Carbetocin

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Carbetocin
Carbetocin.svg
Systematic (IUPAC) name
(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
Clinical data
Trade names Duratocin, Pabal, Lonactene
AHFS/Drugs.com Micromedex Detailed Consumer Information
Legal status
  • UK: POM (Prescription only)
  • Not available (U.S.)
Routes of
administration		 Intravenous, intramuscular
Pharmacokinetic data
Bioavailability 80% (IM)
Biological half-life 85–100 minutes (peripheral)[1]
Identifiers
CAS Number 37025-55-1 YesY
ATC code H01BB03 (WHO)
PubChem CID: 16681432
DrugBank DB01282 YesY
ChemSpider 16736854 N
UNII 88TWF8015Y YesY
KEGG D07229 N
Synonyms (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
Chemical data
Formula C45H69N11O12S
Molecular mass 988.162 g/mol
  • 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 N
  • Key:NSTRIRCPWQHTIA-DTRKZRJBSA-N N
 NYesY (what is this?)  (verify)

Carbetocin (INN, BAN) (brand names Duratocin, Pabal, Lonactene, Depotocin, Comoton, Decomoton), or 1-butanoic acid-2-(O-methy-L-tyrosine)-1-carbaoxytocin, is an oxytocic used in obstetrics to control postpartum hemorrhage and bleeding after giving birth, particularly following Cesarean section.[2][3][4] It is an eight amino acid long analogue of oxytocin (a nonapeptide) and, in accordance, has a similar action.[5][6] Carbetocin primarily agonizes peripherally expressed oxytocin receptors. It is manufactured by Ferring Pharmaceuticals and is available in Canada and the United Kingdom and many other countries throughout the world, but notably not in the United States.

Medical uses

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.[7] Carbetocin has been approved for use immediately following an elective Cesarean section when a local or spinal anesthesia has been administered.[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]

Carbetocin has also been shown to stimulate milk letdown through its action on the oxytocin receptors on the myoepithelial cells and there was not a significant amount of carbetocin in breastmilk.[10]

Each dose of Duratocin contains 100 micrograms of carbetocin, 9 mg sodium chloride and ascetic acid. pH is 3.8 and peptide content is greater than 85 percent.

Pharmacokinetics

Carbetocin is to be used in the hospital by prescription only. It can be administered intravenously or intramuscularly, resulting in different pharmacokinetic action. In both cases, the recommended dose for an average adult female is 100 ug, administered slowly over a minute. Contractile effects of the uterus are apparent within two minutes and can be observed for approximately one hour,[13] 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. Administration can be performed only once; further administration would prove risky. If further uterine stimulation is needed, treatment with other forms of oxytocic uterotonic drugs should be used.[13]

Endogenous and synthetic oxytocin has a half-life of approximately 3.5 minutes.[9][14] Carbetocin, in comparison, has a much longer half-life ranging from 85–100 minutes.[9][14] 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.[13] 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.[14] Both elimination and volume of distribution are not dose dependent.[13]

Mechanism of action

Carbetocin functions as an agonist at peripheral oxytocin receptors, particularly in the myometrium, with lesser affinity for myopepithelial cells. Oxytocin receptors are G protein-coupled[15] and their mechanism of action involves second messengers and the production of inositol phosphates.[16] Carbetocin mimics this mechanism.[14] 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.[14][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.[15]

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.[17] Carbetocin should not be used to induce or augment labor since it could cause cardiac or respiratory distress to mother or infant.[8][9]

Interactions with other drugs and neurotransmitter systems

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[18] 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.

Adverse effects

Ten to forty percent of patients will experience nausea, vomiting, abdominal pain, itching skin, increased body temperature, trembling and weakness. One to five percent of patients may experience back and chest pain, dizziness, anemia, chills and sweating, metallic taste, tachycardia and respiratory distress.[13][17][18]

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.[13] Additionally, carbetocin should not be used if a patient 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.[13]

Comparison with other drugs

Due to carbetocin's considerably longer half-life, its effects are longer lasting than other oxytocin homologs such as Pitocin or barusiban.[16] A single carbetocin administration compared to a placebo or an eight-hour intravenous drip of oxytocin in a randomized blind study, necessitated significantly 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]

Legal approval

Carbetocin has been approved for use under the following three brand names in 23 countries, not including the United States: 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). Duratocin has also been approved for veterinary use in Poland, Germany, Italy, Belgium, Luxembourg, France and the Netherlands.[17]

See also

References

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  8. ↑ 8.0 8.1 8.2 Lua error in package.lua at line 80: module 'strict' not found.
  9. ↑ 9.0 9.1 9.2 9.3 9.4 Lua error in package.lua at line 80: module 'strict' not found.
  10. ↑ 10.0 10.1 10.2 Lua error in package.lua at line 80: module 'strict' not found.
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  13. ↑ 13.0 13.1 13.2 13.3 13.4 13.5 13.6 Lua error in package.lua at line 80: module 'strict' not found.
  14. ↑ 14.0 14.1 14.2 14.3 14.4 Lua error in package.lua at line 80: module 'strict' not found.
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  16. ↑ 16.0 16.1 16.2 16.3 16.4 Lua error in package.lua at line 80: module 'strict' not found.
  17. ↑ 17.0 17.1 17.2 Lua error in package.lua at line 80: module 'strict' not found.
  18. ↑ 18.0 18.1 Lua error in package.lua at line 80: module 'strict' not found.

External links

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