Misoprostol

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Misoprostol
Misoprostol.svg
Clinical data
Trade names Cytotec, Misodel, others
AHFS/Drugs.com Monograph
MedlinePlus a689009
License data
Pregnancy
category
Routes of
administration 		By mouth, rectal, vaginal, under the tongue
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability extensively absorbed
Protein binding 80–90% (active metabolite, misoprostol acid)
Metabolism Liver (extensive to misoprostic acid)
Elimination half-life 20–40 minutes
Excretion Urine (80%)
Identifiers
  • Methyl 7-((1R,2R,3R)-3-hydroxy-2-((S,E)-4-hydroxy-4-methyloct-1-enyl)-5-oxocyclopentyl)heptanoate
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.190.521 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C22H38O5
Molar mass 382.541 g·mol−1
3D model (JSmol)
  • CCCC[C@](C)(O)C/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)OC
  • InChI=1S/C22H38O5/c1-4-5-14-22(2,26)15-10-12-18-17(19(23)16-20(18)24)11-8-6-7-9-13-21(25)27-3/h10,12,17-18,20,24,26H,4-9,11,13-16H2,1-3H3/b12-10+/t17-,18-,20-,22?/m1/s1 Yes check.svgY
  • Key:OJLOPKGSLYJEMD-URPKTTJQSA-N Yes check.svgY
   (verify)

Misoprostol is a synthetic prostaglandin medication used to prevent and treat stomach and duodenal ulcers, induce labor, cause an abortion, and treat postpartum bleeding due to poor contraction of the uterus. [10] [11] It is taken by mouth when used to prevent gastric ulcers in people taking nonsteroidal anti-inflammatory drugs (NSAID). [11] For abortions it is used by itself or in conjunction with mifepristone or methotrexate. [12] By itself, effectiveness for abortion is between 66% and 90%. [13] [14] For labor induction or abortion, it is taken by mouth, dissolved in the mouth, or placed in the vagina. [12] [15] [16] [17] [18] For postpartum bleeding it may also be used rectally. [19]

Contents

Common side effects include diarrhea and abdominal pain. [11] It is in pregnancy category X, meaning that it is known to result in negative outcomes for the fetus if taken during pregnancy. [11] In rare cases, uterine rupture may occur. [11] It is a prostaglandin analogue—specifically, a synthetic prostaglandin E1 (PGE1). [11]

Misoprostol was developed in 1973. [20] It is on the World Health Organization's List of Essential Medicines. [21] It is available as a generic medication. [11]

Medical uses

Ulcer prevention

Misoprostol is used for the prevention of NSAID-induced gastric ulcers. It acts upon gastric parietal cells, inhibiting the secretion of gastric acid by 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. Misoprostol is sometimes coprescribed with NSAIDs to prevent their common adverse effect of gastric ulceration (e.g., with diclofenac in Arthrotec ).[ citation needed ]

However, even in the treatment of NSAID-induced ulcers, omeprazole proved to be at least as effective as misoprostol, [22] but was significantly better tolerated, so misoprostol should not be considered a first-line treatment. Misoprostol-induced diarrhea and the need for multiple daily doses (typically four) are the main issues impairing compliance with therapy.[ medical citation needed ]

Labor induction

Misoprostol is commonly used for labor induction. It causes uterine contractions and the ripening (effacement or thinning) of the cervix. [23] It can be less expensive than the other commonly used ripening agent, dinoprostone. [24]

Oxytocin has long been used as the standard agent for labor induction, but does not work well when the cervix is not yet ripe. Misoprostol also may be used in conjunction with oxytocin. [24]

Between 2002 and 2012, a misoprostol vaginal insert was studied, and was approved in the EU. [25] [26] [27] It was not approved for use in the United States, and the US FDA still considers cervical ripening and labor induction to be outside of the approved uses for misoprostol. [28] [29]

Myomectomy

When administered prior to myomectomy in women with uterine fibroids, misoprostol reduces operative blood loss and requirement of blood transfusion. [30]

Abortion

Misoprostol is used either alone or in conjunction with another medication (mifepristone or methotrexate) for medical abortions as an alternative to surgical abortion. [31] Medical abortion has the advantage of being less invasive, and more autonomous, self-directed, and discreet. It is preferred by some women because it feels more natural, as the drugs induce a miscarriage. [32] It is also more easily accessible in places where abortion is illegal. [33] The World Health Organization (WHO) provides clear guidelines on the use, benefits and risks of misoprostol for abortions. [34]

Misoprostol is most effective when it is used in combination with methotrexate or mifepristone (RU-486). [35] Mifepristone blocks signaling by progesterone, causing the uterine lining to degrade, the blood vessels of the cervix and uterus to dilate and causing uterine contraction, similar to a menstrual period, which causes the embryo to detach from the uterine walls. [36] Misoprostol then dilates the cervix and induces muscle contractions which clear the uterus.[ citation needed ] Misoprostol alone is less effective (typically 88% up to eight-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 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. [37]

Most large studies recommend a protocol for the use of misoprostol in combination with mifepristone. [38] [39] Together they are effective in around 95% for early pregnancies. [40] Misoprostol alone may be more effective in earlier gestation. [41]

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 osmotic dilators). Vaginal misoprostol can also be used to facilitate intrauterine device insertion after previous insertion failure. [42]

Misoprostol by mouth is the least effective treatment for producing complete abortion in a period of 24 hours due to the liver's first-pass effect which reduces the bioavailability of the misoprostol. Vaginal and sublingual routes result in greater efficacy and extended duration of action because these routes of administration allow the drug to be directly absorbed into circulation by bypassing the liver first-pass effect. [43] [17] [18]

Hematocrit or Hb tests and Rh testing are recommended before use for abortion confirmation of pregnancy. [44] Following use, it is recommended that people attend a follow-up visit 2 weeks after treatment. If used for treatment of complete abortion, a pregnancy test, physical examination of the uterus, and ultrasound should be performed to ensure success of treatment. Surgical management is possible in the case of failed treatment. [43]

Early pregnancy loss

Misoprostol may be used to complete a miscarriage or missed abortion when the body does not expel the embryo or fetus on its own. Compared to no medication or placebo, it could decrease the time to complete expulsion. [45] Use of a single dose of misoprostol vaginally or buccally is preferred, with additional doses as needed. It also can be used in combination with mifepristone, with a similar regimen to medical abortion. [17] [18]

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.

Postpartum bleeding

Misoprostol is also used to prevent and treat post-partum bleeding. Orally administered misoprostol was marginally less effective than oxytocin. [46] The use of rectally administered misoprostol is optimal in cases of bleeding; it was shown to be associated with lower rates of side effects compared to other routes. Rectally administered misoprostol was reported in a variety of case reports and randomised controlled trials. [47] [48] 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. [49] A randomised control trial of misoprostol use found a 38% reduction in maternal deaths due to post partum haemorrhage in resource-poor communities. [50] Misoprostol is recommended due to its cost, effectiveness, stability, and low rate of side effects. [51] 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. [52]

Insertion of intrauterine contraceptive device

In women with prior caesarean section or prior failure of insertion of an intrauterine contraceptive device, pre-procedure administration of misoprostol reduces the rate of failure of insertion of intrauterine contraceptive device. However, due to a higher rate of adverse effects, routine use of misoprostol for this purpose in other women is not supported by the data. [53]

Other

For cervical ripening in advance of endometrial biopsy to reduce the need for use of a tenaculum or cervical dilator.[ citation needed ]

There is limited evidence supporting the use of misoprostol for the treatment of trigeminal neuralgia in patients with multiple sclerosis. [54] [55]

Adverse effects

The most commonly reported adverse effect of taking misoprostol by mouth for the prevention of stomach ulcers is diarrhea. In clinical trials, an average 13% of people 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 people) required discontinuation of misoprostol. [56]

The next most commonly reported adverse effects of taking misoprostol by mouth for the prevention of gastric ulcers are: abdominal pain, nausea, flatulence, headache, dyspepsia, vomiting, and constipation, but none of these adverse effects occurred more often than when taking placebos. [56]

There are increased side effects with sublingual or oral misoprostol, compared to a low dose (400 μg) vaginal misoprostol. However, low dose vaginal misoprostol was linked with low complete abortion rate. [43] The study concluded that sublingually administered misoprostol dosed at 600 μg or 400 μg had greater instances of fever and diarrhea due to its quicker onset of action, higher peak concentration and bioavailability in comparison to vaginal or oral misoprostol. [43]

For the indication of medical abortion, bleeding and cramping is commonly experienced after administration of misoprostol. Bleeding and cramping is likely to be greater than that experienced with menses, however, emergency care is advised if bleeding is excessive. [44]

Misoprostol should not be taken by pregnant women with wanted pregnancies 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. [56] [57]

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. [58] 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. [59] 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 around 61,000 people enrolled in randomized controlled trials to detect a difference in serious fetal complications and about 155,000 people to detect a difference in serious maternal complications. [60]

Contraindications

It is recommended that medical treatment for missed abortion with misoprostol should only be considered in people without the following contraindications: suspected ectopic pregnancy, use of non-steroidal drugs, signs of pelvic infections or sepsis, unstable hemodynamics, known allergy to misoprostol, previous caesarean section, mitral stenosis, hypertension, glaucoma, bronchial asthma, and remote areas without a hospital nearby. [43]

Pharmacology

Mechanism of action

Misoprostol, a prostaglandin analogue, 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. Misoprostol binds to and stimulates prostaglandin EP2 receptors, prostaglandin EP3 receptor and prostaglandin EP4 receptor but not prostaglandin EP1 receptor and therefore is expected to have a more restricted range of physiological and potentially toxic actions than prostaglandin E2 or other analogs which activate all four prostaglandin receptors. [61]

Society and culture

In August 2000, a letter from G.D. Searle, LLC, the inventor of the drug, [62] [63] generated controversy by warning against its use by pregnant women because of its ability to induce abortion, citing reports of maternal and fetal deaths when it was used to induce labor. [64] 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 response to the Searle letter. [65] It is on the World Health Organization's List of Essential Medicines. [21]

A vaginal form of the medication is sold in the EU under the names Misodel [66] and Mysodelle [67] for use in labor induction.[ medical citation needed ]

Black market

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 medical abortions. Failed misoprostol abortions are associated with birth defects in some cases. [68] [69] [70] [71] [72] Low-income and immigrant populations in New York City 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). [73] The drug is readily available in Mexico. [74] Use of misoprostol has also increased in Texas in response to increased regulation of abortion providers. [75] Following the United States Supreme Court decision of Dobbs v. Jackson Women's Health Organization, many states restricted access to legal abortion services, including medication abortion using misoprostol. As a result of these restrictions, it was reported that there was an increase in self-managed abortions by women in the United States. Many women purchased the pills from overseas online pharmacies or obtained misoprostol from Mexico. [76]

Related Research Articles

Abortion is the termination of a pregnancy by removal or expulsion of an embryo or fetus. An abortion that occurs without intervention is known as a miscarriage or "spontaneous abortion"; these occur in approximately 30% to 40% of all pregnancies. When deliberate steps are taken to end a pregnancy, it is called an induced abortion, or less frequently "induced miscarriage". The unmodified word abortion generally refers to an induced abortion. The most common reasons women give for having an abortion are for birth-timing and limiting family size. Other reasons reported include maternal health, an inability to afford a child, domestic violence, lack of support, feeling they are too young, wishing to complete education or advance a career, and not being able or willing to raise a child conceived as a result of rape or incest.

<span class="mw-page-title-main">Mifepristone</span> Medication

Mifepristone, also known by its developmental code name RU-486, is a medication typically used in combination with misoprostol to bring about a medical abortion during pregnancy and manage early miscarriage. This combination is 97% effective during the first 63 days of pregnancy. It is also effective in the second trimester of pregnancy. It is taken by mouth.

Labor induction is the process or treatment that stimulates childbirth and delivery. Inducing (starting) labor can be accomplished with pharmaceutical or non-pharmaceutical methods. In Western countries, it is estimated that one-quarter of pregnant women have their labor medically induced with drug treatment. Inductions are most often performed either with prostaglandin drug treatment alone, or with a combination of prostaglandin and intravenous oxytocin treatment.

Cervical dilation is the opening of the cervix, the entrance to the uterus, during childbirth, miscarriage, induced abortion, or gynecological surgery. Cervical dilation may occur naturally, or may be induced surgically or medically.

Bloody show or show is the passage of a small amount of blood or blood-tinged mucus through the vagina near the end of pregnancy. It is caused by thinning and dilation of the cervix, leading to detachment of the cervical mucus plug that seals the cervix during pregnancy and tearing of small cervical blood vessels, and is one of the signs that labor may be imminent. The bloody show may be expelled from the vagina in pieces or altogether and often appears as a jelly-like piece of mucus stained with blood. Although the bloody show may be alarming at first, it is not a concern of patient health after 37 weeks gestation.

<span class="mw-page-title-main">Self-induced abortion</span> Abortion performed by a pregnant person themselves outside the recognized medical system

A self-induced abortion is an abortion performed by the pregnant woman herself, or with the help of other, non-medical assistance. Although the term includes abortions induced outside of a clinical setting with legal, sometimes over-the-counter medication, it also refers to efforts to terminate a pregnancy through alternative, potentially more dangerous methods. Such practices may present a threat to the health of women.

<span class="mw-page-title-main">Cervical effacement</span> Thinning and shortening of the cervix

Cervical effacement or cervical ripening refers to the thinning and shortening of the cervix. This process occurs during labor to prepare the cervix for dilation to allow the fetus to pass through the vagina. While this is a normal, physiological process that occurs at the later end of pregnancy, it can also be induced through medications and procedures.

Prostaglandin E<sub>2</sub> Chemical compound

Prostaglandin E2 (PGE2), also known as dinoprostone, is a naturally occurring prostaglandin with oxytocic properties that is used as a medication. Dinoprostone is used in labor induction, bleeding after delivery, termination of pregnancy, and in newborn babies to keep the ductus arteriosus open. In babies it is used in those with congenital heart defects until surgery can be carried out. It is also used to manage gestational trophoblastic disease. It may be used within the vagina or by injection into a vein.

<span class="mw-page-title-main">Uterine atony</span> Loss of tone in the uterine musculature

Uterine atony is the failure of the uterus to contract adequately following delivery. Contraction of the uterine muscles during labor compresses the blood vessels and slows flow, which helps prevent hemorrhage and facilitates coagulation. Therefore, a lack of uterine muscle contraction can lead to an acute hemorrhage, as the vasculature is not being sufficiently compressed. Uterine atony is the most common cause of postpartum hemorrhage, which is an emergency and potential cause of fatality. Across the globe, postpartum hemorrhage is among the top five causes of maternal death. Recognition of the warning signs of uterine atony in the setting of extensive postpartum bleeding should initiate interventions aimed at regaining stable uterine contraction.

<span class="mw-page-title-main">Carboprost</span> Chemical compound

Carboprost is a synthetic prostaglandin analogue of PGF2α with oxytocic properties.

<span class="mw-page-title-main">Postpartum bleeding</span> Loss of blood following childbirth

Postpartum bleeding or postpartum hemorrhage (PPH) is often defined as the loss of more than 500 ml or 1,000 ml of blood following childbirth. Some have added the requirement that there also be signs or symptoms of low blood volume for the condition to exist. Signs and symptoms may initially include: an increased heart rate, feeling faint upon standing, and an increased breathing rate. As more blood is lost, the patient may feel cold, blood pressure may drop, and they may become restless or unconscious. In severe cases circulatory collapse, disseminated intravascular coagulation and death can occur. The condition can occur up to twelve weeks following delivery in the secondary form. The most common cause is poor contraction of the uterus following childbirth. Not all of the placenta being delivered, a tear of the uterus, or poor blood clotting are other possible causes. It occurs more commonly in those who already have a low amount of red blood, are Asian, have a larger fetus or more than one fetus, are obese or are older than 40 years of age. It also occurs more commonly following caesarean sections, those in whom medications are used to start labor, those requiring the use of a vacuum or forceps, and those who have an episiotomy.

Prostaglandin E<sub>1</sub> Erectile dysfunction medication

Prostaglandin E1 (PGE1) is a naturally occurring prostaglandin and is also used as a medication (alprostadil).

<span class="mw-page-title-main">Carbetocin</span> Medication used for preventing postpartum bleeding

Carbetocin, sold under the brand names Pabal among others, is a medication used to prevent excessive bleeding after childbirth, particularly following Cesarean section. It appears to work as well as oxytocin. Due to it being less economical than other options, use is not recommended by NHS Scotland. It is given by injection into a vein or muscle.

<span class="mw-page-title-main">Vaginal delivery</span> Delivery through the vagina

A vaginal delivery is the birth of offspring in mammals through the vagina. It is the most common method of childbirth worldwide. It is considered the preferred method of delivery, as it is correlated with lower morbidity and mortality than caesarean sections (C-sections), though it is not clear whether this is causal.

<span class="mw-page-title-main">Osmotic dilator</span> Medical device to dilate the uterine cervix

Osmotic dilators are medical implements used to dilate the uterine cervix by swelling as they absorb fluid from surrounding tissue. They may be composed of natural or synthetic materials. A laminaria stick or tent is a thin rod made of the stems of dried Laminaria, a genus of kelp. Laminaria sticks can be generated from Laminaria japonica and Laminaria digitata. Synthetic osmotic dilators are commonly referred to by their brand names, such as Dilapan. Dilapan-S are composed of polyacrylonitrile, a plastic polymer. The hygroscopic nature of the polymer causes the dilator to absorb fluid and expand.

<span class="mw-page-title-main">Sulprostone</span> Chemical compound

Sulprostone is an analogue of prostaglandin E2 (PGE2) that has oxytocic activity in assays of rat kidney cells and tissues. There are four known receptors which mediate various but often different cellular and tissue responses to PGE2: prostaglandin EP1 receptor, prostaglandin EP2 receptor, prostaglandin EP3 receptor, and prostaglandin EP4 receptor. Sulprosotone binds to and activates the prostaglandin EP3 receptor with far greater efficacy than the other PGE2 receptors and also has the advantage of being relatively resistant, compared with PGE2, to becoming metabolically degraded. It is listed as a comparatively weak receptor agonist of the prostaglandin EP1 receptor. In all events, this as well as other potent synthetic EP3 receptor antagonists have the realized or potential ability to promote the beneficial effects of prostaglandin EP3 receptor activation.

A uterotonic, also known as an oxytocic or ecbolic, is a type of medication used to induce contraction or greater tonicity of the uterus. Uterotonics are used both to induce labor and to reduce postpartum hemorrhage.

Uterine hyperstimulation or hypertonic uterine dysfunction is a potential complication of labor induction. This is displayed as Uterine tachysystole- the contraction frequency numbering more than five in a 10-minute time frame or as contractions exceeding more than two minutes in duration. Uterine hyperstimulation may result in fetal heart rate abnormalities, uterine rupture, or placental abruption. It is usually treated by administering terbutaline.

Uterine Tachysystole is a condition of excessively frequent uterine contractions during pregnancy. It is most often seen in induced or augmented labor, though it can also occur during spontaneous labor, and this may result in fetal hypoxia and acidosis. This may have serious effects on both the mother and the fetus including hemorrhaging and death. There are still major gaps in understanding treatment as well as clinical outcomes of this condition. Uterine tachysystole is defined as more than 5 contractions in 10 minutes, averaged over a 30-minute period.

A medical abortion, also known as medication abortion or non-surgical abortion, occurs when drugs (medication) are used to bring about an abortion. Medical abortions are an alternative to surgical abortions such as vacuum aspiration or dilation and curettage. Medical abortions are more common than surgical abortions in most places around the world.

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