Biguanide

Biguanide can be obtained from the reaction of dicyandiamide with ammonia, via a Pinner-type process.

:$\backslash mathrm\{C\_2H\_4N\_4\; +\; NH\_3\; \backslash longrightarrow\; C\_2H\_7N\_5\}$

Biguanide was first synthesized by Bernhard Rathke in 1879.{{cite journal |last1=Rathke |first1=B. |title=Ueber Biguanid |journal=Berichte der Deutschen Chemischen Gesellschaft |date=January 1879 |volume=12 |issue=1 |pages=776–784 |doi=10.1002/cber.187901201219|url=https://zenodo.org/record/2048781 }}

A variety of derivatives of biguanide are used as pharmaceutical drugs.

The term "biguanidine" often refers specifically to a class of drugs that function as oral antihyperglycemic drugs used for diabetes mellitus or prediabetes treatment.{{cite book | vauthors = Rang HP, Dale MM, Ritter KM, Moore PK |title=Pharmacology |date=2003 |publisher=Churchill Livingstone |location=Edinburgh |isbn=0-443-07145-4 |edition=5th | page = 388}}

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• Phenformin - withdrawn from the market in most countries due to toxic effects
• Buformin - withdrawn from the market due to toxic effects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.

{{details|metformin#History}}

Galega officinalis (French lilac) was used in diabetes treatment for centuries.{{cite journal |author=Witters L |title=The blooming of the French lilac |journal=J Clin Invest |volume=108 |issue=8 |pages=1105–7 |year=2001 |pmid=11602616 |doi=10.1172/JCI14178 |pmc=209536 |url=}} 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).{{cite book | vauthors = Tonascia S, Meinert CL |title=Clinical trials: design, conduct, and analysis |publisher=Oxford University Press |location=Oxford [Oxfordshire] |year=1986 |pages=53–54, 59 |isbn=0-19-503568-2}} Metformin has a much better safety profile, and it is the principal biguanide drug used in pharmacotherapy worldwide.

The mechanism of action of biguanides is not fully understood, and many mechanisms have been proposed for metformin.{{cn|date=January 2024}}

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.{{cn|date=January 2024}}

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.{{cn|date=January 2024}}

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.{{cn|date=January 2024}}

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)).{{cite journal |last1=Solier |first1=Stéphanie |last2=Müller |first2=Sebastian |last3=Tatiana |first3=Cañeque |last4=Antoine |first4=Versini |last5=Arnaud |first5=Mansart |last6=Fabien |first6=Sindikubwabo |last7=Leeroy |first7=Baron |last8=Laila |first8=Emam |last9=Pierre |first9=Gestraud |last10=G. Dan |first10=Pantoș |last11=Vincent |first11=Gandon |last12=Christine |first12=Gaillet |last13=Ting-Di |first13=Wu |last14=Florent |first14=Dingli |last15=Damarys |first15=Loew |last16=Sylvain |first16=Baulande |last17=Sylvère |first17=Durand |last18=Valentin |first18=Sencio |last19=Cyril |first19=Robil |last20=François |first20=Trottein |last21=David |first21=Péricat |last22=Emmanuelle |first22=Näser |last23=Céline |first23=Cougoule |last24=Etienne |first24=Meunier |last25=Anne-Laure |first25=Bègue |last26=Hélène |first26=Salmon |last27=Nicolas |first27=Manel |last28=Alain |first28=Puisieux |last29=Sarah |first29=Watson |last30=Mark A. |first30=Dawson |last31=Nicolas |first31=Servant |last32=Guido |first32=Kroemer |last33=Djillali |first33=Annane |last34=Raphaël |first34=Rodriguez |title=A druggable copper-signalling pathway that drives inflammation |journal=Nature |date=2023 |pages=1-9 |doi=10.1038/s41586-023-06017-4 |pmid=37100912 |url=https://www.nature.com/articles/s41586-023-06017-4|pmc=10131557 }}

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.{{cn|date=January 2024}}

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:{{cn|date=January 2024}}

• Proguanil (>cycloguanil)
• Chlorproguanil

{{see also|Bisbiguanide}}

The disinfectants chlorhexidine, polyaminopropyl biguanide (PAPB), polihexanide, and alexidine feature biguanide functional groups.{{cite journal | vauthors = Tanzer JM, Slee AM, Kamay BA | title = Structural requirements of guanide, biguanide, and bisbiguanide agents for antiplaque activity | journal = Antimicrobial Agents and Chemotherapy | volume = 12 | issue = 6 | pages = 721–9 | date = December 1977 | pmid = 931371 | pmc = 430011 | doi = 10.1128/aac.12.6.721 }}

{{reflist}}

{{oral hypoglycemics}}

{{antimalarials}}

Category:Guanidines

Category:Substances discovered in the 19th century