Source: Medicines and Medical Devices Safety Authority (NZ) Revision Year: 2021 Publisher: Provive 1% is distributed in New Zealand by: Baxter Healthcare Ltd, 33 Vestey Drive, Mt Wellington, Auckland 1060 Baxter Healthcare Ltd, PO Box 14 062, Panmure, Auckland 1741 Phone (09) 574 2400
Pharmacotherapeutic group: Other general anaesthetics
ATC code: N01AX10
Propofol 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, as for other general anaesthetics, is poorly understood. It is thought that propofol produces its sedative/anaesthetic effects by the positive modulation of the inhibitory function of the neurotransmitter GABA through the ligand‐gated GABAA receptors. The majority of pharmacodynamic properties exhibited by propofol are proportional to the dose or concentration in the blood. These dose or dose rate dependent properties include the desired therapeutic effects of mild sedation through to anaesthesia, but also include the increasing incidence of cardiac and respiratory depression seen with increasing dose.
The cardiovascular effects of propofol range from a minimal reduction in blood pressure through to arterial hypotension, and a decrease in heart rate. 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 propofol, any effects are qualitatively similar to those of other intravenous anaesthetic agents and are readily manageable in clinical practice.
It has been reported that in patients with normal intraocular pressure that propofol anaesthesia produces a decrease in intraocular pressure, which may be associated with a concomitant decrease in systemic vascular resistance.
In combination with hypocarbia, propofol increases cerebrovascular resistance, decreases cerebral blood flow, cerebral metabolic oxygen consumption and intracranial pressure, but does not affect cerebrovascular reactivity to changes in arterial carbon dioxide tension.
It has been stated that limited experience in susceptible patients does not indicate any propensity of propofol to induce malignant hyperthermia.
Propofol does not suppress the adrenal response to adrenocorticotrophic hormone (ACTH).
The pharmacokinetics of propofol show a three‐compartment open model with compartments representing the plasma, rapidly equilibrating tissues, and slowly equilibrating tissues. Following an intravenous bolus dose, there is rapid equilibration between the plasma and the highly perfused tissue of the brain, thus accounting for the rapid onset of anaesthesia. Plasma levels initially decline rapidly as a result of both distribution and metabolic clearance. The initial (distribution) half‐life is between two and four minutes, followed by a rapid elimination phase with a half‐life of 30–60 minutes and followed by a slower final phase, representative of redistribution of propofol from poorly perfused tissue. Accumulation may occur if higher than necessary infusion rates are used.
In the adult, propofol clearance ranges from 1.5–2L/minute (21–29mL/kg/minute). Propofol is primarily metabolised by the liver to predominantly glucuronide conjugates and their corresponding quinols, which are inactive. These are excreted via the kidney. The pharmacokinetics of propofol are linear over the recommended range of infusion rates of the product. Moderate hepatic or renal impairment do not alter these pharmacokinetics. Patients with severe hepatic or renal impairment have not been adequately studied.
In older patients for a given dose, a higher peak plasma concentration is observed. The VD (volume of distribution) and clearance are also decreased; which may explain the decreasing dose requirement with increasing age and the sensitivity of older patients to the other dose related effects of propofol.
Discontinuation of propofol after the maintenance of anaesthesia for approximately one hour, or of Intensive Care Unit (ICU) sedation for one day, results in a prompt decrease in blood propofol concentrations and rapid awakening, usually within five minutes. Longer infusions (ten days of ICU sedation) result in accumulation of significant tissue stores of propofol, such that the reduction in circulating propofol is slowed and the time to awakening may be increased by up to 15 minutes.
Animal carcinogenicity studies have not been performed with propofol. Propofol was not genotoxic in a series of assays for gene mutation (Salmonella typhimurium, Saccharomyces cerevisiae), chromosomal damage (dominant lethal, micronucleus and cytogenetics assays) and other genotoxic effects (accharomyces cerevisiae gene conversion).
Published studies in animals demonstrate that the use of anaesthetic and sedative agents during the period of rapid brain growth or synaptogenesis results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis. Based on comparisons across species, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester through the first several months of life but may extend out to approximately 3 years of age in humans.
In primates, exposure to 3 hours of an anaesthetic regimen that produced a light surgical plane of anaesthesia did not increase neuronal cell loss, however, treatment regimens of 5 hours or longer increased neuronal cell loss. Data in rodents and in primates suggest that the neuronal and oligodendrocyte cell losses are associated with prolonged cognitive deficits in learning and memory.
In a published study conducted on rhesus monkeys, administration of an anaesthetic dose of ketamine for 24 hours on Gestation Day 122 increased neuronal apoptosis in the developing brain of the foetus. In other published studies, administration of either isoflurane or propofol for 5 hours on Gestation Day 120 resulted in increased neuronal and oligodendrocyte apoptosis in the developing brain of the offspring of rhesus macaques. With respect to brain development, this time period corresponds to the third trimester of gestation in the human. The clinical significance of these findings is not clear; however, studies in juvenile animals suggest neuroapoptosis correlates with long‐term cognitive deficits. Healthcare providers should balance the benefits of appropriate anaesthesia in pregnant women, neonates and young children who require procedures with the potential risks suggested by the nonclinical data.
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