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[Description]
Etomidate , ethyl (R)-(+)-1(α-
methylbenzyl)-imidazole-5-carboxylate, Mr
224.28, is a white to yellowish crystalline or
amorphous powder. It is insoluble
in water at pH 7, but soluble in acidic
aqueous solutions at pH<3. Etomidate is soluble
in propylene glycol and readily soluble in
alcohol. |
[Chemical Properties]
Colourless solid |
[Originator]
Hypnomidate,Janssen,W. Germany,1977 |
[Uses]
Etomidate is a GABAA receptors agonist with short-acting sedative, hypnotic, and general anesthetic properties. It is a unique drug used for induction of general anesthesia and sedation. It is also a hypnotic. Hypnotic effect of Etomidate is strong , and its efficacy is about 12 times higher than thiopental, it has no analgesic effect. |
[Definition]
ChEBI: The ethyl ester of 1-[(1R)-1-phenylethyl]-1H-imidazole-5-carboxylic acid. It is an intravenous general anaesthetic with no analgesic activity. |
[Indications]
Etomidate is administered intravenously as
a short-acting anesthetic for the induction of
lengthy anesthesia, especially for the induction
of neuroleptanalgesia and inhalation
anesthesia . Etomidate produces
3 – 5 min of sleep. |
[Manufacturing Process]
To a mixture of 1,115 parts dl-1-phenylethylamine and 950 parts
dimethylformamide are added successively 655 parts triethylamine and 1,130
parts ethyl chloroacetate. After the addition is complete, the whole is stirred
overnight. Then there are added 5,600 parts anhydrous ether and the whole
is filtered.
The filtrate is washed four times with water, dried and evaporated, yielding dl-
N-[(ethoxycarbonyl)methyl] -1-phenylethylamine. This residue is dissolved in 4,800 parts xylene while refluxing and to this solution are added 450 parts
formic acid. After boiling for a few hours, the mixture is cooled and washed
successively three times with a 20% solution of formic acid, water, sodium
hydrogen carbonate solution.
The organic layer is then dried, filtered and evaporated. The oily residue is
distilled in vacuo, yielding 1,600 parts dl-N-formyl-N-
[(ethoxycarbonyl)methyl]-1-phenylethylamine (boiling point 160°C to 170°C
at 0.8 mm pressure). 30 parts of a sodium dispersion, 50% in paraffin oil are
added to 450 parts tetrahydrofuran and the whole is slowly heated to a
temperature of 40°C, while stirring. While maintaining this temperature
(cooling on a water bath is necessary) there are added portionwise 30 parts
ethanol.
After the addition is complete, the whole is cooled on an ice bath and there is
added dropwise a solution of 144 parts dl-N-formyl-N-
[(ethoxycarbonyl)methyl]-1-phenylethylamine in 133 parts ethyl formate.
After the addition is complete, the mixture is stirred overnight at room
temperature.
Then there are added 160 parts ether. After stirring for 5 minutes the mixture
is poured into 1,500 parts water. The aqueous layer is separated, washed
twice with 80 parts diisopropyl ether and then there are added successively
114 parts concentrated hydrochloric acid and 90 parts potassium thiocyanate
in 200 parts water. The mixture is stirred for 24 hours, where upon an oil is
separated.
After the addition of 750 parts water, a crystalline product is precipitated. The
mixture is further stirred overnight. The solid is then filtered off and
recrystallized from a mixture of ethanol and water (1:1 by volume) to yield dl-
1-(phenylethyl)-2-mercapto-5-(ethoxycarbonyl)imidazole; its melting point is
129.8°C to 130.8°C.
To a stirred mixture of 140 parts nitric acid (d = 1.37), 1 part sodium nitrate
and 240 parts water are added portionwise 89 parts dl-1-(1-phenylethyl)-2-
mercapto-5-(ethoxycarbonyl)imidazole. After the addition is complete, the
whole is stirred for 2 hours at room temperature. The free base is liberated by
addition of solid sodium carbonate and the whole is extracted with 120 parts
anhydrous ether while heating. The aqueous layer is separated and extracted
twice with 80 parts anhydrous ether.
The combined extracts are dried over magnesium sulfate, filtered and to the
filtrate is added 2-propanol previously saturated with gaseous hydrogen
chloride. The precipitated salt is filtered off, dried for 2 days at 60°C, to yield
dl-1-(1-phenylethyl)-5-(ethoxycarbonyl)imidazole hydrochloride. It has a
melting point 142°C to 142.8°C. |
[Brand name]
Amidate (Hospira);Hypnomidate concentrate;Hypnomidate injection;Hypromidate;Nalgol;Sibu. |
[Therapeutic Function]
Hypnotic |
[World Health Organization (WHO)]
Etomidate, a potent hypnotic agent, was introduced in 1977 for
use as an intravenous anaesthetic. Its prolonged use can inhibit adrenal
steroidogenesis and, following reports of reduced serum cortisol levels
unresponsive to ACTH injection, the manufacturer suspended promotion of
etomidate for sedation in intensive care in 1983. In 1985 regulatory action taken
only in the United Kingdom further restricted use of the drug to induction of
anaesthesia. Etomidate remains widely available and is currently registered for
induction of anaesthesia in 34 countries and for maintenance of anaesthesia in 17
countries. It has never been registered for sedation. |
[Biological Functions]
The pharmacological properties of etomidate (Amidate)
are similar to those of the barbiturates, although its use
may provide a greater margin of safety because of its
limited effects on the cardiovascular and respiratory
systems. Since it has a relatively short elimination halflife
(t1/2β = 2.9 hours), in addition to its use as an induction agent, etomidate has been used as a supplement to
maintain anesthesia in some critically ill patients.
Etomidate is rapidly hydrolyzed in the liver. |
[General Description]
Etomidate is a carboxylated imidazole intended for the inductionof general anesthesia. It is marketed as the morepotent R (+) isomer. It is believed to exert its anestheticeffect via positive modulation of the GABAA receptor. Itis not water soluble and is available in the United States as a2-mg/mL solution containing 35% v/v propylene glycol andin Europe as a soybean oil and medium-chain triglyceridesformulation. The propylene glycol has been associatedwith moderate-to-severe pain on injection and irritation ofthe vascular tissue. A high incidence of skeletal musclemovements were noted in about 32% of patients followingetomidate injection. Case reports of seizures are also foundin the literature. |
[Biological Activity]
General anesthetic with GABA modulatory and GABA-mimetic actions; selectively interacts with β 2- and β 3-subunit containing GABA A receptors. Short acting and potent hypnotic, with low toxicity. |
[Biochem/physiol Actions]
Etomidate is a general anesthetic; potentiates GABAA transmission. The possible neuroprotective effect of etomidate against streptozotocin-induced (STZ-induced) hyperglycaemia were investigated in the rat brain and spinal cord. Etomidate treatment demonstrated neuroprotective effect on the neuronal tissue against the diabetic oxidative damage |
[Clinical Use]
Etomidate should only beused for induction of anesthesia when the cardiac benefitsoutweigh the risks associated with adrenal insufficiency.Etomidate is quickly distributed throughout most organsin the body after intravenous administration and the tissueconcentrations equal and sometimes exceed the plasmaconcentrations. The lipid solubility of the drug allows it torapidly penetrate into the brain with peak concentrationsoccurring within 1 minute of administration. Etomidate israpidly metabolized in the plasma and liver via esterases.About 75% of the drug is eliminated in the urine as the inactiveester hydrolyzed carboxylic acid. |
[Side effects]
Etomidate may cause pain on injection and may produce
myoclonic muscle movements in approximately
40% of patients during its use as an induction anesthetic.
In addition, etomidate can suppress the adrenocortical
response to stress, an effect that may last up to 10 hours. |
[Synthesis]
The preparation of etomidate involves
a modification of Jones’ synthesis: α-
phenylethylamine is alkylated with ethyl chloroacetate
to the N-(α-phenylethyl)-glycine ester,
whose NH group is formylated. This product
is condensed with methyl formate and cyclized
withHCl-KSCNto yield ethyl 2-mercapto-1-(α-
methylbenzyl)-5-imidazolecarboxylate, which
is then oxidatively desulfurized . The (R)
isomer is obtained by separating the racemic
acid with (R)-(+)-1-phenylethylamine.
 |
[Veterinary Drugs and Treatments]
Etomidate may be useful as an alternative to thiopental or propofol
for anesthetic induction in small animals, particularly in patients
with preexisting cardiac dysfunction, head trauma, or that are critically
ill. |
[Drug interactions]
Potentially hazardous interactions with other drugsAdrenergic neurone blockers: enhanced hypotensive
effect.Antihypertensives: enhanced hypotensive effect. Antidepressants: avoid MAOIs for 2 weeks
before surgery; increased risk of arrhythmias and
hypotension with tricyclics. Antipsychotics: enhanced hypotensive effect. |
[Metabolism]
Etomidate is hydrolyzed by hepatic esterases to the corresponding inactive carboxylic acid, with subsequent renal and biliary excretion terminating its action. Its apparent elimination half-life is approximately 5 to 6 hours, with a volume of distribution of 5 to 7 L/kg. Changes in hepatic blood flow or hepatic metabolism will have only moderate effects on etomidate disposition. Concerns regarding the ability of etomidate to precipitate myoclonic jerks and inhibit adrenal steroid synthesis have been reported. |
[storage]
Room temperature |
[Mode of action]
The exact mechanism of action of etomidate is unknown. It is felt to induce sedation by interaction with GABA receptors. and likely enhances the activity of a-aminobutyric acid. However, it is not structurally related to benzodiazepines or to barbiturates. Of significantnote, etomidate exhibits no analgesic properties. |