Walter L. Way

Ketamine—Its Pharmacology and Therapeutic Uses

Ketamine—Its Pharmacology and Therapeutic Uses Paul white;Walter Way;anthony Trevor; Anesthesiology

Pharmacology of ketamine isomers in surgical patients.

To assess the intraoperative and postoperative effects of the optical isomers of ketamine. compared with the racemic mixture as sole anesthetics, equianesthetic doses of racemic ketamine (RK), 2 mg/kg, (+)ketamine (PK), 1 mg/kg, and (−)ketamine (MK), 3 mg/kg, were administered intravenously in a randomized, double-blind fashion to 60 healthy patients undergoing elective outpatient operations. Intraoperative effects, adequacy of anesthesia, and need for adjunctive agents were assessed by the same two anesthesiologists. Psychologic assessment was achieved utilizing a trait anxiety scale, a profile of mood states questionnaire, an open-ended sentence-completion form, and a postoperative check list, as well as observations made by a psychologist in the recovery room. Samples of plasma and urine were obtained for gas chromatographic analysis of ketamine and its major metabolites. The durations of anesthesia (35 ± 4 min) were the same in all three groups; however, the amounts of drug needed ranged from 2.4 mg/kg in the PK group to 8.5 mg/kg in the MK group. At the termination of anesthesia, mean plasma levels of the parent compounds were 0.9 (RK), 0.5 (PK), and 1.7 pg/ml (MK), consistent with a PK:MK potency ratio of 3.4:1. The slopes of the plasma decay curves were not significantly different among the three groups. PK was judged to produce more effective anesthesia than RK or MK (95 vs. 75 vs. 68 per cent). Verbal responses in the postanesthetic period suggested significantly more psychic emergence reactions after MK than after RK or PK (37 vs. 15 vs. 5 per cent). Furthermore, MK produced more agitated behavior than did RK or PK (26 vs. 10 vs. 0 per cent). Postoperative pain occurred more commonly in the RK (10 per cent) and MK (16 per cent) groups than in the PK group (0 per cent). The incidences of dreaming (84 per cent) were the same in all three groups. Relative to preoperatively, fear was decreased to a greater extent postoperatively in the PK group than in the RK and MK groups (43 vs. 13 vs. 30 per cent). Finally, patients found PK more acceptable than either RK or MK (85 vs. 65 vs. 63 per cent). The study disclosed differences in anesthetic potencies, intraoperative effects, analgesia, physical side effects, incidences and types of postanesthetic emergence phenomena, and anesthetic preferences among the optical isomers of ketamine. Parallelism of the plasma decay curves and similarities in the patterns of appearance and excretion of the ketamine metabolites for the three groups suggest that the differences were due to pharmacodynamic factors.

Distribution in the Brain and Metabolism of Ketamine in the Rat after Intravenous Administration

The anesthetic effects of ketamine and its distribution to CNS tissue were examined in rats following intravenous administration. Peak brain levels of ketamine were achieved less than a minute following injection. At all times studied, brain:plasma ratios of ketamine were 6.5:1. Study of regional brain levels indicated a preferential distribution of ketamine to the cerebral cortex 30 seconds and one minute after injection. The x-de-methylated metabolite of ketamine also accumulated in the brain, reaching levels appreciably higher than that in plasma 10 minutes after administration. No evidence of the presence of the other metabolite, the cyclohexanone oxidation product, was found in either plasma or brain. Studies of biotransformation in citro showed that brain tissue was incapable of metabolizing ketamine, while liver homogenates metabolized ketamine to the x-demethylated product exclusively. These observations on the disposition of ketamine and its metabolite are discussed in relation to the diverse actions of this dissociative anesthetic agent in the central nervous system.

Comparative pharmacology of the optical isomers of ketamine in mice

Relative pharmacological potencies of the optical isomers of ketamine have been estimated in ICR mice. The (+)-isomer was 3X more potent than (-)-ketamine as an analgesic using the phenylquinone writhing test, only 1.5X more potent in terms of hypnotic activity and 1.8X more potent in causing locomotor stimulation. At equianalgesic doses (+)-ketamine caused less stimulation of locomotor activity than the (-)-isomer. These potency differences did not appear to be due to differences in biodisposition although stereoselective metabolism was demonstrated in vivo. Analgesia induced by ketamine was reversed by 10 mg/kg of naloxone.

The Effects of Alpha-methyldopa, Reserpine, Guanethidine, and Iproniazid on Minimum Alveolar Anesthetic Requirement (MAC)

The effects of prior administration of alphamethyldopa, reserpine, and guanethidine on the minimum alveolar concentration (MAC) of halohane were studied in dogs. The effect of iproniazid, a monoamine oxidase inhibitor, on cyclopropane MAC was studied in rats. Prior administration of alpha-methyldopa or reserpine, which reduce both central and peripheral norepinephrine levels, was associated with a reduction in MAC which was dose-related. Conversely, prior administration of iproniazid, which elevates central norepinephrine levels, resulted in an increase in MAC. MAC was not altered by prior administration of guanethidine, which reduces norepinephrine peripherally but not centrally. These results suggest that anesthetic requirement may be related in part to changes in norepinephrinc content in the brain.

The dependence of pancuronium- and d-tubocurarine-induced neuromuscular blockades on alveolar concentrations of halothane and forane.

The neuromuscular blocking effects of pancuronium and d-tubocurarine were directly related to alveolar anesthetic concentrations in a study of 54 patients anesthetized with Forane and 70 per cent nitrous oxide and 54 patients anesthetized with halothane and 70 per cent nitrous oxide. The median effective doses of pancuronium necessary for 50 per cent depression of twitch height (ED21) were 0.60, 0.36, and 0.18 mg/m2 during 0.5, 1.0, and 1.5 per cent Forane anesthesia, and 0.82, 0.49, and 0.35 mg/m2 during 0.4, 0.8, and 1.2 per cent halothane anesthesia, respectively. The ED21‘s of d-tubocurarine were 2.40, 1.87, and 1.46 mg/m2 during 0.5, 1.0, and 1.5 per cent Forane anesthesia, and 6.40, 3.90, and 2.45 mg/m2 during 0.4, 0.8, and 1.2 per cent halothane anesthesia, respectively. The authors conclude that smaller doses of pancuronium and d-tubo-curarine are needed for adequate relaxation with higher alveolar concentrations of Forane and halothane. Also, during comparative neuromuscular studies of pancuronium and d-tubocurarine, anesthetic concentrations of Forane and halothane should be monitored in arterial blood or alveolar gas.

Comparative Neuromuscular Effects of Forane and Halothane Alone and in Combination with d-Tubocurarine in Man

In human volunteers, Forane failed to alter twitch height, but increased average neuromuscular refractory period and prevented a sustained response to stimulation at higher frequencies of tetanus. These effects were dose-related. Surgical patients anesthetized with 1.25 MAC Forane were unable to sustain tetanus at more than 120 Hz. In contrast, patients anesthetized with 1.25 MAC halothane were able to sustain tetanus at 200 Hz. In 15 patients anesthetized with 1.25 MAC Forane, the median effective dose of d-tubocurarine needed to produce a 50 per cent depression of twitch height (ED50) was 1.70 mg/m2. In contrast, the ED50 of d-tubocurarine in 17 patients anesthetized with 1.25 MAC halothane was 5.69 mg/m2. Thus, 3.3 times as much d-tubocurarine was needed to produce a 50 per cent depression of twitch height with halothane.

Alteration of Anesthetic Requirement by Amphetamine

The effects of acute and chronic administration of dextroamphetamine (DA) on halothane MAC in dogs were evaluated. Acute intravenous administration of DA, 0.1, 0.5, and 1 mg/kg, during halo thane anesthesia was associated with increases of MAC to 19 ±8, 67 ± 11, and 96 ± 15 per cent above control values. Blood pressure increased 40, 112, and 109 per cent, respectively, at the three dose levels, and in 12 of 15 acute-administration trials the dogs developed cardiac arrhythmias. Body temperature increased 0.4 to 2.1 C following acute administration of DA. The large change in MAC produced by interaction of DA with halothane could be decreased by respiratory alkalosis. In contrast, chronically-treated dogs receiving 5 mg/kg/day of DA intramuscularly for seven days had decreases in MAC of 21 ± 3 per cent from control values. These data support the hypothesis that catecholamines that act on the central nervous system may alter anesthetic requirements.

Comparative Times to Peak Effect and Durations of Action of Neostigmine and Pyridostigmine

In 30 patients anesthetized with halothane and 60 per cent nitrous oxide, and in 12 cats anesthetized with chloralose and urethane, d-tobo-curarine (dTc) was continuously infused to produce constant 90 per cent depression of twitch height prior to injection of neostigmine or pyridostigmine. Mean times from neostigmine, 0.6, 1.2, or 1.8 mg/m2, or pyridostigmine, 3, 6, or 9 mg/m2 administration to peak antagonism (onset time) of dTc were 11.1, 8.5, and 7.1 minutes with neo-stigmine and 15.8, 16.9, and 12.2 minutes with pyridostigmine in man. Mean times from administration of the same doses of neostigmine and pyridostigmine to 50 per cent return to the dTc-depressed twitch (duration of action) were 37.8, 41.0, and 57.2 minutes with neostigmine and 51.4, 78.8, and 83.6 minutes with pyridostigmine in man. The onset and duration of action times also were longer with pyridostigmine than with neostigmine in the cat. The doses of pyridostigmine and neostigmine needed for 50 per cent antagonism of the dTc-induced depression of twitch height were 4.0 mg/m2 and 0.92 mg/m2 for man and 120 μg/kg and 13 μg/kg for the cat, respectively. Thus, the potency ratio of pyridostigmine to neostigmine is 4.35 (4.0/0.92) in man and 9.3 (120/13) in the cat. We conclude that pyridostigmine has a slower onset and longer duration of action than neostigmine.

Comparative Neuromuscular Effects of Pancuronium, Gallamine, and Succinylcholine during Forane and Halothane Anesthesia in Man

Pancuronium, gallamine, and succinylcholine produced more profound neuromuscular blockade in 36 patients anesthetized with 1.25 MAC Forane than in 36 patients anesthetized with 1.25 MAC halothane. The median effective dose of pancuronium necessary to produce 50 per cent depression of twitch height (ED20) was 0.27 mg/m2 during Forane and 0.49 mg/m2 during halothane anesthesia, giving a halothane/Forane potency ratio of 1.8. The ED20 of gallamine was 9.4 mg/m2 during Forane anesthesia and 22.5 mg/m2 during halothane anesthesia, for a potency ratio of 2.4. The ED20 of succinylcholine was 3.4 mg/m2 during Forane anesthesia and 5.1 mg/m2 during halothane anesthesia, for a potency ratio of 1.5.