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NMDA Receptor Antagonism: Ketamine is primarily known as a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, which is a subtype of glutamate receptor. By inhibiting the NMDA receptor, ketamine reduces the excitatory effects of glutamate, leading to its anesthetic, analgesic, and dissociative effects.

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Other Receptors: Besides NMDA receptors, ketamine also interacts with several other receptors and systems, including:

• Opioid Receptors: Ketamine has some affinity for mu and kappa opioid receptors, contributing to its analgesic properties.

• Monoaminergic Receptors: Ketamine affects the reuptake of serotonin, nonrepinephrine, and dopamine, which can influence mood and contribute to it's antidepressant effects.

• Cholinergic Receptors: It can inhibit nicotinic and muscarinic acetylcholine receptors, affecting cognition and memory.

• GABAergic System: Ketamine modulates the GABAergic system, contributing to its anesthetic effects.

Absorption

• Routes of Administration: Ketamine can be administered via several routes, including intravenous (IV), intramuscular (IM), oral, nasal, and sublingual.

• Bioavailability: IV administration provides 100% bioavailability, while IM administration has about 93% bioavailability. Oral bioavailability is lower, around 16-24%, due to first-pass metabolism in the liver. Nasal administration provides intermediate bioavailability, approximately 45-50%.

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Distribution​

• Volume of Distribution (Vd): Ketamine has a large volume of distribution, indicating extensive distribution into tissues. The Vd is approximately 3-5 L/kg.

• Protein Binding: Ketamine is moderately bound to plasma proteins, with a binding rate of around 12-50%.

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Metabolism

• Primary Metabolism: Ketamine is extensively metabolized in the liver, primarily by the cytochrome P450 enzyme system (CYP3A4, CYP2B6​, and CYP2C9)

• Major Metabolites: The primary metabolite is norketamine, which retains some pharmacologic activity. Further metabolism of norketamine produces dehydronorketamine. 

• First-Pass Effect: Oral administration of ketamine undergoes significant first-pass metabolism, reducing its bioavailability.

 

Excretion

• Elimination Half-Life: The elimination half-life of ketamine is approximately 2-3 hours, but this can vary based on the route of administration and individual patient factors.

• Renal Excretion: Ketamine and its metabolites are primarily excreted via the kidneys. Approximately 90% of the administered dose is excreted in urine, with the majority of metabolites.

Clinical Effects

• Anesthetic Effects: Ketamine induces a trance-like state characterized by profound analgesia, sedation, immobility, and amnesia, often described as "dissociative anesthesia." Patients may appear awake but are detached from their environment.​

• Analgesic Effect: Effective in providing pain relief, particularly in cases of acute pain, chronic pain, and during surgical procedures. Its analgesic effects are partly due to NMDA receptor antagonism and opioid receptor activity.​

• Antidepressant Effects: At sub-anesthetic doses, ketamine has rapid antidepressant effects, which can occur within hours and last for days to weeks. The exact mechanism is not fully understood but is thought to involve NMDA receptor antagonism and downstream effects on synaptic plasticity and neurotrophic factors.​

• Psychedelic and Psychotomimetic Effects: At certain doses, ketamine can induce profound hallucinations, altered perceptions, and a deep sense of detachment from reality, creating an experience often described as transcendent and otherworldly.

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Cardiovascular Effects

• Cardiovascular Stimulation: Ketamine is unique among anesthetics in that it stimulates the cardiovascular system, leading to increased heart rate, blood pressure, and cardiac output. This is primarily due to its sympathomimetic effects.

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Respiratory Effects

• Minimal Respiratory Depression: Unlike many anesthetics, ketamine has minimal effects on respiratory drive, making it relatively safe in terms of maintaining airway reflexes and breathing.

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Neuroprotective Effects

• Neuroprotection: Ketamine's NMDA antagonism has neuroprotective properties, reducing excitotoxicity and protecting neurons from damage due to excessive glutamate activity.

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Immune Modulation

• Anti-inflammatory Effects: Ketamine has been shown to have anti-inflammatory properties, which may contribute to its effects in certain conditions like chronic pain and depression.