Pharmacology Overview of Ketamine
The number of reviews examining the pharmacology of ketamine is growing. The ketamine molecule has a chiral center with a cyclohexanone ring and the racemic mixture contains R(−) and S(+) optical stereoisomers. The S(+) type is esketamine or Ketanest S™, which has a fourfold greater affinity for the NMDA receptor and is the more potent anesthetic agent than the R(-) type. There are indications from animal studies that the R(−) enantiomer has greater efficacy as an antidepressant. We do not yet know which type, R(−) and S(+), is more beneficial for pain control ans an analgesic. Esketamine is available in various European countries, while in the rest of the world the racemic mixture is exclusively marketed under the name Ketalar™.
Route of administration
The most frequent route of ketamine administration is intravenous or intramuscular. Other routes have emerged over the past several years. Now, the routes of ketamine administration have grown to include oral, nasal, transdermal, subcutaneous, and rectal. Most recently, a groups has developed an inhaled route of preservative-free ketamine which may have useful applications under special circumstances such as palliative, geriatric, and preclinical emergency care as well as administration at remote locations such as on a battlefield.
The cytochrome P450 CYP 3A4 system of the liver metabolizes a good portion of ketamine. In humans, the main metabolic pathway is N-demethylation of ketamine to norketamine, and subsequently cyclohexanone ring hydroxylation of norketamine to 4-, 5-, and 6-hydroxynorketamine. All metabolic products are glucuronidated and cleared via kidney and bile.
During intravenous ketamine treatment, the amount of ketamine and norketamine are present in similar amounts in the body. However, after the end of the infusion, ketamine concentrations decrease rapidly but norketamine concentrations remain elevated for hours. Preliminary studies suggest that ketamine provides most of the pain relief with little or no analgesic contribution from its metabolite norketamine. In fact, norketamine may cause a small increase in pain shortly after the end of an infusion due to its lasting effects of hyperalgesia and allodynia in patients with neuropathic pain.
Pharmacokinetics and pharmacodynamics
Ketamine easily corsses the blood-brain barrier as it is a lipophilic compound which causes a rapid onset of action. Fast-acting pain relief comes from ketamine’s effect driven by its pharmacokinetics through actions at NMDA receptors and mu-opioid receptors. Slow-acting pain relief and depression relief happen even when ketamine and its metabolites are reduced below detection levels. The slow onset and offset of ketamine in the treatment of chronic (neuropathic pain) may be explained by thinking that ketamine initiates a cascade of receptor-signaling events.
One research groups recently showed in rodents that activation of the innate repair receptor (IRR) by ketamine is a prerequisite for relief of neuropathic pain symptoms. The IRR is a receptor complex composed of the erythropoietin receptor and the beta-common-receptor (CD131). Activation of the IRR results in tissue repair and anti-inflammation. Endogenous activation is by erythropoietin (the natural anti-tumor necrosis factor cytokine), which is released upon tissue damage (for example, from ischemia, infection, and peripheral nerve damage). A final mechanism through which ketamine induces pain relief is the reinforcement of the endogenous pain modulatory system by activation of descending inhibitory pathways involved in analgesia at the spinal level.