Chemical formula: C₂₀H₂₈N₂O₅ Molecular mass: 376.447 g/mol PubChem compound: 60815
Remifentanil is a selective mu-opioid agonist with a rapid onset and very short duration of action. The mu-opioid activity of remifentanil is antagonized by narcotic antagonists, such as naloxone.
Assays of histamine in patients and normal volunteers have shown no elevation in histamine levels after administration of remifentanil in bolus doses up to 30 micrograms/kg.
Following administration of the recommended doses of remifentanil, the effective half-life is 3-10 minutes. The average clearance of remifentanil in young healthy adults is 40ml/min/kg, the central volume of distribution is 100ml/kg and the steady-state volume of distribution is 350ml/kg. Blood concentrations of remifentanil are proportional to the dose administered throughout the recommended dose range. For every 0.1 microgram/kg/min increase in infusion rate, the blood concentration of remifentanil will rise 2.5ng/ml. Remifentanil is approximately 70% bound to plasma proteins.
Remifentanil is an esterase metabolised opioid that is susceptible to metabolism by non-specific blood and tissue esterases. The metabolism of remifentanil results in the formation of a carboxylic acid metabolite which in dogs is 1/4600th as potent as remifentanil. Studies in man indicate that all pharmacological activity is associated with the parent compound. The activity of this metabolite is therefore not of any clinical consequence. The half-life of the metabolite in healthy adults is 2 hours. In patients with normal renal function, the time for 95% elimination of the primary metabolite of remifentanil by the kidneys, is approximately 7-10 hours. Remifentanil is not a substrate for plasma cholinesterase.
Placental transfer studies in rats and rabbits showed that pups are exposed to remifentanil and/or its metabolites during growth and development. Remifentanil-related material is transferred to the milk of lactating rats. In a human clinical trial, the concentration of remifentanil in foetal blood was approximately 50% of that in maternal blood. The foetal arterio-venous ratio of remifentanil concentrations was approximately 30%, suggesting metabolism of remifentanil in the neonate.
The clearance of remifentanil is reduced by approximately 20% during hypothermic (28°C) cardiopulmonary bypass. A decrease in body temperature lowers elimination clearance by 3% per degree centigrade.
In the clinical studies conducted to date, the rapid recovery from remifentanil-based analgesia appears unaffected by renal status.
The pharmacokinetics of remifentanil are not significantly changed in patients with varying degrees of renal impairment even after administration for up to 3 days in the intensive care setting.
The clearance of the carboxylic acid metabolite is reduced in patients with renal impairment. In intensive care patients with moderate/severe renal impairment, the concentration of the carboxylic acid metabolite may exceed 250-fold the level of remifentanil at steady-state in some patients. Clinical data demonstrates that accumulation of the metabolite does not result in clinically relevant µ-opioid effects even after administration of remifentanil infusions for up to 3 days in these patients.
There is no evidence that remifentanil is extracted during renal replacement therapy.
The carboxylic acid metabolite is extracted during haemodialysis by at least 30%.
The pharmacokinetics of remifentanil are not changed in patients with severe hepatic impairment awaiting liver transplant, or during the anhepatic phase of liver transplant surgery. Patients with severe hepatic impairment may be slightly more sensitive to the respiratory depressant effects of remifentanil. These patients should be closely monitored and the dose of remifentanil should be titrated to the individual patient need.
The average clearance and steady state volume of distribution of remifentanil are increased in younger children and decline to young healthy adult values by age 17. The elimination half-life of remifentanil in neonates is not significantly different from that of young healthy adults. Changes in analgesic effect after changes in infusion rate of remifentanil should be rapid and similar to those seen in young healthy adults. The pharmacokinetics of the carboxylic acid metabolite in paediatric patients 2-17 years of age are similar to those seen in adults after correcting for differences in body weight.
The clearance of remifentanil is slightly reduced in elderly patients (>65 years) compared to young patients. The pharmacodynamic activity of remifentanil increases with increasing age. Elderly patients have a remifentanil EC50 for formation of delta waves on the electroencephalogram (EEG) that is 50% lower than young patients; therefore, the initial dose of remifentanil should be reduced by 50% in elderly patients and then carefully titrated to meet the individual patient need.
Expected signs of mu-opioid intoxication were observed in non-ventilated mice, rats, and dogs after large single bolus intravenous doses of remifentanil. In these studies, the most sensitive species, the male rat, survived following administration of 5mg/kg. Hypoxia-induced brain microhaemorrhages observed in dogs were reversed within 14 days after completion of dosing.
Bolus doses of remifentanil administered to non-ventilated rats and dogs resulted in respiratory depression in all dose groups, and in reversible brain microhaemorrhages in dogs. Subsequent investigations showed that the microhaemorrhages resulted from hypoxia and were not specific to remifentanil. Brain microhaemorrhages were not observed in infusion studies in nonventilated rats and dogs because these studies were conducted at doses that did not cause severe respiratory depression.
It is to be derived from preclinical studies that respiratory depression and associated sequelae are the most likely cause of potentially serious adverse events in humans
Intrathecal administration to dogs of the glycine formulation alone (i.e., without remifentanil) caused agitation, pain and hind limb dysfunction and incoordination. These effects are believed to be secondary to the glycine excipient. Because of the better buffering properties of blood, the more rapid dilution, and the low glycine concentration of the remifentanil formulation, this finding has no clinical relevance for intravenous administration of remifentanil.
Remifentanil reduced fertility in male rats after daily injection for at least 70 days. A no-effect dose was not demonstrated. Fertility was not affected in female rats. Teratogenic effects were not seen in rats or rabbits. Administration of remifentanil to rats throughout late gestation and lactation did not significantly affect the survival, development, or reproductive performance of the F1 generation.
Remifentanil did not yield positive findings in a series of in vitro and in vivo genotoxicity tests, except in the in vitro mouse lymphoma tk assay, which gave a positive result with metabolic activation. Since the mouse lymphoma results could not be confirmed in further in vitro and in vivo tests, treatment with remifentanil is not considered to pose a genotoxic hazard to patients.
Long-term carcinogenicity studies were not performed.
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