What is the pharmacology of ketamine, including its mechanism of action, pharmacokinetics, dosing for anesthesia, analgesia, and treatment‑resistant depression, adverse effects, contraindications, and alternative therapies?

Pharmacology of Ketamine

Mechanism of Action

Ketamine is a non-competitive, open-channel antagonist of NMDA (N-methyl-D-aspartate) receptors that blocks glutamate binding in the central nervous system, producing dissociative anesthesia, analgesia, and rapid antidepressant effects through distinct concentration-dependent mechanisms. 1

• At anesthetic concentrations, ketamine binds deep within the NMDA receptor pore to block current influx, producing complete channel blockade 2, 3
• At sub-anesthetic (antidepressant) concentrations, ketamine interacts with membrane-accessible hydrophobic sites on NMDA receptors, stabilizing pre-open states and producing incomplete, voltage- and pH-dependent inhibition that preferentially reduces tonic receptor activation while sparing brief synaptic transmission 3
• NMDA receptor antagonism initiates a downstream cascade enhancing AMPA receptor throughput, activating mTOR-dependent structural plasticity via BDNF and protein synthesis in the medial prefrontal cortex 1, 4
• Additional mechanisms contributing to ketamine's effects include interactions with sigma-1 receptors, monoaminergic systems, opioid and cannabinoid systems, voltage-gated calcium channels, and cholinergic pathways 5

Pharmacokinetics

Ketamine is highly lipid-soluble with rapid onset (1 minute IV) and short duration of action (15-30 minutes for sedation), yet antidepressant effects persist 2-3 days after a single infusion due to sustained neuroplastic changes. 6, 7

• The redistribution half-life from the central nervous system is approximately 2.5 hours 1
• Clinical antidepressant and anti-PTSD effects last 2-3 days after single infusion, with significant improvements remaining through day 7 when added to ongoing antidepressant treatment 7, 8
• The drug is rapidly cleared and metabolized, with effects extending well beyond plasma elimination half-life 4

Dosing Regimens

Anesthesia and Procedural Sedation

For procedural sedation in children, ketamine 1-2 mg/kg IV or 4 mg/kg IM produces effective dissociative anesthesia with 100% adequacy for procedure completion. 6

• High doses (anesthetic range) are required to achieve complete sedation or induction of anesthesia as monotherapy 6
• Ketamine/midazolam combinations (1-2 mg/kg ketamine with 0.05-0.1 mg/kg midazolam) demonstrate superior efficacy compared to other sedation regimens for orthopedic procedures and laceration repair 6
• Low-dose intramuscular ketamine (2.5 mg/kg) is superior to intranasal midazolam for laceration repair 6

Analgesia

At lower doses, ketamine provides mild sedative, anti-shivering, and analgesic effects that are synergistic with other drugs, particularly for suppressing rib fracture pain during ventilator weaning. 6

• Sub-anesthetic doses produce analgesia and may limit central sensitization, hyperalgesia, and opioid tolerance 6
• Limited data suggest modest analgesic potential for ketamine as an adjuvant to opioids in cancer pain management, though evidence remains insufficient for routine recommendation 6
• Ketamine possesses both analgesic and sedative properties, distinguishing it from many other sedation agents 6

Treatment-Resistant Depression

The American Psychiatric Association recommends IV ketamine 0.5 mg/kg infused over 40 minutes for treatment-resistant depression, administered twice weekly until remission or completion of 4-6 total infusions. 7, 8

• Patients must have failed at least 2 adequate antidepressant trials (4-6 weeks at therapeutic doses) to confirm treatment resistance 7
• Response assessment should evaluate for ≥50% reduction in depressive symptoms at 24 hours post-infusion 7
• Alternative schedules include three times per week for 2 weeks 7, 9
• Responders (59% after repeated infusions) can receive maintenance infusions once weekly to sustain antidepressant effects 9
• For bipolar depression, concurrent mood stabilizer therapy (lithium or valproate) is mandatory to mitigate manic switch risk 7, 8
• Median of three infusions required before achieving response, with cumulative antidepressant effects from repeated infusions 9

Acute Suicidal Ideation

For patients with acute suicidal ideation in emergency settings, ketamine 0.2-0.25 mg/kg IV over 1-2 minutes produces rapid reduction in suicidal ideation beginning within 40 minutes, with effects persisting up to 10 days. 7, 8

• Effect sizes for suicidal ideation reduction are largest at 40 minutes (d=1.05), with substantially larger effects in patients with high baseline suicidal ideation (d=2.36 at 40 minutes) 8
• Antisuicidal effects may be partially independent of general antidepressant effects 7, 8
• Lower doses minimize psychotomimetic effects while providing antisuicidal benefits 8

PTSD

In adults with treatment-refractory PTSD, a single IV infusion of ketamine 0.5 mg/kg over 40 minutes produces rapid reduction in symptom severity within 24 hours, with benefits persisting for several days. 1

• Sub-anesthetic dosing yields therapeutic improvement with tolerable dissociative symptoms 1
• Higher, anesthetic-level doses may exacerbate PTSD symptoms through heightened psychomimetic effects 1

Adverse Effects

Psychotomimetic Effects

At the standard 0.5 mg/kg infusion dose, transient psychotomimetic events occur in approximately 20% of patients (hallucinations) and 12% (nightmares), typically resolving without intervention. 1, 7

• Emergence reactions (floating sensations, vivid dreams, hallucinations, delirium) occur in 10-30% of adults receiving anesthetic doses 6
• Psychotomimetic effects are dose-dependent, with higher incidence at doses approaching or exceeding 0.5 mg/kg 8
• Co-administration of midazolam minimizes emergence reactions 6
• At minimal doses (0.015 mg/kg/h infusion without bolus), ketamine does not significantly increase delirium or sleep disturbances compared to placebo 8

Cardiovascular Effects

Ketamine produces dose-dependent increases in heart rate, blood pressure, and cardiac output through sympathetic nervous system stimulation, which can mitigate hypotension associated with other sedatives. 6

• Ketamine has sympathomimetic effects that counteract the vasodilation and hypotension common to other analgesics and sedatives 6
• Unlike other sedatives, ketamine does not ablate sympathetic tone to the same degree 6

Respiratory Effects

Unlike benzodiazepines and opioids, ketamine preserves respiratory drive and functions as a potent bronchodilator, offering superior respiratory safety for patients with compromised airway function. 6, 1

• Ketamine does not depress airway or cardiovascular reflexes even at doses 5-100 times greater than intended 6
• May not suppress respiratory drive during spontaneous ventilation 6
• Transient hypoxemia is rare (1% in pediatric ketamine/midazolam studies) 6

Respiratory Depression with Combination Therapy

When ketamine is combined with benzodiazepines and opioids, particularly fentanyl/midazolam combinations, the risk of respiratory depression increases to 10-20%, requiring close monitoring and readiness to treat apnea. 6

• Minor respiratory events requiring oxygen or stimulation occur in approximately 10-20% of patients receiving fentanyl/midazolam combinations 6
• Life-threatening events remain near zero with appropriate monitoring 6
• Bag-valve-mask ventilation or intubation is rarely required 6

Contraindications and Precautions

Monitoring Requirements

Esketamine requires REMS certification and mandatory 2-hour post-treatment monitoring due to psychotomimetic effects and potential for abuse. 7, 8

• Close monitoring for signs of respiratory depression is essential when ketamine is combined with benzodiazepines and opioids 6
• Appropriate training and support to treat apnea must be available 6

Amnesia Considerations

Ketamine must be combined with a GABA agonist (benzodiazepine or propofol) to provide amnesia during neuromuscular blockade, as ketamine alone does not provide adequate amnestic effects. 6

• GABA agonist sedative-hypnotics have strong amnestic effects essential for patients requiring neuromuscular blockade 6

Cardiac Considerations

FDA guidelines recommend limiting transdermal buprenorphine to maximum 20 mcg/hour due to QT prolongation concerns, making ketamine a potentially safer alternative for patients on QT-prolonging cancer treatments, though ketamine's cardiovascular stimulation requires monitoring. 6

Alternative Therapies

For Sedation and Analgesia

Fentanyl and remifentanil are first-line agents for analgesia and sedation in mechanically ventilated patients, with propofol preferred over benzodiazepines when GABA agonist sedation is required due to shorter half-life and lower delirium risk. 6

• Dexmedetomidine (central alpha-2 adrenergic agonist) has sedative, anti-shivering, and analgesic opioid-sparing effects with lower delirium risk, particularly useful during ventilator weaning 6
• Dexmedetomidine is often ineffective for severe ventilator dyssynchrony or deep sedation requirements 6
• Continuous benzodiazepine infusions should be avoided whenever possible due to higher delirium risk 6

For Treatment-Resistant Depression

Traditional antidepressants like venlafaxine require weeks to months for therapeutic effect and do not provide rapid relief, whereas ketamine provides symptom reduction within hours, making it the preferred option when rapid symptom reduction is the primary goal. 8

• Even ECT may not provide reduction in suicidal ideation for 1-2 weeks, highlighting ketamine's unique rapid-acting profile 8
• Long-term efficacy and safety data for ketamine remain limited, with most evidence from small sample sizes 7, 8
• Optimal maintenance strategies are not well-established 8

Clinical Pitfalls and Caveats

• Resedation risk: Flumazenil's effects (1 hour duration) may be shorter than midazolam's effects (80+ minutes), potentially causing resedation if benzodiazepines were co-administered 6
• Dose-dependent effects: Ketamine has dramatically different effect profiles at different doses—lower doses provide mild sedation and analgesia, while high doses produce complete dissociative anesthesia 6
• Combination therapy risks: While ketamine alone preserves respiratory drive, combining it with benzodiazepines and opioids increases respiratory depression risk to levels comparable to other sedative combinations 6
• Treatment resistance verification: Before initiating ketamine for depression, verify at least 2 adequate antidepressant trials have failed (4-6 weeks at therapeutic doses) 7
• Bipolar precautions: Always add mood stabilizers (lithium or valproate) when using ketamine for bipolar depression to prevent manic switch 7, 8
• Limited long-term data: Effectiveness of esketamine in preventing suicide has not been established despite FDA approval for acute suicidal ideation 8