Carbetocin

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Carbetocin
Carbetocin.svg
Clinical data
Trade names Duratocin, Pabal, Lonactene, others
Other names(2-O-Methyltyrosine)deamino-1-carbaoxytocin; Deamino-2-O-methyltyrosine-1-carbaoxytocin; 1-Butanoic acid-2-(O-methy-L-tyrosine)-1-carbaoxytocin; 1-butyric acid-2-[3-(4-methoxyphenyl)-L-alanine]oxytocin
AHFS/Drugs.com Micromedex Detailed Consumer Information
Routes of
administration 		Intravenous, intramuscular
ATC code
Legal status
Legal status
  • UK: POM (Prescription only)
Pharmacokinetic data
Bioavailability 80% (IM)
Elimination half-life 85–100 minutes [1]
Identifiers
  • (2S)-1-[(3S,6S,9S,12S,15S)-12-[(2S)-butan-2-yl]-
    9-(2-carbamoylethyl)-6-(carbamoylmethyl)-15-
    [(4-hydroxyphenyl)methyl]-16-methyl-5,8,11,14,17-
    pentaoxo-1-thia-4,7,10,13,16-pentazacycloicosane-
    3-carbonyl]-N-[(1S)-1-(carbamoylmethylcarbamoyl)-
    3-methyl-butyl]pyrrolidine-2-carboxamide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
CompTox Dashboard (EPA)
ECHA InfoCard 100.048.450 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C45H69N11O12S
Molar mass 988.17 g·mol−1
3D model (JSmol)
  • CC[C@H](C)[C@H]1C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@@H](CSCCCC(=O)N[C@H](C(=O)N1)Cc2ccc(cc2)OC)C(=O)N3CCC[C@H]3C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N)CC(=O)N)CCC(=O)N
  • InChI=1S/C45H69N11O12S/c1-6-25(4)38-44(66)51-28(15-16-34(46)57)40(62)52-31(21-35(47)58)41(63)54-32(23-69-18-8-10-37(60)50-30(42(64)55-38)20-26-11-13-27(68-5)14-12-26)45(67)56-17-7-9-33(56)43(65)53-29(19-24(2)3)39(61)49-22-36(48)59/h11-14,24-25,28-33,38H,6-10,15-23H2,1-5H3,(H2,46,57)(H2,47,58)(H2,48,59)(H,49,61)(H,50,60)(H,51,66)(H,52,62)(H,53,65)(H,54,63)(H,55,64)/t25-,28-,29-,30-,31-,32-,33-,38-/m0/s1 X mark.svgN
  • Key:NSTRIRCPWQHTIA-DTRKZRJBSA-N X mark.svgN
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Carbetocin, sold under the brand names Pabal among others, is a medication used to prevent excessive bleeding after childbirth, particularly following Cesarean section. [2] It appears to work as well as oxytocin. [3] Due to it being less economical than other options, use is not recommended by NHS Scotland. [2] It is given by injection into a vein or muscle. [3]

Contents

Side effects differ little from that of no treatment or placebo. [3] Use is not recommended in people with epilepsy or eclampsia. [2] Carbetocin is a manufactured long acting form of oxytocin. [3] It works by activating the oxytocin receptor which causes the uterus to contract. [4] [3]

Carbetocin was first described in 1974. [5] It was approved for medical use in Canada and the United Kingdom in 1997. [3] It is on the World Health Organization's List of Essential Medicines. [6] It is not available in the United States or Japan. [7] [3]

Medical uses

Carbetocin has been approved for use immediately following an elective Cesarean section when a local or spinal anesthesia has been used. [8] Since the uterus cannot contract on its own following incision during a Cesarean section, exogenous administration of oxytocin or an analog is necessary to restore uterine tone and prevent hemorrhage. [8] [9]

Safety of carbetocin following vaginal births and emergency Cesarean sections has not been established, though studies have suggested efficacy following vaginal births to that following Cesarean sections. Some studies have shown that a 10-70 ug dose following vaginal delivery caused contractions and no adverse side effects. [10] Carbetocin has also been shown to increase uterine involution (the return of the uterus to its contracted state after the birth of the baby) in humans, horses and cows. [11] [12]

Comparison with other medication

In 2018, heat-stable carbetocin, a formulation that does not require strict refrigeration, was found to be as good as oxytocin for reduction of postpartum hemorrhage after vaginal delivery. [13] It is hoped that this will make oxytocic hemorrhage control more widely available and less expensive, [13] which will be particularly useful in regions of developing countries where the cold chain (in drug transport and storage) is unreliable because of power outages or equipment problems. [14] [15]

Due to carbetocin's considerably longer half-life, its effects are longer lasting than other oxytocin homologs such as oxytocin or barusiban. [16] A single carbetocin dose compared to a placebo or an eight-hour intravenous drip of oxytocin in a randomized blind study, necessitated less additional oxytocin therapy following a Cesarean section. Oxytocin receptor antagonists, such as barusiban or atosiban have the opposite effect of depressing oxytocin receptor activity and can be used to stop premature labor and uterine contractions. [16]

Adverse effects

Ten to forty percent of people will experience nausea, vomiting, abdominal pain, itching skin, increased body temperature, trembling and weakness. One to five percent of peoples may experience back and chest pain, dizziness, anemia, chills and sweating, metallic taste, tachycardia and respiratory distress. [17] [18] [19]

Contraindications for the use of carbetocin include inappropriate timing during labor and delivery (such as before parturition or to induce labor) or allergic reactions to carbetocin or other oxytocin homologues. [17] Additionally, carbetocin should not be used if a person has high blood pressure or cardiovascular problems. Overdosage or repeated use of carbetocin, particularly if used during pregnancy, could cause hyper-excitation of the oxytocin receptors resulting in excessive and prolonged stimulation of uterine contractions, increasing risk of uterine rupture, placental abruption, fetal respiratory distress and postpartum hemorrhage. [17]

Interactions

Due to oxytocin's close sequence homology with vasopressin, oxytocin analogs often bind with much lower affinity to vasopressin receptors V1, in the uterine lining, and V2, in the kidneys [19] and may consequently interact with or disrupt the vasopressin circuitry and feedback loops. Carbetocin may work synergistically with drugs such as dinoprostone and misoprostol that ripen the cervix. Concurrent use of these drugs can be risky, particularly during pregnancy and prenatal care, possibly causing premature labor or abortion.[ medical citation needed ]

Pharmacology

Mechanism of action

Carbetocin works as an oxytocic, antihemorrhagic and uterotonic drug in the peripheral nervous system. The most common causes of postpartum hemorrhage are lack of tone in the uterus from overstretching or the use of an anesthetic. [20]

Carbetocin functions as an agonist at peripheral oxytocin receptors, particularly in the myometrium, with lesser affinity for myoepithelial cells. Oxytocin receptors are G protein-coupled [21] and their mechanism of action involves second messengers and the production of inositol phosphates. [16] Carbetocin mimics this mechanism. [22] Binding for carbetocin and other oxytocin agonists has been shown to be nonselective at the extracellular N-terminus and loops E2 and E3. [16] While the oxytocin receptor shows equal affinity for oxytocin and carbetocin, the biological effect of carbetocin is almost 50% that of endogenous or exogenous oxytocin. [22] [16] Carbetocin has a much longer lasting effect than oxytocin, necessitating only a single dose. Carbetocin inhibits endogenous oxytocin release, interrupting the uterine feedback loop with the hypothalamus and decreasing both central and peripheral release of oxytocin. [21] Carbetocin is a biased agonist of the oxytocin receptor. [23]

During pregnancy, the synthesis of oxytocin receptors in the uterus greatly increases, reaching a peak during labor and delivery. Consequently, the administration of carbetocin or another oxytocin analog during or immediately following birth will have increased uterotonic and contractile effect. The application of carbetocin does not affect a non-pregnant uterus with lower oxytocin receptor expression. [9] Carbetocin also functions to thicken the blood, further preventing post-partum hemorrhage. [18] Carbetocin should not be used to induce or augment labor since it could cause cardiac or respiratory distress to mother or infant. [8] [9]

Pharmacokinetics

Carbetocin is to be used in the hospital by prescription only. It can be administered intravenously or intramuscularly. In both cases, the recommended dose for an average adult female is 100 ug. Contractile effects of the uterus are apparent within two minutes and can be observed for approximately one hour, [17] though maximum binding occurs about 30 minutes after intramuscular injection. Administration is performed immediately following parturition to minimize risk of postpartum hemorrhage by inducing uterine contractions, increasing muscle tone and thickening the blood. If further uterine stimulation is needed, treatment with other forms of oxytocic uterotonic drugs should be used. [17]

Endogenous and synthetic oxytocin has a half-life of approximately 3.5 minutes. [9] [22] Carbetocin, in comparison, has a much longer half-life ranging from 85 to 100 minutes. [9] [22] The bioavailable dose is around 80%. [10] The elimination half-life following intravenous administration is around 40 minutes, though the elimination mechanism is not entirely known. [17] Studies have shown that elimination is only minimally renal (0.7%), but may occur at least partially through enzymatic degradation of peptides, primarily on the C-terminal end. [22] Both elimination and volume of distribution are not dose dependent. [17]

Society and culture

Carbetocin has been approved for use under the following three brand names in 23 countries: Duratocin (Argentina, Australia, Bahrain, Canada, China, Hong Kong, Italy, Malaysia, Singapore, New Zealand), Lonactene (Mexico), and Pabal (Austria, Belgium, Switzerland, Germany, Estonia, France, UK, Hungary, Lithuania, Luxembourg, Finland). Duratocin has also been approved for veterinary use in Poland, Germany, Italy, Belgium, Luxembourg, France and the Netherlands. [18]

Brand names

Duratocin, Pabal, Lonactene, Depotocin, Comoton, and Decomoton.[ citation needed ]

Related Research Articles

<span class="mw-page-title-main">Misoprostol</span> Medication to induce abortion and treat ulcers

Misoprostol is a synthetic prostaglandin medication used to prevent and treat stomach and duodenal ulcers, induce labor, cause an abortion, and treat postpartum bleeding due to poor contraction of the uterus. It is taken by mouth when used to prevent gastric ulcers in people taking nonsteroidal anti-inflammatory drugs (NSAID). For abortions it is used by itself or in conjunction with mifepristone or methotrexate. By itself, effectiveness for abortion is between 66% and 90%. For labor induction or abortion, it is taken by mouth, dissolved in the mouth, or placed in the vagina. For postpartum bleeding it may also be used rectally.

Uterine contractions are muscle contractions of the uterine smooth muscle that occur during the menstrual cycle and labour. Uterine contractions occur throughout the menstrual cycle in the non-pregnant state and throughout gestation.

<span class="mw-page-title-main">Atosiban</span> Chemical compound

Atosiban, sold under the brand name Tractocile among others, is an inhibitor of the hormones oxytocin and vasopressin. It is used as an intravenous medication as a labour repressant (tocolytic) to halt premature labor. It was developed by Ferring Pharmaceuticals in Sweden and first reported in the literature in 1985. Originally marketed by Ferring Pharmaceuticals, it is licensed in proprietary and generic forms for the delay of imminent preterm birth in pregnant adult women.

<span class="mw-page-title-main">Uterine rupture</span> Medical condition

Uterine rupture is when the muscular wall of the uterus tears during pregnancy or childbirth. Symptoms, while classically including increased pain, vaginal bleeding, or a change in contractions, are not always present. Disability or death of the mother or baby may result.

<span class="mw-page-title-main">Cervical effacement</span>

Cervical effacement or cervical ripening refers to the thinning and shortening of the cervix. This process occurs during labor to prepare the cervix for dilation to allow the fetus to pass through the vagina. While this a normal, physiological process that occurs at the later end of pregnancy, it can also be induced through medications and procedures.

Prostaglandin E<sub>2</sub> Chemical compound

Prostaglandin E2 (PGE2), also known as dinoprostone, is a naturally occurring prostaglandin with oxytocic properties that is used as a medication. Dinoprostone is used in labor induction, bleeding after delivery, termination of pregnancy, and in newborn babies to keep the ductus arteriosus open. In babies it is used in those with congenital heart defects until surgery can be carried out. It is also used to manage gestational trophoblastic disease. It may be used within the vagina or by injection into a vein.

<span class="mw-page-title-main">Uterine atony</span> Loss of tone in the uterine musculature

Uterine atony is the failure of the uterus to contract adequately following delivery. Contraction of the uterine muscles during labor compresses the blood vessels and slows flow, which helps prevent hemorrhage and facilitates coagulation. Therefore, a lack of uterine muscle contraction can lead to an acute hemorrhage, as the vasculature is not being sufficiently compressed. Uterine atony is the most common cause of postpartum hemorrhage, which is an emergency and potential cause of fatality. Across the globe, postpartum hemorrhage is among the top five causes of maternal death. Recognition of the warning signs of uterine atony in the setting of extensive postpartum bleeding should initiate interventions aimed at regaining stable uterine contraction.

<span class="mw-page-title-main">Postpartum bleeding</span> Loss of blood following childbirth

Postpartum bleeding or postpartum hemorrhage (PPH) is often defined as the loss of more than 500 ml or 1,000 ml of blood following childbirth. Some have added the requirement that there also be signs or symptoms of low blood volume for the condition to exist. Signs and symptoms may initially include: an increased heart rate, feeling faint upon standing, and an increased breathing rate. As more blood is lost, the patient may feel cold, blood pressure may drop, and they may become restless or unconscious. The condition can occur up to six weeks following delivery.

<span class="mw-page-title-main">Oxytocin receptor</span> Genes on human chromosome 3

The oxytocin receptor, also known as OXTR, is a protein which functions as receptor for the hormone and neurotransmitter oxytocin. In humans, the oxytocin receptor is encoded by the OXTR gene which has been localized to human chromosome 3p25.

<span class="mw-page-title-main">Vaginal delivery</span> Delivery through the vagina

A vaginal delivery is the birth of offspring in mammals through the vagina. It is the most common method of childbirth worldwide. It is considered the preferred method of delivery, with lower morbidity and mortality than caesarean sections (C-sections).

<span class="mw-page-title-main">Sulprostone</span> Chemical compound

Sulprostone is an analogue of prostaglandin E2 (PGE2) that has oxytocic activity in assays of rat kidney cells and tissues. There are four known receptors which mediate various but often different cellular and tissue responses to PGE2: prostaglandin EP1 receptor, prostaglandin EP2 receptor, prostaglandin EP3 receptor, and prostaglandin EP4 receptor. Sulprosotone binds to and activates the prostaglandin EP3 receptor with far greater efficacy than the other PGE2 receptors and also has the advantage of being relatively resistant, compared with PGE2, to becoming metabolically degraded. It is listed as a comparatively weak receptor agonist of the prostaglandin EP1 receptor. In all events, this as well as other potent synthetic EP3 receptor antagonists have the realized or potential ability to promote the beneficial effects of prostaglandin EP3 receptor activation.

<span class="mw-page-title-main">Demoxytocin</span> Chemical compound

Demoxytocin (INN), also known as desaminooxytocin or deaminooxytocin, as well as 1-(3-mercaptopropanoic acid)oxytocin ([Mpa1]OT), is an oxytocic peptide drug that is used to induce labor, promote lactation, and to prevent and treat puerperal (postpartum) mastitis. Demoxytocin is a synthetic analogue of oxytocin and has similar activities, but is more potent and has a longer half-life in comparison. Unlike oxytocin, which is given via intravenous injection, demoxytocin is administered as a buccal tablet formulation.

A uterotonic, also known as an oxytocic or ecbolic, is a type of medication used to induce contraction or greater tonicity of the uterus. Uterotonics are used both to induce labor and to reduce postpartum hemorrhage.

Uterine Tachysystole is a condition of excessively frequent uterine contractions during pregnancy. It is most often seen in induced or augmented labor, though it can also occur during spontaneous labor, and this may result in fetal hypoxia and acidosis. This may have serious effects on both the mother and the fetus including hemorrhaging and death. There are still major gaps in understanding treatment as well as clinical outcomes of this condition. Uterine tachysystole is defined as more than 5 contractions in 10 minutes, averaged over a 30-minute period.

Retained placenta is a condition in which all or part of the placenta or membranes remain in the uterus during the third stage of labour. Retained placenta can be broadly divided into:

<span class="mw-page-title-main">Placental expulsion</span>

Placental expulsion occurs when the placenta comes out of the birth canal after childbirth. The period from just after the baby is expelled until just after the placenta is expelled is called the third stage of labor.

<span class="mw-page-title-main">Epelsiban</span> Chemical compound

Epelsiban is an orally bioavailable drug which acts as a selective and potent oxytocin receptor antagonist. It was initially developed by GlaxoSmithKline (GSK) for the treatment of premature ejaculation in men and then as an agent to enhance embryo or blastocyst implantation in women undergoing embryo or blastocyst transfer associated with in vitro fertilization (IVF)., and was also investigated for use in the treatment of adenomyosis.

<span class="mw-page-title-main">Retosiban</span> Chemical compound

Retosiban also known as GSK-221,149-A is an oral drug which acts as an oxytocin receptor antagonist. It is being developed by GlaxoSmithKline for the treatment of preterm labour. Retosiban has high affinity for the oxytocin receptor and has greater than 1400-fold selectivity over the related vasopressin receptors

<span class="mw-page-title-main">Oxytocin (medication)</span> Medication made from the peptide oxytocin

Synthetic oxytocin, sold under the brand name Pitocin among others, is a medication made from the peptide oxytocin. As a medication, it is used to cause contraction of the uterus to start labor, increase the speed of labor, and to stop bleeding following delivery. For this purpose, it is given by injection either into a muscle or into a vein.

The postpartum physiological changes are those expected changes that occur in the woman's body after childbirth, in the postpartum period. These changes mark the beginning of the return of pre-pregnancy physiology and of breastfeeding. Most of the time these postnatal changes are normal and can be managed with medication and comfort measures, but in a few situations complications may develop. Postpartum physiological changes may be different for women delivering by cesarean section. Other postpartum changes, may indicate developing complications such as, postpartum bleeding, engorged breasts, postpartum infections.

References

  1. ↑ MacDonald K, Feifel D (2015). "Helping Oxytocin Deliver: Considerations in the Development of Oxytocin-Based Therapeutics for Brain Disorders". In Shalev I, Ebstein RP (eds.). Social Hormones and Human Behavior: What Do We Know and Where Do We Go from Here. Frontiers Media SA. pp. 51–. ISBN   978-2-88919-407-0.
  2. 1 2 3 British National Formulary: BNF 76 (76th ed.). Pharmaceutical Press. 2018. p. 804. ISBN   978-0-85711-338-2.
  3. 1 2 3 4 5 6 7 "Proposal for Inclusion of Carbetocin in the Who List of Essential Medicines" (PDF). WHO. Retrieved 25 October 2019.
  4. ↑ Morton IK, Hall JM (2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 65–. ISBN   978-94-011-4439-1.
  5. ↑ Elks J (2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 214–. ISBN   978-1-4757-2085-3.
  6. ↑ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  7. ↑ "Carbetocin Drug Information, Professional". Drugs.com. Archived from the original on 28 November 2020. Retrieved 12 November 2019.
  8. 1 2 3 Attilakos G, Psaroudakis D, Ash J, Buchanan R, Winter C, Donald F, et al. (July 2010). "Carbetocin versus oxytocin for the prevention of postpartum haemorrhage following caesarean section: the results of a double-blind randomised trial". BJOG. 117 (8): 929–936. doi:10.1111/j.1471-0528.2010.02585.x. PMID   20482535. S2CID   205616218.
  9. 1 2 3 4 5 Moertl MG, Friedrich S, Kraschl J, Wadsack C, Lang U, Schlembach D (October 2011). "Haemodynamic effects of carbetocin and oxytocin given as intravenous bolus on women undergoing caesarean delivery: a randomised trial". BJOG. 118 (11): 1349–1356. doi: 10.1111/j.1471-0528.2011.03022.x . PMID   21668768. S2CID   41172212.
  10. 1 2 Silcox J, Schulz P, Horbay GL, Wassenaar W (September 1993). "Transfer of carbetocin into human breast milk". Obstetrics and Gynecology. 82 (3): 456–459. PMID   8355953.
  11. ↑ Bajcsy AC, Szenci O, van der Weijden GC, Doornenbal A, Maassen F, Bartyik J, Taverne MA (January 2006). "The effect of a single oxytocin or carbetocin treatment on uterine contractility in early postpartum dairy cows". Theriogenology. 65 (2): 400–414. doi:10.1016/j.theriogenology.2005.05.040. PMID   15993938.
  12. ↑ Schramme AR, Pinto CR, Davis J, Whisnant CS, Whitacre MD (November 2008). "Pharmacokinetics of carbetocin, a long-acting oxytocin analogue, following intravenous administration in horses". Equine Veterinary Journal. 40 (7): 658–661. doi:10.2746/042516408X334343. PMID   19165935.
  13. 1 2 Widmer M, Piaggio G, Nguyen TM, Osoti A, Owa OO, Misra S, et al. (August 2018). "Heat-Stable Carbetocin versus Oxytocin to Prevent Hemorrhage after Vaginal Birth". The New England Journal of Medicine. 379 (8): 743–752. doi: 10.1056/NEJMoa1805489 . PMID   29949473. S2CID   205103322.
  14. ↑ Malm M, Madsen I, Kjellström J (June 2018). "Development and stability of a heat-stable formulation of carbetocin for the prevention of postpartum haemorrhage for use in low and middle-income countries". Journal of Peptide Science. 24 (6): e3082. doi:10.1002/psc.3082. PMC   6001700 . PMID   29700898.
  15. ↑ Mundasad S (28 June 2018). "Revamped drug could save lives of many new mothers: WHO". BBC News. Retrieved 28 June 2018.
  16. 1 2 3 4 5 Gimpl G, Postina R, Fahrenholz F, Reinheimer T (March 2005). "Binding domains of the oxytocin receptor for the selective oxytocin receptor antagonist barusiban in comparison to the agonists oxytocin and carbetocin". European Journal of Pharmacology. 510 (1–2): 9–16. doi:10.1016/j.ejphar.2005.01.010. PMID   15740719.
  17. 1 2 3 4 5 6 7 "Product Information - Duratocin". healthlinks.net. Archived from the original on 15 November 2011. Retrieved 5 June 2012.
  18. 1 2 3 "Carbetocin". drugs.com. Archived from the original on 3 March 2016. Retrieved 5 June 2012.
  19. 1 2 "Duratocin - Detailed Prescribing Information (Membership Required)". MIMS Malaysia. Archived from the original on 17 January 2014. Retrieved 5 June 2012.
  20. ↑ "Therapeutic Areas - Reproductive Health". Ferring Pharmaceuticals. Archived from the original on 25 May 2012. Retrieved 5 June 2012.
  21. 1 2 Gimpl G, Fahrenholz F (April 2001). "The oxytocin receptor system: structure, function, and regulation". Physiological Reviews. 81 (2): 629–683. doi:10.1152/physrev.2001.81.2.629. PMID   11274341. S2CID   13265083.
  22. 1 2 3 4 5 Engstrøm T, Barth T, Melin P, Vilhardt H (August 1998). "Oxytocin receptor binding and uterotonic activity of carbetocin and its metabolites following enzymatic degradation". European Journal of Pharmacology. 355 (2–3): 203–210. doi:10.1016/S0014-2999(98)00513-5. PMID   9760035.
  23. ↑ Gulliver D, Werry E, Reekie TA, Katte TA, Jorgensen W, Kassiou M (January 2019). "Targeting the Oxytocin System: New Pharmacotherapeutic Approaches". Trends in Pharmacological Sciences. 40 (1): 22–37. doi:10.1016/j.tips.2018.11.001. PMID   30509888. S2CID   54559394.
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