Six months ago most lay people had no idea what propofol was, what it was used for, or even if it was a drug. However, since Michael Jackson's untimely death a few short months ago, the notoriety of propofol has climaxed. If Michael Jackson's death was related to the administration of the powerful anesthetic propofol, then he must have been injected with more propofol than his personal physician reportedly told police he gave to Jackson, medical experts have said. According to court records unsealed in Houston on August 24, 2009, Dr. Conrad Murray told police that he had given Jackson 50 mg of propofol each night over a 6-week period. In a 3-hr interview with police, Murray said on the night of Jackson's death, the physician gave him a combination of benzodiazepines before yielding to Jackson's demands for more propofol. According to court documents, Murray gave Jackson only 25 mg of propofol on the night of the star's death. But 25 mg is less than the dosage required to anesthetize someone and keep him or her asleep, several experts have said (Yoshino, 2009). This article will discuss the indications, adverse effects, and actions of propofol.
PROPOFOL ABUSE
Propofol is not a controlled substance and is mainly used in operating rooms, procedure rooms, and intensive care units. Propofol abuse was originally limited to anesthesia professionals who have ready access to the drug. With a self-administered intravenous dose, propofol offers effects ranging from a brief sense of well-being to unconsciousness without any "hangover." Propofol's brief effects, quick metabolism, and no "hangover" offer specific advantages for use in operating rooms, yet propofol poses a narrow therapeutic index for abusers. Propofol's potency and narrow dose range leave little margin for error and provide effects ranging from euphoria to unconsciousness and apnea. Abusers of propofol are powerless to fight effects of the drug and may injure themselves immediately after self-administration by falling. In 1989, the Food and Drug Administration approved propofol with little thought of its potential abuse. Yet even before the Michael Jackson media coverage, the Food and Drug Administration was petitioned to make propofol a controlled substance. Propofol has addictive potential and may cause intense dreams, amorous behavior, and hallucinations.
Propofol is supplied in a 1% solution, providing 10 mg of drug in an aqueous solution of 10% soybean oil, 2.25% glycerol, and 1.2% egg phosphatide. Propofol is a substituted isopropylphenol with the chemical name of 2,6-diisopropylphenol.
Why has propofol become a popular drug for anesthesia? Propofol has the most rapid and complete awakening of any induction drug, rendering it ideal for use in plastic surgery. The most important advantage of propofol is the rapid return of consciousness with minimal residual central nervous system effects.
PHARMACOKINETICS OF PROPOFOL
Propofol interacts with [gamma]-aminobutyric acid (GABA), the principal inhibitory neurotransmitter. GABA receptors are large macromolecules exclusively located in the central nervous system that contain physically separate receptor sites for a variety of drugs including propofol, benzodiazepines, and alcohol. Propofol exerts its pharmacologic effects by interaction with GABA receptors located in the reticular activating system, the chemoreceptor trigger zone, and the medullary and pontine ventilatory centers. Other body systems are without GABA receptors, thus limiting propofol activity to the central nervous system. Propofol causes a slower rate of dissociation of GABA from receptors, and an increased duration of GABA-activated opening of chloride channels resulting in hyperpolarization of cell membranes, resulting in sedation, unconsciousness, and centrally mediated ventilatory depression.
Clearance of propofol from plasma is due to rapid hepatic and extra-hepatic metabolism and tissue uptake by the vessel rich group. Hepatic metabolism of propofol is rapid and extensive with less than 0.3% excreted unchanged in urine. The metabolism rate of propofol exceeds hepatic blood flow rates, confirming extra-hepatic metabolism sites. Metabolites, excreted in the urine, are all pharmacologically inactive, water-soluble sulfate and glucuronic acid compounds.
Propofol's elimination 1/2 time is 0.5 to 1.5 hr. The context sensitive 1/2 time (time of a single compartment plasma concentration reduction by 50%) is less than 40 min for infusions. The length of a propofol infusion does not significantly alter context sensitive 1/2 time. Propofol metabolism is so rapid that as soon as propofol leaves tissue storage sites it is broken down so plasma concentrations do not increase.
Propofol has a short effect-site equilibration, which means that a dose of propofol provides a rapid onset of effects. There is no impairment of propofol elimination with cirrhosis or renal failure. Propofol crosses the placental barrier but is rapidly cleared from fetal circulation.
INDICATIONS FOR PROPOFOL
Appropriate use of propofol is as an induction drug for anesthesia, especially in outpatient plastic surgery settings, when rapid wakeup is desirable. Propofol doses for anesthesia induction are 1.5-2.5 mg/kg. Induction doses are often given incrementally to avoid hypotension. For induction of anesthesia, a dose of 1.5-2.5 mg/kg produces blood levels of 2-6 [mu]g/ml, which produce unconsciousness. Children need greater doses up to 2.5-3.5 mg/kg due to larger central distribution volumes and greater clearance rates. The elderly need smaller doses due to smaller central distribution volumes and smaller clearance rates. A 1.5-2.5 mg/kg dose of propofol has equal potency to 4-5 mg/kg thiopental or 1.5 mg/kg methohexital.
Propofol may be given by continuous infusion for conscious sedation during plastic surgery procedures performed utilizing local anesthesia. Consciousness sedation doses range from 25 to 100 [mu]g/kg/min and produce minimal analgesia effects, so time should be allowed for local anesthetics to work before surgical incision when using propofol sedation. Significant amnesia effects and the reduction of postoperative nausea and vomiting make the use of propofol beneficial in plastic surgery. Propofol's short context sensitive 1/2 time and effect site equilibration provide easy titration during plastic surgery procedures, allowing levels of sedation to be adjusted according to clinical demands.
Propofol sedation may be supplemented with benzodiazepines or opioids necessitating a lower dose of propofol. Propofol provides control of the stress response and possesses anticonvulsant and amnesia properties. Postoperative nausea and vomiting is reduced when propofol is given anytime during an anesthetic induction. Small doses may be effectively used in the postanesthesia care unit, especially if the nausea and vomiting is not vagal in origin. Propofol treats nausea and vomiting in doses that do not produce sedation, that is, a 10-mg bolus followed by 10 [mu]g/kg/min infusion. Subhypnotic propofol doses are even effective against chemotherapy-induced nausea and vomiting.
Propofol has a unique profile of central nervous system depression. Propofol uniformly depresses central nervous system structures including subcortical areas where propofol's anti-emetic actions may be exerted. Propofol has a direct depressant effect on the vomiting center, although the mechanism is unclear. Propofol in 10-mg doses treats pruitis. The mechanism by which propofol treats pruitis is unclear, perhaps because of decreased segmental spinal cord activity.
SIDE EFFECTS OF PROPOFOL
Propofol has anti-convulsant properties due to GABA-mediated pre- and postsynaptic inhibition. Propofol decreases cerebral metabolic oxygen requirements, cerebral blood flow, and intracranial pressures. Large propofol doses may reduce blood pressure enough to lower cerebral perfusion pressures. Propofol produces EEG cortical changes similar to thiopental including burst suppression in high doses but does not alter evoked potential monitoring.
Propofol may significantly lower systemic blood pressure. Propofol may have negative inotropic effects by decreasing intracellular calcium (Ca++) levels via inhibition of transsarcolemmal calcium influx. Propofol inhibits sympathetic vasoconstrictor nerve activity. Hypotensive effects of propofol are greater with hypovolemia, the elderly, impaired left ventricular function, and atherosclerotic coronary artery disease. Hydration may lessen hypotensive effects of propofol.
Rare asystole occurs with the administration of propofol. There is a questionable benefit from premedication with anticholinegics. The incidence of asystole with propofol has been reported as less than 1.4 in 100,000 administrations. Propofol may reduce sympathetic nervous system activity more than parasympathetic activity in patients who experience asystole.
Propofol causes a dose-dependent ventilatory depression with apnea occurring in 25%-35% of propofol inductions of anesthesia. A propofol infusion decreases both tidal volume and respiratory rate with ventilator responses to CO2 and blunts arterial hypoxemia. Propofol may cause bronchodilation and reduce wheezing in asthmatic patients.
Convulsion mimicking movements are rarely seen with propofol use and are not real seizures but rather spontaneous excitatory movements of subcortical origin.
Propofol supports Escherichia coli and pseudomonas growth. When opening propofol vials, use aseptic technique and administer the propofol as quickly as possible after being drawn up.
True allergic reactions with first-dose propofol can occur, typically seen in patients with prior exposures to diisopropyl radicals found in skin preparations, patients with multiple other allergies, or neuromuscular blocker allergies. The most common adverse effect of propofol is pain on injection, occurring in 10% of patients. Pain on injection may be avoided by using large veins for injection, opioids, and xylocaine. The incidence of phlebitis with propofol administration is less than 1%.
CONCLUSION
Could a 25-mg dose of propofol have caused the death of Michael Jackson? Toxicology results revealed that Jackson had the benzodiazepines lorazepam and diazepam in his system at the time of death. Is it possible that benzodiazepines and a 25-mg dose of propofol had sufficient cumulative effects to result in apnea? Midazolam did not alter the induction or maintenance dose requirements for propofol in one study of patients undergoing minor gynecological surgery (Oxorn, Ferris, Crsych, & Orser, 1997). Doses of propofol necessary for endotracheal intubation in dogs were not found to be altered with the administration of diazepam 0.25 mg/kg (Braun, Hofmeister, Lockwood, & Parfitt, 2007). However, respiratory depression and even apnea are known to occur with larger propofol doses necessary for the induction of anesthesia. Propofol causes dose-dependent ventilatory depression with apnea in 25%-35% of inductions (Stoelting & Hillier, 2005).
The precise cause of Michael Jackson's death may never be fully understood. What is clear, however, is that the administration of propofol requires preparation for the treatment of respiratory depression, which may progress to apnea. With propofol's widespread use in plastic surgery, vigilance by nursing staff is necessary to minimize respiratory depressant effects of propofol.
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