27 May 2007


General Anesthetics

Description: Propofol (2,6-diisopropylphenol) is an intravenous, nonbarbiturate anesthetic that is chemically unrelated to other intravenous anesthetics. Propofol is used to induce anesthesia that can be maintained by continuous infusion or with inhalation anesthetics. Propofol induces anesthesia as quickly as thiopental, but emergence from anesthesia is 10-times more rapid than with thiopental and is associated with minimal postoperative confusion. Only desflurane has a more rapid recovery time than propofol, but desflurane is associated with nausea/vomiting. Propofol has no analgesic activity and causes sedation at a lower dosage than that needed for anesthesia. Unlike many other general anesthetics, propofol possesses antiemetic activity. Propofol (Diprivan®) received FDA approval in October 1989. In March 1997, the FDA granted exclusivity until 2015 to Zeneca for a modified formulation that contains disodium edetate (EDTA) to retard microorganism growth. A generic formulation of propofol is available, but it contains sodium metabisulfite and not EDTA as the preservative.

Mechanism of Action: Propofol appears to inhibit the NMDA subtype of glutamate receptors by channel gating modulation and has agonistic activity at the GABAA receptor. Propofol enhances the amplitude of currents evoked by subthreshold concentrations of gamma-aminobutyric acid (GABA) and directly activates the GABAA receptor in the absence of GABA. Propofol activates chloride channels in the β1 subunit of GABAA, but it is unknown if propofol binds directly to the receptor, binding sites, or if the effects are a result of mediation of distinct mechanisms, such as second messengers. Propofol and benzodiazepines have similar effects on GABAA receptor deactivation but different effects on desensitization. Receptor desensitization causes a fall from a peak (activation) due to agonist application to an apparent steady state. Deactivation is the rate of decay to baseline following the termination of drug application. Both drugs slow the rate of deactivation, but only propofol decreases the rate and extent of receptor desensitization in the presence of saturating concentrations of GABA. In the presence of sub-maximal concentrations of GABA, both drugs slow the rate and extent of receptor desensitization. The anesthetic and amnesic properties of propofol may be or partly a result of NMDA-mediated excitatory neurotransmission depression. The utility of propofol for refractory migraine, status epilepticus, and delirium tremens may be due to enhanced inhibitory synaptic transmission from GABAA receptor agonism or glutamate receptor inhibition.

Propofol with hypocarbia increases cerebrovascular resistance and decreases cerebral blood flow, cerebral metabolic oxygen consumption, and intracranial pressure. The decrease in cerebral blood flow and intraocular pressure is likely a result of a decrease in systemic vascular resistance. Propofol does not affect cerebrovascular reactivity to changes in arterial carbon dioxide tension.

Propofol has been shown to possess antiemetic properties. Propofol reduces the concentration of serotonin and 5-hydroxyindoleacetic acid in the area postrema. The reduction may be mediated by the GABAA receptor. Propofol also reduces the synaptic transmission in the olfactory cortex, which suggests a decrease in the release of excitatory amino acids like glutamate and aspartate. Propofol does not affect gastric emptying time or dopamine D2 receptors.

Pharmacokinetics: Propofol is administered intravenously and, due to its high lipophilicity, is rapidly distributed to all tissues in the body. There is fast equilibration between the plasma and the brain. Loss of consciousness usually occurs within 40 seconds, although the onset of action varies with the dose, rate of administration, and extent of premedication. Propofol crosses the placenta and is distributed into breast milk. Propofol is 95—99% protein-bound. The time to tissue saturation depends on the rate and duration of the infusion. Propofol is metabolized in the liver where it rapidly undergoes glucuronide conjugation to inactive metabolites. Initially, the fall in plasma concentration is roughly 50% due to tissue distribution and 50% due to metabolic clearance. The duration of action of a 2—2.5 mg/kg bolus injection is 3—5 minutes despite a delayed release of drug from deep compartments. The steady state concentration is generally proportional to the infusion rate. The clearance of propofol exceeds estimated hepatic blood flow, which suggests extrahepatic routes of metabolism. The elimination half-life of 3—12 hours is the result of slow release of propofol from fat stores. About 70% of a single dose is excreted renally in 24 hours (90% in 5 days). The terminal half-life is 1—3 days after a 10-day infusion.

Recovery from anesthesia is rapid (8—19 minutes for 2 hours of anesthesia) and is associated with minimal psychomotor impairment. The time to awakening is affected by the tissue drug concentration. The longer the infusion, the greater time to awakening, which usually occurs at a propofol concentration of 0.5 µg/mL or less. Emergence from light sedation (Ramsey score from 3 to 2) is usually less than 35 minutes if the infusion has lasted 3 days or less. The emergence time could be up to 3.5 hours or longer for patients that receive more than 3 days of propofol even if the sedation score is kept at 3. The more heavily sedated the patient, the longer the emergence time will likely be, especially for long infusion times. Longer emergence times may occur in obese patients. Significant propofol accumulation may occur with long-term propofol use. Due to peripheral tissue saturation, the rate at which the propofol concentration will fall becomes more dependent on metabolic clearance than tissue redistribution.

Special populations: Total body clearance and volume of distribution of propofol are decreased in the elderly whereas these values in children between 3 and 12 years of age are similar to those of adults. The pharmacokinetics of propofol do not appear to be affected by chronic hepatic or renal disease.

Van Hemelrijck J, Smith I, White PF. Use of desflurane for outpatient anesthesia. A comparison with propofol and nitrous oxide. Anesthesiology 1991;75:197—203.