A variety of
derivatives of biguanide are used as pharmaceutical drugs.
Antihyperglycemic agents The term "biguanidine" often refers specifically to a class of drugs that function as oral antihyperglycemic
drugs used for
diabetes mellitus or
prediabetes treatment. Examples include: •
Metformin - widely used in treatment of
diabetes mellitus type 2 •
Phenformin - withdrawn from the market in most countries due to toxic effects •
Buformin - withdrawn from the market due to toxic effects File:Metformin.svg|
Metformin, could be referred to as asymmetric dimethylbiguanidine File:Buformin.svg|
Buformin. A
butyl derivative of biguanidine. File:Phenformin.svg|
Phenformin. A phenethylated biguanidine.
History Galega officinalis (French lilac) was used in diabetes treatment for centuries. In the 1920s,
guanidine compounds were discovered in
Galega extracts. Animal studies showed that these compounds lowered blood glucose levels. Some less toxic derivatives,
synthalin A and synthalin B, were used for diabetes treatment, but after the discovery of
insulin, their use declined. Biguanides were reintroduced into Type 2
diabetes treatment in the late 1950s. Initially
phenformin was widely used, but its potential for sometimes fatal
lactic acidosis resulted in its withdrawal from most pharmacopeias (in the U.S. in 1978). Metformin has a much better safety profile, and it is the principal biguanide drug used in pharmacotherapy worldwide.
Mechanism of action The
mechanism of action of biguanides is not fully understood, and many mechanisms have been proposed for metformin. Biguanides do not affect the output of insulin, unlike other
hypoglycemic agents such as
sulfonylureas and
meglitinides. Therefore, they are effective in Type 2 diabetics; and in Type 1 diabetes when used in conjunction with insulin therapy. Mainly used in Type II diabetes, metformin is considered to increase insulin sensitivity in vivo, resulting in reduced plasma glucose concentrations, increased glucose uptake, and decreased gluconeogenesis. However, in hyperinsulinemia, biguanides can lower fasting levels of insulin in plasma. Their therapeutic uses derive from their tendency to reduce
gluconeogenesis in the liver, and, as a result, reduce the level of glucose in the blood. Biguanides also tend to make the cells of the body more willing to absorb glucose already present in the bloodstream, and there again reducing the level of glucose in the plasma. Biguanides have been shown to interact with copper, specifically in mitochondria, where they interfere with cell metabolism by chelating Copper in its 2+ oxidation state (Cu(II)).
Side effects and toxicity The most common side effect is
diarrhea and dyspepsia, occurring in up to 30% of patients. The most important and serious side effect is
lactic acidosis, therefore metformin is contraindicated in advanced
chronic kidney disease. Kidney function should be assessed before starting metformin. Phenformin and buformin are more prone to cause acidosis than metformin; therefore they have been practically replaced by it. However, when metformin is combined with other drugs (combination therapy),
hypoglycemia and other side effects are possible.
Antimalarial During WWII a British team led by
Frank Rose discovered (see details there) that some biguanides are useful as
antimalarial drugs. Much later it was demonstrated that they are prodrugs metabolised into active
dihydrotriazine derivatives which, until recently, were believed to work by
inhibiting dihydrofolate reductase. Examples include: •
Proguanil (>
cycloguanil) •
Chlorproguanil Disinfectants The disinfectants
chlorhexidine,
polyaminopropyl biguanide (PAPB),
polihexanide, and
alexidine feature biguanide
functional groups. == References ==