|Systematic (IUPAC) name|
|Legal status||℞ Prescription only|
|Routes||Oral, Vaginal, Sublingual|
|Metabolism||de-esterified to misoprostol acid, then to prostaglandin F analogs|
|ATC code||A02 G02|
|Mol. mass||382.534 g/mol|
| (what is this?)
Misoprostol is a synthetic prostaglandin E1 (PGE1) analog that is used with nonsteroidal anti-inflammatory drug (NSAID) to prevent gastric ulcers, to treat missed miscarriage, to induce labor, and to induce abortion. 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.
- 1 Ulcer prevention
- 2 Labor induction
- 3 Controversy
- 4 Induced abortion
- 5 Missed miscarriage
- 6 Post-partum hemorrhage
- 7 Other gynecological uses
- 8 Erectile dysfunction
- 9 Pharmacology
- 10 Side effects and contraindications
- 11 Veterinary medicine
- 12 References
- 13 External links and further reading
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, 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.
Misoprostol is commonly used for labor induction. It causes uterine contractions and the ripening (effacement or thinning) of the cervix. It is significantly less expensive than the other commonly used ripening agent, dinoprostone (trade names Cervidil and Prepidil).
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.
Protocols for inducing labor with misoprostol typically call for 25 μg to be administered vaginally. 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.
Between 2002 and 2012, extensive safety testing of a controlled-delivery formulation misoprostol was performed, and misoprostol (under the brand name "Misodel") was approved by the EU. However, in 2013 the USA FDA refused to accept this formulation as safe, and misoprostol remains unapproved for labor induction in the USA.
The label for Cytotec lists 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. 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. Other rare complications include amniotic fluid embolism; a 2006 study showed that the use of drugs to induce labor nearly doubled the risk. 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.
This letter generated much controversy over the use of misoprostol in labor inductions. 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. Misoprostol is also on the WHO essential drug list for labor induction.
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.
Misoprostol is used for medical abortions as an alternative to surgical abortion. Medical abortion has the advantage of being cheaper, simpler, less invasive, not requiring anesthesia, as well as not having the risk of scarring and adhesions that can be associated with surgical abortion.
Most protocols recommend that misoprostol be used with another drug. The American Congress of Obstetricians and Gynecologists (ACOG) recommends mifepristone/misoprostol 200 mg/800mcg.
Misoprostol alone is less effective (typically 88% up to 8 weeks gestation). It is not inherently unsafe if medically supervised, but 1% of women will have heavy bleeding requiring medical attention, some women may have potentially fatal ectopic pregnancy, and the 12% of pregnancies that continue after misoprostol failure are more likely to have birth defects and are usually followed up with a more effective method of abortion.
No large studies have established a protocol for the use of misoprostol alone, and the range of efficacy is 65%–93% depending on sample size, gestational age, and other test variables; Misoprostol alone may be more effective in earlier gestation. 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. 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). The drug is readily available in Mexico.
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).
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.
Misoprostol is also used to prevent and treat post-partum hemorrhage. Orally administered misoprostol at a dosage of 600 µg 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. 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 800 µg or 1000 µg was reported in a variety of case reports and randomised controlled trials. 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. A randomised control trial of misoprostol use found a 38% reduction in maternal deaths due to post-partum haemorrhage in resource-poor communities. Misoprostol is recommended due to its cost, effectiveness, stability, and low rate of side effects. 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.
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).
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. 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."
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
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.
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. 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.
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.
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- The Mechanism of Action and Pharmacology of Mifepristone, Misoprostol, and Methotrexate