Lactic acidosis phenformin

A class of drug derived from guanidine, including metformin and phenformin. Metformin is currently widely used in humans for the treatment of type 2 diabetes. Phenformin was formerly also widely used but was withdrawn because of problems with lactic acidosis. 

II.f.2.3. Biguanides. The two important drugs of this class are metformin and phenformin. Phen-formin is now rarely used due to its high risk of lactic acidosis and in many countries it is even taken... 

Adverse gastrointestinal symptoms (nausea, vomiting, anorexia, metallic taste, abdominal discomfort, and diarrhea) occur in up to 20% of individuals taking metformin this can be minimized by starting at a low dose and slowly titrating the dose upward with food. Like phenformin, metformin can cause lactic acidosis, but its occurrence is rare except when renal failure, hypoxemia, or severe congestive heart failure is present or when coadministered with alcohol. Metformin is also contraindicated in persons with hepatic dysfunction, but it appears to be safe for use in the hepatic steatosis that often occurs with fatty infiltration of the liver in poorly controlled type II diabetics. 

Adverse effects include anorexia, nausea, bitter or metallic taste in mouth, abdominal discomfort, tolerance and lactic acidosis which is the most serious complication and more common with phenformin. 

The structure of metformin is shown below. Phenformin (an older biguanide) was discontinued in the USA because of its association with lactic acidosis and because there was no documentation of any long-term benefit from its use. 

The most common toxic effects of metformin are gastrointestinal (anorexia, nausea, vomiting, abdominal discomfort, and diarrhea), which occur in up to 20% of patients. They are dose-related, tend to occur at the onset of therapy, and are often transient. However, metformin may have to be discontinued in 3-5% of patients because of persistent diarrhea. Absorption of vitamin B12 appears to be reduced during long-term metformin therapy, and annual screening of serum vitamin B12 levels and red blood cell parameters has been encouraged by the manufacturer to determine the need for vitamin B12 injections. In the absence of hypoxia or renal or hepatic insufficiency, lactic acidosis is less common with metformin therapy than with phenformin therapy. 

Adverse effect Lactic acidosis due to biguanides Dose-relation toxic effect Time-course time-independent Susceptibility factors genetic (slow phenformin metabolizers) age disease (impaired liver, kidney, or cardiac function, alcoholism)... 

In patients taking metformin, lactic acidosis is rare (3 per 100 000 patient-years) and is most often seen when contraindications to metformin (impaired kidney or liver function, alcoholism, circulatory problems, old age) are neglected or not detected (64). Although the relative risk of lactic acidosis with metformin is significantly lower than with phenformin or buformin (65), it has been repeatedly reported (SEDA-6, 371) (66), even in the absence of known contraindications (67). 

In 11 797 patients (22 296 person-years) in Saskatchewan who took metformin from 1980-95 there were 9 cases of lactic acidosis per 100 000 patient-years (69), a much lower incidence than the estimated rate of 40-64 cases for phenformin. 

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

The results of hemodialysis in biguanide-induced lactic acidosis are variable. Metformin and buformin are dialy-sable, but phenformin is poorly eliminated. Successful continuous venovenous hemofiltration has been reported (81). 

The authors reported that two other cases of metformin-associated lactic acidosis with concurrent NSAID therapy have been reported to the Committee on Safety of Medicines in the UK. Indometacin can impair kidney function and may have done so in this case. Phenformin can cause tubular damage and oliguria in animals (145) and so it is conceivable that metformin-induced renal damage may also have contributed. 

Kwong SC, Brubacher J. Phenformin and lactic acidosis a case report and review. J Emerg Med 1998 16(6) 881-6. 

Mariano F, Benzi L, Cecchetti P, Rosatello A, Merante D, Goia F, Capra L, Lanza G, Curto V, Cavalli PL. Efficacy of continuous venovenous haemofiltration (CWH) in the treatment of severe phenformin-induced lactic acidosis. Nephrol Dial Transplant 1998 13(4) 1012-5. 

Abdominal discomfort is frequent with metformin (15-25%), and nausea, vomiting, and diarrhea occur even in the absence of lactic acidosis. Other effects include flatulence, abdominal bloating, anorexia, and a metallic taste. Anorexia and weight loss are often seen at the beginning of treatment. Phenformin can cause hemorrhagic gastritis (65). 

Sulfonylureas became widely available in I9.S.S for the ireatincnl of nun-ketusis-prune mild diabetes and are still the drugs of choice. A second class of compounds, the bigui-nidcs. in the furm of a single drug, phenformin. ha.s bees used since 1957. Phenformin was withdrawn from the U. S. market, however, because it causes lactic acidosis, (rom which fataiities have been reported. 

Phenformin is the only biguanide to have been marketed in the United States and removed from the market by the US Food and Drug Administration (FDA) in 1977 because of its association with the development of lactic acidosis, a metabolic aberration that results in mortality in 50-75% of cases. Ethanol intake before the administration of phenformin therapeutic doses or excessive dose appears to predispose the patient to the development of lactic acidosis with a serious outcome. Phenformin and its other relative biguanides are still sold in European and other countries worldwide. 

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... 

Metformin (Glucophage, others) and phenformin were introduced in 1957, and buformin was introduced in 1958. The latter was of limited use, but metformin and phenformin were used widely. Phenformin was withdrawn in many countries during the 1970s because of an association with lactic acidosis. Metformin has been associated only rarely with that complication, and has been used widely in Europe and Canada it became available in the United States in 1995. Metformin given alone or in combination with a sulfonylurea improves glycemic control and lipid concentrations in patients who respond poorly to diet or to a sulfonylurea alone. 

Biguanides, especially the older drug phenformin, have been associated with lactic acidosis. Thus metformin should be avoided in patients with conditions that increase the risk of lactic acidosis, including alcoholism. The answer is (D). 

Lowering of blood glucose by the infusion of guanidine [89], biguanides and two linked guanidine moieties has proved to be useful for the treatment of diabetes meUims. Three compounds became available for diabetes therapy, phenformin (51), buformin (52) and metformin (53) (Figure 10.12). Phenformin (51) was withdrawn due to lactic acidosis [90]. Metformin (53), a less lipophilic biguanide, was recently approved for use in the USA after 20 years of use in Europe [91]. 

B. Lactic acidosis from metformin or phenformin may begin with nonspecific symptoms such as malaise, vomiting, myalgias, and respiratory distress. The mortality rate for severe lactic acidosis is reportedly as high as 50%. 

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