Etomidate
Encyclopedia
Etomidate (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.
derivative that has anesthetic
and amnestic
properties, but that has no analgesic properties.
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 ipisilateral 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.
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 unit
s 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.
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.
containing β3 subunits.
and is metabolised by hepatic and plasma esterase
s to inactive products. It exhibits a bi-exponential decline.
, 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.
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.
General anaesthesia
General anaesthesia is a state of unconsciousness and loss of protective reflexes resulting from the administration of one or more general anaesthetic agents...
and for sedation
Sedation
Sedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure...
for short procedures such as reduction of dislocated joints, tracheal intubation
Tracheal intubation
Tracheal intubation, usually simply referred to as intubation, is the placement of a flexible plastic or rubber tube into the trachea to maintain an open airway or to serve as a conduit through which to administer certain drugs...
and cardioversion
Cardioversion
Cardioversion is a medical procedure by which an abnormally fast heart rate or cardiac arrhythmia is converted to a normal rhythm, using electricity or drugs. Synchronized electrical cardioversion uses a therapeutic dose of electric current to the heart, at a specific moment in the cardiac cycle...
. It was discovered at Janssen Pharmaceutica
Janssen Pharmaceutica
Janssen Pharmaceutica is pharmaceutical company, established in Belgium in 1953 by Paul Janssen. Its headquarters are located in Beerse, in the Campine region of the province of Antwerp, Belgium. It was created not as a subsidiary of a chemical factory but solely with the aim of conducting...
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 imidazoleImidazole
Imidazole is an organic compound with the formula C3H4N2. This aromatic heterocyclic is a diazole and is classified as an alkaloid. Imidazole refers to the parent compound, whereas imidazoles are a class of heterocycles with similar ring structure, but varying substituents...
derivative that has anesthetic
Anesthesia
Anesthesia, or anaesthesia , traditionally meant the condition of having sensation blocked or temporarily taken away...
and amnestic
Amnesia
Amnesia is a condition in which one's memory is lost. The causes of amnesia have traditionally been divided into categories. Memory appears to be stored in several parts of the limbic system of the brain, and any condition that interferes with the function of this system can cause amnesia...
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 inductionRapid sequence induction
Rapid Sequence Induction is a medical procedure involving the expeditious induction of general anesthesia and subsequent intubation of the trachea. RSI is generally used in an emergency setting or for patients who have an increased risk of aspirating stomach contents into the lungs...
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 ipisilateral 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 corticosteroidCorticosteroid
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex. Corticosteroids are involved in a wide range of physiologic systems such as stress response, immune response and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte...
synthesis in the adrenal cortex by reversibly inhibiting 11-beta-hydroxylase
Steroid 11-beta-hydroxylase
Steroid 11β-hydroxylase is a steroid hydroxylase found in the zona fasciculata. Named officially the cytochrome P450 11B1, mitochondrial, it is a protein that in humans is encoded by the CYP11B1 gene....
, an enzyme important in adrenal steroid production; it leads to primary adrenal suppression. Using a continuous etomidate infusion for sedation
Sedation
Sedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure...
of critically ill trauma patients in intensive care unit
Intensive Care Unit
thumb|220px|ICU roomAn intensive-care unit , critical-care unit , intensive-therapy unit/intensive-treatment unit is a specialized department in a hospital that provides intensive-care medicine...
s 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
EEG
EEG commonly refers to electroencephalography, a measurement of the electrical activity of the brain.EEG may also refer to:* Emperor Entertainment Group, a Hong Kong-based entertainment company...
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
Effective dose
Effective dose may refer to:*Effective dose the dose of pharmacologic agent which will have a therapeutic effect in some fraction of the population receiving the drug...
and the lethal dose
Lethal dose
A lethal dose is an indication of the lethality of a given substance or type of radiation. Because resistance varies from one individual to another, the 'lethal dose' represents a dose at which a given percentage of subjects will die...
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 receptorsReceptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
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 plasmaBlood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
and is metabolised by hepatic and plasma esterase
Esterase
An esterase is a hydrolase enzyme that splits esters into an acid and an alcohol in a chemical reaction with water called hydrolysis.A wide range of different esterases exist that differ in their substrate specificity, their protein structure, and their biological function.- EC classification/list...
s 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 glycolPropylene glycol
Propylene glycol, also called 1,2-propanediol or propane-1,2-diol, is an organic compound with formula C3H8O2 or HO-CH2-CHOH-CH3...
, although a lipid
Lipid
Lipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...
emulsion
Emulsion
An emulsion is a mixture of two or more liquids that are normally immiscible . Emulsions are part of a more general class of two-phase systems of matter called colloids. Although the terms colloid and emulsion are sometimes used interchangeably, emulsion is used when both the dispersed and the...
preparation (of equivalent strength) has also been introduced. Etomidate is presented as a racemic
Racemic
In chemistry, a racemic mixture, or racemate , is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule. The first known racemic mixture was "racemic acid", which Louis Pasteur found to be a mixture of the two enantiomeric isomers of tartaric acid.- Nomenclature :A...
mixture, but only the D-isomer
Isomer
In chemistry, isomers are compounds with the same molecular formula but different structural formulas. Isomers do not necessarily share similar properties, unless they also have the same functional groups. There are many different classes of isomers, like stereoisomers, enantiomers, geometrical...
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 thiocyanateThiocyanate
Thiocyanate is the anion [SCN]−. It is the conjugate base of thiocyanic acid. Common derivatives include the colourless salts potassium thiocyanate and sodium thiocyanate. Organic compounds containing the functional group SCN are also called thiocyanates...
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
Thiol
In organic chemistry, a thiol is an organosulfur compound that contains a carbon-bonded sulfhydryl group...
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
Sulfur dioxide
Sulfur dioxide is the chemical compound with the formula . It is released by volcanoes and in various industrial processes. Since coal and petroleum often contain sulfur compounds, their combustion generates sulfur dioxide unless the sulfur compounds are removed before burning the fuel...
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).