors produce fasciculation of skeletal muscle. 

Anticholinesterase agents can be employed in the treatment of adynamic ileus and atony of the urinary bladder, both of which may result from surgery. Neostigmine is most commonly used, and it can be administered subcutaneously or intramuscularly in these conditions. Cholinesterase inhibitors are, of course, contraindicated if mechanical obstruction of the intestine or urinary tract is known to be present. 

Mechanism of Action A cholinesterase inhibitor that enhances and prolongs cholinergic function by increasing the concentration of acetylcholine through inhibition of f he hydrolysis of acefylcholine. Therapeutic Effect Increases muscle strength in myasthenia gravis. 

Mechanism of Action A cholinesterase inhibitor that inhibits the enzyme acetylcholinesterase, thus increasing the concentration of acetylcholine at cholinergic synapses and enhancing cholinergic function in the CNS. Therapeutic Effect Slows the progression of Alzheimer s disease. 

Individual cholinesterase inhibitors differ in their selectivity, mechanism of inhibition of acetylcholinesterase (Schneider 2001), and pharmacokinetic properties (outlined in Table 7-2). 

The organophosphate inhibitors are sometimes referred to as "irreversible" cholinesterase inhibitors, and edrophonium and the carbamates are considered "reversible" inhibitors because of the marked differences in duration of action. However, the molecular mechanisms of action of the three groups do not support this simplistic description. 

These patients may also exhibit symptoms of excessive stimulation of muscarinic receptors (abdominal cramps, diarrhea, increased salivation, excessive bronchial secretions, miosis, bradycardia). Small doses of edrophonium (1-2 mg intravenously) will produce no relief or even worsen weakness if the patient is receiving excessive cholinesterase inhibitor therapy. On the other hand, if the patient improves with edrophonium, an increase in cholinesterase inhibitor dosage may be indicated. Clinical situations in which severe myasthenia (myasthenic crisis) must be distinguished from excessive drug therapy (cholinergic crisis) usually occur in very ill myasthenic patients and must be managed in hospital with adequate emergency support systems (eg, mechanical ventilators) available. 

These findings from the natural history of untreated Alzheimer s disease and how it is modified by cholinesterase inhibitors should help prescribers set realistic expectations for treatment with AChE inhibitors. The hope is that today s improvements from cholinesterase inhibition will be synergistic when combined with agents of differing pharmacologic mechanisms of action in the future and should be considered a very useful first step in treating this devastating illness. 

Galanthamine is a very interesting cholinesterase inhibitor found in snowdrops and daffodils. It may have a dual mechanism of action, matching cholinesterase inhibition with direct nicotinic agonist actions causing acetylcholine release (Fig. 12—29). Early testing in Alzheimer s disease is underway. 

The cholinesterase inhibitor physostigmine has been investigated in a small blinded, placebo-controlled study of moderate to severe OSA patients, and via steady-state intravenous infusion been shown to modestly decrease the overall AHI and severity of oxygen desaturation, predominantly in REM compared with NREM sleep [81]. The exact mechanism of the beneficial action of physostigmine in sleep apnea is not clear. 

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