Anthony J. Trevor

Ketamine—Its Pharmacology and Therapeutic Uses

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

Metabolism of the neurotoxic tertiary amine, MPTP, by brain monoamine oxidase.

The neurotoxic chemical MPTP (1-methyl-4-phenyl-1,2,4,5-tetrahydropyridine) is metabolized by rat brain mitochondrial fractions at a rate of 0.91 +/- 0.02 nmoles/mg protein/min. The major metabolite has been identified as the 1-methyl-4- phenylpyridinium species. This biotransformation process is blocked by 10(-7) M deprenyl and pargyline. MPTP itself inhibited the metabolism of benzylamine by brain mitochondrial fractions. These results are discussed in terms of possible bioactivation mechanisms that may be associated with the neurodegenerative properties of MPTP .

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.

Active uptake of MPP+, a metabolite of MPTP, by brain synaptosomes

Mouse brain synaptosomal preparations were used to study uptake of N-methyl-4-phenylpyridine (MPP+), a metabolite of the neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). The uptake of [3H]-MPP+ by striatal synaptosomes was approximately 25 X greater than that of [3H]-MPTP, with a KM of 0.48 microM and a Vmax of 5.3 nmoles/g tissue/min. Uptake was Na+ dependent and inhibited by ouabain, cocaine and dopamine (Ki 0.12 microM). Synaptosomes prepared from the corpus striatum accumulated [3H]-MPP+ at a rate 5-10 times higher than preparations from other brain regions. This selective uptake of MPP+ may contribute to the specificity of the toxic effects of MPTP on nigrostriatal dopaminergic neurons.

Biochemical Events in the Development of Parkinsonism Induced by 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine

Although only 3 years have passed since the appearance of the first report linking the presence of 1 -methyl-4-phenyl1,2,3,6-tetrahydropyriidine (MPTP) in preparations of an illicitly synthesized meperidine analog to the appearance of parkinsonian symptoms (Langston et al., 1983), progress in clarifying the individual steps leading to the neuropathological symptoms has been remarkable. Although some interesting questions still remain, a plausible mechanistic picture has emerged so that the time seems right to review current knowledge of the individual biochemical events involved in the expression of the selective neurotoxicity of MPTP. One reason for the rapid progress has been the worldwide interest generated by the availability of the first animal model for parkinsonism and the hope that elucidation of the mechanism of the neurotoxicity of MPTP may yield clues to some of the causes of idiopathic Parkinson’s disease. To the extent that this has been achieved, the accidental presence of this potent neurotoxin in some batches of “new heroin” may benefit mankind, despite the tragic consequences to the individuals exposed to it and the alarming social and medical problems of “designer drugs” that it has brought into sharp focus.

Oxidation of the neurotoxic amine 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by monoamine oxidases A and B and suicide inactivation of the enzymes by MPTP

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a thermal breakdown product of a meperidine-like narcotic analgetic used by drug abusers as a synthetic heroin, causes Parkinsonian symptoms in humans and degeneration of the substantia nigra in monkeys. MPTP is oxidized by brain mitochondrial preparations in a process which is blocked by deprenyl and pargyline, implying catalysis by monoamine oxidase B. The present paper demonstrates that pure MAO B isolated from beef liver oxidizes MPTP 38% as fast as benzylamine with a comparable Km value. Additionally, MAO A, isolated from human placenta, oxidizes MPTP to the same product at about 12% of the rate of kynuramine, again with a comparable Km value. The latter reaction is blocked by clorgyline. Both forms of MAO are progressively inactivated by MPTP by a process which follows first order kinetics. This progressive inactivation and the fact that the activity of MAO B is not significantly regenerated following gel exclusion chromatography suggest the formation of a covalent adduct with enzyme. Thus, MPTP appears to be a suicide inactivator of MAO.

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.

V. Potential bioactivation pathways for the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

The metabolism of the selective nigrostriatal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been studied in rat brain mitochondrial incubation mixtures. The 1-methyl-4-phenylpyridinium species MPP+ has been characterized by chemical ionization mass spectral and 1H NMR analysis. Evidence also was obtained for the formation of an intermediate product which, with the aid of deuterium incorporation studies, was tentatively identified as the alpha-carbon oxidation product, the 1-methyl-4-phenyl-2,3-dihydropyridinium species MPDP+. Comparison of the diode array UV spectrum of this metabolite with that of the synthetic perchlorate salt of MPDP+ confirmed this assignment. The oxidation of MPTP to MPDP+ but not of MPDP+ to MPP+ is completely inhibited by 10(-7) M pargyline. MPDP+, on the other hand, is unstable and rapidly undergoes disproportionation to MPTP and MPP+. Based on these results, we speculate that the neurotoxicity of MPTP is mediated by its intraneuronal oxidation to MPDP+, a reaction which appears to be catalyzed by MAO. The interactions of MPDP+ and/or MPP+ with dopamine, a readily oxidizable compound present in high concentration in the nigrostriatum, to form neurotoxic species may account for the selective toxic properties of the parent drug.

Mechanism of the neurotoxicity of 1-methyl-4-phenylpyridinium (MPP)+, the toxic bioactivation product of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)☆

It is widely believed that the nigrostriatal toxicity of MPTP is due to its oxidation by brain monoamine oxidase first to MPDP+, and eventually to MPP+. Following uptake by the synaptic dopamine reuptake system, it is concentrated in the matrix of striatal mitochondria by an energy-dependent carrier, energized by the electrical gradient of the membrane. At the very high intramitochondrial concentrations thus reached, MPP+ combines with NADH dehydrogenase at a point distal to its iron-sulfur clusters but prior to the Q10 combining site. This leads to cessation of oxidative phosphorylation, ATP depletion, and cell death. Other pyridine derivatives act similarly on NADH dehydrogenase but they are not acutely toxic unless concentrated by the MPP+ carrier.