What is ketamine?

What is Ketamine

Ketamine is a dissociative anesthetic agent that functions primarily as a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, producing profound analgesia, cardiovascular stimulation, and preserved airway reflexes while maintaining a unique safety profile distinct from other sedatives. 1, 2, 3

Chemical Structure and Formulation

• Ketamine hydrochloride is a white crystalline powder with the chemical name dl-2-(o-Chlorophenyl)-2-(methylamino) cyclohexanone hydrochloride and molecular weight of 274.19. 3
• It exists as a racemic mixture of two optical isomers, with the S(+)-enantiomer being approximately four times more potent as an anesthetic and analgesic than the R(-)-enantiomer. 4
• The drug is formulated as a slightly acidic (pH 3.5 to 5.5) sterile solution available in concentrations of 10 mg/mL, 50 mg/mL, or 100 mg/mL for intravenous or intramuscular injection. 3

Primary Mechanism of Action

• Ketamine blocks NMDA receptors non-competitively, preventing glutamate signaling in the central nervous system and creating functional dissociation between limbic and cortical systems. 2
• This NMDA antagonism selectively depresses the cortex and thalamus while stimulating parts of the limbic system, producing the characteristic dissociative state. 1, 2
• Ketamine directly blocks opioid receptors in the brain and spinal cord, contributing significantly to its analgesic effect beyond NMDA antagonism. 1, 2
• At subanesthetic doses, ketamine modulates central sensitization, prevents hyperalgesia, and blocks the development of opioid tolerance. 1, 2

Pharmacokinetics

• Intravenous ketamine has an onset of action within 1 minute and provides sedation for 15–30 minutes, with an initial distribution half-life of 10 to 15 minutes. 1, 5, 3
• Intramuscular administration produces onset within 3-5 minutes (average 4 minutes 42 seconds). 1
• The redistribution half-life from the central nervous system is approximately 2.5 hours. 5, 3
• Ketamine is highly lipophilic, allowing rapid penetration into the CNS with brain levels 10-40 times higher than blood levels. 1
• The drug undergoes extensive first-pass metabolism primarily by CYP2B6 and CYP3A4 to the active metabolite norketamine, which has approximately one-third the potency of ketamine. 1, 3, 4
• Oral bioavailability is poor due to extensive first-pass metabolism, making ketamine vulnerable to pharmacokinetic drug interactions. 4

Clinical Effects and Unique Properties

Dissociative Anesthetic State

• Ketamine produces a dissociative anesthetic state characterized by profound analgesia, normal pharyngeal-laryngeal reflexes, and normal or slightly enhanced skeletal muscle tone. 1, 3
• The drug can produce nystagmus with pupillary dilation, salivation, lacrimation, and spontaneous limb movements with increased muscle tone through indirect sympathomimetic activity. 3

Cardiovascular Effects

• Ketamine increases blood pressure, heart rate, and cardiac output through inhibition of both central and peripheral catecholamine reuptake. 1, 2, 5
• Blood pressure elevation reaches a maximum within a few minutes and typically peaks 10-50% above preanesthetic levels, usually returning to baseline within 15 minutes. 1, 3
• This sympathomimetic activity distinguishes ketamine from other anesthetics that typically depress cardiovascular function, making it suitable for hemodynamically unstable patients. 2, 5

Respiratory Effects

• Ketamine is a potent bronchodilator suitable for anesthetizing patients at high risk for bronchospasm. 3, 6
• The drug preserves spontaneous respiratory drive and does not depress respiratory or cardiovascular reflexes, even at doses 5-100 times higher than intended. 1, 5
• Unlike other sedatives, ketamine maintains normal airway reflexes and produces minimal respiratory depression when used alone. 2, 5

Clinical Applications

Anesthesia and Procedural Sedation

• Standard IV induction dose is 1-2 mg/kg, providing 100% procedural success for dissociative anesthesia. 1, 5
• Intramuscular dosing of 4 mg/kg is recommended for wound repair, burn care, or lumbar puncture. 1, 5
• High (anesthetic-range) doses are required for complete sedation or induction when ketamine is used as monotherapy. 5

Analgesia

• Subanesthetic doses deliver mild sedation, anti-shivering, and analgesia that synergize with other agents. 5
• Ketamine functions primarily as an "anti-hyperalgesic," "anti-allodynic," or "tolerance-protective" agent rather than as a traditional analgesic. 7
• The drug has a role in treating opioid-resistant or pathological pain (central sensitization with hyperalgesia or allodynia, opioid-induced hyperalgesia, neuropathic pain). 7

Psychiatric Applications

• For treatment-resistant depression, the American Psychiatric Association recommends IV ketamine 0.5 mg/kg infused over 40 minutes, administered twice weekly until remission or 4-6 total infusions. 5
• A single infusion yields antidepressant effects that persist for 2-3 days due to sustained neuroplastic changes, with benefits potentially extending through day 7 when added to ongoing antidepressant therapy. 5
• For acute suicidal ideation, IV ketamine 0.2-0.25 mg/kg over 1-2 minutes produces rapid reduction in suicidal thoughts beginning within 40 minutes, with effects lasting up to 10 days. 5
• The antisuicidal effect size is large at 40 minutes (Cohen d = 1.05) and even larger in patients with high baseline ideation (d = 2.36), with benefits appearing partially independent of broader antidepressant effects. 5

Adverse Effects

Psychotomimetic Effects

• Emergence reactions (floating sensations, vivid dreams, hallucinations, delirium) occur in 10-30% of adults receiving anesthetic doses. 1, 5
• At the standard 0.5 mg/kg infusion, transient hallucinations occur in approximately 20% of patients and nightmares in approximately 12%. 5
• Incidence is dose-dependent, increasing markedly at doses ≥0.5 mg/kg. 5
• Co-administration of midazolam reduces the frequency and severity of emergence reactions. 1, 5

Respiratory Depression with Combination Therapy

• When combined with benzodiazepines and opioids, the risk of respiratory depression rises to 10-20%, necessitating close monitoring. 5
• Minor respiratory events (requiring oxygen or stimulation) occur in approximately 10-20% of patients receiving combination therapy, while life-threatening events remain near zero with appropriate monitoring. 5

Dependence and Tolerance

• Physical dependence has been reported with prolonged use of ketamine, manifested by withdrawal signs and symptoms after abrupt discontinuation. 3
• Reported withdrawal symptoms associated with daily intake of large doses include craving, fatigue, poor appetite, and anxiety. 3
• Tolerance is characterized by a reduced response to the drug after repeated administration, requiring higher doses to produce the same effect. 3

Contraindications and Precautions

• Ketamine should be avoided in patients with uncontrolled cardiovascular disease, active psychosis, severe hepatic dysfunction, or elevated intracranial/ocular pressure. 1
• Esketamine administration requires REMS certification and mandatory 2-hour post-treatment monitoring due to psychotomimetic potential and abuse risk. 5
• Ketamine alone does not provide adequate amnesia for neuromuscular blockade; a GABA-agonist (benzodiazepine or propofol) must be co-administered to ensure amnesia. 5
• For bipolar depression, concurrent mood-stabilizer therapy (lithium or valproate) is mandatory to prevent manic switching. 5

Routes of Administration

• Ketamine is solvable in aqueous and lipid solutions, providing convenient administration via multiple routes including oral, nasal, rectal, intravenous, intramuscular, subcutaneous, transdermal, sublingual, and intraosseous. 6
• Sublingual and nasal formulations produce rapid maximum plasma concentrations with relatively high bioavailability compared to oral administration. 4
• Intranasal ketamine shows inferior efficacy compared to IM ketamine for procedural sedation. 1