Misoprostol

Article Author:
Marissa Krugh
Article Editor:
Christopher Maani
Updated:
4/5/2019 12:31:17 AM
PubMed Link:
Misoprostol

Indications

Misoprostol has four main effects. 

  1. Cytoprotection of the gastrointestinal mucosa 
  2. Uterotonic
  3. Diarrhea 
  4. Abdominal pain (diarrhea and abdominal pain are considered adverse effects).[1] 

Currently, misoprostol is FDA approved only for the prevention and treatment of NSAID-induced gastric ulcers in patients taking NSAIDs and at high risk for ulceration. It has an indication (but not FDA approved) in the short-term treatment of active duodenal or gastric ulcers with other etiologies.[2]

Although misoprostol is used around the world in gynecology and obstetrics, however, none of these indications are FDA approved. 

The combination of misoprostol and mifepristone has reported widespread use for medical abortions with an acceptable safety profile. Unfortunately, reports of significant adverse events without significant data have hindered FDA approval. Therefore, there is an extensive debate between the governing societies regarding the dosing standardization of this regimen. It may receive approval once there is additional research, and there is an agreed dosing strategy.[1]

It is used for termination of pregnancy in the first and second trimesters as either monotherapy or in combination with intramuscular methotrexate.[1] Clinicians also use misoprostol as expectant management of missed and incomplete abortions. 

At much smaller doses, misoprostol is used to induce cervical ripening and induce labor in full-term pregnancies. It may also be employed to induce labor following intrauterine fetal demise.[3]

After labor, it also has a use for the treatment of postpartum uterine bleeding upon failure of uterine massage, and/or when other uterotonic medications are not readily available.[4]

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, caffeine, etc.  This effect tends to have a dose-dependent relationship. 

Misoprostol induces mucus and bicarbonate secretion as well edema of the mucosa and submucosa which causes thickening of the mucosal bilayer, which results in a reduced backflow of hydrogen ions and improved regulation of mucosal blood flow, which 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 its abortifacient properties, as well as its ability to promote labor and cervical ripening. Cervical dilation is produced primarily via degradation of collagen in the connective tissue of the stroma and reduction in cervical tone from increased amplitude and frequency of contractions. Its uterotonic properties are also used to decrease postpartum bleeding.[5][6]

Abdominal pain and diarrhea are thought to be a result of exposure to the misoprostolic acid released during metabolism, as symptoms seem to correlate with the misoprostolic acid peak plasma concentration.[1]

Administration

Currently, the only FDA approved route of administration is oral.  Although not FDA approved, misoprostol may also be administered sublingually, buccally, vaginally, or rectally via digital placement of tablets or suppositories. Despite a plethora of studies comparing the efficacy and safety profiles of the different routes of administration for obstetric uses, there are no definitive conclusions regarding this use.[7] 

It is best to take medication at night time with meals to minimize GI upset when given orally. Do not take with magnesium-containing antacids, as this combination may contribute to misoprostol-induced diarrhea. 

Adverse Effects

The most commonly reported adverse effects are generally mild and include shivering/chills, diarrhea, abdominal pain, hyperthermia, nausea, vomiting, flatulence, constipation, dyspepsia, headache, breakthrough bleeding, and menstrual irregularity. Less reported mild side 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 side effects include self-limiting diarrhea and abdominal pain, thought to be secondary to exposure to the misoprostolic acid released during its metabolism. The basis for this line of reasoning is the observation that symptom severity tends to correlate with misoprostolic acid’s peak plasma concentration.[1]

Fever and chills are relatively common and thought to be secondary to the effect of prostaglandin on the hypothalamus. These mild side effects occur most commonly when misoprostol is administered in relatively large doses, such as to treat postpartum hemorrhage.[8] 

Congenital defects correlate with exposure to misoprostol in early pregnancy. However, no data shows misoprostol to be directly related to embryotoxic/fetotoxic or teratogenic effects. Mutagenetic studies have been negative. Defects are thought to be due to a decrease in fetal blood supply during contractions induced by misoprostol. Additionally, there seems to be a relationship between the time of exposure and the range of defects observed. Most common defects are in the central nervous system and limbs. Mobius syndrome also correlates with misoprostol exposure.[8]

The use of prostaglandins in cervical ripening correlates with an increased risk of tachysystole, non-reassuring fetal heart rate, and fetal hypoxemia.[6]

There is a risk for uterine rupture with misoprostol use. This risk tends to be highest when misoprostol is used for labor induction in the third trimester, especially in conjunction with other risk factors such as previous caesarian section. Rupture is rare during a first-trimester medical abortion using misoprostol. However, as with all uterine ruptures, there is a risk for subsequent uterine infection.[8]

Contraindications

Misoprostol is contraindicated in those with previous allergic reaction or hypersensitivity to prostaglandin. Those at risk for gastric ulcers secondary to NSAID use and are pregnant should not take misoprostol given the adverse effects reported during pregnancy.

Besides allergic reactions, there are no absolute contraindications for misoprostol's gynecologic and obstetric indications given the lack of society-approved guidelines for these uses. Contraindications are relative to the drug's desired effect and should be individualized depending on each patients 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.[9] 

Monitoring

Misoprostol is a generally safe and well-tolerated drug. Currently, there are no monitoring guidelines when being used for its FDA approved indication.

Similarly, there are no current guidelines regarding misoprostol’s obstetric and gynecologic indications. When used to induce labor, fetal monitoring is recommended. However, there is some data suggesting induction of labor using misoprostol in an outpatient setting could be feasible.[9]

Toxicity

Misoprostol is a generally safe and well-tolerated drug, and currently, the toxic dose is unknown.[8]

Enhancing Healthcare Team Outcomes

NSAID-induced gastritis is a very common occurrence encountered by a vast spectrum of medical specialties. Data supports the underutilization of strategies to prevent NSAID induced gastritis in those at risk for gastrointestinal complications of NSAID therapy (Level IV).  One retrospective observational cohort study revealed that among new NSAID users, 86.6% of patients with one risk factor for upper gastrointestinal ulcers and 81.2% with two risk factors did not receive appropriate prophylaxis.[10] Experts believe that better compliance with this principle is achievable through education of clinicians and patients alike.[11]

Women who present for medical management of first-trimester miscarriage must be made aware misoprostol does not hold FDA approval for this particular use. Increased healthcare costs may be a result of 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 for complication, emergency department presentations, and the need for surgical evacuation.[1][12] It is imperative public hospitals have protocols in place for these indications as there are no formal guidelines. Private organizations should have a credible system able to withstand peer-review and legal challenges. Otherwise, an adverse outcome could potentially pose a medical-legal hardship for the physician.[1]

When using misoprostol for any indication, a multidisciplinary team approach between physicians and/or mid-level providers (PAs, NPs), pharmacy, and nursing is the optimal care strategy. This is particularly true in the obstetric realm, where FDA approval is lacking, and the patient can benefit form pharmacist input along with nurses who have specialized obstetric training. [Level V]


References

[1] Turner JV,Agatonovic-Kustrn S,Ward H, Off-label use of misoprostol in gynaecology. Facts, views     [PubMed PMID: 27729972]
[2] Kim JW, [NSAID-induced gastroenteropathy]. The Korean journal of gastroenterology = Taehan Sohwagi Hakhoe chi. 2008 Sep;     [PubMed PMID: 19077509]
[3] Pierce S,Bakker R,Myers DA,Edwards RK, Clinical Insights for Cervical Ripening and Labor Induction Using Prostaglandins. AJP reports. 2018 Oct;     [PubMed PMID: 30377555]
[4] Gallos ID,Papadopoulou A,Man R,Athanasopoulos N,Tobias A,Price MJ,Williams MJ,Diaz V,Pasquale J,Chamillard M,Widmer M,Tunçalp Ö,Hofmeyr GJ,Althabe F,Gülmezoglu AM,Vogel JP,Oladapo OT,Coomarasamy A, Uterotonic agents for preventing postpartum haemorrhage: a network meta-analysis. The Cochrane database of systematic reviews. 2018 Dec 19;     [PubMed PMID: 30569545]
[5] Stephenson ML,Wing DA, Misoprostol for induction of labor. Seminars in perinatology. 2015 Oct;     [PubMed PMID: 26601733]
[6] Bakker R,Pierce S,Myers D, The role of prostaglandins E1 and E2, dinoprostone, and misoprostol in cervical ripening and the induction of labor: a mechanistic approach. Archives of gynecology and obstetrics. 2017 Aug;     [PubMed PMID: 28585102]
[7] Alfirevic Z,Aflaifel N,Weeks A, Oral misoprostol for induction of labour. The Cochrane database of systematic reviews. 2014 Jun 13;     [PubMed PMID: 24924489]
[8] Tang OS,Gemzell-Danielsson K,Ho PC, Misoprostol: pharmacokinetic profiles, effects on the uterus and side-effects. International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics. 2007 Dec;     [PubMed PMID: 17963768]
[9] Vogel JP,Osoti AO,Kelly AJ,Livio S,Norman JE,Alfirevic Z, Pharmacological and mechanical interventions for labour induction in outpatient settings. The Cochrane database of systematic reviews. 2017 Sep 13;     [PubMed PMID: 28901007]
[10] Sturkenboom MC,Burke TA,Dieleman JP,Tangelder MJ,Lee F,Goldstein JL, Underutilization of preventive strategies in patients receiving NSAIDs. Rheumatology (Oxford, England). 2003 Nov;     [PubMed PMID: 14585915]
[11] den Hollander WJ,Kuipers EJ, Current pharmacotherapy options for gastritis. Expert opinion on pharmacotherapy. 2012 Dec;     [PubMed PMID: 23167300]
[12] Torre A,Huchon C,Bussieres L,Machevin E,Camus E,Fauconnier A, Immediate versus delayed medical treatment for first-trimester miscarriage: a randomized trial. American journal of obstetrics and gynecology. 2012 Mar;     [PubMed PMID: 22381604]