What is ketamine?

What is Ketamine?

Ketamine is a dissociative anesthetic and NMDA receptor antagonist that produces profound analgesia, cardiovascular stimulation, and bronchodilation while maintaining airway reflexes and respiratory drive. 1

Mechanism of Action

Ketamine functions primarily as a non-selective, non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, an ionotropic glutamate receptor in the central nervous system. 1 This antagonism creates a functional dissociation between limbic and cortical systems, selectively depressing the cortex and thalamus while stimulating parts of the limbic system. 2

• Ketamine also directly blocks opioid receptors in the brain and spinal cord, contributing to its analgesic effects. 2, 3
• At subanesthetic doses, it modulates central sensitization, prevents hyperalgesia, and blocks the development of opioid tolerance. 3
• The major circulating metabolite, norketamine, demonstrates activity at the same NMDA receptor with approximately one-third the potency of ketamine. 1

Clinical Pharmacology

Nervous System Effects

• Ketamine produces a dissociative anesthetic state characterized by profound analgesia, normal pharyngeal-laryngeal reflexes, and normal or slightly enhanced skeletal muscle tone. 1
• The onset of action is rapid: 1 minute intravenously and 3-5 minutes intramuscularly. 2
• Duration of action is 15-30 minutes after intravenous administration. 2
• Ketamine can produce nystagmus with pupillary dilation, salivation, lacrimation, and spontaneous limb movements through indirect sympathomimetic activity. 1

Cardiovascular Effects

• Ketamine increases blood pressure, heart rate, and cardiac output through inhibition of both central and peripheral catecholamine reuptake. 1
• Blood pressure typically peaks 10-50% above preanesthetic levels shortly after induction, reaching maximum within a few minutes and usually returning to baseline within 15 minutes. 1
• This hemodynamic profile makes ketamine the agent of choice for patients with unstable hemodynamics, such as shocked or hypotensive patients. 4, 5

Respiratory Effects

• Ketamine is a potent bronchodilator suitable for anesthetizing patients at high risk for bronchospasm. 1
• Unlike opioids, ketamine does not depress respiratory or cardiovascular reflexes, even at doses 5-100 times higher than intended. 2, 3
• It maintains both the hypercapnic reflex and residual functional capacity with moderate bronchodilation. 5

Dosing Guidelines

Anesthetic Induction

• Intravenous: 1-2 mg/kg for induction of anesthesia. 2
• Intramuscular: 4 mg/kg for wound repair, burn care, or lumbar puncture. 2
• For brief procedures, 1-1.5 mg/kg IV (with 1.5 mg/kg being more effective, requiring additional doses in only 5.5% of patients). 2

Perioperative Analgesia

• The American Society of Anesthesiologists recommends bolus <0.35 mg/kg followed by continuous infusion at 0.125-0.25 mg/kg/h (maximum 0.5 mg/kg/h) for perioperative pain management. 2, 3
• This regimen consistently reduces opioid consumption when used as an adjunct. 3

Pharmacokinetics

• Metabolism: Ketamine undergoes extensive metabolism via N-dealkylation to norketamine primarily by CYP2B6 and CYP3A4 enzymes. 1
• Distribution: Following IV administration, ketamine has an initial alpha phase lasting about 45 minutes with a half-life of 10-15 minutes, corresponding to the anesthetic effect. 1
• Elimination: The redistribution half-life (beta phase) from the CNS to peripheral tissues is 2.5 hours. 1
• Bioavailability: Oral bioavailability is poor due to extensive first-pass metabolism, but intranasal administration produces rapid maximum plasma concentrations with relatively high bioavailability. 6

Adverse Effects and Contraindications

Common Adverse Effects

• Emergence reactions (floating sensations, vivid dreams, hallucinations, delirium) occur in 10-30% of adults. 2
• Co-administration of midazolam can minimize these emergence reactions but increases the risk of respiratory depression. 2
• Ketamine can cause excessive salivation and bronchial secretions. 2

Contraindications

• Avoid in patients with: uncontrolled cardiovascular disease, active psychosis, severe hepatic dysfunction, or elevated intracranial/ocular pressure. 2

Dependence and Withdrawal

• Physical dependence has been reported with prolonged use of ketamine. 1
• Withdrawal symptoms (craving, fatigue, poor appetite, anxiety) have been reported after discontinuation of frequently used (more than weekly), large doses for long periods. 1
• Tolerance develops with repeated administration. 1

Clinical Applications Beyond Anesthesia

• Acute and chronic pain management: Low-dose ketamine reduces opioid consumption and may reduce chronic postsurgical pain after specific surgical procedures. 7, 6
• Cancer pain: The NCCN notes ketamine has modest analgesic potential as an adjunct when pain is refractory to opioids, though data are limited. 7, 3
• Topical formulations: Amitriptyline-ketamine combinations (0.5-5% ketamine) can be compounded for localized pain conditions like erythromelalgia. 7
• Antidepressant effects: Ketamine has rapid-acting antidepressant effects useful in therapy-resistant depression, though long-term safety issues remain unresolved. 6, 8

Critical Pitfalls to Avoid

• Do not confuse sedation with analgesia: Unlike propofol, etomidate, and sodium thiopental, ketamine provides both sedation AND analgesia. 9
• Monitor for dose-dependent psychotomimetic effects: Higher doses increase the risk of hallucinations and delirium, particularly problematic in patients at risk for postoperative neurocognitive disorders. 7
• Beware of cardiovascular stimulation: While beneficial in hypotensive patients, the sympathomimetic effects can be problematic in patients with uncontrolled hypertension or cardiovascular disease. 2, 1