Pharmacokinetic Implications for the Clinical Use of Propofol

Abstract

Propofol, the recently marketed intravenous induction agent for anaesthesia, is chemically unrelated to earlier anaesthetic drugs. This highly lipophilic agent has a fast onset and short, predictable duration of action due to its rapid penetration of the blood-brain barrier and distribution to the CNS, followed by redistribution to inactive tissue depots such as muscle and fat. On the basis of pharmacokinetic-pharmacodynamic modelling, a mean blood-brain equilibration half-life of only 2.9 minutes has been calculated. In most studies, the blood concentration curve of propofol has been best fitted to a 3-compartment open model, although in some patients only 2 exponential phases can be defined. The first exponential phase half-life of 2 to 3 minutes mirrors the rapid onset of action, the second (34 to 56 minutes) that of the high metabolic clearance, whereas the long third exponential phase half-life of 184 to 480 minutes describes the slow elimination of a small proportion of the drug remaining in poorly perfused tissues. Thus, after both a single intravenous injection and a continuous intravenous infusion, the blood concentrations rapidly decrease below those necessary to maintain sleep (around 1 mg/L), based on both the rapid distribution, redistribution and metabolism during the first and second exponential phases (more than 70% of the drug is eliminated during these 2 phases). During long term intravenous infusions cumulative drug concentrations and effects might be expected, but even then the recovery times do not appear to be much delayed. The liver is probably the main eliminating organ, and renal clearance appears to play little part in the total clearance of propofol. On the other hand, because the total body clearance may exceed liver blood flow, an extrahepatic metabolism or extrarenal elimination (e.g. via the lungs) has been suggested. Approximately 60% of a radiolabelled dose of propofol is excreted in the urine as 1- and 4-glucuronide and 4-sulphate conjugates of 2.6-diisopropyl 1,4-quinol, and the remainder consists of the propofol glucuronide. Thus for hepatic and renal diseases, co-medication, surgical procedure, gender and obesity do not appear to cause clinically significant changes in the pharmacokinetic profile of propofol, but the decrease in the clearance value in the elderly might produce higher concentrations during a long term infusion, with an increased drug effect. In addition, the lower induction dose observed in relation to increased age might be partly explained by a smaller central volume of distribution.(ABSTRACT TRUNCATED AT 400 WORDS)

Treatment of Refractory Status Epilepticus with Pentobarbital, Propofol, or Midazolam: A Systematic Review

“…The pharmacokinetic properties of MDL and PRO (18)(19)(20)(21) suggest that these agents may be advantageous for terminating seizures more quickly than PTB. Data in our systematic review were not sufficient to compare this important outcome variable.…”

“…MDL (a 1,4-benzodiazepine belonging to the 1,2-anelated subgroup) is a fast-acting water-soluble benzodiazepine (BZD) with a half-life of 1.2 to 12.3 h (18,19). PRO (2,6-diisopropylphenol) is a very fast acting agent with a second exponential phase half-life of 34 to 56 min, reflecting its high rate of metabolic clearance, and a third-phase half-life of 184 to 480 min (20). PTB (sodium-5-ethyl-5,1-methylbutyl barbiturate) is a barbiturate with onset of action after 15-20 min and a half-life of 15-60 h (21).…”

Propofol Sedation Exacerbates Kidney Pathology and Dissemination of Bacteria during Staphylococcus aureus Bloodstream Infections

“…Propofol is lipophilic and is rapidly distributed into tissues and metabolized following the cessation of intravenous administration, a fact that explains why sedation is short-lived (22,57,58). It is possible that metabolites of propofol that persist within tissues for several days lead to the suppression of host immunity against microbial infection.…”

Safety and Efficacy of Deep Sedation with Propofol Alone or Combined with Midazolam Administrated by Nonanesthesiologist for Gastric Endoscopic Submucosal Dissection

“…Propofol also provided significantly better patient cooperation than midazolam. 12,13 However, this agent occasionally decreases systemic vascular resistance, cardiac contractility, and ultimately cardiac output without a concomitant change in heart rate, and respiratory depression can also occur. 5,14,15 Recently, several studies have revealed most adverse events associated with propofol sedation were mild and often transient during advanced interventional endoscopic procedure.…”