Amidate

Name: Amidate

Uses for Amidate

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Induction Anesthesia

Induction of general anesthesia.1 2 3 4 5

Induction results in dose-related hypnotic effects (progressing from light sleep to unconsciousness).1 2 3 4 5 6 9

Particularly useful in patients with compromised cardiopulmonary function because of its minimal hemodynamic effects and decreased respiratory depressant effects relative to other IV anesthetics (barbiturates, propofol).1 2

Carefully weigh the potential benefits of the drug’s hemodynamic effects against the possible risks of very frequent transient skeletal muscle movements associated with etomidate therapy.1 2

Maintenance Anesthesia

Maintenance anesthesia to supplement subpotent anesthetic agents (e.g., nitrous oxide and oxygen) during short-term surgical procedures (e.g., dilatation and curettage, cervical conization).1 2

Amidate Pharmacokinetics

Absorption

Onset

Following IV administration, rapid onset of action;1 2 3 4 5 6 loss of consciousness occurs usually within 1 minute.1 2 4 9

Duration

Dose dependent.1 2 Following IV administration of average doses (0.3 mg/kg), duration of hypnosis is short (about 3–5 minutes).1 2 Recovery from anesthesia is at least as fast as with thiopental (no longer commercially available in the US),1 2 but slower than that associated with propofol.9

Plasma Concentrations

Minimal hypnotic plasma concentrations are at least 0.23 mcg/mL.1 2

Distribution

Extent

Rapidly distributed from blood into CNS with substantial tissue uptake.3 4

Elimination

Metabolism

Rapidly metabolized in the liver, principally by hydrolysis, to etomidate carboxylic acid,1 2 3 4 8 which appears to be pharmacologically inactive.4

Elimination Route

Excreted in urine (75%) within 24 hours, mainly (about 80%) as the carboxylic acid metabolite;1 2 4 13 and 10% of a dose are excreted in feces and bile, respectively.4

Half-life

About 1.25–5 hours.1 2 3 4 8

Special Populations

Elimination half-life approximately doubled in patients with cirrhosis and esophageal varices.1 2

Uses of Amidate

  • It is used to put you to sleep for surgery.
  • It may be given to you for other reasons. Talk with the doctor.

What are some side effects that I need to call my doctor about right away?

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

  • Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
  • Signs of high or low blood pressure like very bad headache or dizziness, passing out, change in eyesight.
  • Trouble breathing, slow breathing, or shallow breathing.
  • Fast or slow heartbeat.
  • A heartbeat that does not feel normal.
  • Muscle stiffness.
  • Trouble controlling body movements.
  • Not able to control eye movements.
  • Redness or swelling where the shot is given.

Description

Amidate (Etomidate Injection, USP) is a sterile, nonpyrogenic solution. Each milliliter contains etomidate, 2 mg, propylene glycol 35% v/v. The pH is 6.0 (4.0 to 7.0).

It is intended for the induction of general anesthesia by intravenous injection.

The drug etomidate is chemically identified as (R)-(+)-ethyl-1-(1-phenylethyl)-1H-imidazole -5-carboxylate and has the following structural formula:

Clinical Pharmacology

Etomidate is a hypnotic drug without analgesic activity. Intravenous injection of etomidate produces hypnosis characterized by a rapid onset of action, usually within one minute. Duration of hypnosis is dose dependent but relatively brief, usually three to five minutes when an average dose of 0.3 mg/kg is employed. Immediate recovery from anesthesia (as assessed by awakening time, time needed to follow simple commands and time to perform simple tests after anesthesia as well as they were performed before anesthesia), based upon data derived from short operative procedures where intravenous etomidate was used for both induction and maintenance of anesthesia, is about as rapid as, or slightly faster than, immediate recovery after similar use of thiopental. These same data revealed that the immediate recovery period will usually be shortened in adult patients by the intravenous administration of approximately 0.1 mg of intravenous fentanyl, one or two minutes before induction of anesthesia, probably because less etomidate is generally required under these circumstances (consult the package insert for fentanyl before using).

The most characteristic effect of intravenous etomidate on the respiratory system is a slight elevation in arterial carbon dioxide tension (PaCO2). See also ADVERSE REACTIONS.

Reduced cortisol plasma levels have been reported with induction doses of 0.3 mg/kg etomidate. These persist for approximately 6 to 8 hours and appear to be unresponsive to ACTH administration.

The intravenous administration of up to 0.6 mg/kg of etomidate to patients with severe cardiovascular disease has little or no effect on myocardial metabolism, cardiac output, peripheral circulation or pulmonary circulation. The hemodynamic effects of etomidate have in most cases been qualitatively similar to those of thiopental sodium, except that the heart rate tended to increase by a moderate amount following administration of thiopental under conditions where there was little or no change in heart rate following administration of etomidate. However, clinical data indicates that etomidate administration in geriatric patients, particularly those with hypertension, may result in decreases in heart rate, cardiac index, and mean arterial blood pressure. There are insufficient data concerning use of etomidate in patients with recent severe trauma or hypovolemia to predict cardiovascular response under such circumstances.

Clinical experience and special studies to date suggest that standard doses of intravenous etomidate ordinarily neither elevate plasma histamine nor cause signs of histamine release.

Limited clinical experience, as well as animal studies, suggests that inadvertent intra-arterial injection of etomidate, unlike thiobarbiturates, will not usually be followed by necrosis of tissue distal to the injection site. Intra-arterial injection of etomidate is, however, not recommended.

Etomidate induction is associated with a transient 20-30% decrease in cerebral blood flow. This reduction in blood flow appears to be uniform in the absence of intracranial space occupying lesions. As with other intravenous induction agents, reduction in cerebral oxygen utilization is roughly proportional to the reduction in cerebral blood flow. In patients with and without intracranial space occupying lesions, etomidate induction is usually followed by a moderate lowering of intracranial pressure, lasting several minutes. All of these studies provided for avoidance of hypercapnia. Information concerning regional cerebral perfusion in patients with intracranial space occupying lesions is too limited to permit definitive conclusions.

Preliminary data suggests that etomidate will usually lower intraocular pressure moderately.

Etomidate is rapidly metabolized in the liver. Minimal hypnotic plasma levels of unchanged drug are equal to or higher than 0.23 ug/mL; they decrease rapidly up to 30 minutes following injection and thereafter more slowly with a half-life value of about 75 minutes. Approximately 75% of the administered dose is excreted in the urine during the first day after injection. The chief metabolite is R-(+)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid, resulting from hydrolysis of etomidate, and accounts for about 80% of the urinary excretion. Limited pharmacokinetic data in patients with cirrhosis and esophageal varices suggest that the volume of distribution and elimination half-life of etomidate are approximately double that seen in healthy subjects.

(Reference: H. Van Beem, et. al., Anaesthesia 38 (Supp 38:61-62, July 1983).

In clinical studies, elderly patients demonstrated decreased initial distribution volumes and total clearance of etomidate. Protein binding of etomidate to serum albumin was also significantly decreased in these individuals.

Reduced plasma cortisol and aldosterone levels have been reported following induction doses of etomidate. These results persist for approximately 6-8 hours and appear to be unresponsive to ACTH stimulation. This probably represents blockage of 11 betahydroxylation within the adrenal cortex.

(References: 1. R.J. Fragen, et. al., Anesthesiology 61:652-656, 1984. 2. R.L. Wagner and P.F. White, Anesthesiology 61:647-651, 1984. 3. F.H. DeJong, et. al., Clin. Endocrinology and Metabolism 59:(6):1143-1147, 1984, and three additional drafts of Metabolic Studies, all submitted to NDA 18-228 on April 1, 1985).

Precautions

Do not administer unless solution is clear and container is undamaged. Discard unused portion (see DOSAGE AND ADMINISTRATION).

  1. Carcinogenesis, Mutagenesis, Impairment of Fertility: No carcinogenesis or mutagenesis studies have been carried out on etomidate. The results of reproduction studies showed no impairment of fertility in male and female rats when etomidate was given prior to pregnancy at 0.31, 1.25 and 5 mg/kg (approximately 1X, 4X and 16X human dosage).
  2. Pregnancy Category C. Etomidate has been shown to have an embryocidal effect in rats when given in doses 1 and 4 times the human dose. There are no adequate and well-controlled studies in pregnant women. Etomidate should be used during pregnancy only if the potential benefit justifies the potential risks to the fetus. Etomidate has not been shown to be teratogenic in animals. Reproduction studies with etomidate have been shown to:
    1. Decrease pup survival at 0.3 and 5 mg/kg in rats (approximately 1X and 16X human dosage) and at 1.5 and 4.5 mg/kg in rabbits (approximately 5X and 15X human dosage). No clear dose-related pattern was observed.
    2. Increase slightly the number of stillborn fetuses in rats at 0.3 and 1.25 mg/kg (approximately 1X and 4X human dosage).
    3. Cause maternal toxicity with deaths of 6/20 rats at 5 mg/kg (approximately 16X human dosage) and 6/20 rabbits at 4.5 mg/kg (approximately 15X human dosage).
  3. Labor and Delivery: There are insufficient data to support use of intravenous etomidate in obstetrics, including Caesarean section deliveries. Therefore, such use is not recommended.
  4. Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when etomidate is administered to a nursing mother.
  5. Pediatric Use: There are inadequate data to make dosage recommendations for induction of anesthesia in patients below the age of ten (10) years; therefore, such use is not recommended (see also DOSAGE AND ADMINISTRATION).
  6. Geriatric Use: Clinical data indicates that etomidate may induce cardiac depression in elderly patients, particularly those with hypertension (see CLINICAL PHARMACOLOGY and OTHER ADVERSE OBSERVATIONS, Circulatory System).
    Elderly patients may require lower doses of etomidate than younger patients. Age-related differences in pharmacokinetic parameters have been observed in clinical studies (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
    This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function.
  7. Plasma Cortisol Levels: Induction doses of etomidate have been associated with reduction in plasma cortisol and aldosterone concentrations (see CLINICAL PHARMACOLOGY). These have not been associated with changes in vital signs or evidence of increased mortality; however, where concern exists for patients undergoing severe stress, exogenous replacement should be considered.

Overdosage

Overdosage may occur from too rapid or repeated injections. Too rapid injection may be followed by a fall in blood pressure. No adverse cardiovascular or respiratory effects attributable to etomidate overdose have been reported.

In the event of suspected or apparent overdosage, the drug should be discontinued, a patent airway established (intubate, if necessary) or maintained and oxygen administered with assisted ventilation, if necessary.

The LD50 of etomidate administered intravenously to rats is 20.4 mg/kg.

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