Propofol

The intravenous anaesthetic propofol can be used both for induction and maintenance of anaesthesia, largely due to its favourable ‘wake up’ profile. Although it is possible to give a bolus dose of propofol without understanding its pharmacokinetics, to use it sensibly by infusion requires some understanding of kinetics.

Propofol is a sterically hindered phenol: the potentially active hydroxyl (-OH) group is shielded by the electron clouds surrounding the attached isopropyl ((CH₃)₂CH-) groups, which reduces its reactivity. So, unlike phenol, propofol is insoluble in water but highly soluble in fat hence its preparation as a lipid emulsion. The phenolic hydroxyl group makes propofol a weak acid, but significant ionisation occurs only at a pH greater than 10. High lipid solubility means that after long infusions there is the risk of accumulation in fatty tissues. There are no active metabolites of propofol. The combination of high lipid solubility and insignificant ionisation means that once propofol distributes into fat it will redistribute back into plasma relatively slowly. The extremely large volume of distribution of propofol is accounted for mainly by the third compartment and although a relatively large amount of drug, in terms of milligrams, may distribute into this volume, the concentration rises only very slowly.

An induction dose of propofol is extensively bound to plasma proteins (98% bound to albumin) following intravenous injection. After the initial bolus dose there is rapid loss of consciousness as the lipid tissue of the central nervous system (CNS) takes up the highly lipophilic drug. Over the next few minutes propofol then distributes to peripheral tissues and the concentration in the CNS falls (see Figure 7.1), such that in the absence of further doses or another anaesthetic agent the patient will wake up. Its distribution half-life is 1–2 minutes and accounts for the rapid fall in plasma levels with a short duration of action. The very rapid elimination of propofol by hepatic and extra-hepatic metabolism also contributes significantly to this rapid reduction in plasma concentration. The terminal elimination half-life is very much longer (5–12 hours) reflecting relatively slow redistribution from the fatty tissues and plays an insignificant role in offset of clinical action following a bolus dose.

Figure 7.1 Time course of a bolus dose of propofol.

The pharmacodynamic profile of propofol lags behind plasma concentration due to the short delay in access to and from the CNS. Time-to-peak effect of a bolus dose of propofol is in the order of a few minutes (‘t’, Figure 7.1) and has been described by different models as 1.7–3.9 minutes, so the brain concentration of propofol is lower than that of plasma on induction but higher during the elimination phase. There is a relationship between plasma concentration and effect when equilibrium is reached between brain and plasma, but the lag-time before equilibrium is reached must be accounted for in a kinetic model. Modelling this lag-time requires use of depth of anaesthesia monitoring, usually the bispectral monitor (BIS), as a surrogate measure of brain (effect compartment) concentration.

Anaesthesia with propofol can be induced and maintained by its delivery according to a three-compartment model with an effect compartment that equilibrates with the central compartment. The lag-time referred to above between plasma and effect compartments is included by considering the effect compartment as one with no volume but a rate constant of elimination, k_eo. The half-life for equilibration is known as the t_1/2keo.

Remifentanil

Remifentanil is a fentanyl derivative that is a pure µ agonist. It has an ester linkage, which is very rapidly broken down by plasma and non-specific tissue esterases, particularly in muscle. The metabolites have minimal pharmacodynamic activity. With increasing age, muscle bulk decreases and this significantly influences the rate of remifentanil metabolism. The offset of clinical activity is rapid and not greatly affected by duration of infusion; as discussed below remifentanil has a relatively constant context-sensitive half-time between 3 and 8 minutes. Therefore, a patient may be maintained on a remifentanil infusion for a long period, without significant drug accumulation as seen with other opioids. The advantage of this pharmacokinetic profile is that a patient may be given prolonged infusions of remifentanil for analgesia during surgery, with rapid offset of action when this is no longer required. The potential disadvantage is that its analgesic effect wears off so rapidly that pain may be a significant problem immediately post-operatively. Inadequate provision of analgesia before discontinuing remifentanil may be associated with hyperalgesia in the recovery area that can be difficult to treat without using high doses of other opiates, which may lead to adverse consequences. Post-operative pain must therefore be anticipated, either by using a regional technique or by the administration of a longer-acting opioid before the end of surgery.

Manual Total Intravenous Anaesthesia: The Bristol Model

The Bristol algorithm provides a simple manual infusion scheme for propofol to achieve a target blood concentration of about 3 µg.ml⁻¹ within 2 minutes and to maintain this level for the duration of surgery (see Figure 7.2). This is based on plasma concentrations obtained from healthy patients premedicated with temazepam and induced with fentanyl 3 µg.kg⁻¹ followed by a propofol bolus of 1 mg.kg⁻¹. Induction is followed by a variable-rate infusion of propofol at 10 mg.kg⁻¹.h⁻¹ for 10 minutes, 8 mg.kg⁻¹.h⁻¹ for 10 minutes then 6 mg.kg⁻¹.h⁻¹ thereafter. This ‘10–8–6’ infusion scheme was supplemented with nitrous oxide and patients were ventilated. Clearly, if higher plasma concentrations of propofol are needed to maintain adequate anaesthesia, then the 10–8–6 algorithm should be adjusted appropriately or an additional intravenous supplement used, such as a remifentanil infusion.

Figure 7.2 The Bristol Model, ‘10–8–6’.

Although anaesthesia can be delivered using a manual infusion, studies have shown that using a TCI provides anaesthesia using a lower total dose of propofol with the associated benefits of more haemodynamic stability and a more rapid awakening.