What drug causes NMDA (N-methyl-D-aspartate) receptor antagonism and calcium channel blockade?

Ketamine is the Drug That Causes NMDA Receptor Antagonism and Calcium Channel Blockade

Ketamine is the primary drug that exhibits both NMDA receptor antagonism and calcium channel blockade properties. 1, 2

Mechanism of Action

Ketamine works through two primary mechanisms:

1. NMDA Receptor Antagonism

   • Acts as a non-competitive antagonist of N-methyl-D-aspartate (NMDA) receptors 1
   • Blocks the calcium channel associated with NMDA glutamate receptors 3
   • Interferes with normal excitatory effects of glutamate and aspartate 4
   • Binds in the central vestibule between the channel gate and selectivity filter 5

2. Calcium Channel Blockade

   • Directly dilates cerebral arteries by acting as a calcium antagonist 2
   • Inhibits calcium uptake through both potential-operated (potassium) and receptor-operated channels in vascular smooth muscle 2
   • Modulates voltage-gated L-type calcium channels 6

Clinical Applications

Ketamine's dual mechanism makes it useful in several clinical scenarios:

Pain Management

• Can be administered with opioids to help reduce overall opioid dose 4
• Particularly effective for neuropathic pain that is refractory to opioids 4
• Sub-anesthetic doses can be used as an adjunct to opioids for pain relief 4

Sedation

• Used for sedation in critically ill patients, particularly after cardiac arrest 4
• Often combined with fentanyl or remifentanil for analgesia and sedation 4

Depression Treatment

• FDA has approved esketamine (S-enantiomer of ketamine) for treatment-resistant depression 6
• Produces rapid (within hours) and long-lasting antidepressant effects 5

Dosing Considerations

• For pain management: Sub-anesthetic doses are typically used 4
• For sedation: Often used in combination with other agents like opioids or benzodiazepines 4
• Available in multiple formulations: 200 mg/20 mL (10 mg/mL), 500 mg/10 mL (50 mg/mL), 1,000 mg/10 mL (100 mg/mL) 1

Side Effects and Precautions

• Hemodynamic effects: Can cause transient increases in blood pressure and heart rate 1
• Emergence reactions: Postoperative confusional states or agitation occur in approximately 12% of patients 1
• Respiratory depression: May occur with overdosage or rapid administration 1
• Psychotomimetic effects: May cause dysphoria, nightmares, or hallucinations 4
• Hepatobiliary dysfunction: Associated with recurrent use 1

Important Clinical Considerations

• Ketamine is contraindicated in patients for whom blood pressure elevation would be hazardous 1
• Does not suppress pharyngeal and laryngeal reflexes, so caution is needed during procedures of the pharynx, larynx, or bronchial tree 1
• Blocks NMDA receptors which may increase neuronal apoptosis in the developing brain - caution in pediatric patients 1
• Incidence of psychological manifestations during emergence may be reduced by using lower doses in conjunction with benzodiazepines 1

Ketamine's unique dual mechanism of NMDA receptor antagonism and calcium channel blockade makes it valuable in multiple clinical scenarios, particularly for pain management and sedation when other agents are insufficient or contraindicated.