Metabolism lactic acidosis, metformin

AMILORIDE METFORMIN T metformin levels and risk of lactic acidosis 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 Theoretical possibility. Requires reduction of metformin dose to be considered, or the avoidance of co-administration... 

Under certain circumstances, and very rarely, the inhibition of gluconeogenesis by metformin may suppress lactic acid metabolism and precipitate a potentially fatal lactic acidosis. Impairment of renal function, liver disease, alcoholism, conditions that give rise to increased lactate production (e.g. congestive heart failure, infections) are therefore contraindications for the application of metformin. 

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... 

T Pancreatic insulin release Metformin Peripheral insulin sensitivity hepatic glucose output/production i intestinal glucose absorption Dose Ist-line (naive pts), 1.25/250 mg PO daily-bid 2nd-line, 2.5/500 mg or 5/500 mg bid (max 20/2000 mg) take w/ meals, slowly T dose hold before 48 h after ionic contrast media Caution [C, -] Contra SCr >1.4 mg/dL in females or >1.5 mg/dL in males hypoxemic conditions (sepsis, recent MI) alcoholism metabolic acidosis liver Dz Disp Tabs SE HA, hypoglycemia, lactic acidosis, anorexia, N/V, rash Additional Interactions T Effects W/ amiloride, ciprofloxacin cimetidine, digoxin, miconazole, morphine, nifedipine, procainamide, quinidine, quinine, ranitidine, triamterene,... 

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. 

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. 

Lactic acidosis is a serious metabolic complication that can occur due to metformin accumulation... 

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. 

The main susceptibility factor for lactic acidosis due to metformin is renal insufficiency (49). In patients taking phenformin, poor oxidative metabolism may contribute (73). 

All patients admitted to a hospital during 6 months who had taken at least one dose of metformin were retrospectively evaluated for susceptibility factors for metformin-associated lactic acidosis (8). There were 263 hospitalizations in 204 patients. In 71 admissions there was at least one contraindication, such as renal or liver disease, renal dysfunction, congestive cardiac failure, metabolic acidosis, or an intravenous iodinated contrast medium given within 48 hours of metformin. In 29 (41%) metformin was continued despite the contraindication. The most frequent contraindication was a raised serum creatinine, but in only eight of the 32 admissions was metformin withdrawn. Of nine patients using metformin who died (not necessarily directly related to metformin), six had an absolute contraindication. In two patients who died and in one who survived, blood lactate was increased and this was temporally related to the use of metformin. 

Six experts in intensive care or metabolic disease reviewed all case reports of lactic acidosis from 1957 to 1999—37 articles reporting 80 cases (85). To be assessed the reports had to meet strict criteria, including a diagnosis of type 2 diabetes, metformin therapy before lactic acidosis, a pH of 7.35 or less, or a plasma bicarbonate concentration below 22 mmol/1 and a lactic acid concentration of at least 5 mmol/1. Because of lack of information, 33 cases were excluded. There were other susceptibility factors for lactic acidosis besides metformin in 46 of 47 cases. Only 13 of the 47 cases were classified as probably due to metformin by at least three experts. The authors suggested a rethink about the relation between lactic acidosis and metformin. However, they still recommended withdrawing therapy in acute renal insufficiency and when contrast dyes are used for radiological investigation. 

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... 

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. ... 

Where an interaction occurs it may be because the cimetidine inhibits the metabolism of the sulphonylurea by the liver, thereby increasing its effects. Cimetidine appears to inhibit the excretion of metformin by the kidneys, and this may have contributed to the case of metformin-assoeiated lactic acidosis described." ... 

The most significant adverse effect of metformin therapy is the potential for the development of metformin-associated lactic acidosis in the suscephble patient. In the presence of certain comorbidities, which lead to decreased metabolism of lactate or increased anaerobic metabolism, metformin should be discontinued at the time of an examination or procedure using IV iodinated contrast media, withheld for 48 h and restarted after reassessment of renal function [1 ]. 

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