Propofol in Anesthesia. Mechanism of Action, Structure-Activity Relationships, and Drug Delivery

Abstract

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 as the main advantages in using propofol, whereas disadvantages include a relatively high incidence of apnea, and blood pressure reductions. Besides a literature summary of the pharmacodynamics, pharmacokinetics, toxicology, and clinical use, this review provides a deeper discussion on the current understanding of mechanism of action and structure-activity relationships, and recent findings on drug delivery technologies as applied to the improvement of propofol formulations. The action of propofol involves a positive modulation of the inhibitory function of the neurotransmitter gama-aminobutyric acid (GABA) through GABAA receptors. Recent results from recombinant human GABAA 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 Bodor's 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.

Propofol enhances both tonic and phasic inhibitory currents in second-order neurons of the solitary tract nucleus (NTS)

“…Hypotension, bradycardia, desaturation and apnea are noted side effects of propofol administration and are consistent with depression of cardiorespiratory control mechanisms (Trapani et al, 2000;Nieuwenhuijs et al, 2000). Neurons responsible for these homeostatic regulatory mechanisms are concentrated in the brainstem (Loewy, 1990;Guyenet, 2006) and actions in the brainstem are consistent with the substantial autonomic impact of propofol in humans (Ebert & Muzi, 1994;Ebert, 2005).…”

Propofol allows precise quantitative arterial spin labelling functional magnetic resonance imaging in the rat

“…Propofol is an intravenous short-acting anaesthetic agent (Vasileiou et al, 2009) introduced in the 1980's and positively modulates gamma-aminobutyric acid (GABA A ) receptors (Dong and Xu, 2002;Trapani et al, 2000). In a recent study, four anaesthetics; isoflurane, propofol, ketamine, and alpha chloralose, were studied for their effect on cerebral blood perfusion in the striatum.…”

Effects of intra‐operative maintenance of general anaesthesia with propofol on postoperative pain outcomes – a systematic review and meta‐analysis

“…Its mechanism of action is not clear, although increasing inhibitory tone in the gamma-aminobutyric acid (GABA) receptors in the central nervous system has been suggested to play a critical role in its anaesthetic effect. GABA is the major inhibitory neurotransmitter in the central nervous system, and propofol is thought to mediate a positive allosteric modulation of GABA A , which increases the activity of the receptor [2]. However, other mechanisms, such as anti-inflammatory effects and free radical scavenging, have been observed in laboratory investigations.…”