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 but complete 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:
- debridement, painful dressings, and skin grafting in burn patients, as well
as other superficial surgical procedures.
- neurodiagnostic procedures such as pneumonencephalograms, ventriculograms,
myelograms, and lumbar punctures. See also PRECAUTIONS
concerning increased intracranial pressure.
- diagnostic and operative procedures of the eye, ear, nose and mouth, including
dental extractions.
- diagnostic and operative procedures of the pharynx, larynx, or bronchial
tree. NOTE: Muscle relaxants, with proper attention to respiration, may be
required (see PRECAUTIONS).
- sigmoidoscopy and minor surgery of the anus and rectum, and circumcision.
- extraperitoneal procedures used in gynecology such as dilatation and curettage.
- orthopedic procedures such as closed reductions, manipulations, femoral
pinning, amputations, and biopsies.
- as an anesthetic in poor-risk patients with depression of vital functions.
- in procedures where the intramuscular route of administration is preferred.
- 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.
Animal Pharmacology And Toxicology
Toxicity
The acute toxicity of ketamine has been studied in several species. In mature
mice and rats, the intraperitoneal LD50 values are approximately
100 times the average human intravenous dose and approximately 20 times the
average human intramuscular dose. A slightly higher acute toxicity observed
in neonatal rats was not sufficiently elevated to suggest an increased hazard
when used in children. Daily intravenous injections in rats of five times the
average human intravenous dose and intramuscular injections in dogs at four
times the average human intramuscular dose demonstrated excellent tolerance
for as long as 6 weeks. Similarly, twice weekly anesthetic sessions of one,
three, or six hours' duration in monkeys over a four- to six-week period were
well tolerated.
Interaction with Other Drugs Commonly Used for Preanesthetic Medication
Large doses (three or more times the equivalent effective human dose) of morphine,
meperidine, and atropine increased the depth and prolonged the duration of anesthesia
produced by a standard anesthetizing dose of ketamine in Rhesus monkeys. The
prolonged duration was not of sufficient magnitude to contraindicate the use
of these drugs for preanesthetic medication in human clinical trials.
Blood Pressure
Blood pressure responses to ketamine vary with the laboratory species and experimental
conditions. Blood pressure is increased in normotensive and renal hypertensive
rats with and without adrenalectomy and under pentobarbital anesthesia.
Intravenous ketamine produces a fall in arterial blood pressure in the Rhesus
monkey and a rise in arterial blood pressure in the dog. In this respect the
dog mimics the cardiovascular effect observed in man. The pressor response to
ketamine injected into intact, unanesthetized dogs is accompanied by a tachycardia,
rise in cardiac output and a fall in total peripheral resistance. It causes
a fall in perfusion pressure following a large dose injected into an artificially
perfused vascular bed (dog hindquarters), and it has little or no potentiating
effect upon vasoconstriction responses of epinephrine or norepinephrine. The
pressor response to ketamine is reduced or blocked by chlorpromazine (central
depressant and peripheral α-adrenergic blockade), by β-adrenergic blockade,
and by ganglionic blockade. The tachycardia and increase in myocardial contractile
force seen in intact animals does not appear in isolated hearts (Langendorff)
at a concentration of 0.1 mg of ketamine nor in Starling dog heart-lung preparations
at a ketamine concentration of 50 mg/kg of HLP. These observations support the
hypothesis that the hypertension produced by ketamine is due to selective activation
of central cardiac stimulating mechanisms leading to an increase in cardiac
output. The dog myocardium is not sensitized to epinephrine and ketamine appears
to have a weak antiarrhythmic activity.
Metabolic Disposition
Ketamine is rapidly absorbed following parenteral administration. Animal experiments indicated that ketamine was rapidly distributed into body tissues, with relatively high concentrations appearing in body fat, liver, lung, and brain; lower concentrations were found in the heart, skeletal muscle, and blood plasma. Placental transfer of the drug was found to occur in pregnant dogs and monkeys. No significant degree of binding to serum albumin was found with ketamine.
Balance studies in rats, dogs, and monkeys resulted in recovery of 85% to 95%
of the dose in the urine, mainly in the form of degradation products. Small
amounts of drug were also excreted in the bile and feces. Balance studies with
tritium-labeled ketamine in human subjects (1 mg/lb given intravenously) resulted
in the mean recovery of 91% of the dose in the urine and 3% in the feces. Peak
plasma levels averaged about 0.75 mcg/mL, and CSF levels were about 0.2 mcg/mL,
1 hour after dosing.
Ketamine undergoes N-demethylation and hydroxylation of the cyclohexanone ring,
with the formation of water-soluble conjugates which are excreted in the urine.
Further oxidation also occurs with the formation of cyclohexanone derivative.
The unconjugated N-demethylated metabolite was found to be less than one-sixth
as potent as ketamine. The unconjugated demethyl cyclohexanone derivative was
found to be less than one-tenth as potent as ketamine. Repeated doses of ketamine
administered to animals did not produce any detectable increase in microsomal
enzyme activity.
Reproduction
Male and female rats, when given five times the average human intravenous dose
of ketamine for three consecutive days about one week before mating, had a reproductive
performance equivalent to that of salineinjected controls. When given to pregnant
rats and rabbits intramuscularly at twice the average human intramuscular dose
during the respective periods of organogenesis, the litter characteristics were
equivalent to those of salineinjected controls. A small group of rabbits was
given a single large dose (six times the average human dose) of ketamine on
Day 6 of pregnancy to simulate the effect of an excessive clinical dose around
the period of nidation. The outcome of pregnancy was equivalent in control and
treated groups.
To determine the effect of ketamine on the perinatal and postnatal period,
pregnant rats were given twice the average human intramuscular dose during Days
18 to 21 of pregnancy. Litter characteristics at birth and through the weaning
period were equivalent to those of the control animals. There was a slight increase
in incidence of delayed parturition by one day in treated dams of this group.
Three groups each of mated beagle bitches were given 2.5 times the average human
intramuscular dose twice weekly for the three weeks of the first, second, and
third trimesters of pregnancy, respectively, without the development of adverse
effects in the pups.
Last updated on RxList: 5/23/2008