This is a continuation of efforts to characterize the pharmacology, especially the pharmacokinetics and pharmacodynamics, of clinically important neuromuscular blocking drugs and their antagonists. There are three specific aims. First, a conceptual model developed during the present granting period will be used to correlate the pharmacokinetics and pharmacodynamics of the antagonists neostigmine, pyridostigmine and edrophonium. The pharmacokinetics of these drugs have been previously determined but have not been correlated with the pharmacodynamics due to the lack of a suitable model -- which this laboratory has now designed and tested. The data obtained in normal patients using this model will be compared with those in patients with altered pathology (e.g. renal failure) or physiology (e.g. hypothermia). Second, the previously described expertise in assay development (e.g. chemical ionization selected ion mass spectrometric assay for pancuronium) will be extended to develop a gas chromatographic and a gas chromatographic mass spectrometric assay for the identification and quantitation of pancuronium, vecuronium and their metabolites. This added analytical capability will facilitate the rapid determination of the pharmacokinetics and metabolic profiles of pancuronium and vecuronium. Third, the basic and clinical pharmacology of atracurium will be studied focusing on the quantitative and qualitative analysis of its spontaneous and enzyme-mediated breakdown products and metabolites. In addition, the pharmacokinetics and clinical pharmacology of the predominant metabolite, laudanosine, a known central nervous system (CNS) stimulant, will be determined. These studies will facilitate the safe administration of neuromuscular blocking drugs and their antagonists, and will help to avoid adverse effects such as prolonged neuromuscular blockade and postoperative respiratory failure.
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