Misoprostol / Diklofenak Sodyum

Clinical Effects:

MISOPROSTOL AND RELATED AGENTS
  • USES: Misoprostol is used orally to reduce the risk of NSAID-induced gastroduodenal ulcers by decreasing gastric acid secretion and thus protecting gastrointestinal mucosa. Misoprostol is also used orally and vaginally for inducing abortion or stimulating labor. It is rarely used in larger oral doses for refractory chronic constipation. Carboprost is used intramuscularly for inducing second trimester abortion (13 to 20 weeks of gestation) or treating postpartum hemorrhage due to uterine atony. Dinoprostone is used intravaginally (inserts, gel, and suppository) for the termination of pregnancy (12 to 20 weeks of gestation), the evacuation of uterine contents in the management of missed abortion or intrauterine fetal death, and the management of nonmetastatic gestational trophoblastic disease (eg, benign hydatidiform mole). PHARMACOLOGY: Misoprostol is a synthetic derivative of prostaglandin E1. It has gastric acid antisecretory effects and also causes edema and thickening of the gastrointestinal mucosa and submucosa. Carboprost is a prostaglandin analogue (15-methyl prostaglandin F2-alpha) similar to dinoprost (prostaglandin F2-alpha). Dinoprostone is a naturally occurring prostaglandin E2. TOXICOLOGY: Adverse effects of misoprostol are varied, and severe toxicity following acute overdose is rare; toxic effects are an extension of therapeutic effects. Misoprostol is teratogenic (Pregnancy Category X). Carboprost and dinoprostone are classified as Pregnancy Category C. Women of childbearing age should not take misoprostol for prevention of gastric ulcers as it can cause a miscarriage, premature labor, and birth defects. It can cause uterine hyperstimulation when given for cervical ripening, and in rare cases it has caused uterine rupture. EPIDEMIOLOGY: Acute overdose with these agents is rare. MILD TO MODERATE TOXICITY: Few cases of severe poisoning exist. Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses. Abdominal cramping, diarrhea, headache, dizziness, and uterine contraction and bleeding may occur. SEVERE TOXICITY: In rare cases, hypertension, tachycardia, fever, tremor, rhabdomyolysis, renal insufficiency, and elevated liver enzymes have occurred. In pregnant patients, uterine contractions, hemorrhage, and fetal death have occurred. One patient developed gastric and esophageal necrosis and upper gastrointestinal bleeding after misoprostol overdose. Misoprostol causes uterine contractions resulting in miscarriage. ADVERSE EFFECTS: Adverse effects of these agents following therapeutic doses include nausea, vomiting, diarrhea, abdominal pain, seizures, headache, dizziness, fatigue, elevated liver enzymes, and uterine bleeding or rupture. Postpartum DIC has been reported during postmarketing use of dinoprostone cervical gel and vaginal insert (less than 1 in 1000 labors for dinoprostone cervical gel).
NONSTEROIDAL ANTIINFLAMMATORY DRUGS
  • USES: Nonsteroidal antiinflammatory drugs (NSAIDs) are used acutely for fever and pain control and for the treatment of several rheumatologic conditions. NOTE: Salicylates, ibuprofen, naproxen, indomethacin, phenylbutazone, mefenamic acid, ketoprofen, and the COX-2 inhibitors (celecoxib, meloxicam, rofecoxib, valdecoxib) are covered under separate managements. PHARMACOLOGY: NSAIDs include at least 20 drugs that share the cyclooxygenase enzyme inhibition leading to decreased prostaglandin production and decreased pain and inflammation. TOXICOLOGY: NSAIDs cause gastrointestinal (GI) irritation directly, and by inhibiting cyclooxygenase 1 (COX-1), which is necessary for the formation of the prostaglandins PG12 and PGE2; decrease in these prostaglandins results in decreased tissue mucus and bicarbonate secretion, increased hydrochloride secretion, and decreased gastric blood flow. The acidosis associated with severe NSAID overdose appears to result from the formation acidic metabolites, and mild hypotension. Prostaglandin inhibition by NSAIDs also causes renal arteriolar constriction, reduced renal blood flow and subsequent renal insufficiency in patients with conditions characterized by high angiotensin and low intravascular volume (eg, congestive heart failure, cirrhosis, hypovolemia). COX-1 inhibition also decreases the formation of thromboxane A2 which is necessary for platelet aggregation, predisposing patients to bleeding. EPIDEMIOLOGY: NSAID overdose is common, but severe toxicity and deaths are very rare. MILD TO MODERATE TOXICITY: Most patients with an NSAID overdose are asymptomatic or have mild GI upset (ie, nausea, vomiting, abdominal pain), and sometimes hematemesis. SEVERE TOXICITY: Massive overdose can cause seizures, delirium, coma, hypotension, renal failure, hepatic dysfunction, hypoprothrombinemia, gastrointestinal bleeding, hyperkalemia and metabolic acidosis. ADVERSE EFFECTS: Dyspepsia, ulceration perforation, GI hemorrhage, acute renal failure, fluid retention, interstitial nephritis, nephrotic syndrome, asthma exacerbation, headache and aseptic meningitis may develop. Agranulocytosis, aplastic anemia, and thrombocytopenia have developed, but appear to be idiosyncratic reactions. VETERINARY/FLURBIPROFEN: Pets exposed to topical pain medications containing flurbiprofen may be at risk of developing significant illness and death. The FDA has received reports of severe illness in several households where pet owners applied the topical medication to themselves (ie, neck and feet). In these cases, it was unclear how the cats became exposed. However, 2 cats in one household developed renal failure and recovered with supportive care and 2 cats in another household developed lethargy, vomiting, melena, and anemia and died despite care.

Range of Toxicity:

MISOPROSTOL AND RELATED AGENTS
  • TOXICITY: ADULTS: Minimum toxic dose is largely unknown and not well-established. Doses of 3 mg to 8.4 mg have caused mild to moderate toxicity. A pregnant adolescent developed necrosis of the stomach and distal esophagus, upper gastrointestinal bleeding, sepsis, multiorgan failure, and died after ingesting 12 mg of misoprostol over 2 days. PEDIATRIC: Toxic dose has not been established. THERAPEUTIC DOSE: ADULT: Varies according to indication. For NSAID gastrointestinal ulcer prevention, 100 to 200 mcg orally 4 times a day is given. Chronic constipation doses are larger at 600 to 2400 mcg/day orally divided 2 to 4 times a day. Early pregnancy termination dosing is 400 mcg orally once in conjunction with mifepristone. 25 mcg per vagina is used for cervical ripening. Carboprost: 250 to 500 mcg IM (abortion), 250 mcg IM (postpartum hemorrhage control), 0.5 to 3 mg intravaginally (abortion). Dinoprostone: For abortion or benign hydatidiform mole, 20 mg suppository, may be repeated at 3- to 5-hr intervals for up to 2 days. For cervical ripening procedure and induction of labor, 10 mg vaginal insert. PEDIATRIC: Dosing for children is not established.
NONSTEROIDAL ANTIINFLAMMATORY DRUGS
  • TOXICITY: The toxic dose varies with each NSAID, but significant symptoms can occur after ingestion of 5 to 10 times the therapeutic dose. THERAPEUTIC DOSE: Varies by agent.

Treatment:

MISOPROSTOL AND RELATED AGENTS
  • Support: MANAGEMENT OF MILD TO MODERATE TOXICITY: Patients may only need observation. Treatment is symptomatic and supportive. MANAGEMENT OF SEVERE TOXICITY: Symptomatic and supportive care is the mainstay of treatment. Consultation should be made with obstetrics and gynecology in cases of uterine hypertonicity or bleeding after ingestion.
  • Decontamination: Because the toxic dose of misoprostol has not been well-established, consider administering activated charcoal in patients taking a dose that is greater than therapeutic dose as well as in any pregnant patient that is not purposely taking misoprostol to induce abortion or labor. PREHOSPITAL: Activated charcoal should be considered early in the course after a significant ingestion in patients who are protecting their airways and have not yet manifested signs of toxicity. If a patient is displaying signs of moderate to severe toxicity, it is likely that most of the drug has been absorbed, and activated charcoal is not likely to be helpful. In this case, activated charcoal can be aspirated if patient becomes somnolent. HOSPITAL: Consider decontamination if a patient presents promptly after an ingestion overdose and is not manifesting symptoms of toxicity. Patients eligible for decontamination with oral charcoal include inadvertent overdoses in children and intentional overdoses in adults. If the drug has been inserted vaginally it should be removed.
  • Airway management: Perform early in patients with symptoms of airway compromise, although this is unlikely to be necessary in misoprostol-only ingestions.
  • Antidote: None.
  • Nausea: Antiemetics may be used to control nausea.
  • Tachycardia: No specific treatment is required. IV fluids should be given if the patient is dehydrated from diarrhea associated with misoprostol ingestion.
  • Headache: Simple oral analgesics can be given, if tolerated. If the patient is nauseated, IV analgesics can be given.
  • Diarrhea: Diarrhea and abdominal cramping should be treated with oral or IV fluids. Oral or IV opioids can be given as well as antispasmotics, such as dicyclomine 20 mg orally.
  • Seizure: Administer IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur.
  • Monitoring of patient: Misoprostol plasma concentrations are not clinically useful or readily available. No specific lab work is needed in most patients. Monitor vital signs and mental status. A CBC, INR, and PTT should be ordered in cases of excessive vaginal bleeding. Monitor serum electrolytes in patients with severe diarrhea and/or dehydration. Monitor liver enzymes in patients with significant symptoms or large overdose. A pregnancy test should be ordered in any woman of childbearing age that presents after ingestion of misoprostol. If the patient is pregnant, monitor the fetus (ultrasound, fetal heart rate, and tocographic monitoring).
  • Enhanced elimination procedure: Hemodialysis is not of value for misoprostol overdose because of the high degree of protein binding.
  • Patient disposition: HOME CRITERIA: Patients should be evaluated by a healthcare professional if they are symptomatic after a therapeutic dose, or if they are/might be pregnant and the medication was not prescribed to terminate pregnancy or induce labor. Any patient reporting an intentional overdose should be evaluated in the emergency department. OBSERVATION CRITERIA: Patients with deliberate ingestions should be sent to a healthcare facility for observation. Any patient with symptoms should be observed until symptoms improve or resolve. ADMISSION CRITERIA: Patients with significant symptoms and/or abnormal vital signs should be admitted. Pregnant patients with symptoms of vaginal bleeding or contractions should be evaluated by an obstetrician/gynecologist. CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear. Obstetrician/gynecologist should be consulted for any case of excessive uterine bleeding or contractions and in the case of inadvertent administration to a pregnant woman who does not desire early pregnancy termination.
NONSTEROIDAL ANTIINFLAMMATORY DRUGS
  • Support: MANAGEMENT OF MILD TO MODERATE TOXICITY: Most toxicity related to NSAID exposure resolves with supportive care; otherwise, healthy patients with a history of NSAID poisoning generally require only gastrointestinal decontamination with activated charcoal, and fluid and electrolyte replacement. SEVERE TOXICITY: Endotracheal intubation and mechanical ventilation may be necessary in patients with CNS depression or recurrent seizures. Treat seizures with benzodiazepines, and hypotension with fluids, adding adrenergic vasopressors, if necessary.
  • Decontamination: PREHOSPITAL: Activated charcoal can be given after a large overdose. HOSPITAL: Activated charcoal binds NSAIDs, but is usually not required as severe toxicity is rare. Charcoal should be administered after a large, recent overdose. Gastric lavage is generally not indicated as life threatening toxicity is very rare.
  • Airway management: Intubation and mechanical ventilation should be considered for patients who present with CNS depression.
  • Antidote: None.
  • Monitoring of patient: Measurement of serum concentrations of NSAIDs are widely available, but are not useful in guiding clinical management. Serum electrolytes, creatinine and BUN concentrations should be measured in patients with an intentional overdose. If significant CNS or respiratory toxicity is present, acid-base status should be assessed. Obtain a serum acetaminophen and salicylate concentration. Monitor vital signs.
  • Enhanced elimination procedure: NSAIDs are highly protein bound and extensively metabolized; therefore, hemodialysis is unlikely to be effective.
  • Patient disposition: HOME CRITERIA: Inadvertent exploratory ingestions in asymptomatic children can generally be managed with dilution and observation at home. OBSERVATION CRITERIA: Patients with a large or deliberate ingestion should be observed for 4 to 6 hours. If they remain asymptomatic with normal laboratory evaluation, they may be discharged after appropriate psychiatric evaluation. ADMISSION CRITERIA: Patients who may have ingested a large dose of NSAIDs and who present with CNS or cardiovascular toxicity or metabolic acidosis, or who have a known risk factor for organ system toxicity associated with NSAIDs should be considered at higher risk of complications and warrant admission.
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