Etomidate

Etomidate (USAN, INN, BAN) (marketed as Amidate) is a short acting intravenous anaesthetic agent used for the induction of general anaesthesia and for sedation for short procedures such as reduction of dislocated joints, tracheal intubation and cardioversion. It was discovered at Janssen Pharmaceutica in 1964 and it was introduced as an intravenous agent in 1972 in Europe and in 1983 in United States.

Drug class
Etomidate is a carboxylated imidazole derivative that has anesthetic and amnestic properties, but that has no analgesic properties.

Medical uses
In emergency settings, etomidate is one of the most frequently used sedative hypnotic agents. It is used by physicians for conscious sedation and as a part of a rapid sequence induction to induce anaesthesia. It is used as an anaesthetic agent since it has a rapid onset of action and a safe cardiovascular risk profile, and therefore is less likely to cause a significant drop in blood pressure than other induction agents. In addition, etomidate is often used because of its easy dosing profile, limited suppression of ventilation, lack of histamine liberation and protection from myocardial and cerebral ischemia. Thus, etomidate is an ideal induction agent for patients who are haemodynamically unstable. Etomidate also has interesting characteristics for patients with traumatic brain injury because it is one of the only anesthetic agents able to decrease intracranial pressure and maintain a normal arterial pressure.

Another use for etomidate is to determine speech lateralization in patients prior to performing lobectomies to remove epileptogenic centres in the brain.This is called the etomidate speech and memory test, or eSAM, and is used at the Montreal Neurological institute. However, there exists only retrospective cohort studies supporting the use and safety of etomidate for this test. Etomidate is injected into the carotid artery and will anesthetize the ipsilateral brain hemisphere for 5–10 minutes. During such time, rudimentary speech and memory tasks are performed in order to determine if removal of a particular part of a hemisphere will affect the patients language abilities or induce severe memory impairments. eSAM is done on patients who show impairments on both verbal and non-verbal learning and memory test during the basic examination or if there is evidence of bitemporal abnormalities in EEG and/or MRI. This procedure is also done on all left-handed or ambidextrous patients because 30% of left-handed or ambidextrous patients have either right hemispheric speech dominance or bilateral speech representation. Prior to the procedure the patient is shown a series of objects and during the procedure shown another series of objects. Once the injection has worn off, the patient is shown some of the same objects and asked whether or not they saw them that day. If the patient doesn't recognize the objects that were shown during the procedure, it is clear that the medial temporal structures that were left un-anesthetized during the procedure are not functioning properly.

Side effects
Etomidate suppresses corticosteroid synthesis in the adrenal cortex by reversibly inhibiting 11-beta-hydroxylase, an enzyme important in adrenal steroid production; it leads to primary adrenal suppression. Using a continuous etomidate infusion for sedation of critically ill trauma patients in intensive care units has been associated with increased mortality due to adrenal suppression. This effect was demonstrated in a landmark study in 1983 by Ledingham and Watt. They showed that continuous intravenous administration of etomidate leads to adrenocortical dysfunction. The mortality of patients exposed to a continuous infusion of etomidate for more than 5 days increased from 25% to 44%, mainly due to infectious causes like pneumonia.

Because of etomidate-induced adrenal suppression, the use of etomidate for patients with sepsis is controversial. Cortisol levels have been reported to be suppressed up to 72 hours after a single bolus of etomidate in this population at risk for adrenal insufficiency. For this reason, many authors have suggested that etomidate should never be used for critically ill patients with septic shock because it could increase mortality. However, other authors continue to defend etomidate’s use for septic patients because of etomidate’s safe haemodynamic profile and lack of clear evidence of harm. A study by Jabre et al. showed that a single dose of etomidate used for Rapid Sequence Induction prior to endrotracheal intubation has no effect on mortality compared to ketamine even though etomidate did cause transient adrenal suppression. In addition, a recent meta-analysis done by Hohl could not conclude that etomidate increased mortality. The authors of this meta-analysis concluded that more studies were needed because of lack of statistical power to conclude definitively about the effect of etomidate on mortality. Thus, Hohl suggests that the burden of proof is to prove that etomidate is safe for use in septic patients and that more research is needed before etomidate is used. Other authors  advise giving a prophylactic dose of steroids (e.g. hydrocortisone) if etomidate is used, but only one small prospective controlled study in patients undergoing colorectal surgery has verified the safety of giving stress dose corticosteroids to all patients receiving etomidate.

In addition, concurrent use of etomidate with opioids and/or benzodiazepines, is hypothesized to exacerbate etomidate related adrenal insufficiency. However, there is only retrospective evidence of this effect and prospective studies are needed to measure the clinical impact of this interaction.

Aside from the adrenal suppression caused by etomidate, seizure-like activity is occasionally seen with anesthetic induction with etomidate. In the absence of concurrent EEG monitoring, it is difficult to ascribe this to cortical activity. Myoclonic movement originating at the spinal cord level is often a likely mechanism. Excitatory phenomena, and epileptiform movements and EEG activity may be observed during induction. Etomidate consistently increases the amplitude of somatosensory evoked potentials (in contrast to most anaesthetic agents).

Etomidate in the propylene glycol formulation may produce pain on injection, a side effect which is less likely with the lipid formulation.

There is a 30-fold difference between the effective dose and the lethal dose of etomidate, making it an extremely safe agent.

Post operative vomiting is more common than with other induction agents.

Dosage
The anaesthetic induction dose for adult humans is 0.3 mg/kg intravenously, with a typical dose ranging from 20–40 mg. Etomidate causes loss of consciousness after one arm-brain circulation time. In very brief procedures such as cardioversion, a 10 mg dose may be used which may be repeated for effect.

DOSING: ADULTS — Anesthesia: I.V.: Initial: 0.2-0.6 mg/kg over 30–60 seconds for induction of anesthesia; maintenance: 5-20 mcg/kg/minute except for patients in sepsis or critically ill at risk of adrenal insufficiency (see side effects).

DOSING: PEDIATRIC – For children > 10 years: Refer to adult dosing.

DOSING: GERIATRIC – Refer to adult dosing.

Pharmacodynamics
Etomidate is a modulator at GABAA receptors containing β3 subunits.

Pharmacokinetics
At the typical dose, anesthesia is induced for about 5–10 minutes even though the half-life of drug metabolism is approximately 75 minutes. This is because etomidate is redistributed from the plasma to other tissues.


 * Onset of action: 30–60 seconds
 * Peak effect: 1 minute
 * Duration: 3–5 minutes; terminated by redistribution
 * Distribution: Vd: 2-4.5 L/kg
 * Protein binding: 76%
 * Metabolism: Hepatic and plasma esterases
 * Half-life distribution: 2.7 minutes
 * Half-life redistribution: 29 minutes
 * Half-life elimination: 2.9 to 5.3 hours

Metabolism
Etomidate is highly protein bound in blood plasma and is metabolised by hepatic and plasma esterases to inactive products. It exhibits a bi-exponential decline.

Formulation
Etomidate is usually presented as a clear colourless solution for injection containing 2 mg/ml of etomidate in an aqueous solution of 35% propylene glycol, although a lipid emulsion preparation (of equivalent strength) has also been introduced. Etomidate is presented as a racemic mixture, but only the D-isomer has pharmacological activity.

Chemistry
Etomidate, ethyl ester of 1-(α-methylbenzyl)imidazole-5-carboxylic acid, is prepared by the following procedure. It illustrates a special case of obtaining derivatives of imidazole by interaction of α-aminocarbonyl compounds with thiocyanates. The reaction of α-methylbenzylamine with ethyl chloroacetate gives N-ethoxycarbonylmethyl-N-1-phenylethylamine, which undergoes further formylation by formic acid. The resulting N-ethoxycarbonylmethyl-N-formyl-N-1-phenylethylamine undergoes further C-formylation by ethylformate in the presence of sodium ethoxide. The product is further processed (without being isolated) by a solution of potassium thiocyanate in hydrochloric acid. As a result of the reaction of thiocyanate ions with the amino group which occurs as a result of acidic hydrolysis of the N-formamide protecting group and further interaction of the obtained intermediate with the newly inserted aldehyde group, a Marckwald reaction type heterocyclization takes place, resulting in formation of 5-ethoxycarbonyl-2-mercapto-1-(1-phenylethyl)imidazole. Finally, the thiol group is removed by oxidative dethionation upon interaction with a mixture of nitric and nitrous acids (nitric acid in the presence of sodium nitrite), which evidently occurs through formation of unstable sulfinic acid, which easily loses sulfur dioxide resulting the desired etomidate.
 * C.A.M.V. Eijken, F.E. Godefroi, (1967).
 * P.A.J. Janssen, C.G.E. Niemegeers, K.H. Lschllekens, F.M. Lenaerts, Arzneim Forsch., 21, 1234(1971).