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Misoprostol
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| Systematic (IUPAC) name | |
| Methyl 7-{3-hydroxy-2- [(E)-4-hydroxy-4-methyloct-1-enyl]- 5-oxocyclopentyl}heptanoate |
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| Identifiers | |
| CAS number | |
| ATC code | A02 |
| PubChem | |
| DrugBank | |
| Chemical data | |
| Formula | C22H38O5 |
| 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 |
Misoprostol is a drug that is FDA-approved in the United States for the prevention of non-steroidal anti-inflammatory drug (NSAID)-induced gastric ulcers. It is also used (and approved in other countries) to induce labor and as an abortifacient. It 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.
Chemically, misoprostol is a synthetic prostaglandin E1 (PGE1) analogue.
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Indicated (in the United States) use
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. Misoprostal 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.
Off label (in the United States) uses
Obstetric and gynecological
Labor induction
Misoprostol is commonly prescribed off-label to cause labor induction by promoting uterine contractions and the ripening (effacement or thinning) of the cervix. Misoprostol is considered to be more effective than oxytocin and dinoprostone, the FDA-approved drugs for medically necessary labor induction. It is also less expensive than either of these two drugs.
Concern has been expressed about the overuse or misuse of misoprostol for labor induction. High doses can cause uterine rupture (especially in women who have previously had a caesarean section), fetal death, and severe fetal brain damage.[1] All induction agents cause uterine contractions – this can affect the blood supply to the fetus, especially if contractions become very frequent. Induction agents therefore need to be used with great care and with close fetal monitoring. One of the problems with induction using prostaglandins (such as dinoprostone or misoprostol) is that once given, the process is difficult to reverse. In contrast, oxytocin has a half-life of about 10 minutes and is administered via intravenous drip, which can be stopped immediately in the event of adverse reaction.[2]
One clinical trial to establish a controlled delivery method for misoprostol[3] was conducted in 2006-2007; the trial showed no difference in effectiveness between misoprostol and dinoprostone when both were introduced via FDA-approved methods.citation needed A recent study demonstrates that intravaginal administration of misoprostol is comparable in safety, but more effective for induction of labor than intravaginal dinoprostone [4]. This result concurs with trial meta-analysis by the Cochrane Collaboration, which demonstrates no difference in efficacy or side effects between inductions undertaken with dinoprostone or misoprostol (when used at the correct dosage).citation needed
The manufacturers of misoprostol have never sought to license misoprostol for labor induction. Recently, however, generic forms of misoprostol have become available, and it is now licensed for labor induction in Egypt and Brazil, and a licensed induction product is expected in the UK in 2008.[5] [6]
The American College of Obstetricians and Gynecologists advocates misoprostol for labor inductions, and it is on the WHO essential drug list for labour induction.[7]
Abortion for elective termination/miscarriage treatment/postpartum retained placenta
Misoprostol is one of the drugs used for medical abortions in lieu of surgical evacuation. Both medical and surgical methods can be used to remove products of conception in the case of missed or incomplete miscarriage, retained postpartum placenta, and for elective abortion. There are some advantages to using drugs instead of surgical intervention in these situations, as drugs are not invasive, reducing the risk from general anesthesia, and secondary infertility due to scarring and intrauterine adhesions (Asherman's Syndrome).citation needed Furthermore it is cheap and easy to administer. 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 fetus and associated matter in approximately 92% of the cases. No large studies have established a protocol for the use of misoprostol alone,[8] and the range of efficacy is 65%–93% depending on sample size, gestational age, and other test variables;[9] Misoprostol alone may be more effective in earlier gestation.[10] 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. [11] [12][13] [14] [15] 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).[16]
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. [17] It 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 tents). 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. [18]
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.[19] 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.[20]
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.[20]
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.[20][21]
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.[22] 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.[23]
References
- ^ Alfonsi, Sharyn (November 30, 2004). Labor Induction Drug Under Fire. CBS Evening News. Retrieved on 2006-08-22.
- ^ Ina May Gaskin (July 11, 2000). Cytotec: Dangerous Experiment or Panacea. Salon.com. Retrieved on 2006-09-08.
- ^ Clinical Trial Description at clinicaltrials.gov. Information on Clinical Trials and Human Research Studies. NIH (August, 2006). Retrieved on 2006-08-29.
- ^ A randomized comparison between intravaginal misoprostol and prostaglandin E2 for labor induction. Sifakis S, Angelakis E, Avgoustinakis E, Fragouli Y, Mantas N, Koukoura O, Vardaki E, Koumantakis E.Arch Gynecol Obstet. 2007;275(4):263-7.
- ^ Misoprostol.org. Misoprostol.org website.
- ^ Alliance Pharmaceuticals. Labour Induction website.
- ^ WHO. WHO Essential drug list 2005 section 22.1 website.
- ^ Annotated Bibliography on Misoprostol Alone for Early Abortion. Gynuity Health Projects. Retrieved on 2006-08-22.
- ^ Medication Abortion: Misoprostol Alone. Ibis. Retrieved on 2006-09-08.
- ^ Instructions for Use: Abortion Induction with Misoprostol in Pregnancies up to 9 Weeks LMP (PDF). Gynuity Health Projects (2003). Retrieved on 2006-08-24.
- ^ Corta, SH et al (1993). "Misoprostol and illegal abortion in Rio de Janeiro, Brazil". Lancet 15 (341): 1258–61. PMID 8098402.
- ^ Coelho, HL et al (1994). "Misoprostol: the experience of women in Fortaleza, Brazil". Contraception 49 (2): 101. doi:. PMID 8143449.
- ^ Barbosa, RM (1993). "The Brazilian Experience with Cytotec". Stud Fam Plann 24 (4): 236–40. doi:. PMID 8212093.
- ^ Rocha, J et al (1994). "Brazil investigates drug's possible link with birth defects". BMJ 309 (6957): 757–8. PMID 7950553.
- ^ 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:. PMID 8368254.
- ^ John Leland: "Abortion Might Outgrow Its Need for Roe v. Wade", The New York Times, October 2, 2005
- ^ Neilson JP et al (2006). "Medical treatment for early fetal death (less than 24 weeks)". Cochrane Database Syst Rev 19 (3). doi:. PMID 16855990.
- ^ J Villar MD et al (2002). Systematic Review of Randomized Controlled Trials of Misoprostol to Prevent Postpartum Hemorrhage. Obstetrics & Gynecology. Retrieved on 2006-09-21.
- ^ Ekmekçioğlu, Demirci, Yilmaz & Tatli (1998). "Intraurethral misoprostol: a different agent in the treatment of erectile dysfunction". Sexual Dysfunction 1: 161. doi:.
- ^ a b c Pfizer (September 2006). Cytotec US Prescribing Information. Retrieved on 2007-03-15.
- ^ Pharmacia (July 2004). Cytotec UK SPC (Summary of Product Characteristics). Retrieved on 2007-03-15.
- ^ 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). "Misoprostol Impairs Female Reproductive Tract Innate Immunity against Clostridium sordellii". J Immunol. 180 (12): 8222–30.. PMID 18523288.
- ^ Newswise: Abortion Drug’s Off-label Use May Have Led to Deaths Retrieved on June 16, 2008.
External links and further reading
- Misoprostol from Drugdigest
- Misoprostol.org an independent website containing dosage guidelines and advice on misoprostol use.
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Wikipedia content modification information:
- This page was last modified on 1 July 2008, at 13:34.
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