Misoprostol: Wikis

  
  

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Misoprostol
Systematic (IUPAC) name
Methyl 7-((1R,2R,3R)-3-hydroxy-2-((S,E)-4-hydroxy-4-methyloct-1-enyl)-5-oxocyclopentyl)heptanoate
Identifiers
CAS number 59122-46-2
ATC code A02BB01
PubChem 5282381
DrugBank APRD00037
ChemSpider 4445541
Chemical data
Formula C 22H38O5  
Mol. mass 382.5 g/mol
Pharmacokinetic data
Bioavailability extensively absorbed
Metabolism de-esterified to misoprostol acid, then to prostaglandin F analogs
Half life 20–40 minutes
Excretion Renal:80%
Fecal:15%
Therapeutic considerations
Pregnancy cat. X
Legal status Prescription only
Routes Oral, Vaginal, Sublingual
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Misoprostol is a drug that is used for the prevention of non-steroidal anti-inflammatory drug (NSAID)-induced gastric ulcers, for early abortion, to treat missed miscarriage, and to induce labor. The last use is controversial in the United States. Misoprostol was invented and marketed by G.D. Searle & Company (now Pfizer) under the trade name Cytotec (often misspelled Cyotec), but other brand-name and generic formulations are now available as well.

Chemically, misoprostol is a synthetic prostaglandin E1 (PGE1) analogue.

Contents

Ulcer prevention

Misoprostol is approved for use in the prevention of NSAID-induced gastric ulcers. It acts upon gastric parietal cells, inhibiting the secretion of gastric acid via G-protein coupled receptor-mediated inhibition of adenylate cyclase, which leads to decreased intracellular cyclic AMP levels and decreased proton pump activity at the apical surface of the parietal cell. Because other classes of drugs, especially H2-receptor antagonists and proton pump inhibitors, are more effective for the treatment of acute peptic ulcers, Misoprostol is only indicated for use by people who are both taking NSAIDs and are at high risk for NSAID-induced ulcers, including the elderly and people with ulcer complications. Misoprostol is sometimes co-prescribed with NSAIDs to prevent their common adverse effect of gastric ulceration (e.g. with Diclofenac in Arthrotec).

Misoprostol has other protective actions, but is only clinically effective at doses high enough to reduce gastric acid secretion. For instance, at lower doses misoprostol may stimulate increased secretion of the protective mucus that lines the gastrointestinal tract and increase mucosal blood flow, thereby increasing mucosal integrity—however, these effects are not pronounced enough to warrant prescription of misoprostol at doses lower than those needed to achieve gastric acid suppression.

Labor induction

Misoprostol is commonly used for labor induction. It causes uterine contractions and the ripening (effacement or thinning) of the cervix.[1] Misoprostol is more effective in starting labor than other drugs used for labor induction.[2]:87 It is also significantly less expensive than the other commonly used ripening agent, dinoprostone (trade names Cervidil and Prepidil).[3]

Oxytocin (trade names Pitocin and Syntocinon) has long been used as the standard agent for labor induction, but doesn't work well when the cervix is not yet ripe. In addition to being used alone to induce labor, misoprostol may be used in conjunction with oxytocin.[3]

Protocols for inducing labor with misoprostol typically call for 25 μg to be administered vaginally.[4] In countries where the only approved use of misoprostol is ulcer prevention, misoprostol is not sold in tablets smaller than 100 μg. When used for induction, the 100 μg tablet is commonly split into two or four pieces.[5]

Controversy

In August 2000, Searle—the manufacturer of misoprostol—distributed a letter warning against the use of misoprostol in pregnant women. In addition to citing the abortifacient nature of the drug, the letter cited reports of uterine rupture and death associated with using misoprostol to induce labor. This letter generated much controversy over the use of misoprostol in labor inductions.[4] Other rare complications include amniotic fluid embolism.[2]:73 Because these complications are rare, it is difficult to determine if misoprostol causes a higher risk than do other cervical ripening agents. One estimate is that it would require approximately 61,000 patients enrolled in randomized controlled trials to detect a clinically significant difference in serious fetal complications and approximately 155,000 patients to detect a clinically significant difference in serious maternal complications.[6]

All cervical-ripening and induction agents can cause uterine hyperstimulation, which can negatively affect the blood supply to the fetus and increases the risk of complicaions such as uterine rupture.[5] Concern has been raised that uterine hyperstimulation that occurs during a misoprostol-induced labor is more difficult to treat than hyperstimulation during labors induced by other drugs.[7]

The American College of Obstetricians and Gynecologists holds that substantial evidence supports the use of misoprostol for induction of labor, a position it reaffirmed in 2000 in response to the Searle letter.[8] Misoprostol is also on the WHO essential drug list for labor induction.[9]

Induced abortion

Earlier pregnancy

Misoprostol is one of the drugs used for medical abortions in lieu of surgical evacuation. The advantages of medical abortion over surgical abortion include reduced invasiveness of the procedure, lack of risks from general anesthesia (which is often used for surgical abortions), and lack of risk of secondary infertility due to scarring and intrauterine adhesions (Asherman's Syndrome). Furthermore, it is less complicated to administer and less expensive.

In many countries it is used in conjunction with mifepristone (RU-486). After mifepristone is taken orally, misoprostol is taken 24–72 hours later, causing the expulsion of the embryo and associated matter in approximately 92% of the cases. No large studies have established a protocol for the use of misoprostol alone,[10] and the range of efficacy is 65%–93% depending on sample size, gestational age, and other test variables;[11] Misoprostol alone may be more effective in earlier gestation.[12] The side effects associated with the misoprostol-only regimen are generally much more severe than those associated with the combined regimens. Misoprostol is used for self-induced abortions in Brazil, where black market prices exceed US $100 per dose. Illegal medically-unsupervised misoprostol abortions in Brazil are associated with a lower complication rate than other forms of illegal self-induced abortion, but are still associated with a higher complication rate than legal, medically supervised surgical and chemical abortions. Failed misoprostol abortions are associated with birth defects in some cases.[13][14][15][16][17] Poor immigrant populations in New York have also been observed to use self-administered misoprostol to induce abortions, as this method is much cheaper than a surgical abortion (about $2 per dose).[18]

Later pregnancy

Misoprostol can also be used to dilate the cervix in preparation for a surgical abortion, particularly in the second trimester (either alone or in combination with laminaria stents).

Missed miscarriage

Misoprostol is sometimes used to treat early fetal death in the absence of spontaneous miscarriage, but further research is needed to establish a safe, effective protocol.[19]

Post-partum hemorrhage

Misoprostol is also used to prevent and treat post-partum hemorrhage, but it has more side effects and is less effective than oxytocin for this purpose.[20] However, it is inexpensive and thermostable (thus does not require refrigeration like oxytocin) making it a cost-effective and valuable drug to use in the developing world.[21]

Other gynecological uses

Although the practice remains uncommon, some gynecologists are now using low doses of misoprostol to soften the cervix prior to the insertion of intrauterine devices (especially in nulliparous women where insertion may be challenging).

Erectile dysfunction

A 1998 study found misoprostol to be helpful as a supplement to a vacuum pump (VED) in the treatment of erectile dysfunction, but not effective by itself.[22] The paper concluded "The intraurethral application of misoprostol significantly improves the quality of VED-induced erections. This agent seems to be a cheap intraurethral adjunct to VED with mild to moderate local side-effects".

Side effects and contraindications

The most commonly reported adverse effect of taking a misoprostol 200 µg tablet by mouth four times a day to reduce the risk of NSAID-induced gastric ulcers is diarrhea. In clinical trials, an average 13% of patients reported diarrhea, which was dose-related and usually developed early in the course of therapy (after 13 days) and was usually self-limiting (often resolving within 8 days), but sometimes (in 2% of patients) required discontinuation of misoprostol.[23]

The next most commonly reported adverse effects of taking a misoprostol 200 µg tablet by mouth four times a day to reduce the risk of NSAID-induced gastric ulcers are: abdominal pain, nausea, flatulence, headache, dyspepsia, vomiting, and constipation, but none of these adverse effects occurred significantly more often than when taking placebos.[23]

Misoprostol should not be taken by pregnant women to reduce the risk of NSAID-induced gastric ulcers because it increases uterine tone and contractions in pregnancy which may cause partial or complete abortions, and because its use in pregnancy has been associated with birth defects.[23][24]

A study published in the Journal of Immunology (June 15, 2008 online) suggests that the immunosuppressive effect of misoprostol, if given vaginally rather than orally along with RU-486 to terminate a pregnancy, is likely the reason a small number of women taking the two-drug combination have contracted a fatal bacterial infection.[25] In animal and cell culture studies, the researchers found that misoprostol, when given directly in the reproductive tract (vaginally), suppresses key immune responses and can allow a normally non-threatening bacterium, Clostridium sordellii, to gain the upper hand and cause deadly infection. When absorbed through the stomach (orally), however, the drug did not compromise immune defenses or cause illness.[26]

References

  1. ^ Goldberg AB, Greenberg MB, Darney PD (January 2001). "Misoprostol and pregnancy". N. Engl. J. Med. 344 (1): 38–47. PMID 11136959.  
  2. ^ a b Wagner, Marsden (2006). Born in the USA: how a broken maternity system must be fixed to put mothers and infants first. Berkeley: University of California Press. ISBN 0-520-24596-2.  
  3. ^ a b Summers L (1997). "Methods of cervical ripening and labor induction". J Nurse Midwifery 42 (2): 71–85. PMID 9107114.  
  4. ^ a b Goldberg AB, Wing DA (2003). "Induction of labor: the misoprostol controversy". J Midwifery Womens Health 48 (4): 244–8. PMID 12867908. http://www.medscape.com/viewarticle/458959. Retrieved 2009-08-03.  
  5. ^ a b Briggs GG, Wan SR (June 2006). "Drug therapy during labor and delivery, part 2". Am J Health Syst Pharm 63 (12): 1131–9. doi:10.2146/ajhp050265.p2. PMID 16754739. http://www.medscape.com/viewarticle/535774. Retrieved 2009-08-03.  
  6. ^ Goldberg (2003), which cites:
    Weeks A, Alfirevic Z (September 2006). "Oral misoprostol administration for labor induction". Clin Obstet Gynecol 49 (3): 658–71. PMID 16885670.  
  7. ^ Wagner (2006), which cites:
    Wing DA, Paul RH (July 1996). "A comparison of differing dosing regimens of vaginally administered misoprostol for preinduction cervical ripening and labor induction". Am. J. Obstet. Gynecol. 175 (1): 158–64. PMID 8694043.  
    Wing DA, Rahall A, Jones MM, Goodwin TM, Paul RH (June 1995). "Misoprostol: an effective agent for cervical ripening and labor induction". Am. J. Obstet. Gynecol. 172 (6): 1811–6. PMID 7778637.  
  8. ^ Goldberg (2003), which cites:
    American College of Obstetricians and Gynecologists (November 1999). "Induction of labor with misoprostol". ACOG committee opinion no. 228 (Washington, DC).  
    American College of Obstetricians and Gynecologists (November 1999). "Response to Searle's drug warning on misoprostol". ACOG committee opinion no. 248 (Washington, DC).  
  9. ^ WHO. "WHO Essential drug list 2005 section 22.1 website" (PDF). http://whqlibdoc.who.int/hq/2005/a87017_eng.pdf. Retrieved 2006-12-06.  
  10. ^ "Annotated Bibliography on Misoprostol Alone for Early Abortion" (PDF). Gynuity Health Projects. http://www.rhtp.org/news/publications/documents/Miso%20for%20Pregnancy%20Termination.Bibliography.pdf. Retrieved 2006-08-22.  
  11. ^ "Medication Abortion: Misoprostol Alone". Ibis. http://www.medicationabortion.com/misoprostol/index.html. Retrieved 2006-09-08.  
  12. ^ "Instructions for Use: Abortion Induction with Misoprostol in Pregnancies up to 9 Weeks LMP" (PDF). Gynuity Health Projects. 2003. http://www.rhtp.org/news/publications/documents/Miso%20for%20Pregnancy%20Termination.IFU.English.pdf#search=%22%20site%3Awww.rhtp.org%20misoprostol%20abortion%20success%20rate%22. Retrieved 2006-08-24.  
  13. ^ Corta, SH et al. (1993). "Misoprostol and illegal abortion in Rio de Janeiro, Brazil". Lancet 15 (341): 1258–61. PMID 8098402.  
  14. ^ Coelho, HL et al. (1994). "Misoprostol: the experience of women in Fortaleza, Brazil". Contraception 49 (2): 101. doi:10.1016/0010-7824(94)90084-1. PMID 8143449.  
  15. ^ Barbosa, RM (1993). "The Brazilian Experience with Cytotec". Stud Fam Plann 24 (4): 236–40. doi:10.2307/2939191. PMID 8212093.  
  16. ^ Rocha, J et al. (1994). "Brazil investigates drug's possible link with birth defects". BMJ 309 (6957): 757–8. PMID 7950553.  
  17. ^ Gonzalez, CH et al. (1993). "Limb deficiency with or without Mobius sequence in seven Brazilian children associated with misoprostol use in the first trimester of pregnancy". Am J Med Genet 47 (1): 59. doi:10.1002/ajmg.1320470113. PMID 8368254.  
  18. ^ John Leland: "Abortion Might Outgrow Its Need for Roe v. Wade", The New York Times, October 2, 2005
  19. ^ Neilson JP et al. (2006). "Medical treatment for early fetal death (less than 24 weeks)". Cochrane Database Syst Rev 19 (3). doi:10.1002/14651858.CD002253.pub3. PMID 16855990.  
  20. ^ J Villar MD et al. (2002). "Systematic Review of Randomized Controlled Trials of Misoprostol to Prevent Postpartum Hemorrhage". Obstetrics & Gynecology. http://www.greenjournal.org/cgi/content/abstract/100/6/1301. Retrieved 2006-09-21.  
  21. ^ Bradley SEK, Prata N, Young-Lin N, Bishai DM (2007). "Cost-effectiveness of misoprostol to control postpartum hemorrhage in low-resource settings." International Journal of Gynecology and Obstetrics, 97: 52–56.
  22. ^ Ekmekçioğlu, Demirci, Yilmaz & Tatli (1998). "Intraurethral misoprostol: a different agent in the treatment of erectile dysfunction". Sexual Dysfunction 1: 161. doi:10.1046/j.1460-2679.1998.00030.x. http://www.blackwell-synergy.com/doi/full/10.1046/j.1460-2679.1998.00030.x.  
  23. ^ a b c Pfizer (September 2006). "Cytotec US Prescribing Information" (PDF). http://www.pfizer.com/pfizer/download/uspi_cytotec.pdf. Retrieved 2007-03-15.  
  24. ^ Pharmacia (July 2004). "Cytotec UK SPC (Summary of Product Characteristics)". http://emc.medicines.org.uk/emc/assets/c/html/displaydoc.asp?documentid=9352. Retrieved 2007-03-15.  
  25. ^ KAronoff DM, Hao Y, Chung J, Coleman N, Lewis C, Peres CM, Serezani CH, Chen GH, Flamand N, Brock TG, Peters-Golden M (June 15, 2008). "Misoprostol Impairs Female Reproductive Tract Innate Immunity against Clostridium sordellii". J Immunol. 180 (12): 8222–30.. PMID 18523288.  
  26. ^ Newswise: Abortion Drug’s Off-label Use May Have Led to Deaths Retrieved on June 16, 2008.

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