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Ketamine (Ketamine Hydrochloride) - Description and Clinical Pharmacology

 
 



Ketamine
Hydrochloride
Injection, USP

CIII

Rx only

SPECIAL NOTE

EMERGENCE REACTIONS HAVE OCCURRED IN APPROXIMATELY 12 PERCENT OF PATIENTS.

THE PSYCHOLOGICAL MANIFESTATIONS VARY IN SEVERITY BETWEEN PLEASANT DREAM-LIKE STATES, VIVID IMAGERY, HALLUCINATIONS, AND EMERGENCE DELIRIUM. IN SOME CASES THESE STATES HAVE BEEN ACCOMPANIED BY CONFUSION, EXCITEMENT, AND IRRATIONAL BEHAVIOR WHICH A FEW PATIENTS RECALL AS AN UNPLEASANT EXPERIENCE. THE DURATION ORDINARILY IS NO MORE THAN A FEW HOURS; IN A FEW CASES, HOWEVER, RECURRENCES HAVE TAKEN PLACE UP TO 24 HOURS POSTOPERATIVELY. NO RESIDUAL PSYCHOLOGICAL EFFECTS ARE KNOWN TO HAVE RESULTED FROM USE OF KETAMINE.

THE INCIDENCE OF THESE EMERGENCE PHENOMENA IS LEAST IN THE ELDERLY (OVER 65 YEARS OF AGE) PATIENT. ALSO, THEY ARE LESS FREQUENT WHEN THE DRUG IS GIVEN INTRAMUSCULARLY AND THE INCIDENCE IS REDUCED AS EXPERIENCE WITH THE DRUG IS GAINED.

THE INCIDENCE OF PSYCHOLOGICAL MANIFESTATIONS DURING EMERGENCE, PARTICULARLY DREAM-LIKE OBSERVATIONS AND EMERGENCE DELIRIUM, MAY BE REDUCED BY USING LOWER RECOMMENDED DOSAGES OF KETAMINE IN CONJUNCTION WITH INTRAVENOUS DIAZEPAM DURING INDUCTION AND MAINTENANCE OF ANESTHESIA. (See DOSAGE AND ADMINISTRATION.) ALSO, THESE REACTIONS MAY BE REDUCED IF VERBAL, TACTILE AND VISUAL STIMULATION OF THE PATIENT IS MINIMIZED DURING THE RECOVERY PERIOD. THIS DOES NOT PRECLUDE THE MONITORING OF VITAL SIGNS.

IN ORDER TO TERMINATE A SEVERE EMERGENCE REACTION THE USE OF A SMALL HYPNOTIC DOSE OF A SHORT-ACTING OR ULTRASHORT-ACTING BARBITURATE MAY BE REQUIRED.

WHEN KETAMINE IS USED ON AN OUTPATIENT BASIS, THE PATIENT SHOULD NOT BE RELEASED UNTIL RECOVERY FROM ANESTHESIA IS COMPLETE AND THEN SHOULD BE ACCOMPANIED BY A RESPONSIBLE ADULT.

DESCRIPTION

Ketamine hydrochloride is a nonbarbiturate anesthetic chemically designated (±)-2-(o-Chlorophenyl)-2-(methylamino) cyclohexanone hydrochloride. It is formulated as a slightly acid (pH 3.5 to 5.5) sterile solution for intravenous or intramuscular injection in concentrations containing the equivalent of either 50 or 100 mg ketamine base per milliliter and contains not more than 0.1 mg/mL benzethonium chloride added as a preservative. Ketamine hydrochloride has a molecular formula of C13H16ClNO• HCl, a molecular weight of 274.19 and the following structural formula:

CLINICAL PHARMACOLOGY

Ketamine is a rapid-acting general anesthetic producing an anesthetic state characterized by profound analgesia, normal pharyngeal-laryngeal reflexes, normal or slightly enhanced skeletal muscle tone, cardiovascular and respiratory stimulation, and occasionally a transient and minimal respiratory depression.

A patent airway is maintained partly by virtue of unimpaired pharyngeal and laryngeal reflexes. (See WARNINGS and PRECAUTIONS.)

The biotransformation of ketamine includes N-dealkylation (metabolite I), hydroxylation of the cyclohexone ring (metabolites III and IV), conjugation with glucuronic acid and dehydration of the hydroxylated metabolites to form the cyclohexene derivative (metabolite II).

Following intravenous administration, the ketamine concentration has an initial slope (alpha phase) lasting about 45 minutes with a half-life of 10 to 15 minutes. This first phase corresponds clinically to the anesthetic effect of the drug. The anesthetic action is terminated by a combination of redistribution from the CNS to slower equilibrating peripheral tissues and by hepatic biotransformation to metabolite I. This metabolite is about 1/3 as active as ketamine in reducing halothane requirements (MAC) of the rat. The later half-life of ketamine (beta phase) is 2.5 hours.

The anesthetic state produced by ketamine has been termed “dissociative anesthesia” in that it appears to selectively interrupt association pathways of the brain before producing somesthetic sensory blockade. It may selectively depress the thalamoneocortical system before significantly obtunding the more ancient cerebral centers and pathways (reticular-activating and limbic systems).

Elevation of blood pressure begins shortly after injection, reaches a maximum within a few minutes and usually returns to preanesthetic values within 15 minutes after injection. In the majority of cases, the systolic and diastolic blood pressure peaks from 10% to 50% above preanesthetic levels shortly after induction of anesthesia, but the elevation can be higher or longer in individual cases (see CONTRAINDICATIONS).

Ketamine has a wide margin of safety; several instances of unintentional administration of overdoses of ketamine (up to ten times that usually required) have been followed by prolonged butcomplete recovery.

Ketamine has been studied in over 12,000 operative and diagnostic procedures, involving over 10,000 patients from 105 separate studies. During the course of these studies ketamine hydrochloride was administered as the sole agent, as induction for other general agents, or to supplement low-potency agents.

Specific areas of application have included the following:

  1. debridement, painful dressings, and skin grafting in burn patients, as well as other superficial surgical procedures.

  2. neurodiagnostic procedures such as pneumonencephalograms, ventriculograms, myelograms, and lumbar punctures. See also PRECAUTION concerning increased intracranial pressure.

  3. diagnostic and operative procedures of the eye, ear, nose, and mouth, including dental extractions.

  4. diagnostic and operative procedures of the pharynx, larynx, or bronchial tree. NOTE: Muscle relaxants, with proper attention to respiration, may be required (see PRECAUTIONS section).

  5. sigmoidoscopy and minor surgery of the anus and rectum, and circumcision.

  6. extraperitoneal procedures used in gynecology such as dilatation and curettage.

  7. orthopedic procedures such as closed reductions, manipulations, femoral pinning, amputations, and biopsies.

  8. as an anesthetic in poor-risk patients with depression of vital functions.

  9. in procedures where the intramuscular route of administration is preferred.

  10. in cardiac catheterization procedures.

In these studies, the anesthesia was rated either “excellent” or “good” by the anesthesiologist and the surgeon at 90% and 93%, respectively; rated “fair” at 6% and 4%, respectively; and rated “poor” at 4% and 3%, respectively. In a second method of evaluation, the anesthesia was rated “adequate” in at least 90% and “inadequate” in 10% or less of the procedures.

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