Remifentanil

Remifentanil

Systematic (IUPAC) name
methyl 1-(3-methoxy-3-oxopropyl)-4-(N-phenylpropanamido)piperidine-4-carboxylate
Clinical data
AHFS/Drugs.com	monograph
Pregnancy cat.	?
Legal status	? (UK) Schedule II (US)
Routes	Intravenous
Pharmacokinetic data
Bioavailability	Not applicable (intravenous administration)
Protein binding	70% (bound to plasma proteins)
Metabolism	cleaved by non-specific plasma and tissue esterases
Half-life	1-20 minutes
Identifiers
CAS number	132875-61-7 Y
ATC code	N01AH06
PubChem	CID 60815
DrugBank	APRD01216
ChemSpider	54803 Y
UNII	P10582JYYK Y
KEGG	D08473 Y
ChEBI	CHEBI:8802 Y
ChEMBL	CHEMBL1005 Y
Synonyms	methyl 1-(2-methoxycarbonylethyl)-4-(phenyl-propanoyl-amino)-piperidine-4-carboxylate
Chemical data
Formula	C20H28N2O5
Mol. mass	376.447 g/mol
SMILES	eMolecules & PubChem
InChI InChI=1S/C20H28N2O5/c1-4-17(23)22(16-8-6-5-7-9-16)20(19(25)27-3)11-14-21(15-12-20)13-10-18(24)26-2/h5-9H,4,10-15H2,1-3H3 Y Key:ZTVQQQVZCWLTDF-UHFFFAOYSA-N Y
Physical data
Melt. point	5 °C (41 °F)
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Remifentanil (marketed by GlaxoSmithKline and Abbott as Ultiva) is a potent ultra short-acting synthetic opioid analgesic drug. It is given to patients during surgery to relieve pain and as an adjunct to an anaesthetic. Remifentanil is used for sedation as well as combined with other medications for use in general anesthesia. The use of remifentanil has made possible the use of high dose opioid and low dose hypnotic anesthesia, due to synergism between remifentanil and various hypnotic drugs and volatile anesthetics.

Administration

It is administered in the form remifentanil hydrochloride and in adults is given as an intravenous infusion in doses ranging from 0.1 microgram per kilogram per minute to 0.5 (µg/kg)/min. Children may require higher infusion rates (up to 1.0 (µg/kg)/min).^[1] Doses listed in the package insert from its manufacturer are much higher than those used in actual clinical practice. The clinically useful infusion rates are 0.025-0.1 (µg/kg)/min for sedation (rates adjusted to age of patient, severity of their illness and invasiveness of surgical procedure). Small amounts of other sedative medications are usually co-administered with remifentanil to produce sedation. Clinically useful infusion rates in general anesthesia vary but are usually 0.1-1 µg/kg/min[1].

Remifentanil can be administered as part of an anaesthesia technique called TIVA (Total Intravenous Anaesthesia) using computer controlled infusion pumps in a process called target controlled infusion or TCI. A target plasma concentration is entered as ng/ml into the pump, which calculates its infusion rate according to patient factors like age and weight. Induction levels of 4 ng/ml are commonly used, but it generally varies between 3-8 ng/ml. For certain surgical procedures that produce particularly strong stimuli a level of up to 15 ng/ml might be needed. The relatively short context-sensitive half-life of Remifentanil allows the desired blood plasma level to be achieved quickly and also for the same reason recovery occurs quickly.

Metabolism

Unlike other synthetic opioids which are hepatically metabolised, remifentanil has an ester linkage which undergoes rapid hydrolysis by non-specific tissue and plasma esterases. This means that accumulation does not occur with remifentanil and its context-sensitive half-life remains at 4 minutes after a 4 hour infusion.

Remifentanil is metabolized to a compound (remifentanil acid) which has 1/4600th the potency of the parent compound.^[2]

Owing to its quick metabolism and short effects remifentanil has opened up new possibilities in anesthesia. When remifentanil is used together with a hypnotic (i.e. one that produces sleep) it can be used in relative high doses. This is because remifentanil will be rapidly eliminated from the blood plasma on termination of the remifentanil infusion, hence the effects of the drug will quickly dissipate even after very long infusions. Owing to synergism between remifentanil and hypnotic drugs (such as propofol) the dose of the hypnotic can be substantially reduced.^[3] This leads often to more haemodynamic stability during surgery and a quicker post-operative recovery time.

Side-effects

Remifentanil is a specific μ-receptor agonist.^[3] Hence, it causes a reduction in sympathetic nervous system tone, respiratory depression and analgesia. The drug's effects include a dose-dependent decrease in heart rate and arterial pressure and respiratory rate and tidal volume. Muscle rigidity is sometimes noted.

The most common side effects reported by patients receiving this medication are a sense of extreme "dizziness" (often short lived, a common side effect of other fast-acting synthetic phenylpiperidine narcotics such as fentanyl and alfentanil) and intense itching (pruritus), often around the face. These side effects are often controlled by either altering the administered dose (decreasing or in some cases, increasing the dose) or by administering other sedatives that allow the patient to tolerate or lose awareness of the side effect.

Because pruritus is due to excessive serum histamine levels, antihistamines such as diphenhydramine (Benadryl) are often co-administered. This is done with care, however, as excessive sedation may occur.

Nausea can occur as a side effect of remifentanil, however, it is usually transient in nature due to the drug's short half-life which rapidly removes it from the patient's circulation once the infusion is terminated.

Potency

Circumventing Naltrexone

Remifentanil has been used with some success to circumvent naltrexone in patients who are in need of pain management.

Regulation

In Hong Kong, Remifentanil is regulated under Schedule 1 of Hong Kong's Chapter 134 Dangerous Drugs Ordinance. It can only be used legally by health professionals and for university research purposes. The substance can be given by pharmacists under a prescription. Anyone who supplies the substance without prescription can be fined $10000 (HKD). The penalty for trafficking or manufacturing the substance is a $5,000,000 (HKD) fine and life imprisonment. Possession of the substance for consumption without license from the Department of Health is illegal with a $1,000,000 (HKD) fine and/or 7 years of jail time.

Regulation in the US is as a schedule II narcotic.

References