What is the mechanism of action of ketamine?

Ketamine Mechanism of Action

Ketamine functions primarily as a non-selective, non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, an ionotropic glutamate receptor in the central nervous system, which underlies its dissociative anesthetic, analgesic, and rapid antidepressant properties. 1

Primary Mechanism: NMDA Receptor Antagonism

• Ketamine blocks NMDA receptors non-competitively, preventing glutamate signaling in the central nervous system and creating functional dissociation between limbic and cortical systems 2, 1
• This NMDA antagonism selectively depresses the cortex and thalamus while stimulating parts of the limbic system, producing the characteristic dissociative state 2
• The major circulating metabolite norketamine also demonstrates activity at the NMDA receptor, though with approximately one-third the potency of the parent compound 1
• NMDA antagonism is the central mechanism contributing to ketamine's amnesic, analgesic, anesthetic, psychotomimetic, and neuroprotective actions 3

Secondary Mechanisms Contributing to Clinical Effects

Direct Opioid Receptor Blockade

• Ketamine directly blocks opioid receptors in the brain and spinal cord, contributing significantly to its analgesic effect 2, 4
• This opioid receptor interaction explains ketamine's ability to reduce opioid consumption when used as an adjunct and its synergy with opioid pathways 4

Modulation of Central Sensitization

• At subanesthetic doses, ketamine modulates central sensitization and prevents hyperalgesia through its NMDA antagonism 2
• This mechanism blocks the development of opioid tolerance, making it valuable as an adjuvant analgesic 2

Cardiovascular Stimulation

• Ketamine's cardiovascular effects (increased heart rate, blood pressure, and cardiac output) are mediated indirectly through inhibition of both central and peripheral catecholamine reuptake 5, 1
• This sympathomimetic activity distinguishes ketamine from other anesthetics that typically depress cardiovascular function 5

Additional Receptor Interactions

• Evidence suggests involvement of non-NMDA glutamate receptors, muscarinic and nicotinic cholinergic transmission, interactions with 5-HT receptors, and L-Type Ca²⁺ channels in some of ketamine's anesthetic and neuroprotective properties 3
• The role of opioid receptors remains somewhat uncertain in the broader context, though direct blockade is documented 3

Rapid Antidepressant Mechanism

• Subanesthetic doses of ketamine produce rapid antidepressant effects through improved neuroplasticity and neurogenesis, mediated by NMDA receptor antagonism 5
• This rapid-acting property has generated significant interest in treating suicidal ideation, with effects potentially independent of general mood improvement 6

Pharmacokinetic Considerations

• Ketamine is highly lipophilic, allowing rapid penetration into the central nervous system with onset of action within 1 minute intravenously 5, 2
• Metabolism occurs primarily via N-dealkylation by CYP2B6 and CYP3A4 to form the active metabolite norketamine 1
• The redistribution half-life from the CNS to peripheral tissues is approximately 2.5 hours 1

Clinical Implications of Mechanism

• The NMDA antagonism produces profound analgesia while maintaining normal pharyngeal-laryngeal reflexes, unlike other sedatives 5, 1
• Ketamine does not depress respiratory or cardiovascular reflexes, even at doses 5-100 times greater than intended, due to its unique mechanism 5, 2
• Emergence reactions (floating sensations, vivid dreams, hallucinations, delirium) occur in 10-30% of adults, directly related to its effects on higher brain centers and NMDA receptor antagonism 5, 2

Important Caveats

• The mechanism of action is complex and involves multiple receptor systems beyond NMDA antagonism, though NMDA blockade remains the primary therapeutic target 3
• Ketamine's effects are highly dose-dependent, with stimulant effects predominating at low doses and psychedelic effects at higher doses 7
• The blocking effect on NMDA receptors is enhanced and prolonged in developing neurons compared to mature neurons, which may explain increased neurotoxicity concerns in pediatric populations 8