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High dosages of metformin and other biguanides are liked to lactic acidosis. What is the pharmacological mechanism behind this?

I am aware the people have survived doses as high as 63 grams, but at what amount will the majority of the population experience lactic acidosis?

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Metformin, a dimethylbiguanide, is a widely used oral antihyperglycaemic drug for the long term treatment of type 2 diabetes mellitus. It lowers blood glucose in multiple ways, including suppression of hepatic gluconeogenesis, increased peripheral insulin-mediated glucose uptake, decreased fatty acid oxidation, and increased intestinal glucose consumption. Metformin reaches maximal plasma concentration approximately 2 hours after ingestion, and its half-life ranges from 2.5 to 4.9 hours. Approximately 90% of it is eliminated in the urine in 12 hours. Among many side effects of the drug, metformin-associated lactic acidosis is one of them but rare. Although metformin-associated lactic acidosis is a rare condition, with an estimated prevalence of one to five cases per 100 000 population, it has a reported mortality of 30-50%.

The pathophysiology of lactic acidosis from metformin is likely due to inhibition of gluconeogenesis by blocking pyruvate carboxylase, the first step of gluconeogenesis, which converts pyruvate to oxaloacetate. Blocking this enzyme leads to the accumulation of lactic acid. Biguanides also decrease the hepatic metabolism of lactate and have a negative ionotropic effect on the heart, both of which elevate lactate levels. Metformin dose, along with the duration of exposure from accumulation in patients with decreased renal clearance, can cause lactic acidosis. The other contributing factors of lactic acidosis are congestive heart failure, liver disease, shock, alcohol use, hypoxic states, renal failure, sepsis, and advanced age.Link

The number of documented cases of metformin-associated lactic acidosis is small when one considers how widely metformin is used. That metformin has been used safely in patients with contraindications can be viewed as evidence that it does not cause lactic acidosis. On the other hand, cases of lactic acidosis from metformin overdose, particularly in young people without risk factor, suggest that metformin can cause lactic acidosis if given in large doses.

For immediate-release, the maximum recommended dose of metformin is 2550mg/day and for extended-release, the maximum recommended dose is 2000mg/day and dose adjustment should be done for elderly patients, patients with renal impairment, hepatic impairment, and other complications.drugs.com,mayoclinic.org

Studies suggesting that a metformin plasma level of at least 40 mg/L (10 times the therapeutic level) may be necessary to cause lactic acidosis. Link

Source:

https://care.diabetesjournals.org/content/27/7/1791

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3222034/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4264704/

https://www.bmj.com/content/339/bmj.b3660.full

https://www.medscape.com/viewarticle/714920

https://cjasn.asnjournals.org/content/10/8/1476

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