Propofol in Anesthesia. Mechanism of Action, Structure-Activity Relationships, and Drug Delivery
The action of propofol involves a positive modulation of the inhibitory function of the neurotransmitter g-aminobutyric acid (GABA) through GABA A receptors. Recent results from recombinant human GABA A receptor experiments and findings from the work exploring the effects at other receptors (e.g., glycine, nicotinic, and M1 muscarinic receptors) are reviewed. Studies showing its antiepileptic and anxiolytic properties are also discussed. The structure-activity relationships (SAR) of series of alkylphenols and p-X-substituted congeners have been reinvestigated. Interestingly, unlike the other congeners tested sofar, p-iodo-2,6- diisopropylphenol displayed anticonvulsant and anticonflict effects, but not sedative-hypnotic and anesthetic properties. Due to its high lipid-solubility, propofol was initially formulated as a solution with the surfactant Cremophor EL, but the occurrence of pain on injection and anaphylactoid reactions prompted to search for alternative formulations. Results from using cyclodextrins, water-soluble prodrugs, and adopting Bodors approach to the site-specific chemical delivery system (CDS), as well as the advantages provided by computer-controlled infusion systems, are examined in some detail.
Keywords: 2 diisoprovpylphenol; Anesthesia; CLINICAL USE; GABAa receptor; STERIMOL Descriptors; alkylphenols; aminobutyric acid GABA; anticonvulsant; anxiolytic effects; chemical delivery systems CDS; cloned GABA A Receptor; drug delivery; drug monitoring; hypnotic activity; lipid formulations; metabolism; pharmacokinetic; prodrugs; propofol; saccharomices cerevisiae; salmonella mutation; site specific chemical delivery system CDS; target controlled infusion TCI; tomidate; toxicology
Document Type: Review Article
Publication date: 2000-02-01
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