Propofol - How It Works
Clinical pharmacology details from the US FDA-approved label: how Propofol works in your body, how it's absorbed, how long it stays active, and how it's eliminated.
Mechanism of Action
12.1 Mechanism of Action The mechanism of action, like all general anesthetics, is poorly understood. However, propofol is thought to produce its sedative/anesthetic effects by the positive modulation of the inhibitory function of the neurotransmitter GABA through the ligand-gated GABA A receptors.
12 CLINICAL PHARMACOLOGY Propofol injectable emulsion is an intravenous general anesthetic and sedation drug for use in the induction and maintenance of anesthesia or sedation.
Intravenous injection of a therapeutic dose of propofol induces anesthesia, with minimal excitation, usually within 40 seconds from the start of injection (the time for one arm-brain circulation).
As with other rapidly acting intravenous anesthetic agents, the half-time of the blood-brain equilibration is approximately 1 to 3 minutes, accounting for the rate of induction of anesthesia.
12.1 Mechanism of Action The mechanism of action, like all general anesthetics, is poorly understood.
However, propofol is thought to produce its sedative/anesthetic effects by the positive modulation of the inhibitory function of the neurotransmitter GABA through the ligand-gated GABA A receptors.
12.2 Pharmacodynamics Pharmacodynamic properties of propofol are dependent upon the therapeutic blood propofol concentrations.
Steady-state propofol blood concentrations are generally proportional to infusion rates.
Undesirable side effects, such as cardiorespiratory depression, are likely to occur at higher blood concentrations which result from bolus dosing or rapid increases in infusion rates.
An adequate interval (3 to 5 minutes) must be allowed between dose adjustments in order to assess clinical effects.
The hemodynamic effects of propofol injectable emulsion during induction of anesthesia vary.
If spontaneous ventilation is maintained, the major cardiovascular effect is arterial hypotension (sometimes greater than a 30% decrease) with little or no change in heart rate and no appreciable decrease in cardiac output.
If ventilation is assisted or controlled (positive pressure ventilation), there is an increase in the incidence and the degree of depression of cardiac output.
Addition of an opioid, used as a premedicant, further decreases cardiac output and respiratory drive.
If anesthesia is continued by infusion of propofol injectable emulsion, the stimulation of endotracheal intubation and surgery may return arterial pressure towards normal.
However, cardiac output may remain depressed.
Comparative clinical studies have shown that the hemodynamic effects of propofol injectable emulsion during induction of anesthesia are generally more pronounced than with other intravenous induction agents.
Induction of anesthesia with propofol injectable emulsion is frequently associated with apnea in both adults and pediatric patients.
In adult patients who received propofol injectable emulsion (2 mg/kg to 2.5 mg/kg), apnea lasted less than 30 seconds in 7% of patients, 30 seconds to 60 seconds in 24% of patients, and more than 60 seconds in 12% of patients.
In pediatric patients from birth through 16 years of age assessable for apnea who received bolus doses of propofol injectable emulsion (1 mg/kg to 3.6 mg/kg), apnea lasted less than 30 seconds in 12% of patients, 30 seconds to 60 seconds in 10% of patients, and more than 60 seconds in 5% of patients.
During maintenance of general anesthesia, propofol injectable emulsion causes a decrease in spontaneous minute ventilation usually associated with an increase in carbon dioxide tension which may be marked depending upon the rate of administration and concurrent use of other medications (e.g., opioids, sedatives, etc.).
Pharmacokinetics
12.3 Pharmacokinetics The pharmacokinetics of propofol are well described by a three- compartment linear 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 brain, accounting for the rapid onset of anesthesia. Plasma levels initially decline rapidly as a result of both distribution and metabolic clearance. Distribution accounts for about half of this decline following a bolus of propofol. However, distribution is not constant over time, but decreases as body tissues equilibrate with plasma and become saturated. The rate at which equilibration occurs is a function of the rate and duration of the infusion. When equilibration occurs there is no longer a net transfer of propofol between tissues and plasma. Discontinuation of the recommended doses of propofol injectable emulsion after the maintenance of anesthesia for approximately one hour, or for sedation in the ICU for one day, results in a prompt decrease in blood propofol concentrations and rapid awakening. Longer infusions (10 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 is increased. By daily titration of propofol injectable emulsion dosage to achieve only the minimum effective therapeutic concentration, rapid awakening within 10 to 15 minutes can