Clinical Pharmacokinetics of Cholinesterase Inhibitors

Abstract

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 60 mg pyridostigmine, peak plasma concentrations of 40 to 60 micrograms/L are observed, whereas the plasma concentrations of neostigmine after a 30 mg oral dose are only 1 to 5 micrograms/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.(ABSTRACT TRUNCATED AT 400 WORDS)

Low acetylcholine during slow-wave sleep is critical for declarative memory consolidation

“…Substance administration was in a balanced, randomized, double-blind fashion. The duration of drug administration was chosen on the basis of the 20-30 min elimination half-life of physostigmine in blood (29). Thus, it was ascertained that the substance was effective only during sleep, not during retrieval testing, which took place 1.5 h after the end of substance administration.…”

Midodrine and Pyridostigmine; Novelties in Heart Failure Therapy

“…[4][5][6][7]8 Hypotension was shown to be the cause of 28% of treatment failure in patients with systolic heart failure. 4 In a separate study, Lisinopril use was associated with hypotension or dizziness in 12.8% of patients when given in high dose and in 9% of patients when given in low dose.…”

“…5 This agent has been used for the treatment of symptomatic hypotension in several medical conditions. 6 The potential role of Midodrine in the treatment of heart failure has been examined in two separate studies. Patients with end stage renal disease and symptomatic New York Heart Association class III-IV heart failure, all with symptomatic hypotension during dialysis and with previous hospital admissions for volume overload were included in an observational, small size study by Bregman.…”

“…[18][19][20][21][22] Pyridostigmine is a reversible acetylcholine esterase inhibitor, it augments the effect of the parasympathetic system. [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] It is currently used in the treatment of myasthenia gravis. 23 Several efforts to study the effect of Pyridostigmine in animal models of heart failure have been made.…”

“…This paper will discuss the role of Midodrine -alpha one agonist -, and Pyridostigmine -acetylcholine esterase inhibitor -in heart failure therapy. 5,6 To our own knowledge, this article is the first to provide a comprehensive review of the beneficial effects of the use of Midodrine and Pyridostigmine in heart failure therapy. Data from in vitro studies, studies involving animal models, along with data from human studies will be presented.…”