Propofol in anesthesia. mechanism of action, structure-activity relationships, and drug delivery

Propofol (2,6-diisopropylphenol) is becoming the intravenous anesthetic of choice for ambulatory surgery in outpatients. It is extensively metabolized , with most of the administered dose appearing in the urine as glucuronide conjugates. Favorable operating conditions and rapid recovery are claimed a s the main advantages in using propofol, whereas disadvantages include a re latively high incidence of apnea, and blood pressure reductions. Besides a literature summary of the pharmacodynamics, pharmacokinetics, toxicology, a nd clinical use, this review provides a deeper discussion on the current un derstanding of mechanism of action and structure-activity relationships, an d recent findings on drug delivery technologies as applied to the improveme nt of propofol formulations. The action of propofol involves a positive modulation of the inhibitory fun ction of the neurotransmitter gamma-aminobutyric acid (GABA) through GABA(A ) receptors. Recent results from recombinant human GABAA receptor experimen ts and findings from the work exploring the effects at other receptors (e.g ., glycine, nicotinic, and M1 muscarinic receptors) are reviewed. Studies s howing its antiepileptic and anxiolytic properties are also discussed. The structure-activity relationships (SAR) of series of alkylphenols and p-X-su bstituted congeners have been reinvestigated. Interestingly, unlike the oth er congeners tested sofar, p-iodo-2,6-diisopropylphenol displayed anticonvu lsant and anticonflict effects, but not sedative-hypnotic and anesthetic pr operties. Due to its high lipid-solubility, propofol was initially formulat ed as a solution with the surfactant Cremophor EL, but the occurrence of pa in on injection and anaphylactoid reactions prompted to search for alternat ive formulations. Results from using cyclodextrins, water-soluble prodrugs, and adopting Bodor's approach to the site-specific chemical delivery syste m (CDS), as well as the advantages provided by computer-controlled infusion systems, are examined in some detail.