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Misoprostol: an old drug, new indications. B MoreDepartment of Clinical Pharmacology, Seth G. S. Medical College and K. E. M. Hospital, Parel, Mumbai - 400 012, India., India
Correspondence Address: Source of Support: None, Conflict of Interest: None PMID: 12571404 Keywords: Anti-Ulcer Agents, pharmacology,therapeutic use,Human, Misoprostol, pharmacokinetics,pharmacology,therapeutic use,Oxytocics, therapeutic use,Peptic Ulcer, drug therapy,
Health care providers often develop their own treatments or modify standard regimens in an effort to suit their patients’ needs. Misoprostol, a drug primarily developed for the treatment of peptic ulcer and now being widely used for reproductive health-related conditions, is an ideal example of this. Misoprostol [15-deoxy-16-hydroxy-16methyl-PGE1], was the first synthetic prostaglandin analogue to be made available for the treatment of peptic ulcer. It has been licensed for this condition in over 80 countries.[1] It produces a dose related inhibition of gastric secretions and has cytoprotective actions. Impressed by its stimulant actions on the uterus, Sanchez Ramos in 1993 used it for the management of several obstetric conditions. Although it is not formally registered for use during pregnancy, many countries allow licensed drugs to be used for other indications as well. This has resulted in its widespread use for obstetrical conditions. A lot of information regarding use of Misoprostol in conditions other than peptic ulcer has accumulated. This article focuses on the various uses, potential complications, teratogenic effects, available dosage forms and routes of administration of Misoprostol and on outcome of various clinical trials[2] with the drug.
Prostaglandins belonging to the E series inhibit histamine induced gastric acid secretion. They produce considerable inhibition of volume and pH of gastric secretion. Methyl esterification of the carboxyl group of PGE1 increases the anti-secretory potency and also extends the period of action. Short duration of action and limited activity following oral dosing, is seen with PGE1 (alprostadil) and its methyl ester. They also have a poor tolerability profile. In contrast, transfer of the hydroxy group from C15 to C16 and addition of methyl group at C16 to the methyl ester of PGE1 (forming misoprostol) has no influence on the anti-secretory activity following intravenous administration, but results in improved oral potency and extended duration of action.[3]
Permutations of various pharmacological features of misoprostol contribute to its pharmacodynamic actions. It seems to inhibit the acid secretion by a direct action on the parietal cells. The inhibition of adenylate cyclase may be dependent on guanosine-5’-triphosphate (GTP).[4] The significant cytoprotective actions of misoprostol are related to several mechanisms. These include: 1. Increased secretion of bicarbonate 2. Considerable decrease in the volume and pepsin content of the gastric secretions. 3. It prevents harmful agents from disrupting the tight junctions between the epithelial cells. This, in turn, stops the subsequent back diffusion of H+ ions into the gastric mucosa. 4. Increased thickness of mucus layer. 5. Enhanced mucosal blood flow, as a result of direct vasodilatation. This promotes efficient aerobic metabolism and adequate removal of back-diffused H+ ions. 6. Stabilisation of tissue lysozymes /vascular endothelium 7. Improvement of mucosal regeneration capacity.[6] Actions on the Uterus: Misoprostol causes contractions of uterine smooth muscle. It produces softening of the cervix, promoting enhanced dilation facilitating intra-uterine procedures as well as expulsion of contents of the uterus.
Misoprostol is rapidly absorbed following oral administration and its bioavailability exceeds 80%. Peak plasma concentrations of 2 to 4 ?g /L occur in 30 to 60 minutes, following an oral dose of 200 ?g.[7] It is converted to the active misoprostol acid, which has a half-life of 30- 60 minutes. Its free acid form is highly protein-bound and has a volume of distribution of 14 + 0.4 litres/kg.[8] This free acid is deesterified followed by ? oxidation of ? side chain, ?-oxidation of ?-side chain and reduction to PGF analogues. The metabolites undergo biphasic elimination, where the fast phase lasts for 1.5 hours while the slow phase extends up to 144 to 177 hours.[9] Pharmacokinetic studies carried out during pregnancy show that misoprostol is effectively absorbed across the vaginal mucosa.[10] After oral administration, the plasma concentration increases rapidly to a peak at 30 minutes and then declines rapidly. On vaginal administration, it gradually increases, reaching a peak at 1.5 hours before declining steadily.[11] The action with oral administration is significantly shorter, but duration of stimulation is significantly longer followed by regular uterine contraction following vaginal administration. Hence, vaginal administration appears to be more beneficial in terms of greater abortifacient efficacy and shorter treatment interval.[11]
Concurrent administration of antacids with misoprostol could result in reduced bioavailability of misoprostol.[12] The vaginal administration of citric acid may prove beneficial for misoprostol absorption.[13]
Misoprostol is available as tablets containing 0.2 mg of the drug. The recommended dosage for treatment of patients with benign gastric or duodenal ulcer is 200 ?g four times daily (before meals and at bed time) for at least 4 weeks.[14],[15] It is stable at room temperature. It is cheaper than gemeprost, another PGE1 analogue used as a vaginal suppository.[11] Oral misoprostol is as effective as vaginal misoprostol for cervical ripening.[16] Buccal and sublingual route are other routes of administration of misoprostol. However, sublingual administration is associated with a higher incidence of uterine tachysystole.[10] A comparison of two dosing regimens of intravaginal misoprostol for second trimester pregnancy termination; showed that there was no significant difference with 200 ?g either 6 hourly or 12 hourly.[17] Induction of labour was achieved earlier with vaginal administration than with oral administration. However, the vaginal administration was associated with a higher incidence of uterine hyper-stimulation and need for intervention for foetal distress with.[10]
Misoprostol is primarily used to prevent or treat gastrointestinal injury or blood loss related to non-steroidal anti-inflammatory drug (NSAID) ingestion. It is particularly helpful in patients with arthritis who have to continue taking NSAIDs despite suffering from peptic ulcer that refuses to respond to histamine blockers. The drug promotes healing of these ulcers and may also be effective in individuals who continue to smoke.[6],[18] In addition, it is recommended that certain categories of patients on NSAIDs should receive misoprostol : • Elderly individuals • Those who are Unable to tolerate ulcer complication • Patients receiving steroid therapy[19] • Those receiving high dose of NSAIDs Obstetric and gynecological uses: In obstetric practice, misoprostol and gemeprostol are the two commonly used prostaglandins. Misoprostol is comparatively inexpensive and easy to administer and store. Various workers have used it for the following obstetric conditions:. Induction of Abortion First trimester induction 2nd trimester (Dilatation and evacuation) 3rd trimester (for induction of labour) Cervical priming prior to surgical abortion Uterine Evacuation Intra-uterine foetal death Missed abortion Incomplete abortion Labour and Delivery Cervical softening Induction of Labour Prevention Postpartum haemorrhage
Misoprostol is a well-tolerated drug. Diarrhoea is the most common adverse effect reported, followed by nausea, abdominal pain and headache. Less frequently reported adverse effects include fatigue, rash, vomiting and body ache.[20] The main complaints in ulcer therapy especially in women are abdominal cramps and uterine bleeding. The drug, when given in the first trimester, is known to induce congenital anomalies in the foetus. Hence, it is not used for the treatment of peptic ulcer in pregnant women. Even, continued pregnancy after exposure to misoprostol in the first trimester carries the potential risk of malformed foetus. Incomplete abortion following misoprostol administration is fraught with the risk of protracted and plentiful blood loss and sepsis.[1]
Misoprostol does not relieve pain associated with peptic ulcer disease and this is its major limitation. Its ability to induce uterine contractions forbids its use during pregnancy. It should also be avoided in women who wish to be pregnant. Vaginal administration requires repeated examination, which is inconvenient and unacceptable. Oral administration is difficult in patients having nausea and in those who are unable to swallow the drug. Incomplete abortion, if not properly treated could lead to serious consequences such as prolonged or profuse bleeding.[1] The exposure of misoprostol during conception lead to teratogenicity and vascular abnormalities in the foetus.[33]
Misoprostol use in women with previous caesarean section is associated with a higher frequency of disruption of the uterine incision.[21],[22] It may, however be noted that compared to extra-amniotic prostaglandin F2 alpha gel; misoprostol is associated with fewer Caesarean sections for failure of progression of labour.[23]
Misoprostol in treatment of peptic ulcers There is hardly any data defining the frequency of gastric ulceration following NSAID use. Hence it is difficult to conclude if using misoprostol in patients with chronic arthritis is cost-effective in reducing this incidence.[24] Misoprostol given in the dose 200-400 ?g significantly accelerates the healing of duodenal and gastric ulcers. Candidate patients taking NSAIDs, cigarette smokers, patients with significant duodenal gastric bile reflux derive significant benefit with misoprostol use.[6] The results of studies comparing the efficacy of misoprostol with H2 blockers are summarised in [Table - 1]. Medical termination of pregnancy Many studies have evaluated the use of misoprostol for early termination of pregnancy. The efficacy varies considerably between studies. The oral administration of misoprostol 0.4 mg increases uterine tone but not the regular uterine contractions and only 2 out of 40 women treated, aborted.[25] Encouraging results have been seen in studies where women were treated with 0.8 mg three times in a 24 hour interval and an additional dose administered after abortion. The cumulative abortion rates were 65%, 83%, and 90% after one, two and three doses of misoprostol respectively.[26] Oral methotrexate (50 mg) in combination with misoprostol (0.8 mg 3 doses, every 48 hours) resulted in 90% success rate of abortion.[28] For induction of abortion, Misoprostol is as effective as gemeprost and is a better alternative than mifepristone.[11] Vaginal misoprostol is more effective than oral misoprostol in termination of second trimester pregnancy after pre-treatment with mifeprostone. However, several women prefer the oral route.[29] Induction of labor and cervical ripening Vaginal administration of misoprostol is as effective as dinoprostone for cervical ripening and induction of labor.[30],[31],[32] As compared to extra-amniotic prostaglandin F2 alpha gel, misoprostol is associated with less use of oxytocin in labour, a shorter induction-to-delivery interval and fewer Caesarean sections for failure of progress of labour.[23] Studies comparing the efficacy of misoprostol with different drugs for induction of labour and cervical ripening are summarised in [Table - 2].
Misoprostol is primarily marketed for prevention and treatment of peptic ulcer disease. However, it has been widely used in obstetrics and gynaecology because of its effectiveness, low cost, stability in light and hot climatic conditions and ease of administration compared to its licensed counterparts dinoprost and gemeprost. Absence of clear guidelines regarding its use for gynaecological and obstetrical conditions in combination with easy (over the counter availability) of the drug may lead to its abuse which is fraught with disastrous consequences. Women may take excess of drug resulting in vomiting, nausea, diarrhoea, chills and fever. Inadequate action may result in incomplete abortion with consequent risk of infection and risk of life to the pregnant woman. Failure of action may result in continuation of pregnancy and the foetus may be malformed due to exposure to misoprostol.[33] Three cases of maternal deaths following use of misoprostol have been reported. In two of the cases the drug was used to induce illegal abortion, and in third case maternal death occurred following uterine rupture after misoprostol was used clinically for induction of labour.[34] In studies carried out in India, the combined use of mifepristone plus misoprostol has proved to be feasible, safe and acceptable.[5] With proper guidelines, and education misoprostol can be safely used in the existing setting by qualified practitioners in selected patients.
[Table - 1], [Table - 2]
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