Metformin metabolism

Antidiabetic Drugs other than Insulin. Figure 3 The antihyperglycaemic effect of metformin involves enhanced insulin-mediated suppression of hepatic glucose production and muscle glucose uptake. Metformin also exerts non-insulin-dependent effects on these tissues, including reduced fatty acid oxidation and increased anaerobic glucose metabolism by the intestine. FA, fatty acid f, increase i decrease. 

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. 

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. 

Metformin also has been shown to produce beneficial effects on serum lipid levels and thus has become a first-line agent for type 2 DM patients with metabolic syndrome. Triglyceride and low-density lipoprotein (LDL) cholesterol levels often are reduced by 8% to 15%, whereas high-density lipoprotein (HDL) cholesterol improves by approximately 2%. A modest weight loss of 2 to 3 kg (4.4—6.6 lb) also has been reported with metformin therapy. Metformin often is used in combination with a sulfonylurea or a thiazolidinedione for synergistic effects. 

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... 

Metabolism/Excretion- Metformin is excreted unchanged in the urine and does not undergo hepatic metabolism or biliary excretion. Tubular secretion is the major route of elimination. The elimination half-life is approximately 17.6 hours. 

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. 

Diabetic patients Weight-loss induction by orlistat may be accompanied by improved metabolic control in diabetic patients, which might require a reduction in dose of oral hypoglycemic medication (eg, sulfonylureas, metformin) or insulin. Misuse potential As with any weight-loss agent, the potential exists for misuse of orlistat in inappropriate patient populations (eg, patients with anorexia nervosa or bulimia). 

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,... 

Women with the polycystic ovary syndrome are at increased risk for the metabolic syndrome and associated health risks and metformin, which also reduces hyperinsulinemia, might be effective in treating obese, infertile women with the polycystic ovary syndrome. 

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... 

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... 

If hypoxic states occur, discontinue drug therapy Therapy should be suspended for surgical procedures Alcohol is known to potentiate the effect of metformin on lactate metabolism—patients should be warned about the dangers of excessive alcohol intake... 

Most (70-90%) of a dose of metformin is eliminated via the kidneys with a half-life of 9 hours (6). In contrast, phenformin is mostly eliminated by metabolism its half-life is about 11 hours (7). 

In a placebo-controlled study in 40 patients with impaired glucose tolerance metformin 500 mg bd for 6 months increased insulin-stimulated glucose metabolism by 20% with minimal improvement in glucose tolerance this effect was maintained after 12 months (11). 

One week after starting to take metformin 850 mg in divided dose a 74-year-old man became confused and disoriented and had speech abnormalities and bilateral horizontal gaze-evoked nystagmus. Electroencephalography suggested a toxic-metabolic... 

A 40-year-old man taking metformin 850 mg bd developed severe metabolic acidosis (pH 6.62, base deficit 31 mmol/1, anion gap 37 mmol/1, lactate over 20 mmol/ 1) and hypoglycemia (1.9 mmol/1) (55). 

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. 

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