Repaglinide is an active substance, which is used in the disease diabetes mellitus type 2, when dietary measures, weight reduction and physical training do not sufficiently reduce blood sugar. By inhibiting the potassium channels of the beta cells in the pancreas, the drug leads to the release of insulin. If the dosage and intake conditions are adhered to, repaglinide is well tolerated.
What is repaglinide?
The oral antidiabetic drug repaglinide causes an increase in insulin secretion from the endocrine pancreas. It binds specifically to potassium channels, causing insulin secretion. Repaglinide belongs to the glinide group of drugs and is a benzoic acid derivative. It acts only in the presence of glucose and has a short duration of action.
Pharmacologic effects on the body and organs
The drug repaglinide is rapidly absorbed from the gastrointestinal tract after oral administration. The maximum plasma concentration is reached after one hour and decreases rapidly. After 4-6 hours, the drug is completely eliminated. The pharmacological action of repaglinide is inhibition of the ATP-dependent potassium channel of pancreatic beta cells. The potassium channel is a large complex of various binding sites for endogenous molecules. Adjacent membrane proteins, the sulfonylurea receptors, regulate the opening of the channel. Endogenous molecules, as well as drugs such as repaglinide, interact with these specific receptors. The higher the affinity for the receptors, the more potent the drug. Inhibition of the potassium channel leads to depolarization of beta cells with subsequent opening of calcium channels. The increased calcium influx into the beta cells then induces insulin secretion. Repaglinide acts rapidly and only against postprandial blood glucose. In particular, effective lowering of postprandial blood glucose is currently considered important in reducing long-term cardiovascular events. Fewer hypoglycemic events also occur because, first, the duration of action is short and, second, glinides inhibit the potassium channel only in the presence of sugar. Thus, the effect of repaglinide is attenuated as blood glucose falls and basal insulin secretion is not affected. Degradation of the drug occurs predominantly hepatically via the cytochrome P-450 enzymes CYP2C8 and CYP3A4. CYP28C plays a more important role in this process. Thus, the metabolism of the drug can be sensitively altered if other drugs either inhibit or increase the two enzymes. In particular, inhibition of the enzymes can lead to increased blood levels of repaglinide, potentially causing hypoglycemia. Ninety percent of the drug is excreted through the bile and only about 8% is excreted through the kidneys.
Medical use and use for treatment and prevention.
Repaglinide is used in type 2 diabetes mellitus when normalization of blood glucose cannot be achieved by diet, exercise, and weight loss. It can be administered as monotherapy, but combination with certain other antidiabetic agents is also possible. Due to the rapid action of repaglinide, it is recommended to be taken before main meals, ideally 15 minutes preprandially. The initial dosage is 0.5 mg and can be increased as needed, at 1-2 week intervals, to a maximum single dose of 4 mg. If switching from another antidiabetic drug to repaglinide, then the initial dose is 1 mg. The maximum dose per day is 16 mg. Use of the drug is also possible in renal insufficiency, since repaglinide is hardly eliminated renally. However, depending on the case constellation, a dose reduction should be considered. Regular medical checks of blood glucose levels and glycated hemoglobin (HbA1c) should be performed to ensure adequate therapy. In addition, the effect of repaglinide may decrease in the course of treatment. This so-called secondary failure may occur because of progression of diabetes mellitus or may be a decreased response to the drug.
Risks and side effects
There are some contraindications to the use of repaglinide. For example, it should not be used in a type 1 diabetic. Its use is also contraindicated in liver dysfunction or a derailment of glucose metabolism, in terms of ketoacidosis.Similarly, its use in individuals under 18 years of age and in adults over 75 years of age has not been adequately studied; therefore, administration of repaglinide is not recommended in these patient populations. Repaglinide should not be used during pregnancy or lactation. The risk of overdose, with subsequent hypoglycemia, is low if the dosage is observed and adequate meals are taken. In principle, however, hypoglycemia is possible with repaglinide, as with other antidiabetic agents. However, the risk is reduced due to the short half-life of repaglinide. If hypoglycemic reactions occur, they are usually mild. Other side effects are in very rare cases allergic reactions, liver dysfunction as well as eye dysfunction. More frequently, complaints of the digestive tract occur, such as diarrhea or abdominal pain. There are a number of drugs that interact with repaglinide so that the hypoglycemic potential of repaglinide is enhanced. In particular, these include gemfibrozil, clarithromycin, itraconazole, ketoconazole, trimethoprim, ciclosporin, clopidogrel, other antidiabetic agents, monoamine oxidase inhibitors, ACE inhibitors, salicylates, NSAIDs, alcohol, and anabolic steroids. Above all, combination with gemfibrozil is not advisable because in clinical trials this drug particularly markedly increased the half-life of repaglinide as well as its potency. Hypoglycemia could thus be triggered more frequently. On the other hand, there are drugs, such as rifampicin, which reduce the effect of repaglinide and thus may require an increase in dose. Other physical stresses, such as infections, trauma, and fever, can also increase blood glucose levels, which may require dose adjustment.
