REMIFENTANIL

The Uses of REMIFENTANIL

Analgesic.

Background

Remifentanil (marketed by Abbott as Ultiva) is a potent ultra short-acting synthetic opioid given to patients during surgery for pain relief and adjunctive to an anaesthetic. Remifentanil is a specific mu-type-opioid receptor agonist which means it reduces sympathetic nervous system tone, and causes respiratory depression and analgesia.

Indications

For use during the induction and maintenance of general anesthesia.

Definition

ChEBI: A piperidinecarboxylate ester that is methyl piperidine-4-carboxylate in which the hydrogen attached to the nitrogen is substituted by a 3-methoxy-3-oxopropyl group and the hydrogen at position 4 is substituted the nitrogen of N-propanoy aniline.

brand name

Ultiva (Abbott).

World Health Organization (WHO)

Remifentanil is defined as an opioid narcotic with an addictionforming and addiction-sustaining liability similar to morphine.

General Description

Remifentanil (Ultiva) was designed as a “soft drug.” Softdrugs are designed to undergo metabolism quickly and thushave ultrashort durations of action. In place of the ethylaromatic ring seen on the other piperidine opioids, remifentanilhas an ester group. This ester group is metabolizedby esterases in the blood and tissue to a weaklyactive metabolite (1:300–1:1,000 the potency of remifentanil). The n-octanol/water partition coefficient ofremifentanil is 17.9. The pKa of remifentanil is 7.07, thus itis predominately unionized at physiological pH. Both ofthese properties account for its rapid distribution across theblood-brain barrier (<1 minute). The ester hydrolysis leadsto a quick recovery (5–10 minutes) independent of durationof drug administration, renal, or liver function. The favorablepharmacodynamics of remifentanil have led to its usefor induction and maintenance of surgical anesthesia.

Pharmacokinetics

Remifentanil is an opioid agonist with rapid onset and peak effect and ultra-short duration of action. The opioid activity of remifentanil is antagonized by opioid antagonists such as naloxone. The analgesic effects of remifentanil are rapid in onset and offset. Its effects and side effects are dose dependent and similar to other opioids. Remifentanil in humans has a rapid blood-brain equilibration half-time of 1 ± 1 minutes (mean ± SD) and a rapid onset of action.

Pharmacology

Remifentanil is a MOP agonist with a similar potency to fentanyl and approximately 20 times more than alfentanil. It has a rapid blood–brain equilibration time of just over 1min, with a short context-sensitive half-life of 3–5min, which is unaffected by duration of infusion. This makes it ideally suited for infusion during anaesthesia and in critical care. It may be titrated rapidly to achieve the desired effect. Remifentanil is available as a lyophilised white crystalline powder containing glycine; it should not be administered via the epidural or intrathecal routes. There may be increased opioid sensitivity in hepatic disease, resulting in a lower dosage requirement. Other situations requiring a reduction in dose include haemorrhage and shock and when administering in elderly patients. The high clearance and low VD imply that the offset of effect is caused by metabolism rather than redistribution. Hypothermia, such as may occur in cardiac surgery, may reduce clearance by up to 20%.
There is some evidence to suggest that acute opioid tolerance and hyperalgesia may occur, particularly after remifentanil infusions. If high doses are used without neuromuscular blockade, muscle rigidity may be a problem, though this is less likely if using a concentration of 100 μgml^-1 or less and an infusion rate of 0.2–0.5μgkg^-1 min^-1. Bradycardia has also been reported.

Clinical Use

Analgesic
Induction of anaesthesia

Drug interactions

Potentially hazardous interactions with other drugs
Anti-arrhythmics: delayed absorption of mexiletine.
Antidepressants: possible CNS excitation or depression (hypertension or hypotension) in patients also receiving MAOIs (including moclobemide) - avoid; possibly increased sedative effects with tricyclics.
Antihistamines: sedative effects possibly increased with sedating antihistamines.
Antipsychotics: enhanced sedative and hypotensive effect.
Antivirals: concentration possibly increased by ritonavir (risk of toxicity) - avoid.
Dopaminergics: avoid with selegiline.
Nalmefene: avoid concomitant use.
Sodium oxybate: enhanced effect of sodium oxybate - avoid.

Metabolism

By hydrolysis of the propanoic acid-methyl ester linkage by nonspecific blood and tissue esterases.

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). About 95% of a dose of remifentanil is excreted in the urine as the metabolite.