Ketamine Mechanism of Action
Ketamine functions primarily as a non-competitive, non-selective antagonist of the N-methyl-D-aspartate (NMDA) receptor, an ionotropic glutamate receptor in the central nervous system, which produces its characteristic dissociative anesthetic and analgesic effects. 1, 2
Primary Mechanism
Ketamine blocks the NMDA receptor by binding to a specific site within the receptor channel when it is open, preventing glutamate signaling and creating functional dissociation between limbic and cortical systems while selectively depressing the cortex and thalamus. 1, 2, 3
The drug acts as an uncompetitive antagonist, meaning it only binds when the channel is activated, which contributes to its unique pharmacological profile. 3
Secondary Mechanisms Contributing to Analgesia
Ketamine directly blocks opioid receptors in the brain and spinal cord, which contributes significantly to its analgesic effect beyond NMDA antagonism. 2, 4
At subanesthetic doses, ketamine modulates central sensitization, prevents hyperalgesia, and blocks the development of opioid tolerance through its NMDA antagonism. 5, 4
The American Society of Regional Anesthesia and Pain Medicine recognizes that ketamine's primary role in low doses is as an "anti-hyperalgesic" and "anti-allodynic" agent rather than a pure analgesic. 6
Active Metabolites
The major circulating metabolite norketamine demonstrates activity at the NMDA receptor with approximately one-third the affinity of the parent compound. 1
Norketamine undergoes further metabolism to hydroxynorketamine compounds, which also possess pharmacological activity. 1
Clinical Pharmacodynamic Effects
Unlike opioids and other sedatives, ketamine does not depress respiratory or cardiovascular reflexes, even at doses 5-100 times greater than intended. 7, 2, 4
Ketamine stimulates the cardiovascular system through indirect sympathomimetic activity, producing dose-dependent increases in heart rate, blood pressure, and cardiac output by inhibiting central and peripheral catecholamine reuptake. 7, 1
The drug produces profound analgesia while maintaining normal pharyngeal-laryngeal reflexes and normal or slightly enhanced skeletal muscle tone. 7, 1
Ketamine acts as a potent bronchodilator, making it suitable for patients at high risk for bronchospasm. 1
Neuropsychiatric Mechanism
The American Psychiatric Association notes that ketamine causes emergence reactions (floating sensations, vivid dreams, hallucinations, delirium) in 10-30% of adults through its dissociative effects on consciousness. 7, 2
At subanesthetic doses, ketamine demonstrates rapid antidepressant effects through mechanisms including improved neuroplasticity and neurogenesis via NMDA receptor modulation. 7
Onset and Duration
Ketamine is highly lipophilic, allowing rapid penetration into the central nervous system with onset of action within 1 minute via intravenous administration and 3-5 minutes intramuscularly. 7, 2
The duration of clinical effect is 15-30 minutes, corresponding to the initial alpha phase with a half-life of 10-15 minutes. 7, 1