Glimepiride

Structural formula
General
Non-proprietary name	Glimepiride
other names	3-Ethyl-4-methyl- N - (2- {4 - [( trans -4-methylcyclohexyl) carbamoylsulfamoyl] phenyl} ethyl) -2-oxo-5 H -pyrrole-1-carboxamide ( IUPAC )
Molecular formula	C 24 H 34 N 4 O 5 S
External identifiers / databases
CAS number 93479-97-1 EC number 642-919-5 ECHA InfoCard 100.170.771 PubChem 3476 ChemSpider 3357 DrugBank DB00222 Wikidata Q425027
Drug information
ATC code	A10 BB12
Drug class	Antidiabetic drugs , sulfonylureas
Mechanism of action	Potassium channel blockers
properties
Molar mass	490.62 g · mol -1
Physical state	firmly
Melting point	207 ° C
pK s value	4.99
solubility	almost insoluble in water, soluble in alkalis
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed GHS labeling of hazardous substances danger H and P phrases H: 301-319-331-361 P: ?
Toxicological data	> 10,000 mg kg −1 ( LD 50 ,  rat ,  oral )
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Glimepiride is an oral antidiabetic from the group of sulfonylureas , which increases the release of insulin in the β cells of the pancreas and is used in the therapy of type 2 diabetes mellitus . The active ingredient was patented by Hoechst in 1981 as an antidiabetic and in 1994 for the treatment of atherosclerosis .

Mode of action and pharmacology

Absorption

The active ingredient administered orally is completely bioavailable . Ingestion during a meal does not decrease absorption, it just happens a little more slowly. The maximum glimepiride plasma level is reached about 2.5 hours after swallowing the tablet.

distribution

Glimepiride has a very low volume of distribution of around 8.8 liters and has a high plasma protein binding of over 99%, so that only a small amount of glimepiride will be found outside the bloodstream.

Metabolism

Glimepiride is biotransformed in the liver by the cytochrome P450 isoenzyme 2C9 to form a hydroxymethyl and a carboxy metabolite . Of this, the hydroxymethyl derivative still has 30% of the effectiveness of the starting substance.

elimination

About 58% of the active substance and its derivatives are excreted in the urine and about 35% in the faeces . The mean repeated dose plasma half-life of glimepiride is about 5 to 8 hours, that of the metabolites is about 3 to 6 hours.

Physiology of insulin secretion

The β-cells of the pancreas produce and store insulin in special vesicles so that it can be released into the bloodstream when required . This hormone is needed to lower the blood sugar level after a meal by stimulating the glucose transport proteins in the liver and muscle cells to move the glucose from the blood into the cells. A rapid lowering of the blood sugar level is important, since a permanently too high glucose concentration in the blood damages various body tissues.

If the blood glucose level rises as a result of a meal, a correspondingly increased amount of glucose reaches the β cell via special, low-threshold GLUT2 glucose transporters . Glucose is metabolized via glycolysis and the citric acid cycle , ultimately creating the energy carrier adenosine triphosphate (ATP) , among other things . ATP has an inhibitory effect on the ATP-dependent potassium channel of the β-cell, which closes when the ATP concentration is high enough. This changes the membrane potential of the cell, it depolarizes (to put it clearly, but imprecisely: the positive electrical charge rises inside the cell), which leads to the opening of voltage-sensitive calcium channels . The subsequent calcium influx into the β-cell leads to the migration of the insulin-containing vesicles to the cell membrane . There they exocytose their contents, the insulin, into the bloodstream.

Mode of action

Like the other sulfonylureas, glimepiride closes the ATP-dependent potassium channel in the β-cell. This results in the depolarization and the opening of the voltage-dependent calcium channels with subsequent insulin excretion by exocytosis .

Outside of the β-cell, glimepiride causes increased insulin sensitivity and reduced glucose uptake in the liver cells. In the muscle cells and fat cells, glimepiride increases the number of active glucose transporters in the plasma membranes of the cells, whereby the glucose uptake in these tissues is greatly increased.

application

Glimepiride is used for the treatment of type 2 diabetes mellitus if diet, physical activity and weight reduction or the administration of metformin are unsatisfactory. It is possible to combine glimepiride with insulin therapy . It is taken immediately before or during a meal.

Contraindications

Glimepiride should not be taken if the β cells are no longer producing insulin. The presence of a diabetic coma , ketoacidosis , severe kidney and liver dysfunction also excludes the use of glimepiride. Hypersensitivity to sulfonylureas , sulfonamides and tablet excipients must also not be present. Glimepiride must also not be taken during pregnancy, and since sulfonyl derivatives such as glimepiride are excreted in breast milk , it is also contraindicated during breastfeeding.

Interactions

Glimepiride is indicated by the cytochrome P450 - isoenzyme CYP2C9 metabolised. Medicinal substances that increase the amount of this cytochrome ( enzyme induction ) or slow down the ability to function ( inhibition ) can influence the blood level and thus the effect of glimepiride, which either leads to an excessively high blood sugar level (if the glimepiride level is too low) or (if the glimepiride level is too high ) increases the risk of hypoglycaemia . Ingestion of a significant number of different drugs can lead to abnormalities in blood sugar levels, as many drugs affect CYP2C9.

A stronger blood sugar-lowering is possible by other drugs, including other antidiabetic agents, some anti-inflammatory analgesic , anabolic steroids and some male sex hormones , and some antibiotics and antifungals , some antidepressants , circulation-promoting and anticoagulant drugs, a class of substances to blood pressure-lowering agents and uric acid-lowering gout therapeutics and other drugs .

If the blood sugar level drops too weakly, the intake of certain female sex hormones, certain diuretics (water tablets), thyroid hormones and glucocorticoids , laxatives , glucagon , certain drugs to prevent epilepsy , a special tuberculosis drug and other drugs can occur.

Side effects

The most common side effect of sulfonylureas is hypoglycaemia, which can lead to health hazards in everyday life, which can be particularly problematic when using machines and while driving.

literature

• Information for professionals on Glimepirid-ratiopharm ^® tablets and information for professionals on Amaryl ^®
• Ernst Mutschler, Gerd Geisslinger, Heyo K. Kroemer, Monika Schäfer-Korting: drug effects. Textbook of pharmacology and toxicology . 8th edition. Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart 2001, ISBN 3-8047-1763-2

Trade names

Monopreparations

Amaryl (D, A, CH), Glimegamma (D), Glimerax (CH), Glimeryl (CH), Magna (D), Piridoglim (A), numerous generics (D, A, CH)

Combination preparations

Avaglim (D, A), Tandemact (D, A)

Individual evidence

1. ↑ ^{a b} Entry on glimepiride in the DrugBank of the University of Alberta , accessed July 3, 2020.
2. ↑ ^{a b c d e f} Entry on glimepiride. In: Römpp Online . Georg Thieme Verlag, accessed on July 10, 2019.
3. ↑ There is not yet a harmonized classification for this substance . A label of 1 - [[4- [2- (3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) ethyl] phenyl] sulfonyl] -3 is shown, which is derived from a self-classification by the distributor -trans- (4-methylcyclohexyl) urea in the Classification and Labeling Inventory of the European Chemicals Agency (ECHA), accessed on July 3, 2020.
4. ↑ Entry on glimepiride in the ChemIDplus database of the United States National Library of Medicine (NLM), accessed on July 3, 2020.

This article is about a health issue. It is not used for self-diagnosis and does not replace a diagnosis by a doctor. Please note the information on health issues !