4. Propofol

Propofol is a substituted stable phenolic compound: 2,6-di-isopropylphenol. It is highly lipid-soluble and water-insoluble and is presented as either a 1% or 2% emulsion in soya bean oil. Other constituents include egg lecithin (which is a phospholipid - Egg albumen is antigenic, whereas egg lecithin is not.) and glycerol EDTA) reduces the risk of bacterial contamination. weak organic acid with a pKa of 11.

enhances inhibitory synaptic transmission by activation of the Cl− channel on the β1 subunit of the GABAA receptor = inhibits acetylcholine release in areas such as the prefrontal cortex and parts of the limbic system. inhibits the NMDA subtype of the glutamate receptor

These include induction and maintenance of anaesthesia in adults and children, sedation in intensive care and sedation during procedures under local or regional anaesthesia. Its anti-emetic effects can benefit chemotherapy patients when given by low-dose infusion

The drug is used only intravenously. A dose of 1–2 mg kg−1 will usually induce anaesthesia in adults. Children may require twice this dose. TIVA infusion rates vary greatly, but would typically range between 4 and 12 mg kg−1 h−1 (or 4–8 μg ml–1 effective site concentrations). Propofol is an effective anti-emetic when given at a rate of 0.5–1.0 mg kg−1 hr–1

an induction dose of propofol will lead to rapid loss of consciousness (within a minute). Rapid redistribution to peripheral tissues (distribution half-life is 1–2 minutes) leads to rapid awakening

Propofol is highly protein-bound (98%) and has a large volume of distribution (2–10 l kg−1). As is frequently the case given the heterogeneity of human subjects, the reported pharmacokinetic data vary considerably with its distribution half-life quoted at between 1 and 8 minutes and the elimination half-life at 4–12 hours. It has a relatively short context-sensitive half-life which is quoted as being 40 minutes after infusions of duration up to 8 hours, which therefore makes it a suitable drug for total intravenous anaesthesia. Its metabolism is mainly, although not exclusively, hepatic, with the production of sulphate and glucuronide conjugates and other inactive metabolites which are excreted in urine.

CNS: propofol causes CNS depression and hypnosis. CMRO2 is decreased, as are cerebral blood flow and intracranial pressure. It may be associated with excitatory effects and dystonic movements, particularly in children. Hiccups are common after rapid injection. higher doses it is an effective anti-convulsant, so most anaesthetists ignore the data sheet assertion that it is contraindicated in patients with epilepsy.

Systemic vascular resistance and preload fall, yet it is relatively unusual to see compensatory tachycardia. Relative bradycardia is more common. Propofol is a myocardial depressant, partly via the inhibition of calcium channels, so the reduction in contractility also reduces oxygen demand.

Propofol is a respiratory depressant which also suppresses laryngeal reflexes. (Without this attribute it is unlikely that the use of the laryngeal mask airway would have become so well established. According to the inventor of the device, Dr Archie Brain, his early demonstrations using thiopental for induction did not go at all well.)

: when given by infusion (at a rate of 0.5–1.0 mg kg hr–1) the drug attenuates chemotherapy-induced emesis.

propofol causes pain on injection. Preparations which include medium-chain triglycerides in the formulation have reduced this problem. Longterm infusion, particularly in children but also in adult critical care patients, has been associated with ‘propofol infusion syndrome’. The data sheet for propofol states that it should not be used in pregnancy, but this increasingly is ignored, and many maternity units routinely use propofol for general anaesthesia for caesarean section.

In severe cases this is characterized by hyperlipidaemia, profound metabolic acidosis and rhabdomyolysis which can lead to renal and cardiac failure. The syndrome may be due to effects on mitochondria, either by direct inhibition of the respiratory chain of oxidative phosphorylation or by compromising mitochondrial metabolism of free fatty acids. This remains unproven. It is recommended that infusions should be limited to no more than a rate of 4 mg kg–1 h–1, although this does not eliminate the risk of the syndrome.

: propofol is not a trigger for malignant hyperpyrexia, and it may also be used safely in patients with porphyria. It does not release histamine, and adverse reactions are very rare. It does not have any marked modulating effects on the immune system. (This is in contrast to volatile anaesthetics).

+ good recovery characteristics, avoidance of inhalational agents and their pollution, less nausea cardiostability. - risk of awareness, linked to the wide variability between subjects, the complexity and cost of equipment and the importance of secure intravenous access

It is a highly lipophilic hypnotic that distributes rapidly from blood to the effector site. It then undergoes further rapid redistribution to muscle and fat before being metabolized. The initial distribution half-life, α, of propofol is short (2–3 minutes), whereas intermediate distribution, β1, takes 30–60 minutes. The terminal phase decline, β2, is less steep and takes 3–8 hours. The immediate volume of distribution is 228 ml kg−1, but the steady state volume of distribution in healthy young adults is around 800 litres. CSH Clearance: the whole body clearance of propofol is 2,500 ml min−1.

Context-sensitive half-life (half-time): This is the time taken for the plasma concentration to halve after an infusion designed to maintain constant blood levels is stopped. This is different not only for dissimilar drugs but also for the same drug depending on the duration of infusion. The context-sensitive half-life for propofol is 16 minutes after 2 hours of infusion, 41 minutes after 8 hours. Although this compares less well with remifentanil (4.5 minutes and 9.0 minutes), it means, nonetheless, that accumulation is modest when the drug is infused for moderate periods