Glibenclamide
Glibenclamide is metabolized by CYP2C9, which should be taken into account when used concomitantly with CYP2C9 inducers or inhibitors.
An increase in the hypoglycemic effect of glibenclamide is observed with the simultaneous use of angiotensin-converting enzyme inhibitors, anabolic agents and male sex hormones, other oral hypoglycemic drugs (for example, acarbose, biguanides) and insulin, non-steroidal anti-inflammatory drugs (NSAIDs), azapropazone, beta-blockers, guanethidine, quinine, quinolone derivatives, chloramphenicol, clofibrate, coumarin derivatives, disopyramide, fenfluramine, pheniramidol, fluoxetine, monoamine oxidase inhibitors, antifungals (miconazole, fluconazole), para-aminosalicylic acid, pentoxifylline (in large doses administered parenterally), perhexiline, pyrazolone derivatives, phenylbutazones , phosphamides (e.g. cyclophosphamide, ifosfamide, trofosfamide), probenecid, salicylates, sulfinpyrazone, sulfonamides, tetracyclines, clarithromycin and tritoqualine.
Urine acidifying agents (ammonium chloride, calcium chloride) enhance the effect of glibenclamide by reducing the degree of its dissociation and increasing its reabsorption.
The hypoglycemic effect of glibenclamide may be reduced by concomitant use of barbiturates, isoniazid, cyclosporine, diazoxide, glucocorticosteroids, glucagon, epinephrine, nicotinates (in large doses), phenytoin, phenothiazines, rifampicin, ritordin, clonidine, thiazide diuretics, acetazolamide, estrogens (for example, orally s hormonal contraceptives), preparations of iodine-containing thyroid hormones, blockers of “slow” calcium channels, sympathomimetic agents and lithium salts.
When used simultaneously with pentamidine, in isolated cases a pronounced decrease or increase in the concentration of glucose in the blood is possible.
H2-histamine receptor blockers, clonidine and reserpine can both enhance and weaken the hypoglycemic effect of glibenclamide.
Under the influence of sympatholytic agents such as beta-blockers, clonidine, guanethidine and reserpine, signs of adrenergic counterregulation in response to hypoglycemia may be reduced or absent.
Single or chronic alcohol consumption can either enhance or weaken the hypoglycemic effect of glibenclamide.
Glibenclamide can enhance or weaken the effects of coumarin derivatives. Glibenclamide may increase plasma concentrations of cyclosporine and potentially lead to increased toxicity; therefore, concentration monitoring and dose adjustment of cyclosporine is recommended when used concomitantly with glibenclamide.
When using glibenclamide simultaneously with bosentan, an increase in cases of increased activity of “liver” enzymes was noted, because Glibenclamyl and bosentan inhibit the transfer of bile acids from liver cells, which leads to their intracellular accumulation and increased cytotoxic effect. In this regard, the simultaneous use of glibenclamide and bosentan is contraindicated.
Medicines that inhibit bone marrow hematopoiesis increase the risk of myelosuppression.
pharmachologic effect
Glibenclamide has pancreatic and extrapancreatic effects. Stimulates insulin secretion by reducing the threshold for irritation of pancreatic beta cells by glucose, increases sensitivity to insulin and the degree of its binding to target cells, increases insulin release, enhances the effect of insulin on glucose uptake by muscles and liver, inhibits lipolysis in adipose tissue (extrapancreatic effects) . Acts in the second stage of insulin secretion. It has a hypolipidemic effect, reduces the thrombogenic properties of blood. The hypoglycemic effect develops after 2 hours, reaches a maximum after 7-8 hours and lasts 12 hours. The drug provides a smooth increase in the concentration of insulin and a smooth decrease in the concentration of glucose in the blood plasma, which reduces the risk of hypoglycemic conditions. The activity of glibenclamide occurs when the endocrine function of the pancreas is preserved.
Pharmacokinetics
Absorption
When taken orally, absorption from the gastrointestinal tract is 48-84%. The time to reach maximum concentration in the blood (Tmax) is 1-2 hours. The bioavailability of glibenclamide is 100%. Concomitant food intake does not have a significant effect on the absorption of glibenclamide.
Distribution
Volume of distribution (Vd) 9-10 l. Communication with plasma proteins is 95-99%. The placental barrier does not pass well.
Metabolism
Glibenclamide is almost completely metabolized in the liver to form two inactive metabolites.
Removal
One of the inactive metabolites is excreted by the kidneys, the other through the intestines in approximately equal proportions. Half-life (T1/2) – from 3 to 10-16 hours.
Pharmacokinetics in patients with impaired liver function
In patients with impaired liver function, the removal of the active substance from the blood plasma is slowed down.
Pharmacokinetics in renal failure
In patients with renal failure, the excretion of metabolites through the intestines compensatory increases. With creatinine clearance ≥ 30 ml/min, total excretion remains unchanged; in severe renal failure, cumulation is possible.
Contraindications
· hypersensitivity to glibenclamide and/or any excipient of the drug;
· hypersensitivity to other sulfonylurea derivatives; sulfonamides; diuretics containing a sulfonamide group in the molecule; probenecid, as cross-reactions may occur;
type 1 diabetes mellitus;
Diabetic ketoacidosis, diabetic precoma and coma;
condition after resection of the pancreas;
· severe liver dysfunction;
severe renal impairment (creatinine clearance <30 ml/min);
Severe adrenal insufficiency;
· decompensation of carbohydrate metabolism in infectious diseases, burns, injuries or after major surgical operations, when insulin therapy is indicated;
leukopenia;
· intestinal obstruction, gastric paresis;
· hereditary lactose intolerance, lactase deficiency or glucose and lactose malabsorption syndrome;
·pregnancy and breastfeeding period;
· children under 18 years of age (efficacy and safety have not been studied);
· porphyria;
· deficiency of glucose-6-phosphate dehydrogenase;
·simultaneous use with bosentan.
Carefully
Glibenclamide should be used with caution in febrile syndrome; diseases of the thyroid gland (with dysfunction); insufficiency of the function of the anterior pituitary gland or adrenal cortex; alcoholism, acute alcohol intoxication; conditions accompanied by impaired absorption of food and the risk of hypoglycemia; mild to moderate renal failure (creatinine clearance ≥ 30 ml/min); liver failure and moderate severity; cerebral atherosclerosis; in elderly patients due to the risk of developing hypoglycemia.
Use during pregnancy and breastfeeding
The use of glibenclamide during pregnancy is contraindicated. If pregnancy occurs, the drug should be discontinued. When planning pregnancy, therapy with oral hypoglycemic drugs must be replaced with insulin therapy.
There is no data on the penetration of glibenclamide into breast milk. Since other sulfonylureas pass into breast milk, the use of glibenclamide during breastfeeding is contraindicated.
special instructions
The drug should be taken regularly and, if possible, at the same time.
It is necessary to carefully follow the drug intake regimen and diet. The physician should carefully consider prescribing glibenclamide to patients with impaired liver and kidney function, as well as hypofunction of the thyroid gland, anterior pituitary gland or adrenal cortex. It is necessary to adjust the dose of glibenclamide in case of physical and emotional stress, or changes in diet.
Factors that contribute to the risk of developing hypoglycemia include:
· reluctance or inability of the patient (more often observed in elderly patients) to cooperate with the doctor;
malnutrition, irregular eating or skipping meals;
Imbalance between physical activity and carbohydrate consumption;
·diet change;
· drinking alcohol, especially in combination with skipping meals;
severe renal dysfunction;
· severe liver dysfunction;
· overdose of glibenclamide;
diarrhea, vomiting:
· some decompensated endocrine disorders that disrupt carbohydrate metabolism or adrenergic counterregulation in response to hypoglycemia (for example, some dysfunctions of the thyroid gland and anterior pituitary gland, adrenal insufficiency);
·simultaneous use of certain medications.
Major surgical interventions and injuries, extensive burns, infectious diseases with febrile syndrome may require the abolition of oral hypoglycemic drugs and the prescription of insulin.
During treatment, it is not recommended to stay in the sun for a long time.
The use of sulfonylurea derivatives, which include glibenclamide, in patients with glucose-6-phosphate dehydrogenase deficiency can lead to the development of hemolytic anemia, therefore hypoglycemic agents that are not sulfonylurea derivatives should be used.
Concomitant use of medications that act on the central nervous system and lower blood pressure (including beta-blockers), as well as autonomic neuropathy, can mask the symptoms of hypoglycemia.
In elderly patients, the risk of developing hypoglycemia is slightly higher, so more careful selection of the dose of the drug and regular monitoring of fasting and postprandial blood glucose concentrations are necessary, especially at the beginning of treatment.
Alcohol can provoke the development of hypoglycemia, as well as the development of a disulfiram-like reaction (nausea, vomiting, abdominal pain, a feeling of heat on the face and upper body, tachycardia, dizziness, headache), so you should refrain from drinking alcohol during treatment with Glibenclamide.
With each change of doctor (for example, when hospitalized in a hospital, when sick on vacation), the patient must inform the attending physician that he has diabetes.
Fertility.
There are no data on the effect of glibenclamide on fertility.
Impact on the ability to drive vehicles and machinery
When taking the drug Glibenclamide, hypoglycemia may develop, and, as a result, a decrease in reaction and the ability to concentrate, therefore, during treatment with the drug, care must be taken when driving and engaging in other potentially hazardous activities that require concentration and speed of psychomotor reactions.
Directions for use and doses
Inside. The drug should be taken 20-30 minutes before meals, without chewing and with a sufficient amount of liquid. The drug should be taken at the same time of day.
The dose of the drug is selected individually depending on age, severity of diabetes mellitus, blood glucose concentration on an empty stomach and 2 hours after meals.
The tablet can be divided into 2 equal parts. The daily dose range is from ½ to 3 tablets (2.5 to 15 mg). The initial dose is 2.5-5 mg (½-1 tablet) per day. The maximum daily dose is 15 mg (3 tablets).
The dose should be increased at intervals of several days to 1 week until the required therapeutic dose is reached, which should not exceed the maximum.
Daily doses of the drug up to 2 tablets are usually taken once a day - in the morning. Higher doses are divided into 2 doses - morning and evening doses in a 2:1 ratio.
If one dose of the drug is missed, the next dose of the drug should be taken at the usual time, and a higher dose is not allowed.
Switching from other hypoglycemic drugs
When switching from other hypoglycemic drugs with a similar type of action, the drug Glibenclamide is prescribed according to the scheme given above, and the previous drug is immediately discontinued.
Use in combination therapy with other hypoglycemic drugs
The drug Glibenclamide can be used as part of combination therapy with metformin and other oral hypoglycemic drugs that do not stimulate insulin secretion by pancreatic beta cells.
Use in elderly, debilitated and malnourished patients
In elderly, debilitated or malnourished patients, the initial and maintenance doses should be reduced due to the risk of hypoglycemia.
Use in patients with impaired renal and liver function
The use of Glibenclamide in patients with severe renal and hepatic impairment is contraindicated. In patients with mild to moderate renal impairment (creatinine clearance > 30 ml/min) and mild to moderate hepatic impairment, the initial and maintenance doses should be reduced due to the risk of hypoglycemia.
Side effect
Classification of undesirable side reactions by frequency of development:
often (> 1/100, < 1/10), uncommon (> 1/1000, < 1/100), rare (> 1/10000, < 1/1000), very rare (< 1/10000), including some messages.
Blood and lymphatic system disorders
: rarely: thrombocytopenia, thrombocytopenic purpura, leukocytopenia; very rare: leukopenia, agranulocytosis, erythropenia, hemolytic anemia or pancytopenia, aplastic anemia, bone marrow aplasia, eosinophilia and bleeding disorders.
Immune system disorders
: very rarely, reactions in the form of urticaria can serve as the beginning of the development of severe conditions, accompanied by shortness of breath and a decrease in blood pressure until the onset of life-threatening shock. Isolated cases of severe generalized allergic reactions with skin rash, joint pain, fever, protein in the urine and jaundice have been described. If symptoms of hives appear, you should consult a doctor immediately. Cross-allergy with other sulfonylurea derivatives and sulfonamides is possible.
In some cases, the development of allergic vasculitis is possible, in some cases life-threatening.
Metabolic and nutritional disorders
: often: hypoglycemia, weight gain.
Visual disorders
: very rare: visual impairment and accommodation disorders.
Gastrointestinal disorders
: uncommon: nausea, heartburn, anorexia, belching, vomiting, “metallic” taste in the mouth, feeling of heaviness and fullness in the stomach, abdominal pain and diarrhea; rarely – pancreatitis.
Disorders of the liver and biliary tract
: very rarely: increased activity of liver enzymes (aspartate aminotransferase, alanine aminotransferase), cholestasis, cholestatic hepatitis, granulomatous hepatitis and bilirubinemia. In some cases, hepatitis, elevated liver enzymes and/or cholestasis and jaundice may lead to life-threatening liver failure, but may resolve after discontinuation of glibenclamide.
Skin and subcutaneous tissue disorders
: rarely: skin itching; hives; erythema nodosum; erythematous, maculopapular or bullous rash; psoriasis-like skin reactions.
Renal and urinary tract disorders
: very rarely: increased diuresis, transient proteinuria.
Other side effects observed in isolated cases include photosensitivity; hyponatremia; porphyria cutanea tarda; pellagra-like symptoms.
It is possible to develop an acute reaction of alcohol intolerance after drinking it, which is expressed by complications from the circulatory and respiratory organs (disulfiram-like reaction: vomiting, feeling of heat in the face and upper body, tachycardia, dizziness, headache).
Overdose
In case of overdose, hypoglycemia may develop. This condition can be protracted and contribute to the development of severe conditions, including comatose, life-threatening or fatal. In diabetic polyneuropathy or with concomitant treatment with sympatholytic drugs (see section “Interaction with other drugs”), typical precursors of hypoglycemia may be mild or absent altogether.
Symptoms of hypoglycemia: strong feeling of hunger, sudden profuse sweating, palpitations, pallor and decreased skin temperature, paresthesia of the oral mucosa, trembling, general anxiety, headache, pathological drowsiness, sleep disorders, feelings of fear, impaired coordination of movements, temporary neurological disorders (for example, visual and speech disorders, manifestations of paresis and paralysis, or altered perception of sensations). As hypoglycemia progresses, loss of self-control and consciousness is possible, and a predisposition to seizures develops.
Treatment: For mild or moderate hypoglycemia, it is necessary to take dextrose (glucose) or a sugar solution orally.
In case of severe hypoglycemia, accompanied by loss of consciousness, a 40% dextrose solution is administered intravenously or glucagon intravenously, intramuscularly, or subcutaneously. After regaining consciousness, the patient should be given food rich in carbohydrates to avoid the recurrence of hypoglycemia.
