Misoprostol

Mechanism of Action

Misoprostol is a synthetic prostaglandin E1 analog that inhibits basal and nocturnal gastric acid secretion through direct stimulation of prostaglandin E1 receptors on parietal cells in the stomach. This action inhibits gastric acid secretion secondary to stimulation from food, alcohol, NSAIDs, histamine, and caffeine. This effect tends to have a dose-dependent relationship. 

Misoprostol induces mucus and bicarbonate secretion and edema of the mucosa and submucosa, causing thickening of the mucosal bilayer and resulting in a reduced backflow of hydrogen ions and improved regulation of mucosal blood flow. The effect ultimately leads to the preservation of the mucosa's ability to produce new cells.[1]

Uterotonic effects are caused by prostaglandin binding to smooth muscle cells in the uterine lining; this is responsible for the abortifacient properties and ability to promote labor and cervical ripening. Cervical dilation is produced primarily via the degradation of collagen in the connective tissue of the stroma and reduction in cervical tone from increased amplitude and frequency of contractions. The drug's uterotonic properties are also useful to help decrease postpartum bleeding.[11][12]

Pharmacokinetics

Absorption: Misoprostol is rapidly absorbed after oral administration; peak plasma concentration is 12±3 minutes. The onset of action (inhibition of gastric acid secretion) is approximately 30 minutes after oral administration and persists for about 3 hours.

Distribution: Plasma protein binding of misoprostol acid is <90%. Misoprostol is excreted in breast milk.[13]

Metabolism: Misoprostol is a pro-drug metabolized by de-esterification into the active metabolite misoprostol acid.[14]

Elimination: Misorpostol is primarily excreted in urine as inactive metabolites.[15]

Administration

Available Dosage Forms and Strengths

FDA-approved route of administration is oral and buccal (in combination with mifepristone). Misoprostol may also be administered sublingually, vaginally, or rectally via digital placement of tablets or suppositories.[16]

Adult Dosage

NSAID-induced ulcers: The best practice is to take the medication at night with meals to minimize gastrointestinal upset when given orally. The dosage is 200 mcg, administered 4 times daily (800 mcg/d). Misoprostol 800 mcg/d is superior to 400 mcg/d for gastric ulcers but is associated with significantly adverse effects.[17]

Medical abortion up to 70 days: According to ACOG guidelines, clinicians should confirm pregnancy and estimate gestational age. The regimen for termination of pregnancy is a single dose of mifepristone 200 mg and misoprostol 800 mcg buccally. On day 1, a 200 mg tablet of mifepristone is administered in a single oral dose. On days 2 or 3, four 200 mcg misoprostol tablets should be placed in the buccal pouch, resulting in a total dose of 800 mcg. Misoprostol should be kept in cheek pouches for at least 30 minutes. Misoprostol should be taken within 24 to 48 hours after taking mifepristone.

Misoprostol-only regimen (off-label): ACOG also provides recommendations for a misoprostol-only regimen. The recommended dosage is 800 mcg of misoprostol, repeated every 3 hours for up to 3 doses. The route of administration is vaginal, sublingual, or buccal.[7] 

According to The International Federation of Gynecology and Obstetrics (FIGO) guidelines, misoprostol alone can be used for up to 13 weeks (off-label use) for termination of pregnancy. Recommendations of FIGO are 800 mcg of misoprostol given sublingually administered every 3 hours. An alternate recommendation is 800 mcg of misoprostol administered every 3 to 12 hours for up to 2 or 3 doses (vaginal or buccal route). Intravaginal administration of misoprostol should be avoided if bleeding or infection ensues.[18]

Cervical ripening and induction of labor: According to ACOG, vaginal misoprostol appears to be the most effective method of labor induction before 28 weeks of gestation. Misoprostol can be given for cervical ripening and labor induction at a dose of 25 mcg. The frequency of misoprostol administration should not exceed 3 to 6 hours. Sublingual or buccal routes should be avoided.[19]

Early pregnancy loss: Early pregnancy loss is characterized as an intrauterine pregnancy that is nonviable with either an empty gestational sac or without fetal heart activity before 13 weeks of pregnancy. According to ACOG, 800 mcg of vaginal misoprostol is recommended, with a repeat dose as required. Oral mifepristone 200 mg administered 24 hours before misoprostol can improve treatment efficacy.[20]

Postpartum hemorrhage: Misoprostol is normally used in combination with oxytocin. However, misoprostol monotherapy can be considered for postpartum hemorrhage if oxytocin is unavailable. The dose is 600 mcg to 1000 mcg as a single dose by oral, sublingual, or rectal route.[21]

Specific Patient Populations

Renal impairment: No dosage adjustment is advised for patients with renal impairment, but a dose reduction may be required if the usual dose is not tolerated.

Hepatic impairment: No dosage adjustment is provided in the product labeling.

Pregnancy considerations: Misoprostol should not be used for NSAID-induced ulcers during pregnancy. Misoprostol is associated with the Moebius Sequence (Moebius syndrome) when used during the first trimester of pregnancy. Mobius sequence is characterized by bilateral paralysis of the abducens and facial nerves, craniofacial, ophthalmological, and limb malformations.[22][23] In addition, hydrocephalus, terminal transverse limb, syndactyly, clubfoot, and complete posterior encephalocele are reported.[24]

Breastfeeding considerations: Misoprostol and its active metabolite are present in breast milk. Due to the low concentration of misoprostol in breast milk, no adverse effects are anticipated in breastfed infants. However, caution is required as per the manufacturer's labeling.[25]

Pediatric patients: The safety and efficacy of misoprostol have not been established in pediatric patients. 

Older patients: No dosage adjustment is advised; dose reduction may be required if the usual dose is not tolerated.

Adverse Effects

The most commonly reported adverse effects are generally mild, including shivering/chills, diarrhea, abdominal pain, hyperthermia, nausea, vomiting, flatulence, constipation, dyspepsia, headache, breakthrough bleeding, and menstrual irregularity. Less reported mild adverse effects include syncope, lethargy, weakness, and vertigo. 

Moderate-to-severe reactions are less common and include hypotension, sinus tachycardia, fetal bradycardia, uterine contractions and pain, vaginal bleeding, edema, myocardial infarction, uterine rupture, cervical laceration, fetal death, teratogenesis, pulmonary embolism, anaphylactoid reactions, and thrombosis. 

The most frequently encountered adverse effects include self-limiting diarrhea and abdominal pain, secondary to exposure to the misoprostol acid released during its metabolism. The reasoning is the observation that symptom severity tends to correlate with misoprostol acid's peak plasma concentration.[1]

Fever and chills are relatively common and secondary to prostaglandin's effect on the hypothalamus. These mild adverse effects occur most commonly when misoprostol is administered in relatively large doses, such as to treat postpartum hemorrhage.[26] 

Congenital disabilities correlate with exposure to misoprostol in early pregnancy. However, no data show misoprostol directly related to embryotoxic/fetotoxic or teratogenic effects. Mutagenetic studies have been negative. Defects are due to decreased fetal blood supply during contractions induced by misoprostol. Additionally, a relationship between the exposure time and the range of defects was observed. The most common defects are in the central nervous system and limbs.[26]

Using prostaglandins in cervical ripening correlates with an increased risk of tachysystole, non-reassuring fetal heart rate, and fetal hypoxemia.[12][27]

Drug-Drug Interactions

Antacids: Concurrent administration of misoprostol with magnesium-containing antacids increases the incidence of diarrhea.

Contraindications

Box Warnings

• Misoprostol has been associated with premature birth, congenital disabilities, and abortion when administered to pregnant women.

• A risk of uterine rupture with misoprostol use exists. This risk is highest when misoprostol is used for labor induction beyond 8 weeks of gestation, especially in conjunction with other risk factors such as the previous caesarian section. Rupture is rare during a first-trimester medical abortion using misoprostol. However, as with all uterine ruptures, a risk for subsequent uterine infection exists.[26]

• Misoprostol should not be prescribed for NSAID-induced ulcers in women of childbearing potential. If misoprostol is prescribed for NSAID-induced ulcers in patients with a high risk of complications, clinicians should ensure that the patient has a negative serum pregnancy test within 2 weeks of initiating misoprostol. In addition, patients should be capable of complying with effective contraception. Clinicians should provide oral and written warnings of the risks associated with misoprostol and the risk of contraceptive failure. The patient should be instructed to initiate misoprostol only on the second or third day of the next normal menstrual cycle.

Warnings and Precautions

Misoprostol is contraindicated in those with previous allergic reactions or hypersensitivity to prostaglandin.[21][28] Patients at risk for gastric ulcers secondary to NSAID use and those who are pregnant should not take misoprostol, given the adverse effects reported during pregnancy.  

Contraindications are relative to the drug's desired effect and should be individualized depending on each patient's risk factors. For example, given the increased risk of uterine rupture, those with previous caesarian sections should not take misoprostol to induce a medical abortion.[29]

Monitoring

Misoprostol is a generally safe and well-tolerated drug. However, caution should be utilized when administering misoprostol to patients with pre-existing cardiovascular diseases. Misoprostol-induced coronary vasospasm has been reported.[30]

When using misoprostol for medical abortion, clinicians should perform follow-up evaluations, including medical history, physical examination, human chorionic gonadotropin (hCG) test, and ultrasonography. Rh testing is advised in patients with unknown Rh status before a medical abortion; Rh D immunoglobulin should be administered as indicated.[31]

When used to induce labor, fetal monitoring is recommended. However, some data suggest that induction of labor using misoprostol in an outpatient setting is feasible.[29]

Toxicity

Misoprostol is a generally safe and well-tolerated drug in the usual 400 to 800 mcg dose.[26] A rare case of maternal death has been associated with an overdose of misoprostol. An overdose of 12 mg of oral misoprostol (self-medication) for medical abortion resulted in upper gastrointestinal bleeding, hemodynamic instability, and multiorgan failure. Emergency laparotomy demonstrated gastric and esophageal necrosis. The patient's death was due to cardiac arrest after adequate resuscitation.[32]

Enhancing Healthcare Team Outcomes

NSAID-induced gastritis is a widespread occurrence encountered by many medical specialties. Data support the underutilization of strategies to prevent NSAID-induced gastritis in those at risk for gastrointestinal complications of NSAID therapy.

One retrospective observational cohort study revealed that among new NSAID users, 86.6% of patients with 1 risk factor for upper gastrointestinal ulcers and 81.2% with 2 risk factors did not receive appropriate prophylaxis.[33] Experts believe better compliance with this principle is achievable by educating clinicians and patients.[34] A gastroenterologist should be consulted for NSAID-induced ulcers presenting with complications. Misoprostol is not always well tolerated due to diarrhea and abdominal pain, preventing continued use, and lower doses of misoprostol with reduced adverse effects may also be less effective at mitigating NSAID-induced gastrointestinal events. Proton-pump-inhibiting drugs are more commonly used for this purpose, but the benefits are still somewhat equivocal.[35] 

The mifepristone and misoprostol combination is FDA-approved for medical abortion, with state regulations in place.[6] Women who present for medical management of first-trimester miscarriage must be aware by obstetricians that misoprostol monotherapy can be used off-label. Increased healthcare costs may result from delayed medical management of elective abortion as women contemplate the cost and unease with the "off-label" status. Any delay in abortion increases the risk of complications, emergency department presentations, and the need for surgical evacuation.[1][36] 

Public hospitals must have protocols based on evidence-based medicine and current medical perspectives.[37] Similarly, private organizations should maintain a credible system capable of withstanding peer review and legal scrutiny. Failure to do so could potentially result in medical-legal challenges for the clinician in the event of adverse outcomes. Hence, interprofessional collaborative input from pharmacists, nursing staff, specialists, and administration is imperative.[1]

When using misoprostol for any indication, the optimal care strategy is the interprofessional team approach among prescribing clinicians and advanced practice practitioners, pharmacists, specialists, and nursing staff. This strategy is essential in the obstetric domain, where the patient can benefit from pharmacist input and nurses with specialized obstetric training. With open communication and shared decision-making, this interprofessional paradigm optimizes misoprostol therapy for all indications when the drug is indicated.