Propofol-Lipuro Mechanism of Action

Pharmacotherapeutic group: Other general anaesthetics. ATC code: N01AX10.
Pharmacology: Pharmacodynamics: Mechanism of action, pharmacodynamic effect: After intravenous injection of PROPOFOL-LIPURO EMULSION FOR INJECTION/INFUSION, onset of the hypnotic effect occurs rapidly. 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 due to the rapid metabolism and excretion (4 - 6 minutes).
With the recommended dosage schedule, a clinically relevant accumulation of propofol after repeated bolus injection or after infusion has not been observed.
Patients recover consciousness rapidly.
Bradycardia and hypotension occasionally occur during induction of anaesthesia probably due to a lack of vagolytic activity. The cardio-circulatory situation usually normalises 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: Distribution: After intravenous administration about 98 % of propofol is bound to plasma protein.
After intravenous bolus administration the initial blood level of propofol declines rapidly due to rapid distribution into different compartments (α-phase). The distribution half-life has been calculated as 2 - 4 minutes.
During elimination the decline of blood levels is slower. The elimination half-life during the β-phase is in the range of 30 to 60 minutes. Subsequently a third deep compartment becomes apparent, representing the redistribution of propofol from weakly perfused tissue.
The central volume of distribution is in the range of 0.2 - 0.79 l/kg body weight, the steady-state volume of distribution in the range of 1.8 - 5.3 l/kg body weight.
Biotransformation: Propofol is mainly metabolized in the liver to form glucuronides of propofol and glucuronides and sulphate conjugates of its corresponding quinol. All metabolites are inactive.
Elimination: Propofol is rapidly cleared from the body (total clearance approx. 2 l/min). Clearance occurs by metabolism, mainly in the liver, where it is blood flow dependent. Clearance is higher in paediatric patients compared with adults. About 88 % of an administered dose is excreted in the form of metabolites in urine. Only 0.3 % is excreted unchanged in urine.
Paediatric population: After a single dose of 3 mg/kg intravenously, propofol clearance/kg body weight 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 inter-individual 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).
Toxicology: Preclinical safety data: Preclinical data reveal no specific hazard for humans based on conventional studies on repeated dose toxicity or genotoxicity. Carcinogenicity studies have not been conducted.
Reproductive toxicity studies have shown effects related to pharmacodynamic properties of propofol only at high doses. Teratogenic effects have not been observed.
In local tolerance studies, intramuscular injection resulted in tissue damage around the injection site.