Misoprostol
Encyclopedia
Misoprostol is a drug
that is used for the prevention of non steroidal anti inflammatory drug (NSAID) induced gastric ulcer
s, for early abortion, to treat missed miscarriage, and to induce labor. 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 (often misspelled Cyotec), but other brand-name
and generic
formulations are now available as well.
Pharmacologically, misoprostol is a synthetic prostaglandin E1
(PGE1) analogue.
s, 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 NSAIDs 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 adherence to therapy.
or thinning) of the cervix
. Misoprostol is more effective in starting labor than other drugs used for labor induction. It is also 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.
(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.
s 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
). Furthermore, it is less complicated to administer and less expensive.
In many countries, including China, 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, 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 abortion
s 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).
stents).
, but further research is needed to establish a safe, effective protocol.
for this purpose. 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.
s (especially in nulliparous women where insertion may be challenging).
, but not effective by itself. 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".
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 placebo
s.
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.
One study suggests that misoprostol, if given vaginally rather than orally along with mifepristone to terminate a pregnancy, can increase the risk of serious infection with Clostridium sordellii
.
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
that is used for the prevention of non steroidal anti inflammatory drug (NSAID) induced gastric ulcer
Peptic ulcer
A peptic ulcer, also known as PUD or peptic ulcer disease, is the most common ulcer of an area of the gastrointestinal tract that is usually acidic and thus extremely painful. It is defined as mucosal erosions equal to or greater than 0.5 cm...
s, for early abortion, to treat missed miscarriage, and to induce labor. The latter use is controversial in the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
. Misoprostol was invented and marketed by G.D. Searle & Company (now Pfizer
Pfizer
Pfizer, Inc. is an American multinational pharmaceutical corporation. The company is based in New York City, New York with its research headquarters in Groton, Connecticut, United States...
) under the trade name Cytotec (often misspelled Cyotec), but other brand-name
Brand
The American Marketing Association defines a brand as a "Name, term, design, symbol, or any other feature that identifies one seller's good or service as distinct from those of other sellers."...
and generic
Generic drug
A generic drug is a drug defined as "a drug product that is comparable to brand/reference listed drug product in dosage form, strength, route of administration, quality and performance characteristics, and intended use." It has also been defined as a term referring to any drug marketed under its...
formulations are now available as well.
Pharmacologically, misoprostol is a synthetic prostaglandin E1
Prostaglandin E1
Prostaglandin E1 , known pharmaceutically as alprostadil, is a prostaglandin. It is a drug used in the treatment of erectile dysfunction and has vasodilatory properties.-Sexual dysfunction:...
(PGE1) analogue.
Ulcer prevention
Misoprostol is approved for use in the prevention of NSAID induced gastric ulcers. It acts upon gastric parietal cellParietal cell
Parietal cells, or oxyntic cells, are the stomach epithelium cells that secrete gastric acid and intrinsic factor.Acetylcholine and gastrin . The histamine receptors act by increasing intracellular cAMP, whereas the muscarinic and gastrin receptors increase intracellular Ca2+ levels...
s, inhibiting the secretion of gastric acid
Gastric acid
Gastric acid is a digestive fluid, formed in the stomach. It has a pH of 1 to 2 and is composed of hydrochloric acid , and large quantities of potassium chloride and sodium chloride...
via G-protein coupled receptor mediated inhibition of adenylate cyclase
Adenylate cyclase
Adenylate cyclase is part of the G protein signalling cascade, which transmits chemical signals from outside the cell across the membrane to the inside of the cell ....
, which leads to decreased intracellular cyclic AMP levels and decreased proton pump
Proton pump
A proton pump is an integral membrane protein that is capable of moving protons across a cell membrane, mitochondrion, or other organelle. Mechanisms are based on conformational changes of the protein structure or on the Q cycle.-Function:...
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
Diclofenac
Diclofenac is a non-steroidal anti-inflammatory drug taken to reduce inflammation and as an analgesic reducing pain in certain conditions....
in Arthrotec
Arthrotec
The combination diclofenac/misoprostol is a pharmaceutical product that contains:*Diclofenac sodium: Nonsteroidal anti-inflammatory drug with analgesic properties...
).
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
Mucus
In vertebrates, mucus is a slippery secretion produced by, and covering, mucous membranes. Mucous fluid is typically produced from mucous cells found in mucous glands. Mucous cells secrete products that are rich in glycoproteins and water. Mucous fluid may also originate from mixed glands, which...
that lines the gastrointestinal tract
Gastrointestinal tract
The human gastrointestinal tract refers to the stomach and intestine, and sometimes to all the structures from the mouth to the anus. ....
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 NSAIDs induced ulcers, omeprazole
Omeprazole
Omeprazole is a proton pump inhibitor used in the treatment of dyspepsia, peptic ulcer disease , gastroesophageal reflux disease , laryngopharyngeal reflux and Zollinger–Ellison syndrome...
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 adherence to therapy.
Labor induction
Misoprostol is commonly used for labor induction. It causes uterine contractions and the ripening (effacementEffacement
Cervical effacement refers to a thinning of the cervix. It is a component of the Bishop score.It can be expressed as a percent.Prior to effacement, the cervix is like a long bottleneck, usually about four centimeters in length. Throughout pregnancy, the cervix is tightly closed and protected by a...
or thinning) of the cervix
Cervix
The cervix is the lower, narrow portion of the uterus where it joins with the top end of the vagina. It is cylindrical or conical in shape and protrudes through the upper anterior vaginal wall...
. Misoprostol is more effective in starting labor than other drugs used for labor induction. It is also significantly less expensive than the other commonly used ripening agent, dinoprostone (trade names Cervidil and Prepidil).
Oxytocin
Oxytocin
Oxytocin is a mammalian hormone that acts primarily as a neuromodulator in the brain.Oxytocin is best known for its roles in sexual reproduction, in particular during and after childbirth...
(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.
Controversy
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, SearleG. D. Searle & Company
G.D. Searle & Company or just Searle was a company focusing on life sciences, specifically pharmaceuticals, agriculture, and animal health. It is now part of Pfizer.- History :...
(the manufacturer of Cytotec) distributed a letter warning against the use of misoprostol in pregnant women. In addition to citing the abortifacient
Abortifacient
An abortifacient is a substance that induces abortion. Abortifacients for animals that have mated undesirably are known as mismating shots....
nature of the drug, the letter cited reports of uterine rupture
Uterine rupture
Uterine rupture is a potentially catastrophic event during childbirth by which the integrity of the myometrial wall is breached. In an incomplete rupture the peritoneum is still intact. With a complete rupture the contents of the uterus may spill into the peritoneal cavity or the broad ligament...
and death associated with using misoprostol to induce labor. All cervical ripening and induction agents can cause uterine hyperstimulation
Uterine hyperstimulation
Uterine hyperstimulation or hypertonic uterine dysfunction is a potential complication of labor induction. It is defined as either a series of single contractions lasting 2 minutes or more or a contraction frequency of five or more in 10 minutes. Uterine hyperstimulation may result in fetal heart...
, 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
Amniotic fluid embolism
Amniotic fluid embolism is a rare and incompletely understood obstetric emergency in which amniotic fluid, fetal cells, hair, or other debris enters the mother's blood stream via the placental bed of the uterus and triggers an allergic reaction. This reaction then results in cardiorespiratory ...
; 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.
Earlier pregnancy
Misoprostol is one of the drugs used for medical abortionMedical abortion
A medical abortion is a type of non-surgical abortion in which abortifacient pharmaceutical drugs are used to induce abortion. An oral preparation for medical abortion is commonly referred to as an abortion pill....
s 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
Infertility
Infertility primarily refers to the biological inability of a person to contribute to conception. Infertility may also refer to the state of a woman who is unable to carry a pregnancy to full term...
due to scarring and intrauterine adhesions (Asherman's Syndrome
Asherman's syndrome
Asherman's syndrome , also called "uterine synechiae" or intrauterine adhesions , presents a condition characterized by the presence of adhesions and/or fibrosis within the uterine cavity due to scars...
). Furthermore, it is less complicated to administer and less expensive.
In many countries, including China, it is used in conjunction with mifepristone
Mifepristone
Mifepristone is a synthetic steroid compound used as a pharmaceutical. It is a progesterone receptor antagonist used as an abortifacient in the first months of pregnancy, and in smaller doses as an emergency contraceptive. During early trials, it was known as RU-38486 or simply RU-486, its...
(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, 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 abortion
Self-induced abortion
A self-induced abortion is an abortion performed by the pregnant woman herself outside the recognized medical system. Although the term can include abortions induced through legal, over-the-counter medication, it also refers to efforts to terminate a pregnancy through alternative, often more...
s 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
New York
New York is a state in the Northeastern region of the United States. It is the nation's third most populous state. New York is bordered by New Jersey and Pennsylvania to the south, and by Connecticut, Massachusetts and Vermont to the east...
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).
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 laminariaLaminaria
Laminaria is a genus of 31 species of brown algae , all sharing the common name "kelp". This economically important genus is characterized by long, leathery laminae and relatively large size. Some species are referred to by the common name Devil's apron, due to their shape, or sea colander, due to...
stents).
Missed miscarriage
Misoprostol is sometimes used to treat early fetal death in the absence of spontaneous miscarriageMiscarriage
Miscarriage or spontaneous abortion is the spontaneous end of a pregnancy at a stage where the embryo or fetus is incapable of surviving independently, generally defined in humans at prior to 20 weeks of gestation...
, but further research is needed to establish a safe, effective protocol.
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 oxytocinOxytocin
Oxytocin is a mammalian hormone that acts primarily as a neuromodulator in the brain.Oxytocin is best known for its roles in sexual reproduction, in particular during and after childbirth...
for this purpose. 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.
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 deviceIntrauterine device
A copper IUD is a type of intrauterine device. Most IUDs have a plastic T- or U-shaped frame which is wrapped in copper wire, with the exception of Gynefix, which is a plastic string with several copper beads, affixed to the fundus of the uterus...
s (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 dysfunctionErectile dysfunction
Erectile dysfunction is sexual dysfunction characterized by the inability to develop or maintain an erection of the penis during sexual performance....
, but not effective by itself. 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".
Pharmacology
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 effectAdverse effect
In medicine, an adverse effect is a harmful and undesired effect resulting from a medication or other intervention such as surgery.An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. If it results from an unsuitable or incorrect dosage or...
of taking a misoprostol 200 µg tablet by mouth four times a day to reduce the risk of NSAID induced gastric ulcers is diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
. 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
Abdominal pain
Abdominal pain can be one of the symptoms associated with transient disorders or serious disease. Making a definitive diagnosis of the cause of abdominal pain can be difficult, because many diseases can result in this symptom. Abdominal pain is a common problem...
, nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
, flatulence
Flatulence
Flatulence is the expulsion through the rectum of a mixture of gases that are byproducts of the digestion process of mammals and other animals. The medical term for the mixture of gases is flatus, informally known as a fart, or simply gas...
, headache
Headache
A headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...
, dyspepsia
Dyspepsia
Dyspepsia , also known as upset stomach or indigestion, refers to a condition of impaired digestion. It is a medical condition characterized by chronic or recurrent pain in the upper abdomen, upper abdominal fullness and feeling full earlier than expected when eating...
, vomiting
Vomiting
Vomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...
, and constipation
Constipation
Constipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...
, but none of these adverse effects occurred significantly more often than when taking placebo
Placebo
A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...
s.
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.
One study suggests that misoprostol, if given vaginally rather than orally along with mifepristone to terminate a pregnancy, can increase the risk of serious infection with Clostridium sordellii
Clostridium sordellii
Clostridium sordellii is a rare anaerobic, gram-positive, spore forming rod with peritrichous flagella that is capable of causing pneumonia, endocarditis, arthritis, peritonitis, and myonecrosis. C. sordellii bacteremia and sepsis occur rarely. Most cases of sepsis from C. sordellii occur in...
.
External links and further reading
- Misoprostol.org an independent website containing dosage guidelines and advice on misoprostol use.
- www.yorku.ca A York University study outlining potential links toward autism.
- http://www.medscape.com/viewarticle/429755_3 The Mechanism of Action and Pharmacology of Mifepristone, Misoprostol, and Methotrexate