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Ketafast Actions |
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Pharmacology: Pharmacodynamics: Ketafast is a rapidly acting general anaesthetic for IV or IM use with a distinct pharmacological action. Ketafast HCl produces dissociative anaesthesia characterised by catalepsy, amnesia and marked analgesia which may persist into the recovery period. Pharyngeal-laryngeal reflexes remain normal and skeletal muscle tone may be normal or can be enhanced to varying degrees. Mild cardiac and respiratory stimulation and occasionally respiratory depression occur.
Mechanism of Action: Ketafast induces sedation, immobility, amnesia and marked analgesia. The anaesthetic state produced by Ketafast has been termed "dissociative anaesthesia", in that, it appears to selectively interrupt association pathways of the brain before producing somesthetic sensory blockade. It may selectively depress the thalamoneocortical system before significantly obtunding the more ancient cerebral centres and pathways (reticular-activating and limbic systems). Numerous theories have been proposed to explain the effects of Ketafast, including binding to N-methyl-D-aspartate (NMDA) receptors in the central nervous system (CNS), interactions with opiate receptors at central and spinal sites and interaction with norepinephrine, serotonin and muscarinic cholinergic receptors. The activity on NMDA receptors may be responsible for the analgesic, as well as psychiatric (psychosis) effects of Ketafast. Ketafast has sympathomimetic activity resulting in tachycardia, hypertension, increased myocardial and cerebral oxygen consumption, increased cerebral blood flow and increased intracranial and intraocular pressure. Ketafast is also a potent bronchodilator. Clinical effects observed following Ketafast administration include increased blood pressure, increased muscle tone (may resemble catatonia), opening of eyes (usually accompanied by nystagmus) and increased myocardial oxygen consumption.
Pharmacokinetics: Ketafast is rapidly distributed into perfused tissues including brain and placenta. Animal studies have shown Ketafast to be highly concentrated in body fat, liver and lung. Biotransformation takes place in the liver. Termination of anaesthetic is partly by re-distribution from brain to other tissues and partly by metabolism. Elimination half-life is approximately 2-3 hrs and renal excretion, mostly as conjugated metabolites.
Toxicology: Preclinical Safety Data: Preclinical safety data does not add anything of further significance to the prescriber.
Ketafast is injected into a muscle, or into a vein through an IV. You will receive this injection in a clinic or hospital setting.
Your breathing, blood pressure, heart function, and other vital signs will be watched closely while you are receiving Ketafast.
You may feel strange or slightly confused when you first come out of anesthesia. Tell your caregivers if these feelings are severe or unpleasant.
You may be shown how to use injections at home. Do not self-inject this medicine if you do not fully understand how to give the injection and properly dispose of used needles, IV tubing, and other items used to inject the medicine.
Use a disposable needle only once. Throw away used needles in a puncture-proof container (ask your pharmacist where you can get one and how to dispose of it). Keep this container out of the reach of children and pets.
Store at room temperature away from moisture, heat, and light.
Ketafast is injected into a muscle, or into a vein through an IV. You will receive this injection in a clinic or hospital setting.
Your breathing, blood pressure, heart function, and other vital signs will be watched closely while you are receiving Ketafast.
You may feel strange or slightly confused when you first come out of anesthesia. Tell your caregivers if these feelings are severe or unpleasant.
You may be shown how to use injections at home. Do not self-inject this medicine if you do not fully understand how to give the injection and properly dispose of used needles, IV tubing, and other items used to inject the medicine.
Use a disposable needle only once. Throw away used needles in a puncture-proof container (ask your pharmacist where you can get one and how to dispose of it). Keep this container out of the reach of children and pets.
Store at room temperature away from moisture, heat, and light.
Ketafast 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.
The biotransformation of Ketafast 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 Ketafast 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 Ketafast in reducing halothane requirements (MAC) of the rat. The later half-life of Ketafast (beta phase) is 2.5 hours.
The anesthetic state produced by Ketafast 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.
Ketafast has a wide margin of safety; several instances of unintentional administration of overdoses of Ketafast hydrochloride (up to ten times that usually required) have been followed by prolonged but complete recovery.
Ketafast 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 Ketafast 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:
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 Ketafast 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.
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 Ketafast 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 Ketafast 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 Ketafast 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 Ketafast 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 Ketafast 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 Ketafast hydrochloride or in Starling dog heart-lung preparations at a Ketafast hydrochloride concentration of 50 mg/kg of HLP. These observations support the hypothesis that the hypertension produced by Ketafast 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 Ketafast hydrochloride appears to have a weak antiarrhythmic activity.
Ketafast hydrochloride is rapidly absorbed following parenteral administration. Animal experiments indicated that Ketafast 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 Ketafast 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 Ketafast 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.
Ketafast 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 Ketafast hydrochloride. The unconjugated demethyl cyclohexanone derivative was found to be less than one-tenth as potent as Ketafast hydrochloride. Repeated doses of Ketafast 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 Ketafast 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 Ketafast 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 Ketafast 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.
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Information checked by Dr. Sachin Kumar, MD Pharmacology
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