Ketamine
Ketamine
Generic Name
Ketamine
Mechanism
Ketamine is an arylcyclohexylamine that acts primarily as a non‑competitive NMDA (N-methyl‑D‑aspartate) receptor antagonist at the glutamatergic synapse.
• Blocks the ion channel pore of the NMDA receptor, reducing Ca²⁺ influx and dampening excitatory neurotransmission.
• Inhibits secondary pathways:
• *Opioid receptor* modulation → contributes to analgesia.
• *Cholinergic* and *serotonergic* systems → influence mood‑modifying effects.
• Rapid antidepressant action is associated with increased synaptogenesis via mTOR (mammalian target of rapamycin) signaling and downstream BDNF (brain‑derived neurotrophic factor) release.
*Reference*: Duman, R.S. & Aghajanian, G. “Synaptic dysfunction in depression: potential therapeutic targets” – Nat Rev Neurosci, 2012.
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Pharmacokinetics
- Route: IV, IM, oral (PO), intranasal, subcutaneous.
- Absorption:
- IM rapid onset; PO highly variable (≈30–50% bioavailability).
- Intranasal achieves ~25–30% systemic exposure with peak at ~15 min.
- Distribution: Large volume of distribution (~4–10 L/kg). Lipid‑soluble → crosses the blood‑brain barrier quickly.
- Metabolism: Primarily hepatic via CYP2B6 and CYP3A4, producing norketamine (active) and hydroxynorketamine (possible antidepressant contributor).
- Elimination: Urine (≈65–70% unchanged) and feces.
- Half‑life: 2–4 h for parent drug; active metabolites persist up to 10–12 h.
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Indications
- Anesthesia: Induction and maintenance in adults and children (low‑dose adjunct).
- Analgesia: Short‑term procedural pain, refractory acute pain, opioid escalation.
- Depression & Psychiatric: Rapid‑acting antidepressant for major depressive disorder (MDD), treatment‑resistant depression, and bipolar depression when administered IV or intranasally.
- Palliative Care: Short‑course analgesic and mood support.
- Other: Adjunct in chronic pain (e.g., complex regional pain syndrome), migraine prophylaxis (limited evidence).
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Contraindications
- Absolute: Severe cardiovascular instability (e.g., uncontrolled hypertension, myocardial infarction).
- Relative:
- Uncontrolled glaucoma (increases intra‑ocular pressure).
- Severe liver or kidney disease (altered metabolism/excretion).
- Pregnancy (Category C; limited data).
- Precautions:
- Avoid in patients on monoamine oxidase inhibitors (MAOIs) or serotonergic drugs (serotonin syndrome risk).
- Monitor for psychotomimetic reactions; provide supportive care.
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Dosing
| Indication | Dose | Frequency | Route | Administration Notes |
| Anesthesia induction | 1–2 mg/kg IV | Single dose | IV | Rapid onset ≈30 s; monitor BP & HR |
| Anesthesia maintenance | 0.5–1 mg/kg/30 min (infusion) | Continuous | IV | Target MAC 0.2–0.3; avoid hypercapnia |
| Procedural analgesia | 0.5–1 mg/kg IM | Single | IM | Effective for 45–60 min |
| Opioid‑refractory acute pain | 0.2–0.5 mg/kg IV | Every 30 min | IV | Use 0.25 mg/kg as starting dose |
| MDD (IV) | 0.5 mg/kg over 40 min | One‑off + 0.25 mg/kg 2 h later | IV | Monitor BP, HR, sedation |
| MDD (Intranasal) | 28 mg (56 mg q24‑h) | q24‑h | Intranasal | Use 0.2 mg/kg in <160 kg patients |
| Palliative analgesia | 1–2 mg/kg IV q2–4 h | PRN | IV | Adjust for renal/hepatic function |
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Adverse Effects
- Common (≤10%)
- Dissociative symptoms (hallucinations, “twilight” state)
- Tachycardia, hypertension
- Nausea/vomiting
- Increased salivation
- Serious (≤1%)
- Cardiovascular events (arrhythmias, severe hypertension)
- Psychotic episodes; persistent psychotomimetic reaction
- Bladder toxicity (interstitial cystitis) with chronic use
- Severe respiratory depression (rare, with high doses or opioid combination)
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Monitoring
- Vitals: BP, HR, SpO₂ continuously during infusion.
- CNS: Level of consciousness, agitation, emergence phenomena.
- Respiratory: Rate, depth; ensure airway protection when sedation >1 mg/kg.
- Laboratory: Check renal (CrCl) and hepatic (AST/ALT) status before chronic use.
- Psychiatric: Screen for baseline depression or psychosis before initiating.
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Clinical Pearls
- **“Sweet‑potato” infusion: Use a low‑convective rate (0.1 mg/kg/h) to minimize psychotomimetic side‑effects while maintaining analgesia.
- Intranasal formulation (Spravato®) achieves rapid antidepressant effect with a favorable safety profile; dose reduction (<28 mg) may suffice in patients <100 kg.
- Co‑administration with buprenorphine reduces ketamine’s dissociative side‑effects while preserving analgesia.
- Norketamine metabolites may hold the key to prolonged antidepressant benefit; research into selective metabolite analogs is underway.
- Ketamine can paradoxically lower arterial oxygen tension in patients with pre‑existing lung disease—adjust ventilation and consider lower dose.
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• *Note: All dosing recommendations are general guidelines; clinician judgment and patient‑specific factors should dictate final therapy.*