Introduction

Misoprostol (15-deoxy-16-hydroxy-16-methyl PGE1;Figure 1) is a synthetic prostaglandin E1 analogue. It was developed for the prevention and treatment of peptic ulcers because of its gastric acid anti-secretory properties and its various mucosal protective properties. It has become an important drug in obstetric and gynecological practice because of its uterotonic and cervical priming action. In comparison to other prostaglandin analogues, misoprostol has the advantages of being cheap, widely available, stable at room temperature and having few side effects. Its clinical applications include medical abortion, medical evacuation for miscarriages,cervical priming before surgical procedure, induction of labor and management of postpartum hemorrhage. [1]

Chemistry of misoprostol

The naturally occurring prostaglandin E series was discovered to inhibit gastric acid secretion in 1967 by Robert et al.. However, naturally occurring prostaglandins have three drawbacks that hindered their clinical application. These problems were: (1)rapid metabolism resulting in a lack of oral activity and a short duration of action when given parenterally, (2)numerous side effects, and (3)chemical instability leading to a short shelf life. Misoprostol differs structurally from prostaglandin E by the presence of a methyl ester at C-1, a methyl group at C-16 and a hydroxyl group at C-16 rather than at C-15. The methyl ester at C-1increases the anti-secretory potency and duration of action of misoprostol, whilst the movement of the hydroxyl group fromC-15 to C-16 and the addition of a methyl group at C-16improves oral activity, increases the duration of action, and improves the safety profile of the drug.[1]

The pharmacokinetic properties of misoprostol

Misoprostol is a synthetic analogue of PGE1. It is metabolized in the liver, deesterified and becomes the active metabolite, misoprostol acid. It has the ability to bind to uterine smooth muscle cells, increasing the strength and frequency of uterine contractions. In the uterinecervix, it also promotes the breakdown of collagen inthe connective tissue and a reduction in cervical tonus. Misoprostol can be used orally, vaginally, sublingually and rectally. In oral administration, the drug reaches its maximum peak 20-30 minutes after ingestion, remaining detectable for up to four hours. Misoprostol administered sublingually is absorbed more quickly and has higher peak concentrations than when administered orally, which tends to cause higher rates of gastrointestinal side effects at any dose. Overall bioavailability of the drug used vaginally is greater, since the absorption is slower than in other routes, and the maximum plasmatic peak is reached in 40-60 minutes, remaining stable up to two hours after application. The vaginal route also allows for greater effects on the cervix and uterus. The pharmacokinetics of rectal misoprostolis similar to that of vaginal misoprostol, although with a lower overall bioavailability and a significantly lower peak plasma level. It has been demonstrated that levels of misoprostol in breast milk are known to peak and decline rapidly with an average half-life of around one hour. Although it normally appears in colostrum and milk, the low levels detected suggest that a minimal amount of misoprostol could potentially be ingested by the newborn.[2]

The adverse effects and contraindications for using misoprostol

The most common adverse effects of misoprostol are nausea, vomiting, diarrhea, abdominal pain,chills, shivering and fever. All these effects are dose-dependent. Gastrointestinal effects may occur in approximately 35% of women and are more common after oral or sublingual administration. Diarrhea is the most common adverse effect and is usually mild and self-limited to one day. Shivering and fever are also transitory effects and may occur in 28% and 7.5%, respectively, of women who used 600 mcg of misoprostol orally. The occurrence of fever and shivering from misoprostol in the active management of the third stage favors the routine use of oxytoc in as the drug of choice for the prevention of hemorrhage. Although dose-dependent, uterinehyper stimulation is one of the most frequent adverse effects in labor induction. The risk of uterine hyperstimulation was high with high doses of misoprostol used in the past. With low doses (≤50 mcg of initial dose), the risk is similar to that of dinoprostone, 4-12%, depending on the route and dosage. In a Cochrane meta-analysis, the risk of hyperstimulation with alteration of fetal heart rate was significantly lower with low-dose oral misoprostol (3.4%)compared to vaginal dinoprostone (7.0%; RR: 0.49; 0.40-0.59). In that same meta-analysis, a lower risk of hyperstimulation with fetal cardiac alteration was also found with oral misoprostol (3.9%), compared to the vaginal route (5.7%;RR: 0.69; 0.53-0.92). Fetal distress, the presence of meconium in the amniotic fluid and uterine rupture may occuras a result of hyperstimulation (hypersystole or tachysystole with or without hypertonia). Uterine rupture is themost feared adverse effect of labor induction, especially in women with previous uterine scar. Although extremely rare, there are case reports of uterine rupture during first-trimester abortion induction. Most cases of uterine rupture have been described in third-trimester inductions and associated with previous uterine scar or other risk factors.The risk of uterine rupture in women with induction of labor for vaginal delivery after cesarean section with misoprostol is 6-12%. Therefore, this is usually a contraindication for using the drug. It is important to emphasize that misoprostol can be used in the second trimester in women with a previous cesarean section, since most studies point to a low risk of uterine rupture. A meta-analysis identified that this risk is not significantly different when the woman has had a previous cesarean section (0.47%) compared to no uterine scar (0.08%; RR: 2.36; 0.39-14.32), although it is significantly higher with two or more previous cesarean sections (2.5%; RR: 17 ,55; 3-102.8).[2]

References

1.Tang OS, Gemzell-Danielsson K, Ho PC. Misoprostol: pharmacokinetic profiles, effects on the uterus and side-effects. Int J Gynaecol Obstet. 2007;99 Suppl 2:S160-S167. doi:10.1016/j.ijgo.2007.09.004

2.Coordinator; National Specialized Commission on Maternal Mortality; National Specialized Commission on Fetal Medicine; Misoprostol use in obstetrics. Rev Bras Ginecol Obstet. 2023;45(6):356-368. doi:10.1055/s-0043-1770931