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Nonopioid and Adjuvant Analgesic Agents
Published in Pamela E. Macintyre, Stephan A. Schug, Acute Pain Management, 2021
Pamela E. Macintyre, Stephan A. Schug
The terminal elimination half-life of racemic ketamine is two to three hours. The medicine is metabolized by the liver, and the metabolites are excreted by the kidney. The primary metabolite, norketamine, is also an NMDA receptor antagonist and contributes to its analgesic effect, although it is less potent than ketamine itself.
Critical care, neurology and analgesia
Published in Evelyne Jacqz-Aigrain, Imti Choonara, Paediatric Clinical Pharmacology, 2021
Evelyne Jacqz-Aigrain, Imti Choonara
Ketamine has high lipid solubility with rapid distribution. Ketamine undergoes N-demethylation to form norketamine. Racemic ketamine elimination is complicated by R(-)-ketamine inhibiting the elimination of S(+)-ketamine [45]. Clearance in children is similar to adult rates (80 l/h/70kg, i.e. liver blood flow) within the first six months of life, when corrected for size using allometric models [46,47]. Clearance in the neonate is reduced (26 l/h/70 kg) [46,48]. Volume of distribution at steady state (Vss) decreases with age (in 1/kg): 3.46 at birth; 3.03 in infancy; 1.18 at 4 years; and 0.75 in adulthood. [46]. There is a high hepatic extraction ratio and the relative bioavailability of nasal and rectal formulations is 50% and 30% respectively [49,50].
Ketamine Use in Pain Management
Published in Sahar Swidan, Matthew Bennett, Advanced Therapeutics in Pain Medicine, 2020
Sahar Swidan, Charles E. Schultz
Ketamine is a lipophilic drug that crosses the blood–brain barrier and is available as a racemic mixture or as the S(+) enantiomer. The S(+) enantiomer is twice as potent as racemic ketamine and approximately four times as potent as the R(–) enantiomer.4 Ketamine is N-demethylated via liver microsomes into its major metabolite norketamine. Norketamine is rapidly metabolized to ketamine’s primary secondary metabolite, 6 hydroxynorketamine, and to a lesser extent 4-hydroxyketamine and 6-hydroxyketamine.1 Ketamine's half-life in plasma is approximately 2.3 ± 0.5 hours, and it is primarily eliminated in the urine, mostly as hydroxylated or conjugated norketamine metabolites. Four percent is eliminated in the urine as unchanged ketamine. Less than 5% of ketamine is eliminated in the feces. The onset of action for intravenous ketamine is 1–5 minutes and approximately 30 minutes for intranasal ketamine. The duration of action is 10–15 minutes when parenterally administered and 1 hour when given intranasally.
Ketamine for depression
Published in International Review of Psychiatry, 2021
Ketamine is metabolized in the body to norketamine, hydroxynorketamines, hydroxyketamine and dehyronorketamine (Zarate, Brutsche, Laje, et al., 2012). In preclinical work, 2R,6R-hydroxynorketamine (2R,6R-HNK) has been reported to have antidepressant-like effects without ketamine-related behavioural side-effects (motor incoordination, pre-pulse inhibition deficits, ketamine-related discrimination responses or increased drug self-administration) (Fukumoto et al., 2019; Pham et al., 2018; Zanos et al., 2016), although the literature remains divided (Shirayama & Hashimoto, 2018; Yamaguchi et al., 2018; Yang et al., 2017). The (S)- metabolite (S)-norketamine has also been shown to have antidepressant-like effects that are similarly potent to its parent compound but with fewer associated side-effects (Yang, Kobayashi, et al., 2018).
Emerging concepts on the use of ketamine for chronic pain
Published in Expert Review of Clinical Pharmacology, 2020
Yunpeng Yang, Dermot P. Maher, Steven P. Cohen
Ketamine is hepatically metabolized by several cytochrome enzymes, with 80% being converted to norketamine via N-demethylation[30]. The alpha half-life of ketamine is very short in humans, usually 2–4 minutes, with a much longer beta half-life of 2–4 hours[31]. In animal studies, norketamine possesses approximately one-third of the antinociceptive properties as its parent compound, while its other principal metabolite, (Z)‐6‐hydroxynorketamine, is pharmacologically inert at the NMDA receptor though it is pharmacologically active at other receptors[32]. The plasma concentration of norketamine may exceed ketamine during prolonged infusions [1,33,34]. Norketamine, with an elimination half-life of 1.13 hours, may contribute to the downstream analgesic effects observed following prolonged infusions[35]. In a simulation model based on 621 observations in 70 subjects (57 children), it was estimated that norketamine contributed to the analgesic effects of a single 2 mg/kg ketamine bolus for 4 hours[36]. The S-isomer of ketamine possesses two and four times the antinociceptive properties of the R isomer and the racemic isomer, respectively[31]. The effects of ketamine on the treatment of chronic pain and depression are substantially longer than the sedative/hypnotic effects of ketamine, suggesting that these effects are mediated by a secondary increase in structural synaptic connectivity[37].
An update on ketamine and its two enantiomers as rapid-acting antidepressants
Published in Expert Review of Neurotherapeutics, 2019
Ketamine-induced side effects such as psychotomimetic effects and abuse liability are associated with the potent inhibition of the NMDAR in the brain. (S)-norketamine (Ki = 1.70 μM for NMDAR) is metabolized from (S)-ketamine by the microsomal cytochrome P450 system (Figure 1). Very recently, Yang et al. [86] reported that (S)-norketamine exhibits rapid and sustained antidepressant effects in rodent models of depression. These effects are similar to that of the antidepressant actions of (S)-ketamine. However, unlike (S)-ketamine, (S)-norketamine does not cause behavioral and biochemical abnormalities, such as abuse potential, prepulse inhibition deficits, increases in baseline γ-oscillations, and loss of parvalbumin immunoreactivity in the medial prefrontal cortex [86]. (S)-norketamine may have fewer detrimental side-effects in humans than (S)-ketamine because of the lower affinity of (S)-norketamine for NMDAR. Taken together, (S)-norketamine could be a safer alternative antidepressant than (S)-ketamine for use in humans [86,87].