Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Opioid anaesthetics, ATC code: N01AH06

Remifentanil is a selective mu-opioid agonist with a rapid onset and very short duration of action. The mu-opioid activity, of remifentanil, is antagonised 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.

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 below.
Surgical            Age     Study condition                  Extubation intervention        (y),    (maintenance)                    (min)
(N)                                      (mean (SD))
Lower abdominal     0.5-    TIVA: propofol (5 - 10           11.8 (4.2) / urological        16      mg/kg/h) surgery             (120)   + remifentanil (0.125 - 1.0
μg/kg/min)
Inhalation anaesthesia:          15.0 (5.6) sevoflurane (1.0 - 1.5 MAC)      (p<0.05) and remifentanil (0.125 -
1.0 μg/kg/min)
ENT-surgery         4-11    TIVA: propofol (3 mg/kg/h) +     11 (3.7) (50)    remifentanil (0.5 μg/kg/min)
Inhalation anaesthesia:          9.4 (2.9) desflurane (1.3 MAC) and         Not
N2O                              significant mixture
General or ENT      2-12    TIVA: remifentanil (0.2 - 0.5    Comparable surgery             (153)   μg/kg/min) + propofol (100 -     extubation 200 μg/kg/min)                   times (based
Inhalation anaesthesia:          on limited sevoflurane (1 -                 data)
1.5 MAC) + N2O mixture

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.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties

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 micrograms/kg/min increase in infusion rate, the blood concentration of remifentanil will rise 2.5 nanograms/ml. Remifentanil is approximately 70% bound to plasma proteins.
Biotransformation

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. Especially 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 demonstrate that the accumulation of the metabolite does not result in clinically relevant mu-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 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 2-17 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 arterio-venous ratio of remifentanil concentrations was approximately 30% suggesting metabolism of remifentanil in the neonate.