From the Guidelines
NMDA receptor antagonists work by blocking N-methyl-D-aspartate receptors in the brain, preventing glutamate from activating the receptor and reducing excessive neuronal excitation. These medications, such as ketamine, bind to different sites on the NMDA receptor complex to inhibit its activity, which can protect neurons from excitotoxicity (cell death caused by excessive glutamate stimulation) 1. The mechanism of action of NMDA receptor antagonists involves blocking the glutamate receptor, thereby reducing the excitatory neurotransmission in the brain.
Key Points
- NMDA antagonists, including ketamine, memantine, dextromethorphan, and phencyclidine (PCP), are used to treat various conditions, such as Alzheimer's disease, treatment-resistant depression, and certain pain syndromes 1.
- Ketamine is typically used at low (sub-anesthetic) doses to produce analgesia and limit central sensitization, hyperalgesia, and opioid tolerance 1.
- The use of ketamine as an adjuvant to opioids for managing cancer pain has been studied, but the evidence is limited, and the results are mixed 1.
- NMDA antagonists can induce dissociative effects, particularly at higher doses, due to their impact on glutamatergic pathways involved in perception and consciousness 1.
Clinical Implications
- The most recent and highest quality study suggests that NMDA receptor antagonists, such as ketamine, may have modest analgesic potential for treating cancer-related pain 1.
- However, the evidence is limited, and more research is needed to fully understand the mechanism of action and clinical implications of NMDA receptor antagonists in various conditions 1.
- Clinicians should carefully consider the potential benefits and risks of using NMDA receptor antagonists, including ketamine, in their patients, and monitor them closely for side effects, such as dizziness, confusion, hallucinations, and increased blood pressure and heart rate 1.
From the FDA Drug Label
Ketamine hydrochloride, a racemic mixture of ketamine, is a non-selective, non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, an ionotropic glutamate receptor. Memantine is postulated to exert its therapeutic effect through its action as a low to moderate affinity uncompetitive (open-channel) NMDA receptor antagonist which binds preferentially to the NMDA receptor-operated cation channels.
The mechanism of action of N-methyl-D-aspartate (NMDA) receptor antagonists, such as ketamine and memantine, is through antagonism of NMDA receptors in the central nervous system. This antagonism can produce various effects, including:
- Analgesia: Ketamine produces analgesia by antagonizing NMDA receptors.
- Dissociative anesthetic state: Ketamine induces a dissociative anesthetic state characterized by profound analgesia and normal or slightly enhanced skeletal muscle tone.
- Neuroprotective effects: Memantine may exert its therapeutic effect through its action as a low to moderate affinity uncompetitive NMDA receptor antagonist.
These effects are primarily due to the blockade of NMDA receptor-operated cation channels, which play a crucial role in the regulation of neuronal excitability and synaptic plasticity 2, 2, 3.
From the Research
Mechanism of Action of NMDA Receptor Antagonists
The mechanism of action of N-methyl-D-aspartate (NMDA) receptor antagonists involves blocking the excitatory glutamate-gated NMDA receptors, which play a critical role in synaptic plasticity and transmission. Key aspects of this mechanism include:
- Blocking the NMDA receptor-associated ion channel, thereby reducing the influx of calcium (Ca2+) ions into neurons and preventing toxic intracellular events 4
- Occluding the open channel by binding to a site located within the channel pore, as demonstrated by ketamine's action on NMDA receptors 5
- Decreasing the frequency of channel opening by an allosteric mechanism, in addition to blocking the open channel 5
- Preferential inhibition of distinct NMDAR subpopulations, which may contribute to the differential clinical effects of NMDA receptor antagonists such as memantine and ketamine 6
Key Findings
Some notable findings related to the mechanism of action of NMDA receptor antagonists include:
- Ketamine's ability to block NMDA receptors and reduce the influx of calcium ions into neurons, which contributes to its anesthetic and analgesic properties 5
- Memantine's unique pharmacological features, such as moderate affinity, rapid blocking kinetics, and strong voltage-dependency, which allow it to act as an uncompetitive NMDA receptor antagonist without inducing highly undesirable side effects 7
- The potential for NMDA receptor antagonists to exert antidepressant effects by modulating glutamatergic transmission and synaptic plasticity, as suggested by studies on ketamine and memantine 8, 7