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MISOPROSTOL IN OBSTETRICS

New information adds valuable evidence,  obstetric use of misoprostol is useful .Misoprostol  side‐effects  tolerable, and less prevalent with prescribed doses.Misoprostol can treat the two largest causes of maternal mortality worldwide, -postpartum hemorrhage and -unsafe abortionIt is cheap and readily available, easy to store and, doesn't need skill to use. Information given to women by pharmacy workers needs to be accurate.Effectiveness of obstetric use of misoprostol in low‐resource settings,a real need under a social perspective. 

drsujnanendra
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MISOPROSTOL IN OBSTETRICS

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  1. Misoprostol In Obstetrics Dr.Sujnanendra Mishra

  2. HISTORY The first prostaglandin effects were discovered in 1930. During artificial insemination, in a number of cases, semen injected into the uterine cavity was promptly expelled. (Kurzrok and Lieb, 1930) A powerful vasodilator substance with ability to stimulate muscle activity was discovered from seminal fluid (Goldblatt, 1935) This acid, lipid-soluble, smooth-muscle-stimulating and blood-pressure-lowering principle was named prostaglandin (v. Euler, 1935) as it was found in seminal fluid from the prostate gland. Was shown to consist of highly active, lipid-soluble, unsaturated hydroxyacids (Bergström, 1949). Almost 10 years later, the chemical structure was elucidated and named prostaglandin E (Bergström and Sjövall, 1960) Other prostaglandins, such asPGE2, PGF2, etc., were identified somewhat later. Karim A. worked extensively on use of prostaglandins to induce labour. It is turned into a common method of the induction of labour and abortion.

  3. Nature

  4. Prostaglandins • A family of compounds that have the 20-carbon skeleton of prostanoic acid. Prostaglandins Synthesis

  5. Prostaglandins The PGE1analog Misoprostol (C22 H38 O5, M:W.= 382.5; (11, 13E,16-dihydroxy-16-methyl-9oxoprost-13-en-1-oic acid methyl ester),

  6. Misoprostol Chemistry • Discovered in 1973 • Prostaglandin E1 analogue • Slight structural modifications leads to: • increase anti-secretory potency • increase duration of action (half life of naturally occurring prostaglandins seconds) • improve oral bioavailability • improve safety profile • Misoprostol was registered in 1986 for the prevention and treatment of peptic ulcers resulted from NSAID. • It is safe and well tolerated within the recommended dose of 800 µ g/day.

  7. Distribution & Metabolism • High variability of plasma levels between and within studies • Mean plasma levels after single oral doses show a linear relationship with dose over the range of 200-400 mcg • No accumulation of misoprostol noted in multiple dose studies • Serum protein binding less than 90%, concentration-independent in the therapeutic range • Undergoes rapid de-esterification to produce clinically active misoprostol acid. • Misoprostol acid further metabolized by oxidation, primarily in the liver

  8. Excretion • Mainly urinary excretion- 80% in urine • Plasma elimination half-life reported to be between 20 and 40 minutes • Misoprostol acid is secreted into breast milk • Studies in patients with varying degrees of renal impairment have shown: • approximate doubling of T1/2, C max, and AUC compared to normal controls • no clear correlation between the degree of impairment and AUC. • No routine dosage adjustment recommended in patients with renal impairment, but dosage may need to be reduced if the usual dose is not tolerated • Does not affect the hepatic mixed function oxidase (cytochrome P-450) enzyme systems in animals- • No known drug interactions

  9. Mechanism of action Uterotonic Action • Misoprostol Acid gets attached to its receptor • ↓ • Inhibition of adenyl cyclase • ↓ • Reduction of cAMP (central second messenger) • ↓ • Entry of Ca2+through calcium dependent channels(intra & extracellular) • ↓ • Increase in intracellular calcium levels. • ↓ • uterine contraction.

  10. Misoprostol: an old drug, new indications. ROUTE OF ADMINSTRATION

  11. ORAL • Rapidly absorbed after oral doses • Peak plasma concentrations occur after about 15 to 30 minutes • Food reduces the rate but not the extent of absorption • Concomitant antacid use reduces total availability Buccal • Similar concentration profile to vaginal administration • Lower bioavailability (~50%) Sublingual

  12. Vaginal • Longer time to peak plasma conc. (70-80min.) • Longer duration of action • Greater overall bioavailability (AUC) • Large degree of variation in bioavailability between women • Possible Mechanism for direct vaginal action → transport of the agent in to cervix and uterus proposed. Rectal • Similar concentration profile to vaginal administration • Lower bioavailability (~33%) • Onset of action significantly slower than other routes

  13. New Form of Misoprostol Speeds Up Labor • A novel form of misoprostol designed for induction of labor works faster than a similar vaginal insert of dinoprostone. • Misoprostol vaginal suppository was associated with reduced need for tocolytics and no increase in cesarean deliveries. by Ferring Pharmaceuticals (formerly Cytokine). http://www.medpagetoday.com/MeetingCoverage/SMFM/37406

  14. Pharmacokinetics

  15. Sublingual Oral Vaginal 2-The mean time to peak levels 1- The peak concentration This curve determines the route 3-The Area under the curve Time (minutes) Mean plasma concentrations of misoprostol acid over time.. Tang et al :Human Reproduction, Vol. 17, No. 2, 332-336, February 2002

  16. Pharmacokinetics in Pregnancy There is no clinically significant difference between vaginal misoprostol that is administered dry and vaginal misoprostol moistened with water, saline, or acetic acid. Tang OS et al, “Pharmacokinetics of different routes of administration of misoprostol,” Hum Reprod. 2002;17:332-336.

  17. Mean uterine activity (4 routes)

  18. Pharmacokinetic Profiles: Key Facts * After oral administration, uterine tonus develops, which is not followed by uterine contractions,unless repeated doses are given Tang et al., Int J GynecolObstet (2007) 99, S160–S167

  19. Physiological Effects(on Uterus &Cervix) UTEROTONIC Cervical softening • Single oral dose ↑ tonus (for 1-2h) • Repeated oral doses → regular contractions • Single vaginal dose will produce regular contractions (sustained plasma conc.) • Increased tonus more rapid and more pronounced with oral/sublingual (8/11 min.) compared with vaginal (20 min.) • Durations of action Differ. • Misoprostol reduces the force required for cervical dilatation • Appears to have an action on collagen, encouraging its disintegration and dissolution

  20. “knowledge without application is like a book that is never read” Christopher Crawford, Clinical Applications

  21. Clinical Applications Use in RH Conditions Use in Non RH Conditions • As Uterotonic • Medical management of early pregnancy failure • anembryonic pregnancies and • embryonic demise, and • missed or incomplete abortion • Induction in the first & second trimester • Labor induction with both alive &dead fetus. • Prevention &Treatment of postpartum hemorrhage • Cervical ripening before • Surgical abortion in the first or second trimester • Hysteroscopy • Dilation of cervix • Possibly for infertility • ED as intraurethral cream • Anti-secretory agent • for the prevention and treatment of peptic ulcers resulted from NSAID. • To prevent closure of patent ductus arteriosus in newborns in few con.Cyan.HD • In pulmonary hypertension • In peripheral Arterial diseases. • Treatment of glaucoma (as bimatoprostophthalmic solution) • Penile rehabilitation following surgery (PGE1 as alprostadil). • As an ingredient in eyelash and eyebrow growth beauty products (utilising its side effects of hypertrichosis on prolonged use)

  22. Adversereactions • Diarrhea • Abdominal pain • Headache • Nausea • Vomiting • Flatulence • Chills • Shivering • fever • Common but self limiting • Dose/Route-dependent

  23. RISKS • Uterine rupture • Uterine hyper stimulation • Amniotic fluid embolism • Foetal Distress Every positive value has its price in negative terms... the genius of Einstein leads to Hiroshima. Pablo Picasso

  24. Toxicity No serious side effects 2200 g (11 tablets) Serious side effects: Hyperthermia Rhabdomyolysis Hypoxemia Acid-base balance disorder 6000 g (30 tablets)

  25. AVAILABILITY

  26. World map of misoprostol approval. Produced by Gynuity Health Projects. Access at www.gynuity.org.

  27. International Federation of Gynecology and Obstetrics The International Federation of Gynecology and Obstetrics (FIGO) is an umbrella organization for 124 national professional associations of obstetrics and gynecology around the world. FIGO/WHO - MISOPROSTOL Dosage recommendation

  28. Safe Single Doses Of Vaginal Misoprostol For the first trimester 800µg can be safely used.  In the second trimester 200µg After 24 weeks 25µg 6 hourly is usually used.  Higher dose: Uterine hyperstimulation& rupture or Foetaldistress

  29. a WHO/RHR. Safe abortion: technical and policy guidance for health systems (2nd edition), 2012 b Gemzell-Danielsson et al. IJGO, 2007 1 Only use where legal and with mifepristone, where available 2 Included in the WHO Model List of Essential Medicines 3 Leave to work for 1-2 weeks unless excessive bleeding or infection

  30. Prevention of Postpartum Haemorrhage (management of 3rd stage) Prophylactic oxytocics should be offered routinely in the management of the third stage of labour in all women as they reduce the risk of PPH by 60%. For women without risk factors for PPH delivering vaginally, oxytocin (5 i.u or 10 i.u by intramuscular injection) is the agent of choice for prophylaxis in the third stage of labour. AMTSL RCOG Green-top Guideline No. 52May 2009

  31. Misoprostol For Prevention of Postpartum Haemorrhage Recommended Dosages 600 µg orally or sublingually Where injectable conventional uterotonics are not available. Second dose (for continued atonic hemorrhage): preferably 2 h after the original dose or 6 h if there is pyrexia or marked shivering. WHO Clinical Guidelines Bellagio, Italy in Feb 2007 Gómez Ponce de Leónet al., Int J GynecolObstet(2007) 99, (supp 2):S190.FIGO October 2009 Misoprostol should be used only after the provider has exhausted all standard PPH treatments (oxytocin drip, uterine massage, and/or compression)/injection of quality oxytocin is not possible . All potential causes for PPH should be explored to assure that the PPH is not due to another factor besides uterine atony.

  32. POSSIBLE CONGENITAL ANOMALIES Teratogenicity: While the relative risk of malformations appears real, epidemiological studies indicate that the absolute risk is low but significant. It is < 10 malformations per 1,000 births exposed to misoprostol in utero (<1% ).

  33. Misoprostol and Breastfeeding • Misoprostol is excreted into breast milk , the levels fall very quickly. • Levels become undetectable within 5 hours of maternal ingestion. • However, lactating women should be informed about possibility of infant diarrhea with misoprostol use.

  34. Key points to remember ! • Misoprostol is a prostaglandin E1 analogue that causes uterine contractions, cervical softening and dilation. • Routes of administration include oral, vaginal, rectal, buccal, and sublingual. • Medication abortion with 200 mg of mifepristone and 800 g of buccal or vaginal misoprostol is 95% to 98% effective with evidence-based regimens. • It is an effective cervical ripening agent prior to first-trimester surgical abortion. • Misoprostol for cervical ripening as a substitute for/adjuvant to laminaria prior to second trimester dilation and evacuation. • Misoprostol is an effective cervical ripening agent in premenopausal women prior to hysteroscopy. The greatest benefit is seen in nulliparous women and for operative hysteroscopy. Whether the routine use of misoprostol prior to hysteroscopy is beneficial is still unknown.

  35. Key points to remember ! • Misoprostol for cervical ripening prior to gynecologic procedures in postmenopausal women has not been found to be effective. • Misoprostol is an option for the management of early pregnancy failure and incomplete abortion in women who are hemodynamically stable without signs of infection. A single dose of 800 g vaginally is typically used. • Misoprostol is a proven induction agent in the second trimester for termination of pregnancy or fetal death. One regimen is 400 g vaginally every 6 hours up to 48 hours. • For cervical ripening and induction of labor for a viable fetus, 25 g of vaginal misoprostol every 4 to 6 hours is recommended. • Misoprostol has not been shown to be as effective as injectable uterotonics (oxytocin and methylergotomine) for the prevention and treatment of postpartum hemorrhage. However, it is a valid option when these are not available or fail.

  36. PPH Prevention through platform of antenatal care

  37. Special challenges related to prevention of PPH in low-resource areas: • Many births in the rural setting are attended by Unskilled/minimally trained health providers • Lack in skills for administration of injectable or • Local laws may prohibit their use • In spite of best effort mother may not reach institution • Births may be attended by family/community members and not by SBA. • AMTSL not practiced at all or not practiced properly by SBA • Availability of injectable uterotonics may not be ensured. • Refrigerated storage not possible in remote regions. • Importance of proper storage of uterotonics is ignored by CARE PROVIDERS instead use to cool portable water in the fridge if available.

  38. Components of the ANC Distribution Program • Community Awareness Campaign on Birth Preparedness and PPH Prevention • Radio • Community meetings with CORPs and TBAs • Posters and Pamphlets • Focused ANC with Misoprostol Distribution • ANC Visit • Education Session on PPH and Misoprostol • Misoprostol Distribution at > 32 weeks gestation Reduce PPH at out side institution Births

  39. PPHPrevention: Misoprostolthe “gamechanger” PREGNANCY ANC DELIVERY HealthFacility Home ASHA/HWF The distribution of misoprostol after 32 weeks pregnancy is advisable.

  40. PPHPrevention: Misoprostol the “game changer” PREGNANCY ANC Community Health Worker M DELIVERY HealthFacility M ASHA/HW M Community Home M ASHA

  41. Community-Based Distribution of Misoprostol for Prevention of Postpartum Hemorrhage: Examples from  Uruguay, Bangladeshand Indian trials MISOPROSTOL AT GRASSROOTS

  42. Since 2001 the Maternal Mortality Rate in Urugway due to unsafe abortion among women in Public Hospitals decreased by 87%

  43. (Non-Randomized Controlled Trials)

  44. Results of Pilot Programs Tangail: • 71% of the expected pregnant women were registered. • Among them, of those who delivered at home, 94% used misoprostol. • There were no reported cases of misuse. • 0.4% (39) of users reported minor side effects (fever, shivering). • 0.3% (25) of users reported complications (retained placenta, PPH due to other cause) and were referred to hospital. • An estimated 9 maternal deaths were averted by the use of misoprostol. Cox’s Bazar: • 69% of expected pregnant women were registered. • Among them, of those who delivered at home, 95% used misoprostol. • There were no reported cases of misuse. • 0.8% (134) of users reported minor side effects (fever, shivering). • 0.1% (26) of users reported complications (retained placenta, PPH due to other cause)and were referred to hospital. • An estimated 10 maternal deaths were averted by misoprostol use. • Four women died at home due to obstructed labor and mishandling by TBA.

  45. Bangladesh  Leaflet on use of Misoprostol

  46. Misoprostol Information,  Education and Communication: For Community For SBA

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