Metformin metabolic acidosis with

Five patients with metformin-associated severe lactic acidosis, seen between 1 September 1998 and 31 May 2001, have been reported (58). Two had attempted suicide. All had severe metabolic acidosis with a high anion gap and raised blood lactate concentrations. Four developed profound hypotension and three had acute respiratory failure. Three had normal preceding renal function. Three required conventional hemodialysis and two continuous renal replacement therapy. 

Cimetidine 800 mg daily was found to reduce the renal clearance of metformin in 7 healthy subjects by 27% and increase the AUC by 50%. A 59-year-old woman with type 2 diabetes taking long-term metformin 500 mg three times daily developed severe metabolic acidosis with cardiovascular collapse and acute renal failure. Three months previously she had started orlistat 120 mg three times daily, which caused chronic diarrhoea. During the 4 days before hospital admission, she was prescribed cimetidine 400 mg twice daily for her abdominal pain. The metformin-assoeiated lactic acidosis was considered to have been precipitated by the orlistat , (p.498) and cimetidine. ... 

Metformin is contraindicated in patients with heart failure, renal disease, hypersensitivity to metformin, and acute or chronic metabolic acidosis, including ketoacidosis. The drug is also contraindicated in patients older than 80 years and during pregnancy (Pregnancy Category B) and lactation. 

Renal disease or renal dysfunction (eg, as suggested by serum creatinine levels greater than or equal to 1.5 mg/dL [males], greater than or equal to 1.4 mg/dL [females], or abnormal Ccr) that may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction (Ml), and septicemia CHF requiring pharmacologic treatment hypersensitivity to metformin acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Treat diabetic ketoacidosis with insulin. 

Normally, the sum of the cations exceeds the sum of the anions by no more than 12-16 mEq/L (or 8-12 mEq/L if the formula used for estimating the anion gap omits the potassium level). A larger-than expected anion gap is caused by the presence of unmeasured anions (lactate, etc) accompanying metabolic acidosis. This may occur with numerous conditions, such as diabetic ketoacidosis, renal failure, or shock-induced lactic acidosis. Drugs that may induce an elevated anion gap metabolic acidosis (Table 58-1) include aspirin, metformin, methanol, ethylene glycol, isoniazid, and iron. 

A 73-year-old woman taking metformin 1000 mg bd and warfarin 5 mg/day developed epistaxis, hematuria, gingival bleeding, a retroperitoneal hematoma, and bilateral perinephric blood with obstruction of both collecting systems (152). She received fresh frozen plasma, vitamin K, 10 mg, and packed erythrocytes. In the next 8 hours she developed a metabolic acidosis... 

Renal insufficiency and severe metabolic acidosis developed in a patient with diabetes mellitus taking metformin after recent treatment with indometacin (SEDA-22,118). 

Lactic acidosis Lactic acidosis is a rare, but serious, metabolic complication that can occur because of metformin accumulation during treatment when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis also may occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever... 

Accumulation of metformin can occur in patients with renal insufficiency, and interference with pyruvate metabolism can lead to severe lactic acidosis. Lactic acidosis is more likely in situations associated with anaerobic metabolism, and metformin should not be given to patients with renal disease, liver disease, or severe pulmonary or cardiac disease predisposing to hypoxia. It is recommended to switch patients taking metformin to another oral hypoglycaemic prior to cardiac or other major surgery. 

Metformin has a half-life of 1.5-3 hours, is not bound to plasma proteins, is not metabolized, and is excreted by the kidneys as the active compound. As a consequence of metformin s blockade of gluconeogenesis, the drug may impair the hepatic metabolism of lactic acid. In patients with renal insufficiency, biguanides accumulate and thereby increase the risk of lactic acidosis, which appears to be a dose-related complication. 

METFORMIN H2 RECEPTOR BLOCKERS -CIMETIDINE, RANITIDINE t level of metformin and risk of lactic acidosis. The onset of lactic acidosis is often subtle with symptoms of malaise, myalgia, respiratory distress and t nonspecific abdominal distress. There may be hypothermia and resistant bradyarrhythmias Metformin is not metabolized in humans and is not protein-bound. Competition for renal tubular excretion is the basis for T activity or retention of metformin. Cimetidine competes for the excretory pathway A theoretical possibility. Need to consider l dose of metformin or avoidance of co-administration. Warn patients about hypoglycaemia - For signs and symptoms of hypoglycaemia, see Clinical Features of Some Adverse Drug Interactions, Hypoglycaemia... 

Metformin is slowly and incompletely absorbed and rapidly eliminated without hepatic metabolism. This pharmacokinetic profile may make drug accumulation and lactic acidosis less likely to occur with metformin than with other biguanides. Sales of the longer-acting biguanide phenformin (10), for instance, which is metabolized in the liver by aromatic... 

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