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Pharmacotherapeutic group: Anaesthetics; Other general anaesthetics. ATC-Code: N01AX10.
Pharmacology: Pharmacodynamics: Mechanism of action/Pharmacodynamic effects: Propofol (2,6-diisopropylphenol) is a short-acting general anaesthetic agent with a rapid onset of action. Depending on the rate of injection, the time to induction of anaesthesia is between 30 and 40 seconds. The duration of action after a single bolus administration is short and lasts, depending on the metabolism and elimination, 4 to 6 minutes.
Clinical efficacy and safety: Under the usual maintenance regimen, significant accumulation with either repeated injections or infusions of propofol has not been seen. Patients recover consciousness rapidly.
Bradycardia and hypotension reported during induction of anaesthesia may be caused by a cerebral vagotonic effect or inhibition of sympathetic activity. However, haemodynamics generally reverts to normal during maintenance of anaesthesia.
Paediatric population: Limited studies on the duration of propofol-based anaesthesia in children indicate safety and efficacy is unchanged up to duration of 4 hours. Literature evidence of use in children documents use for prolonged procedures without changes in safety or efficacy.
Pharmacokinetics: Absorption: Propofol is bound to plasma proteins for 98%. Following intravenous administration, the pharmacokinetics of propofol can be described by a 3-compartment model.
Distribution/Biotransformation/Elimination: Propofol is extensively distributed and rapidly cleared from the body (total body clearance: 1.5 - 2 litres/minute). Clearance occurs by metabolic processes, mainly in the liver where it is blood flow dependent, to form inactive conjugates of propofol and its corresponding quinol, which are excreted in urine.
After a single dose of 3 mg/kg intravenously, propofol clearance/kg bodyweight increased with age as follows: Median clearance was considerably lower in neonates <1 month old (n=25) (20 ml/kg/min) compared to older children (n=36, age range 4 months - 7 years). Additionally, interindividual variability was considerable in neonates (range 3.7 - 78 ml/kg/min). Due to this limited trial data that indicates a large variability, no dose recommendations can be given for this age group.
Median propofol clearance in older aged children after a single 3 mg/kg bolus was 37.5 ml/min/kg (4 - 24 months) (n=8), 38.7 ml/min/kg (11 - 43 months) (n=6), 48 ml/min/kg (1 - 3 years) (n=12), 28.2 ml/min/kg (4 - 7 years) (n=10) as compared with 23.6 ml/min/kg in adults (n=6).
Due to the limited data available, the use of target controlled infusion (TCI) in the paediatric population below 2 years of age cannot be recommended.
Toxicology: Preclinical safety data: Preclinical data reveal no special hazard for humans based on conventional studies on repeated dose toxicity or genotoxicity. Carcinogenicity studies have not been conducted. Teratogenic effects have not been observed. In local tolerance studies, intramuscular injection resulted in tissue damage around the injection site, paravenous and subcutaneous injection induced histological reactions marked by inflammatory infiltration and focal fibrosis.
Published studies in animals (including primates) at doses resulting in light to moderate anaesthesia demonstrate that the use of anaesthetic agents during the period of rapid brain growth or synaptogenesis results in cell loss in the developing brain that can be associated with prolonged cognitive deficiencies. The clinical significance of these nonclinical findings is not known.
