AFTER NITROFURANTOIN (50 MG) IV INFUSION, 47% OF THE DOSE WAS EXCRETED UNCHANGED IN THE URINE AND 1.2% WAS RECOVERED AS THE REDUCED METABOLITE AMINOFURANTOIN.
IDENTIFICATION: Nitrofurantoin is an urninary antiseptic and antiinfective drug. It is a lemon yellow solid crystalline material. It is very sightly soluble in water and alcohol. It is soluble in diethylformamide. In the treatment of initial or recurrent urinary tract infections caused by susceptible gram positive and gram negative bacteria including most strains of Escherischia coli. Enterobacter and Klebsiella species are less susceptible and Pseudomonas and most strains of Proteus are resistant to nitrofurantoin. Nitrofurantoin is ineffective in systemic bacterial infections in blood or tissues outside the urinary tract. HUMAN EXPOSURE: Main risks and target organs: The most frequent adverse effects include anorexia, nausea and vomiting. Nitrofurantoin has also been associated with neurological and central nervous system, hepatic, hematological, pulmonary and dermatological toxicity. Apart from gastrointestinal tract symptoms, acute reactions as a result of overdosage of nitrofurantoin have not been reported. Symptoms of toxicity are generally due to hypersensitivity to the drug. Contraindications: Nitrofurantoin is contraindicated in patients who are hypersensitive to the drug or to furan derivatives. It is also relatively contraindicated in renal impairment, diabetes mellitus, electrolyte imbalance, vit.B deficiency as there is an increased risk of developing peripheral neuropathy in these situations. If it has to be used in these cases, extreme care should be taken and treatment stopped at the first sign of toxicity. Hemolysis frequently occurs in Glucose-6-phosphate dehydrogenase deficient patients who take nitrofurantoin. Discontinuation of the drug will often reverse this effect. Nitrofurantoin is contraindicated in pregnant women at term (38-42 weeks gestation) and it should not be administered during labor or just prior to labor to avoid precipitation of hemolytic anemia in the neonate. Neonates are at high risk of hemolysis induced by nitrofurantoin due to their immature enzyme systems. Routes of exposure: Oral: This is the most common route of entry. Absorption by route of exposure: Nitrofurantoin is readily absorbed from the gastrointestinal tract. Absorption occurs mainly in the small intestine. The microcrystalline form of the drug (in suspension, tablets or capsules) is absorbed faster than the macrocrystalline form (in capsules). Presence of food in the gastrointestinal tract or delayed gastric emptying increases the extent of absorption (enhancing the dissolution rate of the drug). Bioavailability is a mean of 87% when taken on an empty stomach, and increases to a mean of 94% when ingested with food. Peak plasma concentrations following a single oral dose are usually attained at 1 to 2 hours after ingestion. Distribution by route of exposure: Nitrofurantoin is 25 to 90% bound to plasma protein. It crosses the placenta and is excreted in the milk. Biological half-life by route of exposure: The plasma half life is approximately 20 to 60 minutes in adults with normal renal function after a therapeutic oral dose. The half-life is prolonged in patients with impaired renal function. Metabolism: Approximately 2/3 of a dose is metabolized in the liver. A small fraction is reduced to aminofurantoin. Elimination by route of exposure: 20 to 44% of an oral dose is excreted unchanged in the urine within 24 hours. 1% is excreted as aminofurantoin. Nitrofurantoin is dialyzable. Mode of action: Toxicodynamics: Nitrofurantoin causes hepatic injury (acute and chronic) through an immunological or metabolic mechanism. Cholestatic jaundice and hepatocellular damage result in elevation of alkaline phosphatase and aspartate transaminase levels. Development of antinuclear antibodies and antismooth muscle antibodies has also been reported. Pulmonary toxicity is attributed to nitrofurantoin production of superoxide anion free radicals with subsequent chain reactions and uncontrolled destructive oxidation, suggested that nitrofurantoin mediated oxidant injury to the lung may be due to direct cytotoxicity or indirectly through recruitment of activated neutrophils. Nitrofurantoin can cause an acute non-cardiogenic pulmonary edema, or subacute interstitial pneumonitis which may progress to interstitial fibrosis. The acute reaction is generally considered to be a hypersensitivity reaction. There is evidence pointing to an immunological mechanism for injury and an increase in T-Lymphocytes in broncheo-alveolar lavage. Peripheral neuropathy is a complication of nitrofurantoin therapy especially in patients with pre-existing renal impairment or diabetes mellitus. Nitrofurantoin triggers a degenerative process in the nerve cell axon with subsequent impairment of sensation and motor strength in the distal extent of the axonal process. Pharmacodynamics: Nitrofurantoin is bacteriostatic or bacteriocidal depending on the concentration and the susceptibility of the microorganism. Its antibacterial activity is enhanced in an acidic pH. It is thought that nitrofurantoin is reduced by bacterial flavoprotein enzymes to an active intermediate which inhibits the microorganism's proteins, DNA, RNA and cell wall synthesis. Nitrofurantoin is active against most strains of Gram positive and Gram negative urinary tract pathogens but generally less active against most strains of Klebsiella, Enterobacter, Pseudomonas and Proteus. Toxicity: Human data: Adults: Acute toxic exposures to nitrofurantoin have not been reported and there have been no acute ingestions causing fatalities. No toxic or lethal levels have been determined for nitrofurantoin. However there are a number of adverse effects and hypersensitivity reactions reported which have included fatalities. The duration of exposure before the onset of symptoms of acute pulmonary toxicity varies from two or three days to several weeks. Teratogenicity: case of a 14 month old girl with asymmetrical paralysis limited to the upper limbs with signs suggesting an early prenatal onset was reported. Nitrofurantoin and Bendectin (R) taken during early pregnancy were suspected to be the cause. Mutagenicity: There are data demonstrating mutagenicity in human cells Interactions: Food significantly enhances the bioavailability and duration of the therapeutic concentration of nitrofurantoin. Uricosuric agents (probenecid or sulfinpyrazone) may inhibit renal excretion of nitrofurantoin and hence increase its plasma level, reduce its effectiveness, and increase its toxicity. Antacids: specifically magnesium trisilicate were reported to decrease the rate and extent of nitrofurantoin absorption through an adsorption mechanism. Quinolones antibacterial activity in vitro is antagonized by nitrofurantoin. It is possible that this interaction could occur in vivo as well. Drugs which acidify the urine decrease the excretion of nitrofurantoin. Main adverse effects: The most frequent adverse effects of nitrofurantoin are anorexia, nausea, and vomiting, which are dose related. Peripheral polyneuropathy and optic neuritis are serious adverse effects of nitrofurantoin and call for immediate withdrawal of the drug. They occur especially in pre-existing renal impairment and the presence of vitamin B deficiency. Peripheral neuropathy was reported in 10 month to 18 year old children. Hepatic damage with nitrofurantoin is reversible on discontinuation of the drug. Hepatic reactions range from acute self-limiting hepatitis to chronic active hepatitis and necrosis associated with long term use. Pulmonary hypersensitivity reactions to nitrofurantoin can be life threatening and nitrofurantoin should be stopped immediately on occurance of symptoms. Impaired pulmonary function may remain even after cessation of therapy. Deaths as a result of cardiopulmonary collapse and of alveolar hemorrhage have been reported. Hematological disorders - and of special significance, hemolytic anaemia associated with use in patients with G-6-PD deficiency have been reported in association with nitrofurantoin use. Additional hematologic effects include leukopenia, granulocytopenia, agranulocytosis, thrombocytopenia, and aplastic anemia. Dermatologic reactions include Stevens Johnson syndrome and other rashes. ANIMAL STUDIES: Carcinogenicity: Nitrofurantoin does not appear to be carcinogenic. There is increased ovarian cancer in mice with chronic, high dose administration. It was found to be carcinogenic in B6C3F female mice and in F344/N male rats. Teratogenicity: There is no evidence to link nitrofurantoin to birth defects in animals.
Nitrofurantoin is currently one of the most common causes of drug induced liver injury. Liver injury from nitrofurantoin can cause either an acute or chronic hepatitis-like syndrome. The acute form is typically associated with a 1 or 2 week course of treatment with nitrofurantoin and is rare (~0.3 cases per 100,000 prescriptions). Acute liver injury typically presents within a few weeks of starting nitrofurantoin and can arise up to a few weeks after stopping a defined course of treatment. The pattern of liver injury is usually hepatocellular with or without jaundice, and typically is accompanied by symptoms of fever and rash. The acute injury due to nitrofurantoin usually resolves rapidly once the medication is stopped, but severe and fatal instances have been reported. In some instances, autoimmune features are present, but these are more common with the chronic presentation of nitrofurantoin hepatotoxicity. The course and outcome of acute nitrofurantoin hepatotoxicity is variable, severe forms with acute liver failure can occur, and nitrofurantoin is regularly listed as one of the major causes of acute liver failure due to medications.
The chronic form of nitrofurantoin hepatotoxicity is more common than the acute form and typically presents months to years after initiation of long term prophylactic therapy. The estimated incidence of liver injury from nitrofurantoin is approximately 1 per 1500 persons exposed. The presentation is usually insidious and marked initially by fatigue and weakness followed by dark urine and jaundice. The clinical pattern and laboratory features can mimic autoimmune hepatitis with marked elevations in serum ALT levels, increases in gamma globulin levels, and the presence of antinuclear and anti-smooth muscle antibodies. In some instances, the onset is abrupt and resembles acute hepatitis. However, immunoallergic features of fever and rash are less common than with the acute form of nitrofurantoin hepatotoxicity. Liver histology typically demonstrates features of chronic hepatitis with inflammation, interface hepatitis, focal or centrilobular bridging necrosis and variable degrees of fibrosis. Cirrhosis as a result of nitrofurantoin hepatotoxicity has been reported and, if not recognized as due to the medication, can progress to end stage liver disease. There is a female preponderance and the risk of injury appears to increase with age particularly the chronic forms.
Likelihood score: A (well known cause of clinically apparent liver injury).
Nitrofurantoin reaches a Cmax of 0.875-0.963mg/L with an AUC of 2.21-2.42mg\*h/L. It is 38.8-44.3% bioavailable. Taking nitrofurantoin with food increases the absorption and duration of therapeutic concentrations in the urine.
.../IT/ IS RAPIDLY & COMPLETELY ABSORBED FROM GI TRACT. ... PLASMA HALF-LIFE IS 0.3 TO 1 HR; ABOUT 40% IS EXCRETED UNCHANGED INTO URINE. AVG DOSE OF NITROFURANTOIN YIELDS URINE CONCN OF APPROX 200 UG/ML. ... RATE OF EXCRETION IS LINEARLY RELATED TO CREATININE CLEARANCE...
