Skeletal Muscle Relaxants: Pharmacodynamics and Pharmacokinetics in Different Patient Groups

Booij, L.H.D.J.; Vree, T. B.

doi:10.1111/j.1742-1241.2000.tb10917.x

Int J Clinical Practice

2000

DOI: 10.1111/j.1742-1241.2000.tb10917.x

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Skeletal Muscle Relaxants: Pharmacodynamics and Pharmacokinetics in Different Patient Groups

L.H.D.J. Booij

T. B. Vree

Abstract: SUMMARYMuscle relaxants can be safely administered during anaesthesia, providing the basic pharmacodynamic and pharmacokinetic characteristics of the compounds together with the physiological status of the patient are known. In this review the pharmacodynamics and pharmacokinetics of the neuromuscular blocking agents are discussed and related to the physical health or disease state of groups of patients.

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Cited by 2 publications

References 104 publications

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Synergy Between Pairs of Competitive Antagonists at Adult Human Muscle Acetylcholine Receptors

Liu

Dilger

2008

Anesthesia &Amp; Analgesia

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Background Synergistic neuromuscular blocking effects have been observed clinically with certain pairs of nicotinic acetylcholine receptor (nAChR) competitive antagonists. The mechanism for synergy has not been elucidated. We tested the hypothesis that synergy arises from a differential selectivity of antagonists for the two ligand binding sites on adult human nAChR. Methods We expressed nAChR in BOSC23 cells. We applied ACh with or without antagonists to outside-out patches and measured macroscopic currents at room temperature. We determined the IC90 for (+)-tubocurarine, metocurine, pancuronium, vecuronium, cisatracurium, rocuronium, and atracurium. For 15 combinations of two antagonists, we determined the IC90 for one antagonist in the presence of the IC70 of a second antagonist. We constructed isobolograms for 90% inhibition. For single antagonists, we measured inhibition of receptors containing mutations in the ε- and δ-subunits to determine site selectivity. Results Two pairs of antagonists, metocurine+cisatracurium and cisatracurium+atracurium exhibited additive inhibition. Ten combinations, including (+)-tubocurarine+pancuronium and pancuronium+vecuronium, were highly synergistic such that the combination was 2−3 times more effective than expected for additivity. Three combinations were 1.5−1.6 times more effective than expected for additivity. Inhibition by (+)-tubocurarine and metocurine was sensitive to mutations in the ε-subunit only. Vecuronium was affected by the δ-subunit mutation only. Inhibition by other antagonists was decreased by mutations in either subunit. Conclusions Many combinations of antagonists exhibited synergistic effects on adult human nAChR. Synergy was observed with structurally similar as well as dissimilar antagonists. The degree of synergy did not always correlate well with site specificity assayed with mutants. In some, but not all cases, the synergy at the receptor level correlated with clinical determinations of synergy. We conclude that the synergistic actions of muscle relaxants can be partially explained by direct interactions with adult human nAChR.

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Synergy Between Pairs of Competitive Antagonists at Adult Human Muscle Acetylcholine Receptors

Liu

Dilger

2008

Anesthesia &Amp; Analgesia

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Drug absorption, distribution, metabolism and excretion considerations in critically ill adults

Roberts

Hall

2013

Expert Opinion on Drug Metabolism & Toxicology

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Dosage pharmacokinetics determined from single-dose or limited-duration administration studies in healthy volunteers may not apply to critically ill patients. Organ dysfunction among these patients may be due to pre-existing disease or the effects of a systemic or locoregional inflammatory response precipitated by their illness. Alterations in pharmacokinetics observed among the critically ill include altered bioavailability after enteral administration, increased volume of distribution and blood-brain barrier permeability and changes in P-glycoprotein and cytochrome P450 enzyme function. However, the effect of these changes on clinically important outcomes remains uncertain and poorly studied. Future investigations should examine not only pharmacokinetic changes among the critically ill, but also whether recognition of these changes and alterations in drug therapy directed as a consequence of their observation alters patient outcomes.

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Skeletal Muscle Relaxants: Pharmacodynamics and Pharmacokinetics in Different Patient Groups

Cited by 2 publications

References 104 publications

Synergy Between Pairs of Competitive Antagonists at Adult Human Muscle Acetylcholine Receptors

Synergy Between Pairs of Competitive Antagonists at Adult Human Muscle Acetylcholine Receptors

Drug absorption, distribution, metabolism and excretion considerations in critically ill adults

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