Biguanidine
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Biguanide () is the organic compound with the formula HN(C(NH)NH2)2. It is a colorless solid that dissolves in water to give highly basic solution. These solutions slowly hydrolyse to
ammonia Ammonia is an inorganic compound of nitrogen and hydrogen with the formula . A stable binary hydride, and the simplest pnictogen hydride, ammonia is a colourless gas with a distinct pungent smell. Biologically, it is a common nitrogenous was ...
and
urea Urea, also known as carbamide, is an organic compound with chemical formula . This amide has two amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest amide of carbamic acid. Urea serves an important r ...
.


Synthesis

Biguanide can be obtained from the reaction of
dicyandiamide 2-Cyanoguanidine is a nitrile derived from guanidine. It is a dimer of cyanamide, from which it can be prepared. 2-Cyanoguanidine is a colourless solid that is soluble in water, acetone, and alcohol, but not nonpolar organic solvents. Production ...
with
ammonia Ammonia is an inorganic compound of nitrogen and hydrogen with the formula . A stable binary hydride, and the simplest pnictogen hydride, ammonia is a colourless gas with a distinct pungent smell. Biologically, it is a common nitrogenous was ...
, via a
Pinner Pinner is a London suburb in the London borough of Harrow, Greater London, England, northwest of Charing Cross, close to the border with Hillingdon, historically in the county of Middlesex. The population was 31,130 in 2011. Originally a med ...
-type process. :\mathrm Biguanide was first synthesized by Bernhard Rathke in 1879.


Biguanidine drugs

A variety of
derivatives The derivative of a function is the rate of change of the function's output relative to its input value. Derivative may also refer to: In mathematics and economics * Brzozowski derivative in the theory of formal languages * Formal derivative, an ...
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
drug A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via insuffla ...
s used for
diabetes mellitus Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...
or
prediabetes Prediabetes is a component of the metabolic syndrome and is characterized by elevated blood sugar levels that fall below the threshold to diagnose diabetes mellitus. It usually does not cause symptoms but people with prediabetes often have obesit ...
treatment. Examples include: *
Metformin Metformin, sold under the brand name Glucophage, among others, is the main first-line medication for the treatment of type 2 diabetes, particularly in people who are overweight. It is also used in the treatment of polycystic ovary syndrome. ...
- widely used in treatment of
diabetes mellitus type 2 Type 2 diabetes, formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urination, ...
*
Phenformin Phenformin is an antidiabetic drug from the biguanide class. It was marketed as DBI by Ciba-Geigy, but was withdrawn from most markets in the late 1970s due to a high risk of lactic acidosis, which was fatal in 50% of cases. Phenformin was develo ...
- withdrawn from the market in most countries due to toxic effects *
Buformin Buformin (1-butylbiguanide) is an oral antidiabetic drug of the biguanide class, chemically related to metformin and phenformin. Buformin was marketed by German pharmaceutical company Grünenthal as Silubin. Chemistry and animal toxicology Bufor ...
- withdrawn from the market due to toxic effects File:Metformin.svg,
Metformin Metformin, sold under the brand name Glucophage, among others, is the main first-line medication for the treatment of type 2 diabetes, particularly in people who are overweight. It is also used in the treatment of polycystic ovary syndrome. ...
, an asymmetric dimethylbiguanidine File:Buformin.svg,
Buformin Buformin (1-butylbiguanide) is an oral antidiabetic drug of the biguanide class, chemically related to metformin and phenformin. Buformin was marketed by German pharmaceutical company Grünenthal as Silubin. Chemistry and animal toxicology Bufor ...
. A
butyl In organic chemistry, butyl is a four-carbon alkyl radical or substituent group with general chemical formula , derived from either of the two isomers (''n''-butane and isobutane) of butane. The isomer ''n''-butane can connect in two ways, givi ...
derivative of biguanidine. File:Phenformin.svg,
Phenformin Phenformin is an antidiabetic drug from the biguanide class. It was marketed as DBI by Ciba-Geigy, but was withdrawn from most markets in the late 1970s due to a high risk of lactic acidosis, which was fatal in 50% of cases. Phenformin was develo ...
. A phenethylated biguanidine.


History

''
Galega officinalis ''Galega officinalis'', commonly known as galega or goat's-rue, is an herbaceous plant in the subfamily Faboideae of the legume family Fabaceae. It is native to parts of northern Africa, western Asia and Europe, but is widely cultivated and natu ...
'' (French lilac) was used in diabetes treatment for centuries. In the 1920s,
guanidine Guanidine is the compound with the formula HNC(NH2)2. It is a colourless solid that dissolves in polar solvents. It is a strong base that is used in the production of plastics and explosives. It is found in urine predominantly in patients experie ...
compounds were discovered in ''Galega'' extracts. Animal studies showed that these compounds lowered blood glucose levels. Some less toxic derivatives,
synthalin Synthalin was an oral anti-diabetic drug. Discovered in 1926 it was marketed in Europe by Schering AG of Berlin as a synthetic drug with insulin-like properties that could be taken orally. However, it was toxic to the liver and kidney and was with ...
A and synthalin B, were used for diabetes treatment, but after the discovery of
insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism o ...
, their use declined. Biguanides were reintroduced into Type 2
diabetes Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...
treatment in the late 1950s. Initially
phenformin Phenformin is an antidiabetic drug from the biguanide class. It was marketed as DBI by Ciba-Geigy, but was withdrawn from most markets in the late 1970s due to a high risk of lactic acidosis, which was fatal in 50% of cases. Phenformin was develo ...
was widely used, but its potential for sometimes fatal
lactic acidosis Lactic acidosis is a medical condition characterized by a build-up of lactate (especially -lactate) in the body, with formation of an excessively low pH in the bloodstream. It is a form of metabolic acidosis, in which excessive acid accumulates ...
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 In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect. A mechanism of action usually includes mention of the specific molecular targe ...
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 agent Drugs used in diabetes treat diabetes mellitus by altering the glucose level in the blood. With the exceptions of insulin, most GLP receptor agonists ( liraglutide, exenatide, and others), and pramlintide, all are administered orally and are th ...
s such as
sulfonylurea Sulfonylureas (UK: sulphonylurea) are a class of organic compounds used in medicine and agriculture, for example as antidiabetic drugs widely used in the management of diabetes mellitus type 2. They act by increasing insulin release from the beta ...
s and
meglitinide Meglitinides or glinides are a class of drugs used to treat type 2 diabetes. Drugs Repaglinide (trade name Prandin) gained US Food and Drug Administration approval in 1997. Other drugs in this class include nateglinide (Starlix) and mitiglinid ...
s. 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 Gluconeogenesis (GNG) is a metabolic pathway that results in the generation of glucose from certain non-carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In vertebrat ...
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.


Side effects and toxicity

The most common side effect is
diarrhea Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin wi ...
and dyspepsia, occurring in up to 30% of patients. The most important and serious side effect is
lactic acidosis Lactic acidosis is a medical condition characterized by a build-up of lactate (especially -lactate) in the body, with formation of an excessively low pH in the bloodstream. It is a form of metabolic acidosis, in which excessive acid accumulates ...
, therefore metformin is contraindicated in advanced
chronic kidney disease Chronic kidney disease (CKD) is a type of kidney disease in which a gradual loss of kidney function occurs over a period of months to years. Initially generally no symptoms are seen, but later symptoms may include leg swelling, feeling tired, vo ...
. 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 Hypoglycemia, also called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's triad is used to properly identify hypoglycemic episodes. It is defined as blood glucose belo ...
and other side effects are possible.


Antimalarial

Some biguanides are also used as
antimalarial drug Antimalarial medications or simply antimalarials are a type of antiparasitic chemical agent, often naturally derived, that can be used to treat or to prevent malaria, in the latter case, most often aiming at two susceptible target groups, young c ...
s. Examples include: * Proguanil *
Chlorproguanil Chlorproguanil is an antimalarial drug. References See also * Proguanil * Chlorproguanil hydrochloride-dapsone-artesunate Chlorproguanil/dapsone/artesunate (abbreviated CDA) was an experimental antimalarial treatment that entered Phase III ...


Disinfectants

The disinfectants
chlorhexidine Chlorhexidine (CHX) (commonly known by the salt forms chlorhexidine gluconate and chlorhexidine digluconate (CHG) or chlorhexidine acetate) is a disinfectant and antiseptic that is used for skin disinfection before surgery and to sterilize surg ...
,
polyaminopropyl biguanide Polyaminopropyl biguanide (PAPB) is a disinfectant and a preservative used for disinfection on skin and in cleaning solutions for contact lenses. It is also an ingredient in many deodorant bodysprays. It is a polymer or oligomer where biguanide ...
(PAPB), polihexanide, and alexidine feature biguanide
functional group In organic chemistry, a functional group is a substituent or moiety in a molecule that causes the molecule's characteristic chemical reactions. The same functional group will undergo the same or similar chemical reactions regardless of the rest ...
s.


References

{{antimalarials Guanidines