Ultiva Mechanism of Action

Pharmacology: Pharmacodynamics: Remifentanil is a selective μ-opioid agonist with a rapid onset and very short duration of action. The μ-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 µg/kg.
Neonates/infants (aged less than 1 year): In a randomised (ratio of 2:1, remifentanil:halothane), open label, parallel group, multicentre study in 60 young infants and neonates ≤8 weeks of age (mean 5.5 weeks) with an ASA physical status of I-II who were undergoing pyloromyotomy, the efficacy and safety of remifentanil (given as a 0.4 μg/kg/min initial continuous infusion plus supplemental doses or infusion rate changes as needed) was compared with halothane (given at 0.4% with supplemental increases as needed). Maintenance of anaesthesia was achieved by the additional administration of 70% nitrous oxide (N20) plus 30% oxygen. Recovery times were superior in the remifentanil relative to the halothane groups (not significant).
Use for Total Intravenous anaesthesia (TIVA) - children aged 6 months to 16 years.
TIVA with remifentanil in paediatric surgery was compared to inhalation anaesthesia in three randomised, open-label studies. The results are summarised in the table as follows. (See Table 1.)

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In the study in lower abdominal/urological surgery comparing remifentanil/propofol with remifentanil/sevoflurane, hypotension occurred significantly more often under remifentanil/sevoflurane, and bradycardia occurred significantly more often under remifentanil/propofol. In the study in ENT surgery comparing remifentanil/propofol with desflurane/nitrous oxide, a significantly higher heart rate was seen in subjects receiving desflurane/nitrous oxide compared with remifentanil/propofol and with baseline values.
Pharmacokinetics: Following administration of the recommended doses of remifentanil, the effective biological half-life is 3-10 minutes. The average clearance of remifentanil in young healthy adults is 40 mL/min/kg, the central volume of distribution is 100 mL/kg and the steady-state volume of distribution is 350 mL/kg. In children aged 1 to 12 years, remifentanil clearance and volume of distribution decreases with increasing age; the values of these parameters in neonates are approximately twice those of healthy young adults.
Blood concentrations of remifentanil are proportional to the dose administered throughout the recommended dose range. For every 0.1 µg/kg/min increase in infusion rate, the blood concentration of remifentanil will rise 2.5 ng/mL. 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 remifentanil is recovered in the urine as the carboxylic acid metabolite. Remifentanil is not a substrate for plasma cholinesterase.
Cardiac anaesthesia: 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.
Renal impairment: The rapid recovery from remifentanil-based sedation and analgesia is 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 25-35%.
Hepatic impairment: 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.
Paediatric patients: 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 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 (>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.
Placental and milk transfer: In a human clinical trial, the mean ratio of maternal arterial to umbilical venous concentration indicated that the neonate was exposed to approximately 50% concentration of remifentanil to that in the mother. The mean umbilical arteriovenous 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 intravenous products and this finding has no relevance for intravenous administration of Ultiva.
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 µM or higher (which are higher than plasma concentrations seen in clinical practice). There were no effects at a concentration of 0.1 µM.
The major metabolite remifentanil acid had no effect on APD up to the maximum tested concentration of 10 µM.
Reproductive toxicity studies: Remifentanil has been shown to reduce fertility in male rats when administered daily by intravenous injection for at least 70 days at a dose of 0.5 mg/kg, or approximately 250 times the maximum recommended human bolus dose of 2 µg/kg. The fertility of female rats was not affected at doses up to 1 mg/kg when administered for at least 15 days prior to mating. No teratogenic effects have been observed with remifentanil at doses up to 5 mg/kg in rats and 0.8 mg/kg in rabbits. Administration of remifentanil to rats throughout late gestation and lactation at doses up to 5mg/kg IV had no significant effect on the survival, development, or reproductive performance of the F₁ generation.
Genotoxicity: Remifentanil was devoid of genotoxic activity in bacteria and in rat liver or mouse bone marrow cells in vivo. However, a positive response was seen in vitro in different mammalian cell systems in the presence of a metabolic activation system. This activity was seen only at concentrations more than three orders of magnitude higher than therapeutic blood levels.