Ultiva Mechanism of Action

ATC Code: N01AH06.
Pharmacology: Pharmacodynamics: Mechanism of Action: Remifentanil is a selective mu-opioid agonist with a rapid onset and very short duration of action. The mu-opioid activity of ULTIVA is antagonized by narcotic antagonists such as naloxone.
Pharmacodynamic Effects: Assays of histamine in patients and normal volunteers have shown no elevation in histamine levels after administration of ULTIVA in bolus doses up to 30 micrograms/kg.
Pharmacokinetics: Absorption: Blood concentrations of ULTIVA are proportional to the dose administered throughout the recommended dose range. For every 0.1 micrograms/kg/min increase in infusion rate, the blood concentration of ULTIVA will rise 2.5 nanograms/ml.
Distribution: The central volume of distribution is 100 ml/kg, and the steady-state volume of distribution is 350 ml/kg.
Remifentanil is approximately 70% bound to plasma proteins.
Metabolism: 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 an essentially inactive carboxylic acid metabolite (1/4600th as potent as remifentanil). The half-life of the metabolite in healthy adults is 2 hours. Approximately 95% of ULTIVA is recovered in the urine as the carboxylic acid metabolite. Remifentanil is not a substrate for plasmacholinesterase.
Elimination: Following administration of the recommended doses of ULTIVA, the effective biological half-life is 3 to 10 minutes. The average clearance of remifentanil in young healthy adults is 40 ml/min/kg.
Special Patient Populations: Cardiac anaesthesia: The clearance of remifentanil is reduced by up to 20% during hypothermic (28°C) cardiopulmonary bypass. A decrease in body temperature lowers elimination clearance by 3% per °C.
Renal impairment: The rapid recovery from remifentanil-based sedation and analgesia is unaffected by renal status. The pharmacokinetics of ULTIVA 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 mu-opioid effects even after administration of ULTIVA 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%.
Hepatic impairment: The pharmacokinetics of ULTIVA 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 ULTIVA should be titrated to the individual patient need.
Paediatric patients: In paediatric patients 5 days to 17 years of age, 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 half-life of remifentanil is not significantly different in neonates suggesting that changes in analgesic effect after changes in infusion rate of ULTIVA should be rapid and similar to that seen in young healthy adults. The pharmacokinetics of the carboxylic acid metabolite in paediatric patients 2 to 17 years of age are similar to those seen in adults after correcting for differences in body weight.
Elderly: The clearance of remifentanil is slightly reduced (approximately 25%) in elderly patients (greater than 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 ULTIVA should be reduced by 50% in elderly patients and then carefully titrated to meet the individual patient need.
Placental and milk transfer: 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.
Toxicology: Pre-Clinical Safety Data: Intrathecal administration of the glycine formulation without remifentanil to dogs caused agitation, pain and hind limb dysfunction and incoordination. These effects are believed to be secondary to the glycine excipient. Glycine is a commonly used excipient in i.v. products and this finding has no relevance for i.v. administration of remifentanil.
Remifentanil, like other opioid agonists, produced increases in action potential duration (APD) in dog isolated Purkinje fibres. For remifentanil, the effects were seen at concentrations of 1 micromolar or higher (which are higher than plasma concentrations seen in clinical practice). There were no effects at a concentration of 0.1 micromolar.
The major metabolite, remifentanil carboxylic acid, had no effect on APD up to the maximum tested concentration of 10 micromolar.
Remifentanil-related material was found in rat milk after dosing with remifentanil. Placental transfer studies in rats and rabbits showed that pups are exposed to ULTIVA and/or its metabolites during growth and development.
There have been no additional findings of clinical relevance.