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KETAMINE — Comprehensive Drug Monograph

Sources: Miller's Anesthesia 10e (Miller), Barash Clinical Anesthesia 9e (Barash), Morgan & Mikhail's Clinical Anesthesiology 7e (Morgan)

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1. Name of Drug / Preparation

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2. Type of Preparation

• Vial (multi-dose vial, for injection)
• Available as aqueous solution for IV or IM injection
• Esketamine (S-ketamine) is additionally available as a nasal spray (Spravato, FDA-approved for treatment-resistant depression)
• Preservative: chlorobutanol (neurotoxic — NOT for intrathecal/epidural use) — Miller

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3. Volume of Preparation

• 10 mg/mL — 20 mL vial (200 mg total)
• 50 mg/mL — 10 mL vial (500 mg total)
• 100 mg/mL — 5 mL vial (500 mg total); most concentrated, commonly used for IM administration

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4. Concentration

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5. Total Drug Content

• Varies by vial: 200 mg (10 mg/mL × 20 mL), 500 mg (50 mg/mL × 10 mL), 500 mg (100 mg/mL × 5 mL)

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6. Additional Contents / Composition

• Active ingredient: Ketamine hydrochloride (racemic mixture of R(−) and S(+) enantiomers)
• Preservative: Chlorobutanol (benzalkonium chloride in some formulations)
• Adjusted to pH 3.5–5.5 with hydrochloric acid
• The S(+) enantiomer single-isomer preparation (Esketamine/Ketanest-S) is not available in the United States but widely available globally — Morgan

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7. Drug Class / Classification

• Primary: Dissociative anesthetic / Phencyclidine derivative
• Receptor class: NMDA (N-methyl-D-aspartate) receptor antagonist
• Additional classifications:
  • Non-barbiturate intravenous anesthetic
  • Analgesic (at subanesthetic doses)
  • Antidepressant (low-dose, off-label/esketamine FDA-approved)
  • Bronchodilator
  • Sympathomimetic

Ketamine is a structural analog of phencyclidine (PCP, angel dust), one-tenth as potent, yet retaining many of its psychotomimetic properties. — Morgan

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8. Mechanism of Action

Primary — NMDA Receptor Antagonism

• Ketamine is a non-competitive, open-channel blocker of the NMDA receptor. It binds within the ion channel pore (use-dependent blockade) at the phencyclidine binding site, blocking calcium influx — Barash
• NMDA receptor blockade interrupts glutamatergic input to the GABAergic system → changing excitatory activity in the cortex and limbic system → unconsciousness — Miller
• At the spinal cord level: potent antinociceptive effects via NMDAr blockade, and inhibition of acetylcholine release — Miller
• S(+)-ketamine is 3–4× more potent than R(−)-ketamine as an NMDA blocker — Barash, Morgan

Secondary Receptors (clinical relevance variable):

Dissociative Anesthesia Mechanism

• Ketamine functionally dissociates sensory impulses from the limbic cortex (awareness area) → trance-like cataleptic state with open eyes, preserved reflexes (may not be protective), profound analgesia, amnesia — Morgan
• Primary CNS site: thalamocortical projection system — depresses function in parts of the cortex, particularly the association areas — Miller

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9. Onset of Action

• Rapid onset due to: low molecular weight, pKa near physiologic pH (7.5), high lipid solubility → rapid BBB penetration — Miller
• No delay between plasma concentration and CNS effect (near-immediate passage across BBB) — Miller

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10. Duration of Action

• Analgesia persists at plasma levels ≥ 0.1 mcg/mL (subanesthetic) → significant postoperative analgesic duration — Miller
• S(+) enantiomer enables quicker recovery by a few minutes (smaller dose needed + 10% faster hepatic biotransformation) — Miller
• Awakening after a single dose is primarily due to redistribution (not elimination) — Morgan

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11. Metabolism

• Hepatic — extensive first-pass metabolism (hepatic extraction ratio ~0.9) — Morgan
• Primary pathway: N-demethylation via cytochrome P-450 (primarily CYP3A4, CYP2B6) to norketamine (active metabolite) — Miller, Morgan
• Norketamine has 1/3 the potency of ketamine (contributes to prolonged analgesia/sedation) — Morgan
• Norketamine further undergoes hydroxylation → hydroxy-norketamine and dehydronorketamine → conjugated to water-soluble glucuronide conjugates → renal excretion — Miller
• S(+) enantiomer: larger elimination clearance and larger Vd than R(−) — Miller
• Enzyme induction: repeated doses (e.g., burn dressing changes) → tolerance, partially explained by hepatic enzyme induction — Morgan

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12. Elimination / Excretion

• Renal — excreted as water-soluble hydroxylated and glucuronide-conjugated metabolites
• Two-compartment pharmacokinetic model (rapid distribution + slower elimination):

• Bioavailability by route: IV = 100%; IM = 93%; intranasal = 25–50%; oral = 16–30% (significant first-pass effect) — Barash, Morgan

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13. Standard Dose

Intravenous:

• Plasma levels for anesthesia (adults): 0.6–2 mcg/mL; children: 0.8–4 mcg/mL — Miller
• Awakening occurs at levels < 0.5 mcg/mL — Miller
• Analgesic plasma threshold: ≥ 0.1 mcg/mL — Miller

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14. Dose Modifications in Special Patients

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15. CNS Effects

Dissociative State

• Dose-related unconsciousness and analgesia — Miller
• Cataleptic trance: eyes open, nystagmus, preserved airway reflexes (but should NOT be assumed protective), no recall — Miller
• Amnesia present but less profound than benzodiazepines — Miller
• Profound analgesia at subanesthetic levels — Barash

Cerebral Metabolism and Blood Flow

• Unique among IV anesthetics — increases both CBF and CMR (cerebral metabolic rate) — Miller
• Subanesthetic doses (0.2–0.3 mg/kg): increase global CMR by ~25% (PET studies) — Miller
• Greatest CMR increase in frontal and anterior cingulate cortex — Miller
• Global CBF increased by ~14% (subanesthetic) and ~36% (anesthetic) doses — Miller
• CBV increased by ~50% — Miller
• S(+)-ketamine substantially increases CMR; R(−)-ketamine tends to decrease CMR — Miller
• Autoregulation maintained during ketamine anesthesia — Miller
• CO₂ responsiveness preserved — Miller

ICP

• Historically avoided in raised ICP; however, systematic reviews show ketamine does NOT increase ICP in head-injured patients under controlled ventilation with adjunctive sedatives (propofol or benzodiazepine) — Miller
• May have neuroprotective properties (NMDA antagonism) — Barash

EEG

• Does not suppress EEG (unlike other IV anesthetics) — may cause high-frequency γ oscillations → dissociative state
• S(+)-ketamine more potent in suppressing EEG than R(−) or racemic mixture — Miller
• Does not lower seizure threshold; may be beneficial in refractory status epilepticus (NMDA block) — Barash

Psychomimetic / Emergence Phenomena

• Hallucinations, emergence delirium, vivid dreams, alterations in mood — primarily mediated via sigma receptor activation
• Incidence: up to 30% with ketamine alone; reduced to < 10% with benzodiazepine premedication — Morgan

Pain / Antinociception

• Inhibits central sensitization and opioid-induced hyperalgesia via NMDA block — Miller
• Antihyperalgesic, antiallodynic, tolerance-protective — Barash

Antidepressant Effect

• Rapid antidepressant effect within 1 hour of administration — Barash
• Decreased depression symptoms and suicidal ideation; FDA-approved esketamine (Spravato nasal spray) for treatment-resistant depression — Barash, Morgan

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16. Cardiovascular Effects

Stimulatory (usual clinical finding):

• Increases heart rate, blood pressure, cardiac output — Barash, Morgan
• Mechanism: central sympathetic activation (inhibits neuronal catecholamine reuptake, releases norepinephrine from sympathetic nerve terminals) — usually overrides direct myocardial depressant effects — Miller
• Typically: ↑HR by 20–30%, ↑MAP by 20–40%, ↑CI — Morgan
• Effect onset: 3–5 minutes after IV; duration ~15 minutes

Direct Myocardial Effect:

• Direct negative inotrope in vitro; however, this is overcome by sympathetic stimulation in most patients — Miller
• In catecholamine-depleted states (terminal shock, severe sepsis), the direct depressant effect may dominate → cardiovascular collapse possible — Morgan, Barash

Modification:

• Modest doses of diazepam, midazolam, or flunitrazepam attenuate hemodynamic effects — Miller
• Continuous infusion technique ± benzodiazepine reduces tachycardia and hypertension — Miller
• β-blockers and α-blockers attenuate cardiovascular stimulation — Morgan

Pulmonary Vasculature:

• May increase pulmonary artery pressure (PAP) — caution in pulmonary hypertension — Morgan

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17. Respiratory Effects

• Ventilatory drive minimally affected at standard induction doses — Morgan
• Transient, dose-related respiratory depression possible; apnea rare unless combined with opioids — Morgan
• S(+)-ketamine can interact with μ-opioid receptors at supraspinal sites → respiratory depression with supraspinal antinociception — Miller
• Potent bronchodilator (racemic form) via sympathomimetic mechanism + direct smooth muscle relaxation — ideal for asthmatic patients — Morgan
• Note: S(+)-ketamine produces minimal bronchodilation (compared to racemic form) — Morgan
• Airway reflexes maintained (but not reliably protective — laryngoscopy/intubation still stimulates) — Miller, Morgan
• Increased salivation and secretions → atropine or glycopyrrolate premedication recommended — Morgan

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18. Other Systemic Effects

Eyes

• Moderate pupil dilation — Miller
• Nystagmus — characteristic finding — Miller
• Increases intraocular pressure (IOP) → contraindicated in open-eye injuries — Morgan
• Increases lacrimation — Miller

Musculoskeletal

• Increased skeletal muscle tone with coordinated but purposeless movements of limbs, trunk, head — Miller
• Does NOT cause muscle relaxation (unlike other IV anesthetics)

GI

• No significant effect on GI motility at standard doses
• Increased secretions → risk of aspiration if reflexes impaired

Genitourinary

• Ketamine uropathy with chronic/recreational use: progressive bladder damage (see Toxicity section)

Immune/Inflammatory

• Some evidence of anti-inflammatory properties; investigated in sepsis
• No adrenocortical suppression (unlike etomidate) — safe for repeated dosing in critically ill — Barash

Pediatric Neurotoxicity (animal data)

• As an NMDA antagonist, ketamine (like other NMDA antagonists) may accentuate apoptosis in the developing brain in animal models — clinical implications in humans remain unclear — Miller

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19. Clinical Uses / Indications

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20. Advantages

1. Unique cardiovascular stimulation — safest IV induction agent in hemodynamically unstable, hypovolemic, or traumatized patients
2. Bronchodilation — ideal for asthmatics
3. Profound analgesia at subanesthetic doses — opioid-sparing
4. Airway reflexes preserved (even if not reliably protective)
5. IM route effective (93% bioavailability) — valuable when IV access is unavailable
6. No adrenocortical suppression — safe repeated dosing
7. Wide therapeutic index — used safely in austere/battlefield conditions
8. No special equipment needed for IM administration
9. Antidepressant effect — rapid onset (used in treatment-resistant depression)
10. Prevents opioid-induced hyperalgesia and central sensitization — key in multimodal analgesia
11. Maintains respiratory drive better than other IV induction agents
12. Anti-epileptic in status epilepticus
13. May be neuroprotective via NMDA blockade

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21. Adverse Effects / Complications

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22. Contraindications / Cautions

Absolute Contraindications:

• Open globe / penetrating eye injury (raises IOP) — Morgan
• Known hypersensitivity to ketamine
• Intrathecal/epidural administration (chlorobutanol preservative is neurotoxic) — Miller

Relative Contraindications:

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23. Drug Interactions

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24. Special Anaesthesia Considerations / Pearls

1. Premedicate with benzodiazepine (midazolam 0.05 mg/kg IV) to reduce emergence reactions — administer before or with ketamine — Morgan
2. Antisialagogue premedication (atropine 0.01 mg/kg or glycopyrrolate 0.005 mg/kg) to reduce hypersalivation and laryngospasm risk — Morgan
3. Airway reflexes are maintained but NOT reliably protective — do NOT assume a full stomach patient is safe — Miller
4. Quiet, low-stimulation recovery environment reduces emergence phenomena — Morgan
5. Avoid verbal stimulation during recovery phase — Morgan
6. Combine with propofol or midazolam for TIVA to reduce psychomimetic effects and blunt cardiovascular response in those where stimulation is undesirable
7. Ideal for: Trauma induction, hypovolemic shock, asthmatic patients, pediatric IM induction, burns, combat/field anesthesia — Miller, Barash, Morgan
8. ICP concerns largely mitigated when used with adjunctive sedatives under controlled ventilation — Miller (systematic review evidence)
9. Subanesthetic ketamine infusion (0.1–0.5 mg/kg/hr) during surgery markedly reduces postoperative opioid consumption
10. S(+)-ketamine (esketamine): 3–4× more potent, faster hepatic metabolism, quicker recovery; used as monotherapy or nasal spray for depression (Spravato)
11. Tolerance develops with daily repeated dosing — particularly relevant in burns units — Morgan
12. "Ketamine-propofol (Ketofol)": 1:1 mixing (ketamine 10 mg/mL + propofol 10 mg/mL) widely used for procedural sedation — cardiovascular neutrality with maintained analgesia
13. In the late-stage, catecholamine-depleted septic patient, ketamine can precipitate cardiac arrest — always have vasopressors ready

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25. Comparison with Similar Drugs

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26. Toxicity / Special Syndrome Associated

A. Ketamine Uropathy (Ketamine Cystitis)

• Seen with chronic recreational or repeated clinical use
• Progressive bladder inflammation and fibrosis → contracted bladder (bladder capacity < 10–20 mL in severe cases)
• Upper urinary tract involvement: hydronephrosis, hydroureter, renal papillary necrosis
• Histology: mucosal ulceration, submucosal fibrosis, interstitial inflammation
• Symptom onset: years after initiation of abuse
• Not fully reversible

B. Hepatotoxicity

• Chronic users: elevated liver enzymes, biliary dilation, cholangiopathy
• Mechanism: chlorobutanol preservative contribution suspected

C. Neurotoxicity / Psychosis

• Chronic use: persistent psychosis, cognitive impairment, white matter changes
• Recreational ketamine ("Special K", "Ket"): NMDA hypofunction model of schizophrenia

D. Neonatal/Pediatric Brain Apoptosis (Animal Data)

• Ketamine and other NMDA antagonists accelerate apoptosis in the neonatal animal brain
• Clinical significance in human neonates: unclear — Miller

E. Emergence Delirium

• Not strictly "toxicity" but the most common acute adverse syndrome
• Characterized by: vivid dreams, hallucinations, out-of-body experiences, agitation
• Risk factors: high dose, rapid IV injection, age 15–65 (paradoxically more common in adults than children/elderly), female sex

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27. Management of Toxicity

No specific receptor antagonist reverses all the CNS effects of ketamine — Miller

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28. Storage Requirements

• Store at room temperature (15–30°C / 59–86°F)
• Protect from light and heat
• Keep in original packaging
• Do not freeze
• Check for particulate matter before use
• Multi-dose vials: once opened, use within the manufacturer-specified period (typically 7 days when stored refrigerated)
• Chlorobutanol-preserved formulations: not for neuraxial use

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29. Preparation / Dilution Compatibility

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30. Monitoring Required During Use

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31. Safety Checks Before Administration

1. Confirm indication — is cardiovascular stimulation desirable, or contraindicated?
2. Check for open globe injury (raises IOP — absolute contraindication)
3. Check for psychiatric history — psychosis, schizophrenia
4. Confirm NOT being used as sole agent in elevated ICP — ensure adjunct (propofol/midazolam) is available
5. Confirm route of administration — never neuraxial (chlorobutanol neurotoxic)
6. Check for thyrotoxicosis, phaeochromocytoma — severe hypertensive crisis risk
7. Premedicate with benzodiazepine (if emergence phenomena likely) and antisialagogue
8. Airway equipment ready — ketamine does NOT guarantee a safe airway
9. Resuscitation equipment available (rare but possible apnea/laryngospasm)
10. Dilute to working concentration before IV infusion to avoid overdose

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32. Examiner Favourite "Why / How" Points

It functionally dissociates sensory input from the limbic cortex (responsible for awareness) — the patient appears conscious (eyes open, nystagmus, preserved reflexes) but cannot process or respond to sensory stimuli. — Morgan

Primarily via central sympathetic stimulation (inhibition of neuronal norepinephrine reuptake) — this overrides its direct myocardial depressant effect in most patients. — Miller

In severely catecholamine-depleted states, the body has "used up" its sympathetic reserves. Ketamine's direct negative inotropic effect is then unmasked, potentially precipitating cardiovascular collapse. — Morgan

Chlorobutanol is neurotoxic — therefore standard commercial ketamine formulations are absolutely contraindicated for neuraxial (intrathecal/epidural) administration. — Miller

Via sympathomimetic-mediated extraocular muscle contraction and increased aqueous humor production. — Morgan

NMDA receptors are central to wind-up and central sensitization. By blocking NMDA receptors, ketamine prevents the "wind-up" phenomenon and long-lasting enhancement in pain sensitivity induced by opioids. — Miller

It is 3–4× more potent (smaller dose needed), has 10% faster hepatic metabolism, quicker recovery, greater potency as NMDA antagonist, and causes fewer psychomimetic effects than the racemic mixture. — Miller, Barash

It is the only IV anesthetic that increases both CBF and CMR — all other IV anesthetics reduce or maintain these parameters. — Miller

Ketamine increases salivary and bronchial secretions (muscarinic-like effect), which can precipitate laryngospasm and airway obstruction, particularly in pediatric patients. Atropine (anticholinergic) reduces secretions. — Morgan

NMDA receptor blockade rapidly modulates glutamate synaptic transmission, promotes BDNF (brain-derived neurotrophic factor) release, and activates mTOR signaling → rapid synaptogenesis in the prefrontal cortex — reversing features of depression within 1 hour. — Barash

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33. Recent Advances / Reversal Agents

Esketamine (Spravato — S(+)-ketamine nasal spray)

• FDA-approved (2019) for treatment-resistant depression (TRD) and major depressive disorder with acute suicidal ideation
• Administered intranasally (56 mg or 84 mg) under healthcare provider supervision
• Rapid antidepressant effect — hours vs weeks for conventional antidepressants — Barash, Morgan

Low-dose Ketamine Infusions

• Increasing evidence for perioperative analgesia and reducing opioid consumption (opioid-sparing strategy)
• Recommended in multimodal analgesic protocols (ERAS — Enhanced Recovery After Surgery)

Ketamine in PTSD

• Emerging evidence for therapeutic use in post-traumatic stress disorder — Barash

Ketamine in Critical Care / Sepsis

• Being investigated as an anti-inflammatory and neuroprotective agent in ICU

Ketamine and Neurocognitive Disorders

• 2024 meta-analysis (PMID: 39639216): Esketamine reduces incidence of postoperative neurocognitive disorders (POD, POCD) in adult surgical patients

Ketamine vs. Etomidate for RSI

• 2024 meta-analysis (PMID: 38368326): In critically ill adults requiring tracheal intubation, ketamine and etomidate have similar outcomes — ketamine avoids adrenocortical suppression (advantage in sepsis)

No Specific Reversal Agent

There is no pharmacologic reversal agent that reverses all the CNS effects of ketamine. Management of adverse effects is supportive ± benzodiazepines for psychomimetic effects. — Miller

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34. Summary Clinical Concluding Line

Ketamine is a pharmacologically unique, phencyclidine-derived, NMDA receptor antagonist that produces a distinctive "dissociative anesthesia" — combining profound analgesia, cardiovascular stimulation, bronchodilation, and preserved airway reflexes in a single agent — making it the preferred induction drug in hemodynamically unstable, hypovolemic, or asthmatic patients; its versatility across IM, IV, and intranasal routes, opioid-sparing analgesic properties, and emerging antidepressant applications (esketamine/Spravato) position it as one of the most clinically indispensable and multifaceted drugs in modern anaesthetic practice, with the crucial caveat that emergence phenomena should be anticipated and managed with benzodiazepine premedication, a quiet recovery environment, and the understanding that while airway reflexes are preserved, they cannot be assumed to be reliably protective.

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• Miller provided the deepest pharmacokinetics (two-compartment model, PK parameters), CNS/CBF/CMR data, and enantiomer pharmacology
• Barash contributed clinical uses (CRPS, depression, acute pain bolus+infusion strategies), cardiovascular mechanism, and the pharmacodynamics table
• Morgan provided the clearest clinical framework: mechanisms, drug interactions, contraindications, comparison table, and practical dosing pearls

1. Only IV agent that increases both CBF and CMR (Miller)
2. No specific reversal agent exists for ketamine
3. Chlorobutanol is neurotoxic — never give neuraxially
4. In catecholamine-depleted states, ketamine can precipitate cardiac collapse
5. Esketamine (Spravato) is FDA-approved for treatment-resistant depression — a paradigm shift in its clinical use