Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1       Pharmacodynamic properties

Pharmacotherapeutic group: Other general anaesthetics,
ATC code: N01AX07.

Mechanism of action, pharmacodynamic effects
The effect of etomidate starts at short notice and the duration of the hypnotic effect is short as a result of redistribution and metabolic inactivation. A single dose of 0.3 mg/kg body weight leads to loss of consciousness in 30-60 seconds and to narcosis of 3 – 5 minutes duration, followed by sleep.
Other pharmacological effects

Etomidate suppresses the function of the adrenal cortex. Etomidate inhibits adrenal cell cortisol production by reversibly blocking the steroid synthesis enzyme 11-β- hydroxylase. The cortisol suppression is unresponsive to ACTH and lasts up to 8 h after a single 0.3 mg/kg dose of etomidate. The inhibition of cortisol synthesis is reversible and depends on the etomidate concentration in plasma.

Involuntary muscle movements observed after administration of etomidate result from disinhibition of physiological diencephalic excitations, similar to myoclonus during physiological sleep.

Etomidate has been reported to possess anticonvulsive properties and a protective effect on brain cells against hypoxic damage.

Since etomidate has no analgesic effect, concurrent administration of an analgesic is required for all surgical procedures.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption
Since Etomidate-Lipuro is administered intravenously, its bioavailability is 100 %.
Distribution
Etomidate rapidly separates from the oil particles upon injection. This is reflected by the etomidate plasma concentration, which is comparable with that of the aqueous formulation.
The plasma protein binding of etomidate (primarily to albumin) is about 75 %, it is reduced in renal dysfunction or chronic liver damage.
Etomidate is rapidly distributed to the brain and other tissues.
The total volume of distribution is about 4.5 l/kg.
Rapid distribution from the central compartment to a peripheral and a deeper peripheral compartment as well as a high elimination rate cause the plasma concentration to fall rapidly for about 30 minutes after a single administration. Then, the plasma concentration declines more slowly.

Biotransformation and elimination
The primary step of biotransformation is the hydrolysis of the ethyl ester in the liver.
A small proportion is also subject to oxidative N-dealkylation. All metabolites discovered are pharmacologically inactive.
The elimination half-life is relatively long (terminal elimination half-life 2 – 5 h) despite a high rate of hepatic extraction due to slow redistribution of etomidate from the deeper peripheral compartment.
About 75 % of the administered dose of etomidate appear in the urine within 24 hours, primarily as metabolites. Other routes of excretion play a minor role.
The major metabolite in the urine (about 80 %) is the hydrolysis product of etomidate, namely R-(+)-1-(-methylbenzyl)-5-imidazolecarboxylic acid. Only 2 % of etomidate are excreted unchanged via the urine.
The half-life of the lipid particles is short.
Accumulation has not been observed.