Misoprostol

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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
Clinical data
Trade names Cytotec
AHFS/Drugs.com monograph
MedlinePlus a689009
Pregnancy cat. X
Legal status ℞ Prescription only
Routes Oral, Vaginal, Sublingual
Pharmacokinetic data
Bioavailability extensively absorbed
Protein binding 85%
Metabolism de-esterified to misoprostol acid, then to prostaglandin F analogs
Half-life 20–40 minutes
Excretion Renal:80%
Fecal:15%
Identifiers
CAS number 59122-46-2 YesY
ATC code A02BB01 G02AD06
PubChem CID 5282381
IUPHAR ligand 1936
DrugBank DB00929
ChemSpider 4445541 YesY
UNII 0E43V0BB57 YesY
KEGG D00419 YesY
ChEMBL CHEMBL606 YesY
Chemical data
Formula C22H38O5 
Mol. mass 382.534 g/mol
 YesY (what is this?)  (verify)

Misoprostol is a synthetic prostaglandin E1 (PGE1) analog that is used for the prevention of nonsteroidal anti-inflammatory drug (NSAID) induced gastric ulcers, to treat missed miscarriage, to induce labor, and as an abortifacient. The latter use is controversial in the United States. Misoprostol was invented and marketed by G.D. Searle & Company (now Pfizer) under the trade name Cytotec, but other brand-name and generic formulations are now available as well.

Contents

Ulcer prevention [edit]

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 coprescribed 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.

However, even in the treatment of NSAID induced ulcers, omeprazole proved to be at least as effective as misoprostol,[1] but significantly better tolerated, and therefore misoprostol should not be considered a first choice treatment. Misoprostol-induced diarrhea and the need of multiple daily doses (typically four) are the main issues impairing compliance with therapy.

Labor induction [edit]

Misoprostol is commonly used for labor induction. It causes uterine contractions and the ripening (effacement or thinning) of the cervix.[2] It is 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]

As of October 2012, misoprostol was not approved by the United States FDA for use as a labor-induction drug; however, an NDA for that purpose has been filed and is under review.[6]

Controversy [edit]

When Cytotec first came on the market, the label listed a contraindication that it not be used on pregnant women. In August 2000, due to increase of "off label" usage, Searle (the manufacturer of Cytotec) 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. 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 complications 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] Other rare complications include amniotic fluid embolism; a 2006 study showed that the use of drugs to induce labor nearly doubled the risk.[8] Because the 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.[9]

This letter generated much controversy over the use of misoprostol in labor inductions.[4] 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.[10] Misoprostol is also on the WHO essential drug list for labor induction.[11]

The largest medical malpractice award of nearly 70 million dollars was awarded due to the use of misoprostol to induce labor in a California hospital. [12]

Induced abortion [edit]

Earlier pregnancy [edit]

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 sometimes used for surgical abortions), and lack of risk of secondary infertility due to scarring and intrauterine adhesions (Asherman's Syndrome).[citation needed] Furthermore, it is less complicated to administer and less expensive.

In many countries,[which?] including China, it is used in conjunction with mifepristone (RU-486).[citation needed] 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,[13] and the range of efficacy is 65%–93% depending on sample size, gestational age, and other test variables;[14] Misoprostol alone may be more effective in earlier gestation.[15] The side effects associated with the misoprostol only regimen are generally much more severe than those associated with the combined regimens.[citation needed] 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.[16][17][18][19][20] 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).[21]

Later pregnancy [edit]

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 [edit]

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.[22]

Misoprostol is regularly used in some Canadian hospitals for labour induction for fetal deaths early in pregnancy, and for termination of pregnancy for fetal anomalies. A low dose is used initially, then doubled for the remaining doses until delivery. In the case of a previous Caesarian Section, however, lower doses are used.

Post-partum hemorrhage [edit]

Misoprostol is also used to prevent and treat post-partum hemorrhage. Orally administered misoprostol at a dosage of 600 ug was tested versus oxytocin 10iu in a large randomised controlled study. The study which involved a substantial number of patients receiving either oral or intravenous oxytocin showed that misoprostol is marginally less effective for this purpose.[23] The use of rectally administered misoprostol is optimal in cases of haemorrhage; it was shown to be associated with lower incidence of side effects compared to other routes for this particular indication. Rectally administered misoprostol at dosages of 800ug or 1000 ug was reported in a variety of case reports and randomised controlled trials.[24][25] 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.[26] A randomised control trial of misoprostol use found a 38% reduction in maternal deaths due to post-partum haemorrhage in resource-poor communities.[27] Misoprostol is recommended due to its cost, effectiveness, stability, and low rate of side effects.[28] Oxytocin must also be given by injection, while misprostol can be given orally or rectally for this use, making it much more useful in areas where nurses and physicians are less available.[29]

Other gynecological uses [edit]

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 [edit]

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.[30] The paper concluded that "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."

Pharmacology [edit]

Misoprostol, a prostaglandin, binds to myometrial cells to cause strong myometrial contractions leading to expulsion of tissue. This agent also causes cervical ripening with softening and dilation of the cervix.

Side effects and contraindications [edit]

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.[31]

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.[31] In practice, fever is almost universal when multiple doses are given every 4 to 6 hours.

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.[31][32]

Veterinary medicine [edit]

Misoprostol is used in veterinary emergency services to treat some drug overdoses, such as with Advil, in dogs. It is also used to prevent gastric ulcers.

References [edit]

  1. ^ Hawkey CJ, Karrasch JA, Szczepañski L, et al. (March 1998). "Omeprazole compared with misoprostol for ulcers associated with nonsteroidal antiinflammatory drugs. Omeprazole versus Misoprostol for NSAID-induced Ulcer Management (OMNIUM) Study Group". N. Engl. J. Med. 338 (11): 727–34. doi:10.1056/NEJM199803123381105. PMID 9494149. 
  2. ^ Wood, Alastair J.J.; Goldberg, Alisa B.; Greenberg, Mara B.; Darney, Philip D. (2001). "Misoprostol and Pregnancy". New England Journal of Medicine 344 (1): 38–47. doi:10.1056/NEJM200101043440107. PMID 11136959. 
  3. ^ a b Summers, L (1997). "Methods of cervical ripening and labor induction". Journal of Nurse-Midwifery 42 (2): 71–85. doi:10.1016/S0091-2182(96)00138-3. PMID 9107114. 
  4. ^ a b Goldberg, A; Wing, D (2003). "Induction of laborthe misoprostol controversy". Journal of Midwifery & Women's Health 48 (4): 244–8. doi:10.1016/S1526-9523(03)00087-4. PMID 12867908. 
  5. ^ a b Briggs, G. G.; Wan, SR (2006). "Drug therapy during labor and delivery, part 2". American Journal of Health-System Pharmacy 63 (12): 1131–9. doi:10.2146/ajhp050265.p2. PMID 16754739. 
  6. ^ "Ferring announces FDA acceptance of NDA filing for controlled release Misoprostol Vagincal Insert for decreasing time to vaginal delivery in women". 
  7. ^ Wagner 2006, which cites:
    Wing, Deborah A.; Paul, Richard H. (1996). "A comparison of differing dosing regimens of vaginally administered misoprostol for preinduction cervical ripening and labor induction". American Journal of Obstetrics and Gynecology 175 (1): 158–64. doi:10.1016/S0002-9378(96)70267-3. PMID 8694043. 
    Wing, Deborah A.; Rahall, Ann; Jones, Margaret M.; Goodwin, T.Murphy; Paul, Richard H. (1995). "Misoprostol: An effective agent for cervical ripening and labor induction". American Journal of Obstetrics and Gynecology 172 (6): 1811–6. doi:10.1016/0002-9378(95)91416-1. PMID 7778637. 
  8. ^ Kramer, Michael S; Rouleau, Jocelyn; Baskett, Thomas F; Joseph, KS; Maternal Health Study Group of the Canadian Perinatal Surveillance System (2006). "Amniotic-fluid embolism and medical induction of labour: A retrospective, population-based cohort study". The Lancet 368 (9545): 1444–8. doi:10.1016/S0140-6736(06)69607-4. PMID 17055946. 
  9. ^ Goldberg & Wing 2003, which cites:
    Weeks, Andrew; Alfirevic, Zarko (2006). "Oral Misoprostol Administration for Labor Induction". Clinical Obstetrics and Gynecology 49 (3): 658–71. doi:10.1097/00003081-200609000-00023. PMID 16885670. 
  10. ^ Goldberg & Wing 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). 
  11. ^ WHO. "WHO Essential drug list 2005 section 22.1 website" (PDF). Retrieved 2006-12-06. 
  12. ^ "Denver attorney receives ‘Case of the Year’ honor". 
  13. ^ "Annotated Bibliography on Misoprostol Alone for Early Abortion" (PDF). Gynuity Health Projects. Retrieved 2006-08-22. 
  14. ^ "Medication Abortion: Misoprostol Alone". Ibis. Retrieved 2006-09-08. 
  15. ^ "Instructions for Use: Abortion Induction with Misoprostol in Pregnancies up to 9 Weeks LMP" (PDF). Gynuity Health Projects. 2003. Retrieved 2006-08-24. 
  16. ^ Costa, S.H; Vessey, M.P (1993). "Misoprostol and illegal abortion in Rio de Janeiro, Brazil". The Lancet 341 (8855): 1258–61. doi:10.1016/0140-6736(93)91156-G. PMID 8098402. 
  17. ^ Coêlho, Helena Lutéscia; Teixeira, Ana Cláudia; De Fátima Cruz, Maria; Gonzaga, Sandra Luzia; Arrais, Paulo Sérgio; Luchini, Laura; La Vecchia, Carlo; Tognoni, Gianni (1994). "Misoprostol: The experience of women in Fortaleza, Brazil". Contraception 49 (2): 101–10. doi:10.1016/0010-7824(94)90084-1. PMID 8143449. 
  18. ^ Barbosa, Regina Maria; Arilha, Margareth (1993). "The Brazilian Experience with Cytotec". Studies in Family Planning 24 (4): 236–40. doi:10.2307/2939191. JSTOR 2939191. PMID 8212093. 
  19. ^ Rocha, J (1994). "Brazil investigates drug's possible link with birth defects". BMJ 309 (6957): 757–8. doi:10.1136/bmj.309.6957.757a. PMID 7950553. 
  20. ^ Gonzalez, Claudette Hajaj; Vargas, Fernando R.; Perez, Ana Beatriz Alvarez; Kim, Chong Ae; Brunoni, Decio; Marques-Dias, Maria Joaquina; Leone, Clea R.; Neto, Jordão Correa et al. (1993). "Limb deficiency with or without Möbius sequence in seven Brazilian children associated with misoprostol use in the first trimester of pregnancy". American Journal of Medical Genetics 47 (1): 59–64. doi:10.1002/ajmg.1320470113. PMID 8368254. 
  21. ^ John Leland: "Abortion Might Outgrow Its Need for Roe v. Wade", The New York Times, October 2, 2005
  22. ^ Neilson, James P; Hickey, Martha; Vazquez, Juan C (2006). "Medical treatment for early fetal death (less than 24 weeks)". In Neilson, James P. Cochrane Database of Systematic Reviews (3): CD002253. doi:10.1002/14651858.CD002253.pub3. PMID 16855990. 
  23. ^ Villar, J; Gülmezoglu, AM; Hofmeyr, GJ; Forna, F (2002). "Systematic review of randomized controlled trials of misoprostol to prevent postpartum hemorrhage". Obstetrics & Gynecology 100 (6): 1301–12. doi:10.1016/S0029-7844(02)02371-2. PMID 12468178. 
  24. ^ O'Brien, P; El-Refaey, H; Gordon, A; Geary, M; Rodeck, CH (1998). "Rectally administered misoprostol for the treatment of postpartum hemorrhage unresponsive to oxytocin and ergometrine: A descriptive study". Obstetrics & Gynecology 92 (2): 212–4. doi:10.1016/S0029-7844(98)00161-6. PMID 9699753. 
  25. ^ Lokugamage, Amali U.; Sullivan, Keith R.; Niculescu, Iosif; Tigere, Patrick; Onyangunga, Felix; Refaey, Hazem El; Moodley, Jagidesa; Rodeck, Charles H. (2001). "A randomized study comparing rectally administered misoprostol versus Syntometrine combined with an oxytocin infusion for the cessation of primary post partum hemorrhage". Acta Obstetricia et Gynecologica Scandinavica 80 (9): 835–9. doi:10.1034/j.1600-0412.2001.080009835.x. PMID 11531635. 
  26. ^ Bradley, S.E.K.; Prata, N.; Young-Lin, N.; Bishai, D.M. (2007). "Cost-effectiveness of misoprostol to control postpartum hemorrhage in low-resource settings". International Journal of Gynecology & Obstetrics 97 (1): 52–6. doi:10.1016/j.ijgo.2006.12.005. PMID 17316646. 
  27. ^ Derman, Richard J; Kodkany, Bhalchandra S; Goudar, Shivaprasad S; Geller, Stacie E; Naik, Vijaya A; Bellad, MB; Patted, Shobhana S; Patel, Ashlesha et al. (2006). "Oral misoprostol in preventing postpartum haemorrhage in resource-poor communities: A randomised controlled trial". The Lancet 368 (9543): 1248–53. doi:10.1016/S0140-6736(06)69522-6. PMID 17027730. 
  28. ^ Sanghvi, Harshad; Zulkarnain, Mohammad; Chanpong, Gail Fraser (2009). In Blouse, Ann; Lewison, Dana. Prevention of Postpartum Hemorrhage at Home Birth: A Program Implementation Guide. United States Agency for International Development. [page needed]
  29. ^ Prata, Ndola; Passano, Paige; Bell, Suzanne; Rowen, Tami; Potts, Malcolm (2012). "New hope: community-based misoprostol use to prevent postpartum haemorrhage". Health Policy and Planning 368 (2012 Aug 9. [Epub ahead of print]). doi:10.1093/heapol/czs068. PMID 22879523. 
  30. ^ Ekmekcioglu; Demirci; Yilmaz; Tatlisen (1998). "Intraurethral misoprostol: A different agent in the treatment of erectile dysfunction". Sexual Dysfunction 1 (3): 161. doi:10.1046/j.1460-2679.1998.00030.x. 
  31. ^ a b c Pfizer (September 2006). "Cytotec US Prescribing Information" (PDF). Retrieved 2007-03-15. 
  32. ^ Pharmacia (July 2004). "Cytotec UK SPC (Summary of Product Characteristics)". Retrieved 2007-03-15. 

External links and further reading [edit]
Precursor
Prostanoids
Prostaglandins (PG) and
analogues
Precursor
Active
D/J
E/F
I
Thromboxanes (TX)
Leukotrienes (LT)
Precursor
Initial
SRS-A
Nonclassic
By function

M: MET

mt, k, c/g/r/p/y/i, f/h/s/l/o/e, a/u, n, m

k, cgrp/y/i, f/h/s/l/o/e, au, n, m, epon

m (A16/C10), i (k, c/g/r/p/y/i, f/h/s/o/e, a/u, n, m)
H2 antagonists ("-tidine")
Prostaglandins (E)/analogues ("-prost-")
Proton-pump inhibitors ("-prazole")
Other
Cervical ripening
Contraction induction
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