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Clinical Pharmacokinetics of Cholinesterase Inhibitors

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Summary

This review deals mainly with the pharmacokinetics of the reversible quaternary cholinesterase inhibitors neostigmine, pyridostigmine and edrophonium,which are mainly used to antagonise non-depolarising neuromuscular blockade in general anaesthesia and in the symptomatic treatment of myasthenia gravis. Only in the last few years, since the introduction of highly sensitive and selective analytical procedures based on gas and liquid chromatography, have proper pharmacokinetic studies of these drugs become possible. Rapid cooling and addition of internal standard to samples before freezing are important precautions in view of the poor stability of the cholinesterase inhibitors in plasma and blood. Plasma clearances of the reversible quaternary cholinesterase inhibitors are in the range 0.5 to 1.0 L/h/kg and their apparent volumes of distribution range from 0.5 to 1.7 L/kg. Accordingly, the drugs have short plasma elimination half-lives, in the order of 30 to 90 minutes.

One to two hours after oral administration of 60mg pyridostigmine, peak plasma concentrations of 40 to 60 µg/L are observed, whereas the plasma concentrations of neostigmine after a 30mg oral dose are only 1 to 5 µg/L. The oral bioavailability of these hydrophilic ionised compounds is low: that of pyridostigmine is approximately 10% and the value for neostigmine is even lower. In spite of the short elimination half-life of pyridostigmine, intraindividual variations in plasma concentration during a dose interval are small in myasthenic patients receiving oral maintenance therapy, probably as a result of slow absorption from the gastrointestinal tract. Severely impaired renal function has been shown to prolong the elimination of neostigmine and pyridostigmine, while methylcellulose has been reported to inhibit the absorption of the latter drug completely. Other pharmacokinetic drug interactions suggested so far do not seem to be of clinical significance.

Although a positive correlation has been demonstrated between the plasma concentrations of these drugs and their pharmacological effects as measured by a decrement in muscle response to repetitive nerve stimulation in a single muscle, this relationship is less clear when a global evaluation of muscular function in myasthenia gravis is used.

Pharmacokinetic studies of the tertiary reversible cholinesterase inhibitor physostigmine, an important tool in experimental cholinergic neuropharmacology, are still in their initial stages. This drug too is characterised by a short plasma elimination half-life of 20 to 30 minutes. Peak plasma concentrations after oral administration of 2 to 4mg of physostigmine are in the order of 1 µg/L. Plasma concentrations of 3 to 5 µg/L seem to be needed to antagonise drug-induced postoperative sedation.

Irreversible cholinesterase inhibitors have a limited use in local treatment of glaucoma, but pharmacokinetic investigations on these drugs seem to be lacking. However, systemic side effects from ecothiopate eye drops have been reported.

Pharmacokinetic studies on metrifonate, which is used in the treatment of schistosomiasis, have shown that this compound is a prodrug representing an ‘intrinsic slow release formulation’ of the active drug dichlorvos, which at least in part exerts its action by irreversibly inhibiting cholinesterase within the parasites.

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Aquilonius, SM., Hartvig, P. Clinical Pharmacokinetics of Cholinesterase Inhibitors. Clin-Pharmacokinet 11, 236–249 (1986). https://doi.org/10.2165/00003088-198611030-00005

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