What is ketamine?
Ketamine is a dissociative anesthetic discovered in 1962 by Dr. Calvin Lee Stevens (Organic Chemist, Wayne State University) and was first approved by FDA in 1970 as an anesthetic and was used in combat (e.g., Vietnam). In 1999, United States government classified Ketamine as Schedule III Controlled Substance
Why is ketamine used?
Ketamine is used 1) to induce or maintain anesthesia, 2) for treatment-refractory analgesia (for pain), 3) for treatment resistant Depression, 4) for chronic suicidal thoughts, and 4) for acute agitation.
How does Ketamine work?
Ketamine has a very complex pharmacological profile
Ketamine has concentration dependent actions on numerous receptors including: N-methyl-D-aspartate (NMDA) receptors, Sigma-1 receptors, Norepinephrine Transporters (NETs), Mu Opioid Receptors, Serotonin Transporters (SERTs)
Ketamine interferes with sensory input to higher brain areas. Therefore, ketamine interferes with higher-order processing of emotions, memory consolidation, learning, and pain (via actions at Mu and Delta opioid receptors as well as Nitric Oxide Synthase/L-arginine/NO/cGMP neuronal pathways. Ketamine’s metabolites (Norketamine and hydroxynorketamine) antagonize alpha-7 nicotinic acetylcholine receptors (nAChR) as well.
Ketamine has been shown to have rapid antidepressive effects
Hypothetical Antidepressant Mechanism:
Ketamine binds non-selectively to voltage-dependent N-methyl-D-aspartate (NMDA) receptors at a site in the channel pore known as the “PCP binding site” where it inhibits the flux of calcium and sodium.
The blockade of NMDA Receptors may lead to an increase in glutamate release downstream. However, the increased glutamate release is unable to activate NMDA receptors in the presence of ketamine but is still able to stimulate AMPA receptors.
AMPA receptor activation leads to induction of neurotrophic signaling cascades such as Brain Derived Neurotrophic Factor (BDNF) signaling and Mammalian Target Of Rapamycin (mTOR) both of which are involved in synaptic remodeling and an increase in the density of dendritic spines. These same effects are seen with classic antidepressant.
Remember that mice that are raised in stimulating environments have more “bushy neuron” (i.e., have higher density of dendritic spines and more axons/dendrites).
ROUTES OF ADMINISTRATION:
- Oral (PO)
- Intramuscular (IM)
- Intravenous (IV)
- Subcutaneous (SC)
- Sublingual (SL)
- Ketamine is lipid soluble and is rapidly distributed to highly perfused tissues (e.g., brain)
DISTRIBUTION HALF-LIFE: 10-15 minutes
- Ketamine: 2-2.5 hours
- Norketamine (active metabolite): 5.3 hours
- DHNK (metabolite): 6.9 hours
- Oral: 17-20%
- Intranasal: 25-50%
- Sublingual: 30%
- Rectal: 30%
- Intramuscular: 93%
- Intravenous: 99-100%
PEAK IN PLASMA:
- Oral: within 30-60 minutes
- Intramuscular: 5-15 minutes
- Intravenous: 1 minute
LOW PLASMA PROTEIN BINDING
- Hepatic (primarily)
- CYP450 2B6, 3A4, and 2C9
- Intramuscular: 6.5mg-13.0 mg/kg
- Intravenous: 1.0-4.5 mg/kg
- Continuous infusion: 0.1-0.5 mg/min
Treatment Resistant Depression:
- 40 minute intravenous infusion of 0.5 mg/kg dose
Treatment Resistant OCD (off label):
- 40 minute intravenous infusion of 0.5 mg/kg dose
NOTABLE SIDE EFFECTS:
- Wide therapeutic index
- 1-3 mg/kg: hallucinations, confusion, delirium, vivid imagery
- Transient Nystagmus
- Respiratory stimulation
- Skin inflammation/rash
- Less common: anorexia, bradycardia, arrythmia, hypotension, respiratory depression
- RARE: Anaphylaxis, sialorrhea, laryngospasm, cystitis, renal dysfunction, neurotoxicity
- Incuders of CYP3A4 (e.g., Rifampin, St. John's wort) induce metabolism of ketamine and norketamine
- Inhibitors of CYP3A4 (e.g., grapefruit juice, clarithromycin) inhibit metabolism of ketamine and norketamine
- Posssible synergistic effects when administered with other sedating medications
3) Treatment resistant depression (nasal spray, esketamine)
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