Ketamine
The general anaesthetic ketamine (Ketalar®, Ketaject™, Vetalar™) is used in human and veterin ary medicine for induction of anaesthesia for short surgical procedures and routine veterinary examination. It was introduced to the market in the 1960s as a unique anaesthetic agent. It is structurally related to phencyclidine (PCP), but has only 25% of the psychotomimetic activity of PCP. The pharmacology of ketamine is complex. Like PCP, ketamine has activity at multiple sites in the brain. It primarily acts as a glutamate antagonist by noncompetitively binding to the PCP receptor located in the ion channel of the N methyl-D-aspartate (NMDA) receptor complex. It sterically blocks the cation channel gated by the NMDA receptor, impeding the flow of Na and Ca2 ions into the neuron and resulting in disruption of glutamate-mediated transmission at these sites throughout the brain. The (S) isomer is more potent in displacing the NMDA ligand from its receptor than is (R)-ketamine. In addition, ketamine facilitates monoamine trans mission by inhibiting the reuptake of dopamine, noradrenaline (norepinephrine) and serotonin, resulting in an accumulation of these neuro transmitters in synapses. It also acts on the opiate system as an agonist at the l-opiate receptor. When abused, ketamine can produce psychotic symptoms and cognitive impairment that may persist for up to 3 days. Clinically, ketamine has been used to induce schizophrenia as a model of psychosis. Like PCP, ketamine induces short-lived psychotic symptoms in non-schizophrenic volunteers. Ketamine is rapidly metabolised, with the principal metabolites being an active metabolite, norketamine, and an inactive metabolite, 6 hydroxynorketamine. Ketamine is demethylated to norketamine by the liver microsomal cytochrome P450 system, specifically the isoforms CYP3A4, CYP2B6 and CYP2C9 (Figure 1). In the USA, ketamine is regulated as a Schedule III controlled substance. Recently, there has been a resurgence of interest in ketamine due to its appearing as a ‘club drug’ at rave parties and at bars. On the streets it is known as ‘K’, ‘Special K’ and ‘Cat Valium’ and by many other names. The primary source for ketamine is diversion from veterinary clinics where it is available as a parenteral solution. Ketamine is used in a liquid form, its pharmaceutical preparation, or as a powder formed by allowing the solvent of the injectable to evaporate. It is taken voluntarily by intramuscular injection or by the intranasal or oral routes. Ketamine can be ingested involuntarily when it is unknowingly added to a drink to induce a stupor for drug-facilitated sexual assault, i.e. as a ‘date-rape’ drug.
Figure 1 Metabolism of ketamine.
