The Mystery of Ketamine


Ketamine is a versatile medication with a fascinating history, complex pharmacology, and a wide range of clinical applications. In this article, we will delve into the various aspects of ketamine, including its history, structure-activity relationship, mechanism of action, pharmacokinetics, clinical uses, and potential side effects.

History of Ketamine
Year of DiscoveryInventorsInitial UseFDA ApprovalControlled Substance
1962Calvin Stevens and Parke-Davis LaboratoriesAnesthetic agent for humans and animalsApproved in 1970Schedule III
Structure-Activity Relationship of Ketamine

Ketamine is a water-soluble molecule with an asymmetric carbon atom, resulting in two optical isomers: S(1)-ketamine and R(2)-ketamine. The racemic form of ketamine is most commonly used, although S(1)-ketamine is clinically available. Here’s a summary of the key differences between these isomers:

PropertyS(1)-KetamineR(2)-KetamineRacemic Ketamine
Analgesic PotencyMore intenseLess intenseIntermediate
Metabolism and RecoveryMore rapidSlowerIntermediate
Emergence ReactionsLower incidenceHigher incidenceIntermediate
Fatigue and Cognitive ImpairmentLessMoreIntermediate
Mechanism of Action

Ketamine interacts with various central nervous system receptors, although its precise mechanism of action is not fully understood. Here are the key receptors and actions associated with ketamine:

N-Methyl-d-Aspartate (NMDA) Receptor Antagonism:

  • Ketamine binds non-competitively to the phencyclidine recognition site on NMDA receptors.
  • Inhibits activation of NMDA receptors by glutamate.
  • Decreases presynaptic release of glutamate.
  • S(1)-ketamine exhibits the greatest affinity for NMDA receptors.

Opioid Receptors:

  • Ketamine interacts with mu (m), delta (d), and kappa (k) opioid receptors.
  • May act as an antagonist at mu receptors and an agonist at kappa receptors.

Monoaminergic Receptors:

  • Ketamine may activate descending inhibitory monoaminergic pain pathways.

Muscarinic Receptors:

  • Ketamine partially antagonizes muscarinic receptors.
  • Produces anticholinergic symptoms, such as emergence delirium and sympathomimetic actions.

Sodium Channels:

  • Interacts with voltage-gated sodium channels, sharing a binding site with local anesthetics.

Neuronal Nicotinic Acetylcholine Receptors:

  • Interacts with a7-type nicotinic acetylcholine receptors, which may contribute to its analgesic effects.
Pharmacokinetics of Ketamine

Ketamine exhibits unique pharmacokinetic properties:

Onset of ActionRapid
Duration of ActionShort
Lipid SolubilityHigh
Peak Plasma ConcentrationsWithin 1 minute after IV administration
Volume of Distribution (Vd)3 L/kg
Elimination Half-Time2 to 3 hours
MetabolismLiver metabolism to active metabolite norketamine and inactive glucuronide metabolites
Renal ExcretionLess than 4% excreted unchanged in urine
Clinical Uses of Ketamine

Ketamine finds diverse applications in the medical field:

Analgesia: Ketamine provides intense analgesia, particularly for somatic pain, and can be used as an adjunct to opioid analgesia.

Induction of Anesthesia: It is widely used for rapid induction of anesthesia, maintaining airway reflexes.

Special Considerations:

  • Ketamine can be used in acutely hypovolemic patients, but caution is needed in patients with coronary artery disease.
  • It is a preferred choice for rapid IV induction in patients with asthma due to its bronchodilatory effects.

Additional Uses: Ketamine has shown potential in opioid tolerance reversal, psychiatric disorders, and restless leg syndrome.

Side Effects of Ketamine

Ketamine administration can lead to various side effects and physiological responses, affecting multiple organ systems, including the central nervous system, cardiovascular system, and airway. These side effects include alterations in cerebral blood flow, cardiovascular stimulation, and bronchodilatory effects, among others.


Ketamine’s rich history, complex pharmacology, and broad clinical utility make it a remarkable drug in the world of medicine. Its unique properties continue to make it a subject of interest and research across various medical disciplines. Understanding its mechanisms, applications, and potential side effects is crucial for its safe and effective use in clinical practice.


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