Ketamine

Mechanism

Mechanism of action

Ketamine acts primarily as a high-affinity, non-competitive antagonist of the calcium channel associated with the excitatory NMDA receptor. It binds directly to the phenylcyclohexyl channel site when it is open, blocking transmembrane ion flow and preventing glutamate-induced cortical stimulation.

This functional disconnection separates the thalamoneocortical system from the limbic emotional support system. Additionally, it inhibits the neuronal and intraneuronal reuptake of catecholamines (norepinephrine, adrenaline) at the synaptic junctions of the sympathetic nervous system, which explains its prominent indirect autonomic effects.

Bronchodilator and Sympathetic Hemodynamic Effect

Through indirect sympathetic stimulation, ketamine induces potent bronchodilation mediated by activation of β₂-adrenergic receptors, making it the induction agent of choice in patients with refractory status asthmaticus requiring endotracheal intubation. Likewise, it temporarily increases systolic blood pressure, cardiac output and heart rate, compensating for the tonic hemodynamic drop common to anesthetic induction.

Differentiation of Isomers: Esketamine vs. Racemic Mixture

Conventional ketamine occurs as a racemic mixture of two enantiomers in identical proportions (R-ketamine and S-ketamine). Esketamine (S-ketamine) is the pure purified isomer of the original formulation, characterized by:

• 3 to 4 times higher binding affinity for the NMDA receptor compared to the R isomer.
• A double analgesic and hypnotic power, allowing the necessary clinical therapeutic doses to be reduced by half.
• Lower cumulative systemic clearance and a lower incidence of delirium and emergency hallucinations.

Indicators and dose

Dosage and Clinical Adjustment

• Induction of General Anesthesia (IV): 1.0 - 2.0 mg/kg slow intravenous route.
• Intramuscular Induction (IM - Pediatrics): 4.0 - 8.0 mg/kg IM (useful for difficult inductions in uncooperative children without venous access).
• Subanesthetic Multimodal Analgesia: Boluses of 0.1 - 0.25 mg/kg IV followed by continuous infusions of 0.1 - 0.2 mg/kg/hour (1.5 - 3 µg/kg/min). Excellent protector against opioid-induced hyperalgesia.

Security

Absolute Contraindications and Precautions

• Severe Intracranial Hypertension with Loss of Autoregulation: Relative contraindication. Although historically outlawed, contemporary studies indicate that ketamine can be used safely if associated with controlled mechanical ventilation and protective benzodiazepines. However, it can increase cerebral blood flow and cerebrospinal fluid pressure.
• Unstable Ischemic Heart Disease: Relative contraindication due to the reflex increase in myocardial oxygen consumption caused by increased afterload and heart rate.
• History of Schizophrenia or Active Psychosis: Contraindication due to the high risk of inducing severe psychotic dissociative reactions or clinical exacerbations upon awakening.

Adverse Effects: Emergency Reactions

About 10% - 30% of adults receiving ketamine as a single inducer experience emergency reactions or delirium upon awakening, characterized by intense vivid dreams, three-dimensional visual hallucinations, psychomotor agitation, and severe temporal disorientation. This phenomenon is effectively prevented by prophylactic coadministration of low doses of benzodiazepines (such as midazolam 1 - 2 mg IV) or propofol before awakening.