Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other general anaesthetics
ATC code: N01AX10

Mechanism of action

Propofol (2, 6-diisopropylphenol) is a short-acting general anaesthetic agent with a rapid onset of action of approximately 30 seconds. Recovery from anaesthesia is usually rapid. The mechanism of action, like all general anaesthetics, is poorly understood. However, propofol is thought to produce its sedative/anaesthetic effects by the positive modulation of the inhibitory function of the neurotransmitter GABA through the ligand-gated GABAA receptors.

Pharmacodynamic properties

In general, falls in mean arterial blood pressure and slight changes in heart rate are observed when Diprofol 1% is administered for induction and maintenance of anaesthesia. However, the haemodynamic parameters normally remain relatively stable during maintenance and the incidence of untoward haemodynamic changes is low.

Although ventilatory depression can occur following administration of Diprofol 1%, any effects are qualitatively similar to those of other intravenous anaesthetic agents and are readily manageable in clinical practice.

Diprofol 1% reduces cerebral blood flow, intracranial pressure and cerebral metabolism. The reduction in intracranial pressure is greater in patients with an elevated baseline intracranial pressure.

Clinical efficacy and safety

Recovery from anaesthesia is usually rapid and clear headed with a low incidence of headache and post-operative nausea and vomiting.

In general, there is less post-operative nausea and vomiting following anaesthesia with Diprofol 1% than following anaesthesia with inhalational agents. There is evidence that this may be related to a reduced emetic potential of propofol.

Diprofol 1%, at the concentrations likely to occur clinically, does not inhibit the synthesis of adrenocortical hormones.

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.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties

Absorption

When Diprofol 1% is used to maintain anaesthesia, blood concentrations asymptotically approach the steady-state value for the given administration rate.

Distribution
Propofol is extensively distributed and rapidly cleared from the body (total body clearance 1.5–2 litres/minute).

Elimination

The decline in propofol concentrations following a bolus dose or following the termination of an infusion can be described by a three compartment open model with very rapid distribution (half-life 2 –4 minutes), rapid elimination (half-life 30 – 60 minutes), and a slower final phase, representative of redistribution of propofol from poorly perfused tissue.

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 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).

Linearity

The pharmacokinetics are linear over the recommended range of infusion rates of Diprofol 1%.