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Pharmacokinetics of Neostigmine, Pyridostigmine, and Edrophonium

The pharmacokinetics of edrophonium, neostigmine, and pyridostigmine is summarized in Table 13-13 . [641] [642] [643] [644] The data indicate several relevant clinical conclusions:

  1. Pyridostigmine has a longer elimination half-life than the other anticholinesterases do, which probably accounts for its longer duration of action.[641] [642]
    2. 524
  2. By comparing elimination half-lives in patients with and without renal failure, renal excretion accounts for about 50% of the excretion of neostigmine and about 75% of that of pyridostigmine and edrophonium. Renal failure decreases the plasma clearance of neostigmine, pyridostigmine, and edrophonium as much as if not more than that of the long-acting neuromuscular blockers. Therefore, if proper doses of anticholinesterase drugs are given and overdoses of neuromuscular blockers are avoided, renal failure should not be associated with "recurarization."[641] [642] This remote possibility is further diminished if the clinician restricts relaxant administration to intermediate- or short-acting drugs in patients with renal failure.
  3. Edrophonium was once thought to be an unsuitable antagonist in clinical practice because its duration of action was believed to be too short. However, when larger doses (i.e., 0.5 to 1.0 mg/kg) are given, sustained antagonism of a nondepolarizing neuromuscular blockade results.[645] [646] In fact, the elimination half-life of edrophonium is similar to that of neostigmine or pyridostigmine (see Table 13-13 ). [643]


TABLE 13-13 -- Pharmacokinetics of neostigmine (N), pyridostigmine (P), and edrophonium (E) in patients without and with renal failure

Without Renal Failure With Renal Failure

N P E N P E
Distribution half-life (t½ α, min) 3.4 6.7 7.2 2.5 3.9 7.0
Elimination half-life (t½ β, min) 77 113 110 181 379 304
Volume of central compartment (L/kg) 0.2 0.3 0.3 0.3 0.4 0.3
Total plasma clearance (mL/kg/min) 9.1 8.6 9.5 4.8 3.1 3.9
Data from Cronnelly and colleagues[641] [642] and Morris and colleagues.[643] [644]

Mild hypothermia (i.e., 34°C to 35°C), as commonly occurs intraoperatively, has an impact on the pharmacokinetics of neostigmine. Its clearance is decreased from 16.2 mL/kg/min at 36.5°C to 13.5 mL/kg/min at 34.5°C.[494] Furthermore, the onset of peak effect of neostigmine is prolonged by mild hypothermia from 4.2 to 5.5 minutes.[494] If hypothermia has any influence on the efficacy of neostigmine-induced reversal, it is more likely to be due to the effect of temperature on the neuromuscular blocker (e.g., prolonged duration of action[477] ) than the pharmacology of neostigmine.

The pharmacokinetics of the anticholinesterases depends on several factors, including metabolism as well as distribution and elimination. In the case of neostigmine, a carbamylated complex with acetylcholinesterase is formed,[576] [578] [647] and it is the rate of dissociation of neostigmine from this complex (i.e., its metabolism) that is probably the major determinant of its duration of action. The decay in its plasma concentration (i.e., its distribution and elimination) may not be as pertinent a determinant of the duration of action of the drug.[648]

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