NMDA antagonists: ketamine and tiletamine (Telazol: dissociative plus benzodiazepine)

NMDA antagonism - receptor associated with learning, memory and neuroplasticity.

As an anesthetic drug, some areas of the CNS are depressed (neocorticothalamic) while others are stimulated (limbic). This gives it variable effects in disease states of the brain.

Increased muscle tone

Spontaneous movement

Open eyelids with a brisk palpebral

Excessive salivation

Seizurogenic (in some types of epilepsy - protective in others)

• Clinical signs of anesthesia are much different than anesthetics that act as depressants.
• The typical gradations of surgical anesthesia are non-existent with ketamine as a single anesthetic (plane 1-4). If the patient is overtly moving during surgery, it is too light, if apneic or convulsing, it is too deep, otherwise, anesthesia is probably adequate (thus it is not used alone, much). It is also not directly analgesic (anti-hyperalgesic), so is not recommended as a sole anesthetic drug.

Metabolism: Liver biotransformation, forming partially active metabolite nor-ketamine, which undergoes conjugation prior to renal excretion. Conjugation is limited in cats which are therefore more dependent on renal excretion of nor-ketamine for recovery.

Systemic Effects

CNS: Seizurogenic: commonly used as adjunctive drugs, do not use in patients susceptible to seizures (epileptics, myelograms, cranial trauma). Increases cerebral blood flow (CBF), oxygen requirement, and intracranial pressure. Caution with use as an induction drug with CNS disease. However, as knowledge about the neuro-protective effects of NMDA antagonists has grown, it has become commonplace to use ketamine as a CRI (at analgesic and mildly supra-analgesic doses) for craniotomy, TBI, spinal cord injuries, and other injuries to nervous system tissues.

Revising a dogma: ketamine for patients with neurological injury? Sabine Himmelseher, MD*, and Marcel E. Durieux, MD, PhD (Anesth Analg. 2005;101:524–34)

Analgesia: Ketamine is a potent anti-hyperalgesic at sub-anesthetic dosages. It also acts as an inhibitor of amplification of pain via the NMDA receptor, and inhibitor of neuro-inflammation and glial. Ketamine is a poor direct analgesic, especially for visceral sources of pain.

Cardiovascular: Increased heart rate, blood pressure and cardiac output: centrally mediated (sympathetic tone). The direct effect of ketamine on the myocardium is depression. Thus, these increases are not seen with pre-existing tachycardia, sympathetic overload, severe sickness, or denervated heart. When stimulation is seen, there will be increased left ventricular work, with increased oxygen requirement. Therefore, beware if oxygenation or myocardial blood flow are compromised, or in heart conditions where myocardial hypoxia is likely (HCM).

Respiratory: Mild respiratory depressant at clinical doses. Apneustic pattern is common. Laryngeal function is maintained to a degree: patients may still swallow, so there may be some retention of function, but the coordination is impaired and aspiration is usually not prevented.

Temperature: Ketamine alone raises body temperature, due to mm rigidity (but ketamine is seldom used alone). As a component of general anesthesia, ketamine will not guard against environmental hypothermia.

Regulatory Update: Human abuse potential has created strong international pressure (China) to increase regulatory control. The commission on narcotic drugs elected not to upgrade the regulation of ketamine to schedule 1 in 2015, but there is still international debate. For more information see the fact sheet that was endorsed by a large number of human and veterinary organizations (in which the WSAVA played an extremely active role) regarding this issue: https://www.asahq.org/~/media/sites/gho/ketamine-fact-sheet-2015 (VIN editor: Link was not accessible as of 2/11/2019).

An important consideration, however, is the human abuse potential of opioids, and the opioid sparing, addiction-mitigating effects of NMDA antagonist drugs.

Le Cornec, Lariby Brenckmann, et al. Is intravenously administered, subdissociative-dose KETAmine non-inferior to MORPHine for prehospital analgesia (the KETAMORPH study): study protocol for a randomized controlled trial trials. 2018 May 2;19(1):260. doi: 10.1186/s13063-018-2634-3.

Usage update: Ketamine uses that bridge: anesthetic (inexpensive and widely available in first through third-world countries), amnesiac, cardiovascular sparing in intensive care, cerebro-protective, anti-glial activation, neuropathic pain and depression suppressing.

The Global Pain Council of the WSAVA utilizes ketamine extensively in the recommendations for countries where opioid analgesics, and safe non-steroidal analgesics are limited.

www.wsava.org/guidelines/global-pain-council-guidelines

Recent human papers evaluating safety in:

• Intensive care and cerebral perfusion in the ICU (not increasing ICP)
• Reduced neurotoxicity and improved perfusion in neuro-anesthesia
• Improved hemodynamics for sedations in ICU
• Modification of neuropathic pain and anxiety disorders
• Replacement for opioid drugs in acute pain in opioid-free and reduced opioid procedures

Veterinary uses: Two primary considerations: Anesthesia and sedation:

Acute analgesia: NMDA antagonism reduces requirement for opioids, reduced post-operative pain, reduced wind-up at the level of the spinal cord and glia.

The Global Pain Council of the WSAVA utilizes ketamine extensively in the recommendations for countries where opioid analgesics, and safe non-steroidal analgesics are limited.

www.wsava.org/guidelines/global-pain-council-guidelines

Chronic analgesia: NMDA antagonism mitigates glial hyper-activity and neuropathic pain.

Spinal cord injury, brain injury peripheral nerve injury

Chronic OA

Low cost and high margin of safety at sub-anesthetic doses

Systemic and peripheral applications

Other (oral) NMDA antagonists:

Amantadine 2–5 mg/kg q 12–24 hours

Memantine 0.3–0.5 mg/kg q 12–24 hours