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 the 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 a 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 saline-injected 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 saline-injected 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.

HOSPIRA, INC., LAKE FOREST, IL 60045 USA

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