Oral sugar-lowering medications

Oral hypoglycemic drugs are divided into 2 groups based on their chemical composition and mechanism of action on the body: sulfonamides and biguanides.

Oral hypoglycemic sulfanilamide drugs (SP) are sulfonylurea derivatives that differ from each other in the type of additional compounds introduced into the main structure. The characteristics of sulfonylurea derivatives used in medical practice are given in the table.

The mechanism of the hypoglycemic action of sulfonamides is associated with stimulation of endogenous insulin secretion, suppression of glucagon production and reduction of glucose entry from the liver into the bloodstream, as well as with an increase in the sensitivity of insulin-dependent tissues to endogenous insulin due to stimulation of receptor binding to it or an increase in its postreceptor mechanism of action. There is evidence that with the simultaneous use of several sulfonamides, the effect on one or another of the listed pathogenetic factors is more effective. This explains the use of a combination of various sulfonamides in clinical practice. Most sulfonamides are metabolized in the liver (except chlorpropamide) and excreted by the kidneys. The prolongation of the hypoglycemic effect inherent in some sulfonamides is due to either the additional hypoglycemic effect of their metabolites (acetohexamide) or binding to plasma proteins (chlorpropamide). Preparations that act for 6-8 hours are quickly metabolized in the body. Fundamentally new sulfanilamide preparations are gliclazide and glurenorm. Gliclazide, in addition to its sugar-lowering effect, also has an angioprotective effect, determined by a decrease in fibrin accumulation in the aorta, a decrease in platelet and erythrocyte aggregation, as well as the pressor effect of catecholamines on peripheral vessels, contributing to the improvement of microcirculation. The preparation is metabolized in the liver and excreted by the kidneys. Glurenorm differs from all sulfanilamide preparations in that 95% of it is excreted by the intestines and only 5% by the kidneys.

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Characteristics of sulfanilamide drugs

Name		Content of the drug in 1 tablet, g	Maximum daily dose, g	Duration of action, h	Country of origin
International	Commercial
First generation drugs
Tolbutamide	Butamide, orabet	0.5	3.0	6-12	Latvia, Germany
Carbutamide	Bukarban, oranil	0.5	3.0	6-12	Hungary, Germany
Chlorpropamide	Chlorpropamide, apochlorpropamide	0.1-0.25; 0.25	0.5	24	Poland, Canada
Second and third generation drugs
Glibenclamide	Antibet, dianti, apogliburide, genglyb, gilemal, glybamide, glibenclamide Teva Glibenclamide	0.0025-0.005; 0.025-0.005; 0.005 0,005	0.02	8-12	India, Canada, Hungary, Israel, Russia, Estonia, Austria, Germany, Croatia
Glipizide	Glucobene Daonil, Maninil Euglucon Antidiabetes Glybenez Glipizide Minidiabetes	0,005 0.00175 -0.0035; 0.005; 0.00175 -0.0035; 0,005 0,005 0.005-0.01 0.005-0.01 0,005	0.02	6-8	Slovenia, Belgium, Italy, Czech Republic, USA, France
Gliclazide	Glucotrol XL Diabeton Medoclazide Predian, Glioral Gliclazide, Diabrezide	0.005-0.01 0.08	0.32	8-12	France, Cyprus, Yugoslavia, Belgium, USA
Glycvidone	Glurenorm	0.03	0.12	8-12	Germany
Glimipiride	Amaryl	From 0.001 to 0.006	0.008	16-24	Germany
Repaglinide	Novonorm	0.0005; 0.001; 0.002	0,016	1-1.5	Denmark

The new drug repaglinide (Novonorm) is characterized by rapid absorption and a short period of hypoglycemic action (1-1.5 hours), which allows it to be used before each meal to eliminate post-alimentary hyperglycemia. It should be noted that small doses of the drug have a pronounced therapeutic effect in the initial mild forms of diabetes mellitus. Patients with long-standing diabetes mellitus of moderate severity require a significant increase in the daily dose or a combination with other sulfanilamide drugs.

Sulfanilamide preparations, as stated earlier, are used in the treatment of patients with type II diabetes, but only in cases where diet therapy is not effective enough. Prescribing sulfanilamide preparations to patients of this contingent usually causes a decrease in glycemia and an increase in carbohydrate tolerance. Treatment should be started with minimal doses, increasing them under the control of the glycemic profile. If the selected sulfanilamide preparation is insufficiently effective, it can be replaced with another one or a complex of sulfanilamide preparations can be prescribed, including 2 or 3 medicinal substances. Considering the angioprotective effect of gliclazide (diamicron, predian, diabetone), it is advisable to include it as one of the components in the set of sulfanilamide preparations. Long-acting sulfanilamide, especially chlorpropamide, should be prescribed with caution in stage I nephropathy and in elderly and senile patients due to the impossibility of its accumulation and the resulting occurrence of hypoglycemic conditions. In the presence of diabetic nephropathy, glurenorm is used as monotherapy or in combination with insulin, regardless of its stage.

Long-term treatment with sulfanilamide drugs (over 5 years) causes decreased sensitivity to them (resistance) in 25-40% of patients, which is caused by decreased binding of the sulfanilamide drug to the receptors of insulin-sensitive tissues, disruption of the post-receptor mechanism, or decreased activity of B-cells of the pancreas. The destructive process in B-cells, accompanied by a decrease in the secretion of endogenous insulin, most often has an autoimmune origin and is detected in 10-20% of patients. Studies of the content of C-peptide in the blood of 30 adult patients who were transferred to insulin after several years of treatment with a sulfanilamide drug revealed a significant decrease in the level of the former in 10% of patients. In other cases, its content corresponded to the norm or exceeded it, which made it possible to again prescribe oral hypoglycemic drugs to patients. In many cases, resistance to the sulfanilamide drug is eliminated after 1-2 months of insulin treatment, and sensitivity to the sulfanilamide drug is completely restored. However, in some cases, especially after hepatitis, against the background of severe hyperlipidemia, despite the high level of C-peptide, it is not possible to compensate for the course of diabetes mellitus without the use of insulin drugs. The dosage of the sulfanilamide drug should not exceed 3-4 tablets per day in 2 doses (for chlorpropamide - no more than 2 tablets), since increasing their dose, without improving the hypoglycemic effect, only increases the risk of side effects of the drugs. First of all, the undesirable effect of the sulfanilamide drug is expressed in the occurrence of hypoglycemic states with an overdose of the drug or against the background of untimely food intake in combination with physical activity or alcohol consumption; with the combined use of a sulfanilamide drug with certain medications that enhance their hypoglycemic effect (salicylic acid, phenylbutazole, PAS, ethionamide, sulfaphenol). The use of sulfanilamide drugs may also result in allergic or toxic reactions (skin itching, urticaria, Quincke's edema, leukopenia, granulocytopenia, thrombocytopenia, hypochromic anemia), less often - dyspeptic phenomena (nausea, pain in the epigastric region, vomiting). Sometimes there is a violation of liver function in the form of jaundice caused by cholestasis. Against the background of the use of chlorpropamide, fluid retention is likely as a result of the potentiation of the effect of antidiuretic hormone. Absolute contraindications for the use of sulfonamide drugs are ketoacidosis, pregnancy, childbirth, lactation, diabetic nephropathy (except glurenorm), blood diseases accompanied by leukopenia and thrombocytopenia, abdominal surgery, acute liver disease.

Large doses of sulfonamide drugs and their repeated use during the day contribute to secondary resistance to them.

Elimination of postalimentary hyperglycemia. Despite the availability of a large set of sulfanilamide drugs used in the treatment of diabetes mellitus, most patients experience postalimentary hyperglycemia, which occurs 1-2 hours after eating, which prevents good compensation of diabetes mellitus.

To eliminate post-alimentary hyperglycemia, several methods are used:

1. taking the drug Novonorm;
2. taking other sulfonamide drugs 1 hour before meals to create a sufficiently high concentration of the drug that coincides in time with the increase in blood sugar;
3. taking acarbose (Glucobay) or guarem before meals, which block the absorption of glucose in the intestine;
4. use of foods rich in fiber (including bran).

Biguanides are derivatives of guanidine:

1. dimethylbiguanides (glucophage, metformin, glyformin, diformin);
2. butylbiguanides (adebit, silubin, buformin).

The duration of action of these substances is 6-8 hours, and retarded forms - 10-12 hours. The characteristics of various biguanide preparations are presented in the table.

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Characteristics of biguanides

Name		Content of the drug in 1 tablet, mg	Maximum daily dose, mg	Duration of action, h	Country of origin
International	Commercial
Metformin Buformin	Glyformin Glycon, metformin Glucophage, metformin BMS, Siofor-500, Siofor-850 Adebit Silubin retard	250 500 500-850 50 100	3000 300	6-8 10-12 6-8 10-12	Russia France, Germany, Canada, Poland, USA Hungary Germany

Their hypoglycemic effect is due to increased glucose utilization by muscle tissue by enhancing anaerobic glycolysis in the presence of endogenous or exogenous insulin. Unlike sulfonamides, biguanides do not stimulate insulin secretion, but have the ability to inhibit its effect at the receptor and postreceptor levels. In addition, their mechanism of action is associated with inhibition of gluconeogenesis and glucose release from the liver and, in part, with a decrease in glucose absorption in the intestine. Increased anaerobic glycolysis causes excessive accumulation of lactic acid, which is the end product of glycolysis, in the blood and tissues. A decrease in pyruvate dehydrogenase activity reduces the rate of conversion of lactic acid to pyruvic acid and the metabolism of the latter in the Krebs cycle. This leads to the accumulation of lactic acid and a shift in pH to the acidic side, which in turn causes or aggravates tissue hypoxia. The butyl biguanide group of drugs has a lower ability to cause lactic acidosis. Metformin and its analogues practically do not cause lactic acid accumulation. Biguanides, in addition to the hypoglycemic effect, have an anorectic (promoting weight loss up to 4 kg per year), hypolipidemic and fibrinolytic effect. Treatment begins with small doses, increasing them if necessary depending on the glycemic and glucosuria indicators. Biguanides are often combined with various sulfonamide drugs if the latter are insufficient. An indication for the use of biguanides is type II diabetes mellitus in combination with obesity. Given the possibility of lactic acidosis, they should be used with caution in patients with concomitant changes in the liver, myocardium, lungs and other organs, since these diseases are associated with an increase in the concentration of lactic acid in the blood even without the use of biguanides. In all cases, it is advisable to use the lactate/pyruvate ratio before prescribing biguanides to patients with diabetes mellitus in the presence of pathology of internal organs and to start treatment only if the norms of this indicator are not exceeded (12:1). Clinical trials of metformin and its domestic analogue, glyformin, conducted at the Department of Endocrinology of the Russian Medical Academy of Postgraduate Education (RMAPO) showed that lactic acid accumulation in the blood and an increase in the lactate/pyruvate ratio in patients with diabetes mellitus do not occur. When using drugs of the adebit group, as well as when treating only with sulfonamides (in patients with concomitant diseases of internal organs), some showed a tendency to an increase in the lactate/pyruvate ratio, which was eliminated by adding dipromonium, a metabolic drug that promotes the activation of pyruvate dehydrogenase, in doses of 0.08-0.12 g / day. Absolute contraindications for the use of biguanides include ketoacidosis, pregnancy, lactation, acute inflammatory diseases,surgical interventions, stage II-III nephropathy, chronic diseases accompanied by tissue hypoxia. The side effect of biguanides is expressed in lactic acidosis, allergic skin reactions, dyspeptic phenomena (nausea, discomfort in the abdomen and profuse diarrhea), exacerbation of diabetic polyneuropathy (due to decreased absorption of vitamin B12 in the small intestine). Hypoglycemic reactions occur rarely.

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