Biguanides

Biguanide derivatives (“ biguanides ”) are chemical derivatives of biguanide that were developed as medicinal substances, especially for the treatment of diabetes mellitus . The only substance left in this indication is metformin , the importance of which as an oral anti-diabetic agent is high despite the development of newer active ingredients and is one of the first-line treatment of type 2 diabetes mellitus among the drug therapies . In a completely different indication, the biguanide proguanil is mainly used in combination therapies for the prophylaxis and therapy of malaria (see there).

Biguanides are structurally related to the alkaloid Galegin , an ingredient of the goat's rue (Galega officinalis). This plant has been used in folk medicine for various ailments for hundreds of years , including: a. it also has a blood sugar lowering effect.

Representative

Metformin (trade names: Glucophage , Siofor , Metformin-CT and others)
Phenformin ( discontinued in 1978)

Buformin (withdrawn from trade in 1978)

Proguanil

Polyhexanide

Effect and use

Biguanides lower the blood sugar level in diabetics without affecting the insulin balance , so they cannot cause hypoglycaemia . They also have an appetite suppressant. Metformin is used in type 2 diabetes . It is an alternative to sulfonylureas , especially for overweight patients , as these often lead to weight gain. In individual cases, metformin can also be used as a supplementary therapy for type 1 diabetes mellitus, if z. B. is an overweight type 1 diabetic with weight-related insulin resistance .

In type 2 diabetes mellitus, metformin is used as an oral first-line therapy. The possible contraindications limit the group of patients. Only patients whose kidney and liver functions are not impaired may be treated with metformin. Serious cardiovascular or pulmonary diseases also speak against the use of metformin. Metformin should be paused if the body is exposed to particular stress such as infectious diseases , operations and pregnancy . After the publication of several large studies, it has been used as the drug of first choice in many type 2 diabetics since the late 1990s. Outside of the approved areas of application, metformin is successfully used in gynecology for polycystic ovary syndrome .

Proguanil, on the other hand, is used in chemoprophylaxis and therapy for malaria . Some biguanides have virucidal properties, such as the heterocyclic moroxydine .

Mechanism of action

The effect of the biguanides is apparently a combination of several mechanisms that have not yet been fully clarified. In contrast to other oral antidiabetic drugs, the blood sugar lowering effect only sets in after several days. In healthy patients, the administration of biguanides has less of an effect on the blood sugar level.

Due to their lipophilicity, biguanides are stored in the membrane of the intestinal epithelial cells and there impair the active transport of glucose and thus its absorption from the intestine .

On the other hand, biguanides also accumulate in liver cells , where they activate the AMP kinase , inhibit substrate transport ( pyruvate ) into the mitochondria and thus interrupt the respiratory chain . The result is reduced gluconeogenesis and ATP synthesis in the liver cells and thus reduced glucose production in the liver. In addition, the utilization of lactate is suppressed, which leads to an accumulation of lactate in the body and can lead to lactic acidosis , which can have fatal consequences, especially in patients with impaired kidney function .

Ultimately, the increase in insulin receptors on the skeletal muscle is likely to lead to an increase in the effectiveness of insulin and thus to an increased consumption of glucose.

The individual biguanides differ in terms of their mechanisms of action, from which differences in effectiveness and undesirable effects can be derived.

unwanted effects

The complex mechanism of action of biguanides leads to sometimes serious side effects . Gastrointestinal complaints such as diarrhea , nausea , and vomiting often occur . Metformin can rarely lead to lactic acidosis through accumulation in renal insufficiency. Several cases of lactic acidosis , some of which were fatal, led to drugs containing phenformin as an active ingredient being withdrawn from the US market in 1977 . In Germany , the approval for phenformin and buformin was withdrawn in 1978, after these drugs had been standard therapy for diabetes for over 20 years. The significantly less lipophilic metformin, which seems to intervene less strongly in the respiratory chain, is subject to a low risk of lactic acidosis if the contraindications are observed .

literature

UK Prospective Diabetes Study (UKPDS) Group: Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). In: Lancet . Volume 352, 1998, pp. 854-865. PMID 9742977 .
Richard Daikeler, Götz Use, Sylke Waibel: Diabetes. Evidence-based diagnosis and therapy. 10th edition. Kitteltaschenbuch, Sinsheim 2015, ISBN 978-3-00-050903-2 , pp. 157f.

Individual evidence

↑ Drug antihyperglycemic therapy of type 2 diabetes mellitus, update of the evidence-based guideline of the German Diabetes Society 2009 (PDF; 815 kB), accessed on August 14, 2012.
↑ Life-saving prophylaxis and therapy , pharmische-zeitung.de
^ W. Arnold, Medicinal Plants, accessed on October 16, 2011 ( Memento from November 20, 2010 in the Internet Archive )
^ German Diabetes Center DDZ Düsseldorf, February 2010, accessed on October 16, 2011
^ LR Harborne et al. a .: Metformin and weight loss in obese women with polycystic ovary syndrome: comparison of doses. In: J Clin Endocrinol Metab 90, 2005, pp. 4593-4598. PMID 15886247 .
^ Harry Auterhoff, Textbook of Pharmaceutical Chemistry . Wissenschaftliche Verlagsgesellschaft Stuttgart, 9th edition, 1978. p. 474.
↑ Richard Daikeler, idols Use, Sylke Waibel: diabetes. Evidence-based diagnosis and therapy. 10th edition. Kitteltaschenbuch, Sinsheim 2015, ISBN 978-3-00-050903-2 , p. 43.
↑ SR Salpeter u. a .: Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. In: Cochrane Database Syst. Rev. Volume 14, 4, 2010.

[1] Drug antihyperglycemic therapy of type 2 diabetes mellitus, update of the evidence-based guideline of the German Diabetes Society 2009 (PDF; 815 kB), accessed on August 14, 2012.

[2] Life-saving prophylaxis and therapy , pharmische-zeitung.de

[3] W. Arnold, Medicinal Plants, accessed on October 16, 2011 ( Memento from November 20, 2010 in the Internet Archive )

[4] German Diabetes Center DDZ Düsseldorf, February 2010, accessed on October 16, 2011

[5] LR Harborne et al. a .: Metformin and weight loss in obese women with polycystic ovary syndrome: comparison of doses. In: J Clin Endocrinol Metab 90, 2005, pp. 4593-4598. PMID 15886247 .

[6] Harry Auterhoff, Textbook of Pharmaceutical Chemistry . Wissenschaftliche Verlagsgesellschaft Stuttgart, 9th edition, 1978. p. 474.

[7] Richard Daikeler, idols Use, Sylke Waibel: diabetes. Evidence-based diagnosis and therapy. 10th edition. Kitteltaschenbuch, Sinsheim 2015, ISBN 978-3-00-050903-2 , p. 43.

[8] SR Salpeter u. a .: Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. In: Cochrane Database Syst. Rev. Volume 14, 4, 2010.