Ketamine: chemistry

Ketamine is a synthetic cyclohexanone compound, chemically C13H16ClNO [1][2]. It belongs to the arylcyclohexylamine family and is structurally related to phencyclidine (PCP) [3][4], sharing similar but somewhat less intense and shorter-lived effects [5].

The molecule has a chiral centre, meaning it exists as two mirror-image forms: S(+)-ketamine ("esketamine") and R(–)-ketamine ("arketamine") [3][6]. These enantiomers are not equivalent — esketamine has approximately four times greater affinity for the NMDAR binding site than arketamine, and increased analgesic potency compared with the racemic (mixed) form [3]; it has also been postulated to be a more potent painkiller than arketamine specifically [6]. Esketamine is licensed for human use as an anaesthetic agent [3], and a preparation of esketamine is separately licensed for treatment-resistant depression in the UK and elsewhere [3][4].

Ketamine's core action is as a non-competitive antagonist at the NMDA receptor [3][7][6]. Ketamine is a rapid-acting, non-barbiturate dissociative anesthetic [4], producing sedation, immobility, amnesia, and marked analgesia [4]. Ketamine also binds mu opioid and sigma/phencyclidine receptors [4], and has no affinity for gamma-aminobutyric acid (GABA) receptors in the central nervous system [6].

Ketamine undergoes oxidative metabolism, mainly to norketamine, by cytochrome P450 (CYP3A and CYP2B6) enzymes [6]; its metabolites, including norketamine and hydroxylated derivatives, are eliminated in the urine and, to a lesser extent, the bile [3]. Urinary excretion of these metabolites is important in the development of ketamine-induced uropathy [3].

References

1. Ketamine | C13H16ClNO | CID 3821 — PubChem, National Institutes of Health
2. ketamine | Ligand page | IUPHAR/BPS Guide to PHARMACOLOGY — IUPHAR/BPS Guide to Pharmacology
3. Ketamine: an updated review of use and harms (accessible) — UK Government (Advisory Council on the Misuse of Drugs)
4. Ketamine (drug fact sheet) — DEA Diversion Control Division
5. Schedules of Controlled Substances: Placement of Ketamine into Schedule III — Federal Register (Drug Enforcement Administration)
6. Ketamine: A Review of Clinical Pharmacokinetics and Pharmacodynamics in Anesthesia and Pain Therapy — Clinical Pharmacokinetics (Springer)
7. Ketamine, an Old–New Drug: Uses and Abuses — MDPI Pharmaceuticals