Ketamine Hydrochloride (Ketamine HCl): Uses, Dosage, Side Effects, Interactions, Warning
Ketamine hydrochloride is a rapid-acting general anesthetic producing an anesthetic state characterized by profound analgesia, normal pharyngeal-laryngeal reflexes, normal or slightly enhanced skeletal muscle tone, cardiovascular and respiratory stimulation, and occasionally a transient and minimal respiratory depression.
A patent airway is maintained partly by virtue of unimpaired pharyngeal and laryngeal reflexes. (See WARNINGS and PRECAUTIONS Sections.)
The biotransformation of ketamine hydrochloride includes N-dealkylation (metabolite I), hydroxylation of the cyclohexone ring (metabolites III and IV), conjugation with glucuronic acid and dehydration of the hydroxylated metabolites to form the cyclohexene derivative (metabolite II).
Following intravenous administration, the ketamine concentration has an initial slope (alpha phase) lasting about 45 minutes with a half-life of 10 to 15 minutes. This first phase corresponds clinically to the anesthetic effect of the drug.
The anesthetic action is terminated by a combination of redistribution from the CNS to slower equilibrating peripheral tissues and by hepatic biotransformation to metabolite I. This metabolite is about 1/3 as active as ketamine in reducing halothane requirements (MAC) of the rat.
The later half-life of ketamine (beta phase) is 2.5 hours.
The anesthetic state produced by ketamine hydrochloride has been termed “dissociative anesthesia” in that it appears to selectively interrupt association pathways of the brain before producing somatesthetic sensory blockade. It may selectively depress the thalamoneocortical system before significantly obtunding the more ancient cerebral centers and pathways (reticular-activating and limbic systems).
Elevation of blood pressure begins shortly after injection, reaches a maximum within a few minutes and usually returns to preanesthetic values within 15 minutes after injection.
In the majority of cases, the systolic and diastolic blood pressure peaks from 10% to 50% above preanesthetic levels shortly after induction of anesthesia, but the elevation can be higher or longer in individual cases (see CONTRAINDICATIONS Section).
Ketamine has a wide margin of safety; several instances of unintentional administration of overdoses of ketamine hydrochloride (up to ten times that usually required) have been followed by prolonged but complete recovery.
Ketamine hydrochloride has been studied in over 12,000 operative and diagnostic procedures, involving over 10,000 patients from 105 separate studies. During the course of these studies ketamine hydrochloride was administered as the sole agent, as induction for other general agents, or to supplement low-potency agents.
Specific areas of application have included the following:
- debridement, painful dressings, and skin grafting in burn patients, as well as other superficial surgical procedures.
- neurodiagnostic procedures such as pneumonencephalograms, ventriculograms, myelograms, and lumbar punctures. See also Precaution concerning increased intracranial pressure.
- diagnostic and operative procedures of the eye, ear, nose, and mouth, including dental extractions.
- diagnostic and operative procedures of the pharynx, larynx, or bronchial tree. NOTE: Muscle relaxants, with proper attention to respiration, may be required (see PRECAUTIONS Section).
- sigmoidoscopy and minor surgery of the anus and rectum, and circumcision.
- extraperitoneal procedures used in gynecology such as dilatation and curettage.
- orthopedic procedures such as closed reductions, manipulations, femoral pinning, amputations, and biopsies.
- as an anesthetic in poor-risk patients with depression of vital functions.
- in procedures where the intramuscular route of administration is preferred.
- in cardiac catheterization procedures.
In these studies, the anesthesia was rated either “excellent” or “good” by the anesthesiologist and the surgeon at 90% and 93%, respectively; rated “fair” at 6% and 4%, respectively; and rated “poor” at 4% and 3%, respectively. In a second method of evaluation, the anesthesia was rated “adequate” in at least 90%, and “inadequate” in 10% or less of the procedures.
The acute toxicity of ketamine hydrochloride has been studied in several species.
In mature mice and rats, the intraperitoneal LD50 values are approximately 100 times the average human intravenous dose and approximately 20 times the average human intramuscular dose.
A slightly higher acute toxicity observed in neonatal rats was not sufficiently elevated to suggest an increased hazard when used in pediatric patients.
Daily intravenous injections in rats of five times the average human intravenous dose and intramuscular injections in dogs at four times the average human intramuscular dose demonstrated excellent tolerance for as long as 6 weeks. Similarly, twice weekly anesthetic sessions of one, three, or six hours' duration in monkeys over a four- to six-week period were well tolerated.
Interaction with Other Drugs Commonly Used for Preanesthetic Medication
Large doses (three or more times the equivalent effective human dose) of morphine, meperidine, and atropine increased the depth and prolonged the duration of anesthesia produced by a standard anesthetizing dose of ketamine hydrochloride in Rhesus monkeys. The prolonged duration was not of sufficient magnitude to contraindicate the use of these drugs for preanesthetic medication in human clinical trials.
Blood pressure responses to ketamine hydrochloride vary with the laboratory species and experimental conditions. Blood pressure is increased in normotensive and renal hypertensive rats with and without adrenalectomy and under pentobarbital anesthesia.
Intravenous ketamine hydrochloride produces a fall in arterial blood pressure in the Rhesus monkey and a rise in arterial blood pressure in the dog. In this respect the dog mimics the cardiovascular effect observed in man.
The pressor response to ketamine hydrochloride injected into intact, unanesthetized dogs is accompanied by a tachycardia, rise in cardiac output and a fall in total peripheral resistance.
It causes a fall in perfusion pressure following a large dose injected into an artificially perfused vascular bed (dog hindquarters), and it has little or no potentiating effect upon vasoconstriction responses of epinephrine or norepinephrine.
The pressor response to ketamine hydrochloride is reduced or blocked by chlorpromazine (central depressant and peripheral α-adrenergic blockade), by β-adrenergic blockade, and by ganglionic blockade. The tachycardia and increase in myocardial contractile force seen in intact animals does not appear in isolated hearts (Langendorff) at a concentration of 0.
1 mg of ketamine hydrochloride or in Starling dog heart-lung preparations at a ketamine hydrochloride concentration of 50 mg/kg of HLP. These observations support the hypothesis that the hypertension produced by ketamine hydrochloride is due to selective activation of central cardiac stimulating mechanisms leading to an increase in cardiac output. The dog myocardium is not sensitized to epinephrine and ketamine hydrochloride appears to have a weak antiarrhythmic activity.
Ketamine hydrochloride is rapidly absorbed following parenteral administration.
Animal experiments indicated that ketamine hydrochloride was rapidly distributed into body tissues, with relatively high concentrations appearing in body fat, liver, lung, and brain; lower concentrations were found in the heart, skeletal muscle, and blood plasma. Placental transfer of the drug was found to occur in pregnant dogs and monkeys. No significant degree of binding to serum albumin was found with ketamine hydrochloride.
Balance studies in rats, dogs, and monkeys resulted in the recovery of 85% to 95% of the dose in the urine, mainly in the form of degradation products. Small amounts of drug were also excreted in the bile and feces.
Balance studies with tritium-labeled ketamine hydrochloride in human subjects (1 mg/lb given intravenously) resulted in the mean recovery of 91% of the dose in the urine and 3% in the feces. Peak plasma levels averaged about 0.
75 μg/mL, and CSF levels were about 0.2 μg/mL, 1 hour after dosing.
Ketamine hydrochloride undergoes N-demethylation and hydroxylation of the cyclohexanone ring, with the formation of water-soluble conjugates which are excreted in the urine. Further oxidation also occurs with the formation of a cyclohexanone derivative.
The unconjugated N-demethylated metabolite was found to be less than one-sixth as potent as ketamine hydrochloride. The unconjugated demethyl cyclohexanone derivative was found to be less than one-tenth as potent as ketamine hydrochloride.
Repeated doses of ketamine hydrochloride administered to animals did not produce any detectable increase in microsomal enzyme activity.
Male and female rats, when given five times the average human intravenous dose of ketamine hydrochloride for three consecutive days about one week before mating, had a reproductive performance equivalent to that of saline-injected controls.
When given to pregnant rats and rabbits intramuscularly at twice the average human intramuscular dose during the respective periods of organogenesis, the litter characteristics were equivalent to those of saline-injected controls.
A small organogenesis, the litter characteristics were equivalent to those of saline-injected controls.
A small group of rabbits was given a single large dose (six times the average human dose) of ketamine hydrochloride on Day 6 of pregnancy to simulate the effect of an excessive clinical dose around the period of nidation. The outcome of pregnancy was equivalent in control and treated groups.
To determine the effect of ketamine hydrochloride on the perinatal and postnatal period, pregnant rats were given twice the average human intramuscular dose during Days 18 to 21 of pregnancy. Litter characteristics at birth and through the weaning period were equivalent to those of the control animals.
There was a slight increase in incidence of delayed parturition by one day in treated dams of this group. Three groups each of mated beagle bitches were given 2.
5 times the average human intramuscular dose twice weekly for the three weeks of the first, second, and third trimesters of pregnancy, respectively, without the development of adverse effects in the pups.
Ketamine: Mechanisms of Action, Uses in Pain Medicine, and Side Effects
|The following article is part of conference coverage from the PAINWeek 2018 conference in Las Vegas, Nevada. Clinical Pain Advisor’s staff will be reporting breaking news associated with research conducted by leading experts in pain medicine. Check back for the latest news from PAINWeek 2018.|
LAS VEGAS — R.
Norman Harden, MD, associate professor at Northwestern University and director of the Center for Pain Studies at the Rehabilitation Institute of Chicago, Illinois, provided an overview of the use of ketamine as an analgesic and its associated side effects at the annual PAINWeek conference, held September 4-8, 2018.1
Ketamine — or RS-2-[2-chlorophenyl]-2-[methylamino] cyclohexanone — exerts its effects mainly by acting as a noncompetitive antagonist to the N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors.
At higher doses, the drug is also thought to bind muscarinic cholinergic and monoaminergic receptors, as well as calcium-gated ion channels and µ-, σ-, κ-, and δ-opioid receptors in the brain and spinal cord. The ketamine molecule is hydrophilic and lipophilic, allowing it to cross the blood-brain barrier.
Some of its cognitive effects are thought to result from ketamine binding to receptors in the prefrontal cortex.
Ketamine also provides dissociative anesthesia as well as analgesia. These properties, combined with its effects on increasing blood pressure and inducing bronchodilation, make it an attractive pharmacologic option in pain medicine.
In addition, ketamine is known to provide twice as much analgesia as morphine and is one of the few drugs with anxiolytic, analgesic, and amnestic properties.
Furthermore, ketamine appears to preserve upper airway muscle tone and pharyngeal reflexes, while having minimal effects on central respiratory depression.
The drug has been used in settings ranging from battlefield medicine (since the Vietnam War in the 1970s) and emergency medicine, to intensive care, and in the treatment of several psychiatric conditions including depression. The first reported use of ketamine in pain medicine dates from 1989.2
A 2015 systematic review of the literature examining the use of ketamine for the management of complex regional pain syndrome determined that only low-quality evidence supported the efficacy of the drug for this condition.3
Ketamine — also known as “special K” — is increasingly used as a recreational drug for some of its effects including hallucinations and a feeling of “separation” from the body, despite other side effects including delirium, nightmares, and nausea. The drug can be taken by multiple routes of administration, from oral and intranasal to intravenous, intramuscular, and intrarectal.
An estimated 2.3 million Americans abuse the drug, but it is not known whether long-term use of the drug may lead to brain damage.
Some probable side effects associated with long-term use of ketamine include effects on kidneys, bladder, and liver, as well as mental health disturbances.
Long-term use of ketamine may have effects on the cardiopulmonary system, as well as cognition and learning.
Disclosure: Dr Harden is a consultant/independent contractor for Biohaven, Takeda, and Neumentum pharmaceuticals.
For more coverage of PAINWeek 2018, click here.