Chemistry:Oxytocin (medication)

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Short description: Medication made from the peptide oxytocin
Oxytocin (medication)
Oxytocin with labels.png
OxitocinaCPK3D.png
Clinical data
Pronunciation/ˌɒksɪˈtoʊsɪn/
Trade namesPitocin, Syntocinon, Viatocinon, others
AHFS/Drugs.comMonograph
MedlinePlusa682685
License data
Pregnancy
category
  • AU: A
Routes of
administration		Intranasal, intravenous, intramuscular
ATC code
Legal status
Legal status
Pharmacokinetic data
MetabolismLiver and elsewhere (via oxytocinases)
Elimination half-life1–6 min (IV)
~2 h (intranasal)[4][5]
ExcretionBile duct and kidney
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC43H66N12O12S2
Molar mass1007.19 g·mol−1
3D model (JSmol)
  (verify)

Synthetic oxytocin, sold under the brand name Pitocin among others, is a medication made from the peptide oxytocin.[6][7] 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.[6] For this purpose, it is given by injection either into a muscle or into a vein.[6]

Oxytocin is also available in intranasal spray form for psychiatric, endocrine and weight management use as a supplement. Intranasal oxytocin works on a different pathway than injected oxytocin, primarily along the olfactory nerve crossing the brain blood barrier to the olfactory lobe in the brain, where dense magnocellular oxytocin neurons receive the dose application.

The use of synthetic oxytocin as an injectable medication for inducing childbirth can result in excessive contraction of the uterus that can risk the health of the baby.[6] Common side effects in the mother include nausea and a slow heart rate.[6] Serious side effects include rupture of the uterus and with excessive dose, water intoxication.[6] Allergic reactions including anaphylaxis may also occur.[6]

The natural occurrence of oxytocin was discovered in 1906.[8][9] It is on the World Health Organization's List of Essential Medicines.[10]

Medical uses

An intravenous infusion of oxytocin is used to induce labor and to support labor in case of slow childbirth if the oxytocin challenge test fails. Whether a high dose is better than a standard dose for labor induction is unclear. It has largely replaced ergometrine as the principal agent to increase uterine tone in acute postpartum hemorrhage. Oxytocin is also used in veterinary medicine to facilitate birth and to stimulate milk release.

The tocolytic agent atosiban (Tractocile) acts as an antagonist of oxytocin receptors. It is registered in many countries for use in suppressing premature labor between 24 and 33 weeks of gestation. It has fewer side effects than drugs previously used for this purpose (such as ritodrine, salbutamol and terbutaline).[11]

Oxytocin has not been found to be useful for improving breastfeeding success.[12]

Contraindications

Oxytocin injection (synthetic) is contraindicated in any of these conditions:[13]

  • Substantial cephalopelvic disproportion
  • Unfavorable fetal position or presentation (e.g., transverse lies) undeliverable without conversion before delivery
  • Obstetric emergencies where maternal or fetal risk-to-benefit ratio favors surgery
  • Fetal distress when delivery is not imminent
  • Umbilical cord prolapse
  • Uterine activity fails to progress adequately
  • Hyperactive or hypertonic uterus
  • Vaginal delivery is contraindicated (e.g., invasive cervical carcinoma, active genital herpes infection, total placenta previa, vasa previa, cord presentation or prolapse)
  • Uterine or cervical scarring from previous cesarean section or major cervical or uterine (e.g., transfundal) surgery
  • Unengaged fetal head
  • History of hypersensitivity to oxytocin or any ingredient in the formulation

Side effects

Oxytocin is relatively safe when used at recommended doses, and side effects are uncommon.[14] These maternal events have been reported:[14]

Excessive dosage or long-term administration (over a period of 24 hours or longer) has been known to result in tetanic uterine contractions, uterine rupture, postpartum hemorrhage, and water intoxication, sometimes fatal.

Oxytocin was added to the Institute for Safe Medication Practices's list of High Alert Medications in Acute Care Settings in 2012.[15] The list includes medications that have a high risk for harm if administered incorrectly.[15]

During pregnancy, increased uterine motility has led to decreased heart rate, cardiac arrhythmia, seizures, brain damage, and death in the fetus or neonate.[14]

Use is linked to an increased risk of postpartum depression in the mother.[16]

Certain learning and memory functions are impaired by centrally administered oxytocin.[17] Also, systemic oxytocin administration can impair memory retrieval in certain aversive memory tasks.[18] However, oxytocin does seem to facilitate learning and memory specifically for social information. Healthy males administered intranasal oxytocin show improved memory for human faces, in particular happy faces.[19][20]

Pharmacokinetics

Routes of administration

A bag of oxytocin for intravenous infusion

One IU of oxytocin is the equivalent of about 2 μg or mcg of pure peptide.

  • Injection: Clinical doses of oxytocin are given by injection either into a muscle or into a vein to cause contraction of the uterus.[6] Very small amounts (< 1%) do appear to enter the central nervous system in humans when peripherally administered.[21][better source needed] The compound has a half-life of typically about 3 minutes in the blood when given intravenously. Intravenous administration requires 40 minutes to reach a steady-state concentration and achieve maximum uterine contraction response.[22]
  • Buccal: Oxytocin was delivered in buccal tablets, but this is not common practice any more.[23]
  • Under the tongue: Oxytocin is poorly absorbed sublingually.[24]
  • Nasal administration: Oxytocin is effectively distributed to the brain when administered intranasally via a nasal spray, after which it reliably crosses the blood–brain barrier and exhibits psychoactive effects in humans.[25][26] No serious adverse effects with short-term application of oxytocin with 18~40 IU (36–80 mcg) have been recorded.[27] Intranasal oxytocin has a central duration of at least 2.25 hours and as long as 4 hours.[4][5]
  • Oral: While it was originally assumed that Oxytocin administered orally would be destroyed in the gastrointestinal tract, studies have shown that Oxytocin is transported by the immunoglobulin RAGE (receptor for advanced glycation end products) across the intestinal epithelium and into the blood. Orally-administered Oxytocin has been shown to increase putamen responses to facial emotions in humans.[28] Oxytocin administered orally produces different effects on human behaviour and brain function than when given intranasally, possibly due to variations in the molecular transport and binding mechanisms.

Chemistry

Peptide analogues of oxytocin with similar actions, for example carbetocin (Duratocin) and demoxytocin (Sandopart), have been developed and marketed for medical use.[29] In addition, small-molecule oxytocin receptor agonists, like TC OT 39, WAY-267464, and LIT-001 have been developed and studied.[29] However, lack of selectivity over vasopressin receptors has so far limited the potential usefulness of small-molecule oxytocin receptor agonists.[29]

History

Oxytocin's uterine-contracting properties were discovered by British pharmacologist Henry Hallett Dale in 1906.[9] Oxytocin's milk ejection property was described by Ott and Scott in 1910[30] and by Schafer and Mackenzie in 1911.[31]

Oxytocin was the first polypeptide hormone to be sequenced[32] or synthesized.[33][34] Du Vigneaud was awarded the Nobel Prize in 1955 for his work.[35]

Etymology

The word oxytocin was coined from the term oxytocic. Greek ὀξύς, oxys, and τόκος, tokos, meaning "quick birth".

Society and culture

Counterfeits

In African countries, some oxytocin products were found to be counterfeit medications.[36][37]

Other uses

The trust-inducing property of oxytocin might help those with social anxiety and depression,[38] anxiety, fear, and social dysfunctions, such as generalized anxiety disorder, post-traumatic stress disorder, and social anxiety disorder, as well as autism and schizophrenia, among others.[39][40] However, in one meta-analysis only autism spectrum disorder showed a significant combined effect size.[41]

People using oxytocin show improved recognition for positive social cues over threatening social cues[42][43] and improved recognition of fear.[44]

  • Autism: Oxytocin may play a role in autism and may be an effective treatment for autism's repetitive and affiliative behaviors.[45]
  • Relationship counseling: The use of oxytocin in relationship counseling for well-being has been suggested.[46]

See also

References

  1. ↑ "Syntocinon 10 IU/ml Concentrate for Solution for Infusion". 25 October 2023. https://www.medicines.org.uk/emc/product/9735/smpc. 
  2. ↑ "Pitocin- oxytocin injection". 10 January 2008. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8fbd0773-6645-4235-9ef2-56edf9c7fb83. 
  3. ↑ "Oxytocin injection, solution". 16 October 2023. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c7fd585a-99b7-4309-b003-a6cbef05372c. 
  4. ↑ 4.0 4.1 "Intranasal oxytocin administration is reflected in human saliva". Psychoneuroendocrinology 37 (9): 1582–86. September 2012. doi:10.1016/j.psyneuen.2012.02.014. PMID 22436536. 
  5. ↑ 5.0 5.1 "Salivary levels of oxytocin remain elevated for more than two hours after intranasal oxytocin administration". Neuro Endocrinology Letters 33 (1): 21–25. 2012. PMID 22467107. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 6.7 6.8 "Oxytocin". The American Society of Health-System Pharmacists. https://www.drugs.com/monograph/oxytocin.html. 
  7. ↑ The Oxford Handbook of Prosocial Behavior. Oxford University Press. 2015. p. 354. ISBN 978-0-19-539981-3. https://books.google.com/books?id=EfzOBwAAQBAJ&pg=PA354. 
  8. ↑ (in en) Behavioral Pharmacology of Neuropeptides: Oxytocin. Springer. 2018. p. 37. ISBN 978-3319637396. https://books.google.com/books?id=lIRjDwAAQBAJ&pg=PA37. 
  9. ↑ 9.0 9.1 "On some physiological actions of ergot". The Journal of Physiology 34 (3): 163–206. May 1906. doi:10.1113/jphysiol.1906.sp001148. PMID 16992821. 
  10. ↑ The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization. 2023. WHO/MHP/HPS/EML/2023.02. 
  11. ↑ "High-dose versus low-dose oxytocin infusion regimens for induction of labour at term". The Cochrane Database of Systematic Reviews 10 (10): CD009701. 9 October 2014. doi:10.1002/14651858.CD009701.pub2. PMID 25300173. 
  12. ↑ "Oxytocin use while Breastfeeding". Drugs.com. https://www.drugs.com/breastfeeding/oxytocin.html. 
  13. ↑ "Oxytocin - FDA prescribing information, side effects and uses". https://www.drugs.com/pro/oxytocin.html. 
  14. ↑ 14.0 14.1 14.2 "Pitocin (drug label for professionals)". Rx List. WebMD. http://www.rxlist.com/pitocin-drug.htm. 
  15. ↑ 15.0 15.1 "High-Alert Medications in Acute Care Settings" (in en). 16 November 2017. https://www.ismp.org/recommendations/high-alert-medications-acute-list. 
  16. ↑ "Association of peripartum synthetic oxytocin administration and depressive and anxiety disorders within the first postpartum year". Depression and Anxiety 34 (2): 137–146. February 2017. doi:10.1002/da.22599. PMID 28133901. 
  17. ↑ "The oxytocin receptor system: structure, function, and regulation". Physiological Reviews 81 (2): 629–83. April 2001. doi:10.1152/physrev.2001.81.2.629. PMID 11274341. 
  18. ↑ "Glucocorticoid-mediated effects of systemic oxytocin upon memory retrieval". Neurobiology of Learning and Memory 87 (1): 67–71. January 2007. doi:10.1016/j.nlm.2006.05.006. PMID 16997585. 
  19. ↑ "Oxytocin enhances the encoding of positive social memories in humans". Biological Psychiatry 64 (3): 256–58. August 2008. doi:10.1016/j.biopsych.2008.02.008. PMID 18343353. 
  20. ↑ Rimmele, Ulrike; Hediger, Karin; Heinrichs, Markus; Klaver, Peter (2009). "Oxytocin Makes a Face in Memory Familiar". The Journal of Neuroscience 29 (1): 38–42. doi:10.1523/JNEUROSCI.4260-08.2009. PMID 19129382. 
  21. ↑ "Oxytocin and vasopressin: linking pituitary neuropeptides and their receptors to social neurocircuits". Frontiers in Neuroscience 9: 335. 2015. doi:10.3389/fnins.2015.00335. PMID 26441508. 
  22. ↑ "Oxytocin augmentation of dysfunctional labor. I. Clinical data". American Journal of Obstetrics and Gynecology 144 (8): 899–905. December 1982. doi:10.1097/00006254-198307000-00010. PMID 7148921. 
  23. ↑ "Buccal and oral drugs: induction of labour". Acta Chirurgica Hungarica 27 (3): 157–63. 1986. PMID 3469841. 
  24. ↑ "Bioavailability and pharmacokinetics of sublingual oxytocin in male volunteers". The Journal of Pharmacy and Pharmacology 47 (7): 571–75. 1995. doi:10.1111/j.2042-7158.1995.tb06716.x. PMID 8568623. https://repository.ubn.ru.nl/bitstream/2066/21581/1/21581___.PDF. 
  25. ↑ "Chapter 7: Neuropeptides". Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. 2009. ISBN 978-0-07-148127-4. "Oxytocin can be delivered to humans via nasal spray following which it crosses the blood–brain barrier. ... In a double-blind experiment, oxytocin spray increased trusting behavior compared to a placebo spray in a monetary game with real money at stake." 
  26. ↑ "From ultrasocial to antisocial: a role for oxytocin in the acute reinforcing effects and long-term adverse consequences of drug use?". British Journal of Pharmacology 154 (2): 358–68. May 2008. doi:10.1038/bjp.2008.132. PMID 18475254. "Recent studies also highlight remarkable anxiolytic and prosocial effects of intranasally administered OT in humans, including increased 'trust', decreased amygdala activation towards fear-inducing stimuli, improved recognition of social cues and increased gaze directed towards the eye regions of others (Kirsch et al., 2005; Kosfeld et al., 2005; Domes et al., 2006; Guastella et al., 2008).". 
  27. ↑ "Is Oxytocin Application for Autism Spectrum Disorder Evidence-Based?". Experimental Neurobiology 24 (4): 312–24. 2015. doi:10.5607/en.2015.24.4.312. PMID 26713079. 
  28. ↑ "In the nose or on the tongue? Contrasting motivational effects of oral and intranasal oxytocin on arousal and reward during social processing". Translational Psychiatry 11 (1): 94. February 2021. doi:10.1038/s41398-021-01241-w. PMID 33542175. 
  29. ↑ 29.0 29.1 29.2 "The Current Status of Drug Discovery for the Oxytocin Receptor". Oxytocin. Methods Mol Biol. 2384. 2022. pp. 153–174. doi:10.1007/978-1-0716-1759-5_10. ISBN 978-1-0716-1758-8. 
  30. ↑ "The Action of Infundibulum upon Mammary Secretion". Proceedings of the Society for Experimental Biology and Medicine 8: 48–49. 1910. doi:10.3181/00379727-8-27. https://zenodo.org/record/1450228. 
  31. ↑ "The Action of Animal Extracts on Milk Secretion". Proceedings of the Royal Society B 84 (568): 16–22. July 1911. doi:10.1098/rspb.1911.0042. Bibcode: 1911RSPSB..84...16S. 
  32. ↑ "The sequence of amino acids in oxytocin, with a proposal for the structure of oxytocin". The Journal of Biological Chemistry 205 (2): 949–57. December 1953. doi:10.1016/S0021-9258(18)49238-1. PMID 13129273. 
  33. ↑ "The synthesis of an octapeptide amide with the hormonal activity of oxytocin". J. Am. Chem. Soc. 75 (19): 4879–80. 1953. doi:10.1021/ja01115a553. 
  34. ↑ "The synthesis of oxytocin". J. Am. Chem. Soc. 76 (12): 3115–21. June 1954. doi:10.1021/ja01641a004. 
  35. ↑ "Trail of sulfur research: from insulin to oxytocin". Science 123 (3205): 967–74. June 1956. doi:10.1126/science.123.3205.967. PMID 13324123. Bibcode: 1956Sci...123..967D. 
  36. ↑ "Quality of oxytocin available in low- and middle-income countries: a systematic review of the literature". BJOG: An International Journal of Obstetrics and Gynaecology 123 (13): 2076–86. December 2016. doi:10.1111/1471-0528.13998. PMID 27006180. 
  37. ↑ "Uterotonic drug quality: an assessment of the potency of injectable uterotonic drugs purchased by simulated clients in three districts in Ghana". BMJ Open 2 (3): e000431. 2012. doi:10.1136/bmjopen-2011-000431. PMID 22556159. 
  38. ↑ "Oxytocin enhances amygdala-dependent, socially reinforced learning and emotional empathy in humans". The Journal of Neuroscience 30 (14): 4999–5007. April 2010. doi:10.1523/JNEUROSCI.5538-09.2010. PMID 20371820. 
  39. ↑ "The role of oxytocin in psychiatric disorders: a review of biological and therapeutic research findings". Harvard Review of Psychiatry 21 (5): 219–47. 2013. doi:10.1097/HRP.0b013e3182a75b7d. PMID 24651556. 
  40. ↑ "Oxytocin in General Anxiety and Social Fear: A Translational Approach". Biological Psychiatry 79 (3): 213–21. 2016. doi:10.1016/j.biopsych.2015.06.004. PMID 26208744. 
  41. ↑ "Sniffing around oxytocin: review and meta-analyses of trials in healthy and clinical groups with implications for pharmacotherapy". Translational Psychiatry 3 (5): e258. 2013. doi:10.1038/tp.2013.34. PMID 23695233. 
  42. ↑ "Oxytocin selectively facilitates recognition of positive sex and relationship words". Psychological Science 19 (11): 1092–94. November 2008. doi:10.1111/j.1467-9280.2008.02206.x. PMID 19076479. 
  43. ↑ "Oxytocin improves specific recognition of positive facial expressions". Psychopharmacology 209 (3): 225–32. April 2010. doi:10.1007/s00213-010-1780-4. PMID 20186397. 
  44. ↑ "The effect of intranasal administration of oxytocin on fear recognition". Neuropsychologia 48 (1): 179–84. 2010. doi:10.1016/j.neuropsychologia.2009.09.003. PMID 19747930. 
  45. ↑ "Oxytocin and experimental therapeutics in autism spectrum disorders". Advances in Vasopressin and Oxytocin – from Genes to Behaviour to Disease. Progress in Brain Research. 170. 2008. pp. 451–62. doi:10.1016/S0079-6123(08)00435-4. ISBN 978-0-444-53201-5. 
  46. ↑ "Could intranasal oxytocin be used to enhance relationships? Research imperatives, clinical policy, and ethical considerations". Current Opinion in Psychiatry 26 (5): 474–84. 2013. doi:10.1097/YCO.0b013e3283642e10. PMID 23880593. 



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