Propofol: A Review of its Pharmacodynamic and Pharmacokinetic Properties and Use as an Intravenous Anaesthetic

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SummarySynopsisPropofol is an intravenous anaesthetic which is chemically unrelated to other anaesthetics. Induction of anaesthesia with propofol is rapid, and maintenance can be achieved by either continuous infusion or intermittent bolus injections, with either nitrous oxide or opioids used to provide analgesia.Comparative studies have shown propofol to be at least as effective as thiopentone, methohexitone or etomidate for anaesthesia during general surgery. The incidence of excitatory effects is lower with propofol than with methohexitone, but apnoea on induction occurs more frequently with propofol than with other anaesthetics. Additionally, a small number of studies of induction and maintenance of anaesthesia have found propofol to be a suitable alternative to induction with thiopentone and maintenance with halothane, isoflurane or enflurane. Propofol is particularly suitable for outpatient surgery since it provides superior operating conditions to methohexitone (particularly less movement), and rapid recovery in the postoperative period associated with a low incidence of nausea and vomiting. When used in combination with fentanyl or alfentanil, propofol is suitable for the provision of total intravenous anaesthesia, and comparative studies found it to be superior to methohexitone or etomidate in this setting.Infusions of subanaesthetic doses of propofol have been used to sedate patients for surgery under regional anaesthesia, and also to provide sedation of patients in intensive care. In the latter situation it is particularly encouraging that propofol did not suppress adrenal responsiveness during short term studies. If this is confirmed during longer term administration this would offer an important advantage over etomidate.Thus, propofol is clearly an effective addition to the limited range of intravenous anaesthetics. While certain areas of its use need further study, as would be expected at this stage of its development, propofol should find a useful role in anaesthetic practice.Pharmacodynamic PropertiesSingle bolus doses of propofol 2 to 2.5 mg/kg produce unconsciousness within 1 minute in a majority of patients, although dose requirements are reduced in older patients and by premedication with opioids. Anaesthesia can be maintained with intermittent bolus doses or continuous infusions: for example, an administration rate of 9 mg/kg/h fully anaesthetised 85% of patients and rates of less than 6 mg/kg/h produced sedation, but not unconsciousness, in most individuals.Recovery from propofol anaesthesia is rapid. Psychomotor impairment following recovery is minimal - following maintenance of anaesthesia with propofol significant increases in reaction times are evident for up to 30 minutes after surgery and a degree of CNS sedation may be detectable for up to 3 hours. Comparative studies indicate that propofol produces slightly less residual impairment of performance than methohexitone. Propofol produces characteristic changes in EEG patterns which are correlated to blood concentrations of the drug. It does not have the antanalgesic properties associated with thiopentone, and has been shown to produce a low incidence of postoperative nausea.Induction doses of propofol 2 mg/kg reduced systolic and diastolic blood pressures by 16 and 11%, respectively, in unpremedicated patients and 2.5 mg/kg reduced mean arterial blood pressure by up to 32% in patients premedicated with papaveretum. These actions of propofol are potentiated by the coadministration of fentanyl, and with this combination of drugs blood pressure increases in response to surgery and intubation are significantly reduced.Induction with propofol is frequently accompanied by apnoea which may last more than 60 seconds, and maintenance of anaesthesia with propofol infusions produces dosedependent decreases in respiratory rate, tidal volumes and minute volumes. This respiratory depression is increased by fentanyl, and when this is the case, the effect may persist into the postoperative period.Propofol was found to be about 1,000 times less potent than etomidate at inhibiting ACTH-induced cortisol production in vitro. In clinical practice plasma cortisol concentrations were reduced in anaesthetised surgical patients and patients sedated using subanaesthetic infusions, but propofol did not inhibit adrenal responses to exogenous ACTH during short term administration.Pharmacokinetic PropertiesFollowing bolus injections of propofol, blood concentrations decline rapidly. Administration by infusion produces an initial rapid increase followed by a slower rise to a virtual steady-state, although blood propofol concentrations continue to increase asymptotically throughout the infusion. The final steady-state concentration resulting from an infusion of 9 mg/kg/h was estimated at 6 mg/L.Propofol distributes rapidly and extensively from blood with a distribution half-life of approximately 2 to 4 minutes and a volume of distribution (Vd) of between 209 and 1008L. In several studies the pharmacokinetic data best fitted an open 3-compartment model, which indicates that propofol is probably distributed into 2 distinct tissue compartments.Propofol is metabolised rapidly, with 88% of an administered dose appearing in the urine as a propofol conjugate (about 40% of urinary excretion products), conjugates of 4-hydroxy propofol (about 60%) and a small amount (< 0.3%) of unchanged propofol. Estimates of total body clearance of propofol vary from 94 to 139 L/h. In studies where a 2-compartment model was used, the elimination half-life (t½) of propofol was usually about 100 minutes, whereas when a 3-compartment model was found more appropriate the elimination of propofol was considered biphasic, with a first-stage half-life (t½β) of 25 to 56 minutes, and a terminal elimination half-life (t½γ) of 184 to 309 minutes following single doses and 277 to 403 minutes following infusions.Data from a small number of elderly patients show that the total clearance and initial volume of distribution of propofol are reduced in old age. Preliminary reports suggest that neither renal nor liver disease alter the pharmacokinetics of propofol. Other anaesthetic drugs may affect the disposition of propofol - in particular the concomitant use of fentanyl reduces its volume of distribution and elimination half-life, and also reduces propofol clearance by about one-third.Clinical StudiesDuring general surgical procedures lasting up to 3 hours using propofol in combination with nitrous oxide and/or opioid analgesics, induction and maintenance of anaesthesia were rated ‘good’ or ‘adequate/acceptable’ in 84 to 100% of patients, with patients always waking within 15 minutes of the end of surgery. In comparative studies, propofol 2 to 2.5 mg/kg was at least as effective as thiopentone 4 to 5 mg/kg and methohexitone 1.5 mg/kg for induction of anaesthesia, with less spontaneous movement than with methohexitone and better recovery than after thiopentone, although propofol produced the highest incidence of apnoea. Propofol was also considered superior to both of these drugs for the maintenance of anaesthesia and usually produced more rapid recovery. Preliminary studies also reported propofol for both induction and maintenance to be a suitable alternative to induction with thiopentone and maintenance with halothane or isoflurane, although this requires further confirmation.Favourable operating conditions and rapid recovery were noted when propofol was used as an anaesthetic for outpatient surgery. When compared with methohexitone in this setting, recovery of normal psychomotor function occurred more rapidly in patients anaesthetised with propofol and post operative nausea and vomiting occurred less frequently.Although an infusion of propofol 12 mg/kg/h alone did not provide adequate anaesthesia, the additional use of alfentanil produced good operating conditions in total intravenous anaesthesia procedures. In comparative studies, propofol was superior to etomidate for maintenance of anaesthesia when used in combination with either alfentanil or fentanyl. The combination of propofol and alfentanil was also superior to methohexitone plus alfentanil in terms of induction and recovery from anaesthesia.Infusions of subanaesthetic doses of propofol (between about 3 and 6 mg/kg/h) have been used to sedate patients for colonoscopy and for surgery using spinal analgesia. Similarly, critically ill patients under intensive care have been sedated with propofol infusions of less than 2 mg/kg/h, and in these circumstances propofol allowed good control of the depth of sedation and rapid recovery of spontaneous breathing when mechanical ventilation was withdrawn. Although plasma cortisol concentrations decreased during propofol infusions, the adrenal response to ACTH was not affected during these short term studies, in contrast to the depression of adrenal responsiveness seen with etomidate. If adrenal function is similarly unaffected during longer term administration of propofol, this will offer an important benefit in the intensive care setting.Side EffectsThe most frequent side effect of propofol is pain during injection. This is experienced by about 30% of patients when veins in the dorsum of the hand are used, but by only 6 to 8% of patients if administration is into the larger veins of the forearm or antecubital fossa. Apnoea is common during induction with propofol and may last for more than 60 seconds. Excitatory effects are seen in about 14% of cases.Isolated instances of bradycardia have occurred in patients anaesthetised with propofol; these are usually associated with vagal stimulation and have not been clearly attributable to propofol itself. Epileptiform movements have also been reported in rare instances, but again these could not be directly related to propofol. The only other serious complications during surgery to which propofol may have contributed are a few reported cases of severe hypotension.Dosage and AdministrationInduction doses of propofol are best given as 40mg increments at 10-second intervals until full anaesthesia is achieved. The dose required in adults is normally 2 to 2.5 mg/kg, but older patients may require a lower dose. The rate of administration should be halved in infirm patients. Anaesthesia can be maintained either with a continuous infusion of propofol (approximately 6 to 12 mg/kg/h) or with bolus injections of propofol 20 to 50mg as required.

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