Biguanide () is the organic compound with the formula HN(C(NH)NH
2)
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 ...
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 ...
.
Synthesis
Biguanide can be obtained from the reaction of
dicyandiamide 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 ...
, via a
Pinner-type process.
:
Biguanide was first synthesized by
Bernhard Rathke
Heinrich Bernhard Rathke (20 January 1840 in Königsberg – 14 August 1923 in Bad Reichenhall) was a German chemist. He was the son of embryologist Martin Rathke.
He studied natural sciences at the University of Königsberg, and afterward ...
in 1879.
Biguanidine drugs
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
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 inhala ...
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 ...
or
prediabetes 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 urinati ...
*
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
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. 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, gi ...
derivative of biguanidine.
File:Phenformin.svg, Phenformin. 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 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
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 ...
, 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 ...
treatment in the late 1950s. Initially
phenformin 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 d ...
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 targ ...
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
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 verteb ...
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 w ...
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 d ...
, 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 bel ...
and other side effects are possible.
Antimalarial
Some biguanides are also used as
antimalarial drugs. Examples include:
*
Proguanil
Proguanil, also known as chlorguanide and chloroguanide, is a medication used to treat and prevent malaria. It is often used together with chloroquine or atovaquone. When used with chloroquine the combination will treat mild chloroquine resista ...
*
Chlorproguanil
Chlorproguanil is an antimalarial drug.
References
See also
* Proguanil
Proguanil, also known as chlorguanide and chloroguanide, is a medication used to treat and prevent malaria. It is often used together with chloroquine or atovaquone. W ...
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 surgi ...
,
polyaminopropyl biguanide (PAPB),
polihexanide, and
alexidine
Alexidine is an antimicrobial of the biguanide
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 and ...
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 r ...
s.
References
{{antimalarials
Guanidines