Does ketamine show tolerance?

To the Editor,

Drug tolerance refers to a pharmacological occurrence wherein the body displays a diminished response to a specific drug following its repetitive administration, thereby requiring higher doses to attain the desired therapeutic outcome. Tolerance can develop due to two main reasons:

1. Pharmacokinetic: This involves the accelerated metabolism of the drug, leading to its reduced effectiveness

2. Pharmacodynamic: Adaptive changes occur, such as an increase or decrease in the number of receptors, as observed with morphine.

Tachyphylaxis is a similar concept to tolerance but occurs when the drug’s action rapidly diminishes due to the depletion of mediators within the nerve endings’ presynaptic membrane. This depletion is caused by the administration of multiple doses of the drug within a short period. However, increasing the dose does not reverse this phenomenon.[1] Let’s consider a case where a 2-month-old child weighing 5 kg, with a Lymphovenous malformation, who was previously exposed to nonoperative room anesthesia (NORA) (with Ketamine administration), was scheduled for a contrast-enhanced computed tomography thorax. Following the ASA monitoring standards for NORA, the child received injection glycopyrrolate (4 μg/kg) and injection midazolam (0.1 mg/kg), followed by injection ketamine. Initially, a dose of injection ketamine (1 mg/kg intravenous) was administered, but the patient remained awake, crying, and moving. Due to this inadequate response, incremental dosing was performed until the patient was anesthetized at a dose of 4 mg/kg ketamine (20 mg). No adverse effects were observed, and the child woke up and cried after 20 minutes. Ketamine acts as an antagonist to N-methyl-D-aspartate receptors, and its metabolites are excreted in urine. Approximately 80% is excreted as conjugates of hydroxylated ketamine metabolites with glucuronic acid, 16% as dehydronorketamine, 2% as norketamine, and 2% is excreted unmetabolized. Tritium-labeled ketamine in studies have shown that for 5 days, out of the 91% of administered radioactivity recovered in urine, the parent drug, norketamine, and 5, 6-dehydronorketamine accounted for only 20%. This indicates the potential presence of undiscovered metabolites of ketamine, which possess distant chemical structures and pharmacological properties that remain to be identified. It has been noted that repeated administration of ketamine can extend its elimination period by as much as 11–14 days.[2] The cyclohexanone ring in ketamine undergoes dehydrogenation to form 5, 6-dehydronorketamine, which has a half-life of 6–10 days. Ketamine has been found to induce multiple hepatic P450 isoforms, including 1A, 2B, 2E1, and 3A, in rat liver microsomes. When given as a single dose, ketamine supresses the activity of cytochrome P450 (CYP) 3A4, an enzyme responsible for breaking down erythromycin through a process called N-demethylation; however, it is important to note that repetitive exposure to Ketamine much like Ethanol can actually stimulate the activity of CYP enzymes. All the mechanisms mentioned above collectively contribute to the concept that long-term use of ketamine can result in tolerance, meaning higher doses are required to achieve the desired clinical effect. These mechanisms include frequent use of Ketamine for sedation, prolonged presence of metabolites such as 5, 6-dehydronorketamine, upregulation of enzymes metabolizing ketamine, and the presence of unknown metabolites. Consequently, higher doses are required to elicit the therapeutic effects of ketamine.

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