Remifentanil

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Remifentanil
Remifentanil2DCSDS.svg
Remifentanil3DanJ.gif
Systematic (IUPAC) name
methyl 1-(3-methoxy-3-oxopropyl)-4-(N-phenylpropanamido)piperidine-4-carboxylate
Clinical data
Trade names Ultiva
AHFS/Drugs.com monograph
Pregnancy
category
  • AU: C
  • US: C (Risk not ruled out)
Legal status
Routes of
administration		 Intravenous
Pharmacokinetic data
Bioavailability Not applicable (intravenous administration)
Protein binding 70% (bound to plasma proteins)
Metabolism cleaved by non-specific plasma and tissue esterases
Biological half-life 1-20 minutes
Identifiers
CAS Number 132875-61-7 YesY
ATC code N01AH06 (WHO)
PubChem CID: 60815
IUPHAR/BPS 7292
DrugBank DB00899 YesY
ChemSpider 54803 YesY
UNII P10582JYYK YesY
KEGG D08473 YesYRamelteon
ChEBI CHEBI:8802 YesY
ChEMBL CHEMBL1005 YesY
Synonyms methyl 1-(2-methoxycarbonylethyl)-4-(phenyl-propanoyl-amino)-piperidine-4-carboxylate
Chemical data
Formula C20H28N2O5
Molecular mass 376.447 g/mol
  • O=C(OC)C2(N(c1ccccc1)C(=O)CC)CCN(CCC(=O)OC)CC2
  • 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 YesY
  • Key:ZTVQQQVZCWLTDF-UHFFFAOYSA-N YesY
Physical data
Melting point 5 °C (41 °F)
  (verify)

Remifentanil (marketed by GlaxoSmithKline and Abbott as Ultiva[1]) is a potent, 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.

Clinical Use

Remifentanil is used as an opioid analgesic that has a rapid onset and rapid recovery time.[1] It has been used effectively during craniotomies,[2] spinal infusions,[3] cardiac surgery,[4] and gastric bypass surgery.[5] While opiates function similarly, with respect to analgesia, the pharmacokinetics of remifentanil[6] allows for quicker post-operative recovery.[7]

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).[8] 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.[9]

Remifentanil can be administered as part of an anaesthesia technique called TIVA (Total Intravenous Anesthesia) 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.

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 with propofol, remifentanil is used for anesthesia of patients undergoing Electroconvulsive therapy.[11]

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.[12]

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.[13] 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.[13] 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

Remifentanil is approximately twice as potent as fentanyl, and 100-200 times as potent as morphine.

Circumventing naltrexone

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

Abuse Potential

Remifentanil, being a μ-receptor agonist, functions like other μ-receptor agonists (e.g., morphine and codeine) and can cause euphoria and has the potential for abuse.[14][15] However, due to its rapid metabolism and short-acting half-life the likelihood of becoming abused is quite low. Nevertheless, there have been some documentations of remifentanil abuse.[16][17]

Development and Marketing

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 anesthesia with an ultra-short and predictable duration that would not have accumulation issues.[18]

Remifentanil is patented by Glaxo Welcome incorporate[19] and was FDA approved on July 12, 1996.[20]

Pricing for Ultiva[21]

  • 1 mg vial - 30.19 USD
  • 3 mg vial - 57.20 USD
  • 5 mg vial - 118.15 USD

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.

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 3750 grams, unchanged from the prior year.

References

  1. ↑ 1.0 1.1 Lua error in package.lua at line 80: module 'strict' not found.
  2. ↑ Gesztesi Z, Mootz BL, White PF. The use of a remifentanil infusion for hemodynamic control during intracranial surgery. Anesth Analg. 1999;89(5):1282-1287
  3. ↑ Grottke O, Dietrich PJ, Wiegels S, Wappler F. Intraoperative wake-up test and postoperative emergence in patients undergoing spinal surgery: a comparison of intravenous and inhaled anesthetic techniques using short-acting anesthetics. Anesth Analg. 2004;99(5):1521-1527.
  4. ↑ Knapik M, Knapik P, Nadziakiewicz P, et al. Comparison of remifentanil or fentanyl administration during isoflurane anesthesia for coronary artery bypass surgery. Med Sci Monit. 2006;12(8):P133-P138
  5. ↑ De Baerdemaeker LEC, Jacobs S, Pattyn P, Mortier EP, Struys MMRF. Influence of intraoperative opioid on postoperative pain and pulmonary function after laparoscopic gastric banding: remifentanil TCI vs sufentanil TCI in morbid obesity. Br J Anaesth. 2007;99(3):404-411.
  6. ↑ Michelsen LG, Hug CC Jr. The pharmacokinetics of remifentanil. J Clin Anesth 1996;8:679–82
  7. ↑ Guy J, Hindman BJ, Baker KZ, et al. Comparison of remifentanil and fentanyl in patients undergoing craniotomy for supratentorial space-occupying lesions. Anesthesiology. 1997;86(3):514-524.
  8. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  9. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  10. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  11. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  12. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  13. ↑ 13.0 13.1 Lua error in package.lua at line 80: module 'strict' not found.
  14. ↑ Ternes, J. W., & O'Brien, C. P. (1990). The opioids: Abuse liability and treatments for dependence. Advances in alcohol & substance abuse, 9(1-2), 27-45.
  15. ↑ Panlilio, L. V., & Schindler, C. W. (2000). Self-administration of remifentanil, an ultra-short acting opioid, under continuous and progressive-ratio schedules of reinforcement in rats. Psychopharmacology, 150(1), 61-66.
  16. ↑ Baylon, G. J., Kaplan, H. L., Somer, G., Busto, U. E., & Sellers, E. M. (2000). Comparative abuse liability of intravenously administered remifentanil and fentanyl. Journal of clinical psychopharmacology, 20(6), 597-606.
  17. ↑ Levine, A. I., & Bryson, E. O. (2010). Intranasal self-administration of remifentanil as the foray into opioid abuse by an anesthesia resident. Anesthesia & Analgesia, 110(2), 524-525.
  18. ↑ Feldman, P. L. (2006). Discovery and Development of the Ultrashort-acting Analgesic Remifentanil. Drug Discovery and Development, Drug Discovery, 1, 339.
  19. ↑ Gatlin, Larry Alan, Shirley Ann Heiman, and Janet Sue Lewis. "Stable formulations of remifentanil." U.S. Patent No. 5,866,591. 2 Feb. 1999.
  20. ↑ US Food and Drug Administration. (2010). Orange book: approved drug products with therapeutic equivalence evaluations. Silver Spring, MD: US FDA.
  21. ↑ Lua error in package.lua at line 80: module 'strict' not found.
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