19. Ketamine - Part 1 Mechanism and Pharmacology

Lecture Summary
Ketamine is a small molecule that works mainly through inhibition of the NMDA receptor in brain and nerve tissue.  It has varying effects at different doses and can be used for a number of medical indications including depression, suicidal ideation, acute and chronic pain, sedation, and anesthesia. Ketamine is a very safe drug when used intermittently and appropriately. However, it can cause both harm and addiction. Many clinicians fear ketamine. This fear is misplaced as ketamine is very forgiving in the clinical setting and safer than other alternatives like opiates.

Key Points
-       Ketamine is a derivative of phencyclidine (PCP) and because it causes much less agitation, aggressive behavior, and sympathomimetic symptoms, it has enjoyed wide-spread and sustained clinical use.
-       Ketamine primarily acts as an inhibitor of the NMDA receptor. However, it has effects at a number of other targets including multiple opioid receptors. Ketamine also inhibits the reuptake of multiple neurotransmitters including serotonin, norepinephrine, and dopamine.
-       Ketamine can be used at lower doses for mental health conditions like depression, anxiety, OCD, and suicidal ideation.
-       NMDA receptors modulate neuronal development, plasticity, and connectivity. The author hypothesizes that acute plasticity afforded by ketamine allows individuals with mental health issues a unique opportunity to leave negative thought patterns and view themselves from a different level of consciousness.
-       Ketamine’s effectiveness in treating both acute and chronic pain makes it very desirable. 
-       At higher doses, ketamine causes sedation with preserved respiratory function. This makes it ideal for resource limited settings.
-       Ketamine can cause a number of side effects. Most notably an emergence reaction some people experience when waking up from dissociative or sedative doses of ketamine.
-       This emergence reaction can be effectively treated by limiting sensory stimulation and administration of benzodiazepines like lorazepam. Alpha antagonists like clonidine and antihistamines like hydroxyzine may also be helpful. Avoiding antipsychotics in this setting is recommended by some due to the risks of dystonic reactions.
-       Ketamine can also cause hematuria, bladder, and urinary tract dysfunction. Particularly with frequent illicit use.
-       Memory impairment and depressive symptoms also can occur with chronic use.
-       Fatalities from ketamine toxicity are almost unheard of. The LD50 in mice was 600 mg/kg. However, accidents can certainly occur and be fatal in recreational use.
-       There is a lot of controversy regarding a number of Ketamine’s effects. For instance, is ketamine neuroprotective in trauma? What is its effect on seizures at lower doses? Does Ketamine raise intercranial pressure? Ketamine can cause hypotension, hypertension, tachycardia, and bradycardia. Its action at multiple receptors, dose dependent effects, and the heterogeneity of human subjects likely explains a lot of this controversy.
-       Ketamine’s proven safety record, low cost, unique clinical properties, multiple uses, as well as its ability to provide full anesthesia without significant respiratory depression, make it an absolute must have, in resource poor settings.

See References In Part 2 Notes