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| Trade names | Ultiva |
| Other names | methyl 1-(2-methoxycarbonylethyl)-4-(phenyl-propanoyl-amino)-piperidine-4-carboxylate |
| AHFS/Drugs.com | Monograph |
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| Routes of administration | Intravenous |
| Drug class | Opioid |
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| Pharmacokinetic data | |
| Bioavailability | IV/IM; 100% |
| Protein binding | 70% (bound to plasma proteins) |
| Metabolism | cleaved by non-specific plasma and tissue esterases |
| Eliminationhalf-life | 1-20 minutes |
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| ECHA InfoCard | 100.211.201 |
| Chemical and physical data | |
| Formula | C20H28N2O5 |
| Molar mass | 376.453 g·mol−1 |
| 3D model (JSmol) | |
| Melting point | 5 °C (41 °F) |
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Remifentanil, marketed under the brand nameUltiva is a potent, short-acting syntheticopioidanalgesicdrug. It is given to patients during surgery to relieve pain and as an adjunct to ananesthetic. Remifentanil is used forsedation as well as combined with other medications for use ingeneral 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 varioushypnotic drugs and volatile anesthetics.
Remifentanil is used as anopioidanalgesic that has a rapid onset and rapid recovery time.[2] It has been used effectively duringcraniotomies,[3] spinal surgery,[4]cardiac surgery,[5] andgastric bypass surgery.[6] While opioids function similarly, with respect to analgesia, thepharmacokinetics of remifentanil[7] allows for quicker post-operative recovery.[8]
Remifentanil can be administered as part of an anesthesia technique called TIVA (total intravenous anesthesia) using computer controlled infusion pumps in a process called TCI (target controlled infusion). 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 40 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 shortcontext-sensitive half-life of remifentanil allows the desiredblood plasma level to be achieved quickly, and also for the same reason, recovery occurs quickly. This allows remifentanil to be used in unique circumstances such as cesarean section.[9]
Remifentanil's short context-sensitive half-life makes it ideal for intense pain of short duration. As such, it has been used for analgesia in labor successfully; however, it is not as effective as epidural analgesia.[10]
In combination withpropofol, remifentanil is used for anesthesia of patients undergoingelectroconvulsive therapy.[11]
It is administered in the formremifentanil hydrochloride and in adults is given as anintravenous 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).[12] 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 ingeneral anesthesia vary but are usually 0.1–1 (μg/kg)/min.[13]
Remifentanil is considered a metabolicsoft drug,[14] one that is rapidly metabolized to an inactive form. Unlike other synthetic opioids which are hepatically metabolized, remifentanil has anester linkage which undergoes rapid hydrolysis by non-specific tissue and plasmaesterases. This means that accumulation does not occur with remifentanil and itscontext-sensitive half-life remains at 4 minutes after a 4-hour infusion.[15]
Remifentanil is metabolized to a compound (remifentanil acid) which has 1/4600th the potency of the parent compound.[16]
Due 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 is rapidly eliminated from the blood plasma on termination of the remifentanil infusion; hence the effects of the drug quickly dissipate even after very long infusions. Owing to synergism between remifentanil and hypnotic drugs (such aspropofol) the dose of the hypnotic can be substantially reduced.[17] This leads often to more hemodynamic stability during surgery and a quicker post-operative recovery time.
Comparing its analgesia-sedation effect in ventilated patients, remifentanil may be superior to morphine[18] but not to fentanyl.[19]
Remifentanil is a specificμ-receptor agonist.[17] Hence, it causes a reduction insympathetic nervous system tone,respiratory depression andanalgesia. The drug's effects include a dose-dependent decrease inheart rate andarterial pressure andrespiratory rate andtidal 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 asfentanyl andalfentanil) 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 othersedatives that allow the patient to tolerate or lose awareness of the side effect.
Because pruritus is partially due to excessive serum histamine levels, antihistamines such asdiphenhydramine (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'scirculation once the infusion is terminated.
Remifentanil, being aμ-receptoragonist, functions like other μ-receptor agonists, such asmorphine andcodeine; it can cause euphoria and has the potential for abuse.[20][21] However, due to its rapid metabolism and short-acting half-life the likelihood of abuse is quite low. Nevertheless, there have been some documentations of remifentanil abuse.[22][23]
Prior to the development of remifentanil, most short-acting hypnotics and amnestics faced issues with prolonged use, where accumulation would result in unfavorable lingering effects during post-operative recovery. Remifentanil was designed to serve as a strong anesthetic with an ultra-short and predictable duration that would not have accumulation issues.[24]
Remifentanil was patented byGlaxo Wellcome Inc.[25] and was FDA approved on July 12, 1996.[26] Its patent ended on the 10th of September 2017.
InHong Kong, remifentanil is regulated under Schedule 1 ofHong Kong's Chapter 134Dangerous 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 finedHK$10,000 (US$1,550). The penalty for trafficking or manufacturing the substance is aHK$5,000,000 (US$775,000) fine and life imprisonment. Possession of the substance for consumption without license from the Department of Health is illegal with aHK$1,000,000 (US$155,000) fine and/or 7 years of jail time.
Remifentanil is a Schedule II narcotic controlled substance in the United States with a DEA ACSCN of 9739 and a 2013 annual aggregate manufacturing quota of 3,750 grams, unchanged from the prior year.
Replacing the methylester on the long chain with atert-butyl ester makes the remifentanil analogue 150.000 times more potent than morphine and 210 times more potent than remifentanil itself, which makes it one of the most potent fentanyl analogues known. The tert-butyl group also makes it more resistant to hydrolysis and extends its half-life in the body.[27]
Remifentanil's half-life is 6 minutes in the dog. This half-life does not increase with increased dosage or prolonged usage and thus remifentanil recovery is very quick. Remifentanil is more effective in dogs than cats, although an increase in the dosage in cats can achieve analgesia and anti-nociception.Hyperalgesia and tolerance has been demonstrated in rodents and rabbits but not dogs and cats. In equines remifentanil can provide long-lasting sedation when combined withxylazine and used as constant rate infusion.[15]
