Ketamine - Mechanism of Action

Mechanism of Action

Central nervous system

Ketamine is a noncompetitive NMDA receptor (NMDAR) antagonist. More specifically, ketamine binds to the allosteric site of the NMDA receptor, effectively inhibiting its channel. The S(+) and R(-) stereoisomers bind with different affinities: K_i = 3200 and 1100 nM, respectively. NMDAR antagonism effects analgesia by preventing central sensitization in dorsal horn neurons; in other words, ketamine's actions interfere with pain transmission in the spinal cord. Ketamine also inhibits nitric oxide synthase, inhibiting production of nitric oxide, a neurotransmitter involved in pain perception, and hence further contributing to analgesia. Ketamine also interacts with sigma and opioid receptors, but with lower affinity and without significantly contributing to analgesia.

Ketamine also interacts with a host of other receptors to effect analgesia. It blocks voltage-sensitive calcium channels and depresses sodium channels, attenuating hyperalgesia; it alters cholinergic neurotransmission, which is implicated in pain mechanisms; and it acts as a noradrenergic and serotonergic uptake inhibitor, which are involved in descending antinociceptive pathways.

Peripheral systems

Ketamine affects catecholaminergic transmission as noted above, producing measurable changes in peripheral organ systems, including the cardiovascular, gastrointestinal, and respiratory systems:

• Cardiovascular: Ketamine inhibits reuptake of catecholamines, stimulating the sympathetic nervous system, resulting in cardiovascular symptoms.
• Gastrointestinal: Inhibition of neuronal uptake and increased serotonergic activity are thought to underly nausea and vomiting.
• Respiratory: Induced catecholamine release and stimulation of β₂ adrenergic receptors effects bronchodilation.

• skeletal formula of (R)-ketamine
• ball-and-stick model of (R)-ketamine
• skeletal formula of (S)-ketamine
• ball-and-stick model of (S)-ketamine