Ketamine

Published on 07/02/2015 by admin

Filed under Anesthesiology

Last modified 22/04/2025

Print this page

This article have been viewed 1647 times

Ketamine

Gilbert A. Blaise, MD

The ketamine molecule (2-(o-chlorophenyl)-2-methylamino-cyclohexamine) is chemically related to phencyclidine and contains a chiral center (C2 carbon of the cyclohexanone ring) with two optical isomers. The S-isomer is four times more potent, is associated with a faster recovery, and has a low incidence of psychomimetic effects, compared with the R-isomer. However, in North America, ketamine is sold primarily as a racemic mixture (Figure 74-1). It also contains benzethonium chloride as a preservative compound.

Figure 74-1 The molecular formula of ketamine hydrochloride, C₁₃H₁₆ClNO•HCl.

Designed to become the ideal anesthetic at a time when other anesthetic agents were particularly toxic and not easy to use, ketamine was introduced as a complete anesthetic agent in 1960. Its popularity was established in the mid-1970s during the Vietnam War, where it was deemed to be an “exceptional battlefield anesthetic.”

Administered intravenously or intramuscularly, it can evoke profound analgesia, loss of consciousness, amnesia, and immobility. The anesthesia produced by ketamine is termed dissociative because patients appear to be dissociated from their environment rather than simply nonreactive. Under ketamine anesthesia, the thalamus is no longer synchronized with the limbic system. Ketamine has a very high therapeutic index compared with other anesthetic medications. Ketamine is also a recreational drug of abuse (best known under the names vitamin K and special K).

Mechanisms of action

Ketamine is not a particularly selective drug, with multiple sites of action, including those in the central and peripheral nervous systems. The properties of ketamine are primarily mediated by noncompetitive antagonism at N-methyl-D-aspartate (NMDA) receptors, but the drug also has local anesthetic properties. The NMDA receptors consist of five subunits surrounding a central ion channel that is permeable to Ca²⁺, Na⁺, and K⁺ (Figure 74-2). Binding sites for Mg²⁺ and ketamine have been found inside this channel.

Figure 74-2 The properties of ketamine are primarily mediated by noncompetitive antagonism at NMDA receptors, which consist of five subunits surrounding a central ion channel that is permeable to Ca²⁺, Na⁺, and K⁺. GLY, Glycine; NMDA, N-methyl-D-aspartic acid; PCP, phencyclidine.

Glutamate is the most prominent excitatory amino acid in the body, and NMDA receptor activation is a major mechanism of the effect of glutamate on the central nervous system, on the peripheral nervous system, and in many other organs and tissues (e.g., lungs, inflammatory cells). NMDA receptors have been implicated in the mechanism of anesthesia, pain transmission, morphine tolerance, memory and cognitive function, long-term potentiation, long-term depression, neuronal toxicity, and chronic neurologic diseases (e.g., Alzheimer disease and major depression) as well as inflammatory responses.

At clinical concentrations, ketamine can also bind to phencyclidine receptors. Ketamine has even been reported to interact with μ, δ, and κ opioid receptors. Ketamine inhibits reuptake of the monoamines epinephrine, dopamine, and serotonin. It is an agonist of purinergic neurotransmission and interacts with adenosine receptors.

Ketamine anesthesia is reversed by anticholinesterases, an antagonistic outcome that is likely to elevate acetylcholine concentrations. There is evidence that ketamine interacts with muscarinic and nicotinic receptors, based on the fact that it produces anticholinergic symptoms (postanesthetic delirium, bronchodilation, and sympathomimetic effects). Ketamine interaction with voltage-sensitive Ca²⁺ channels has been studied extensively, and the local anesthetic effect of ketamine has been explained by its interaction with Na⁺ channels.

Systemic effects

Cardiovascular system

The cardiovascular response to ketamine mimics sympathetic nervous system stimulation, causing increased blood pressure, cardiac output, and myocardial O₂ consumption. Heart rate changes depend on baroreflex activity. This initial action of ketamine on the cardiovascular system is due to amine reuptake inhibition.

Respiratory system

Ketamine alone does not induce respiratory depression, so airway patency is well maintained during ketamine anesthesia; however, if ketamine is combined with respiratory-depressing agents, such as benzodiazepines or opioids, respiratory depression and upper airway obstruction can occur. Because of its anticholinergic and adrenergic effects, ketamine induces bronchodilation and has been administered with success as a sedative to treat patients with asthma.

Central nervous system

Ketamine, a cerebral vasodilator, causes an increase in cerebral blood flow and intracranial pressure in patients with space-occupying intracranial lesions. Intracranial pressure elevation is minimal if ventilation is controlled.

Emergence delirium is reported to occur in 5% to 30% of patients who are administered ketamine as an anesthetic agent; the incidence of delirium is increased in patients over the age of 16 years if the dosage exceeds 2 mg/kg, if the drug is administered rapidly, or if patients have preexisting personality problems. Emergence reactions usually occur early during emergence from anesthesia and may persist for a few hours but can be prolonged to more than 24 h in some patients. These reactions are characterized by visual, auditory, proprioceptive, and confusional illusions, often with associated feelings of excitement, fear, or euphoria (schizophrenia-like reactions).

Clinical use

Ketamine is the only effective NMDA blocker that is available as a medication that can be administered by several routes: intravenously, intramuscularly, subcutaneously, intranasally, sublingually, orally, rectally, cutaneously (patches, ointment on wounds), intrathecally, and epidurally. Ketamine is being studied in perioperative pain management, chronic pain management, inflammatory-response mediation, and the treatment of depression. Because NMDA antagonists have an additive or synergistic action with opioids by reducing hyperalgesia induced by opioids, decreasing tolerance elicited by continuous morphine administration, or reversing opioid-mediated tolerance, ketamine is being used increasingly to provide perioperative analgesia. Ketamine may have a preemptive effect and, if added to another form of multimodal analgesia, could diminish secondary hyperalgesia and the prevalence of chronic pain after abdominal operations. Combining ketamine with opioids improves postoperative analgesia and reduces side effects.

Ketamine has been used as an intravenously administered analgesic or locally applied ointment with some success in the treatment of severe complex regional pain syndrome. Fibromyalgia and chronic fatigue syndrome could be due to pathologic NMDA receptor activation, and if so, ketamine may have a role in treating patients with these disorders. Blocking NMDA receptors is effective therapeutically in severe depression that is unresponsive to standard treatments.

Ketamine, a modulator of inflammatory responses, has been shown to be neuroprotective in several animal models of neurologic ischemia-reperfusion injury.

Several animal studies have shown that ketamine causes apoptosis in developing brains and produces long-term cognitive impairment. Phencyclidine compounds can model irreversible schizophrenic disease in rodents. Delirium can create long-term cognitive deficits in susceptible patients. However, at a low dose, ketamine can prevent postoperative delirium.

Because of the occurrence of emergence reactions, the use of ketamine as an anesthetic agent has declined. This decline has been facilitated by the availability of new anesthetic agents, better monitoring, and the improved knowledge and skills of anesthesiologists. As an anesthetic, ketamine remains useful as an agent well suited for short and very painful procedures performed outside the operating room (e.g., in austere environments, emergency departments, diagnostic clinics) where monitoring and support are limited. Ketamine is still used for induction of anesthesia in hemodynamically unstable patients.

Several questions remain unanswered regarding ketamine; the many effects associated with its use require balancing the beneficial actions of this pharmacologic agent with its potential adverse effects.

Related

Fausts Anesthesiology Review Expert Consult 4e