Oral hypoglycemic drugs

Oral sugar reduction drugs in the chemical composition and mechanism of action on the body are divided into 2 groups: sulfonamides and biguanides.

Oral sugar-reducing sulfanilamide preparations (DP) are derivatives of sulfonylurea, differing in the form of additional compounds introduced into the basic structure. The characteristics of sulfanylurea derivatives used in medical practice are given in the table.

The mechanism of the sugar reduction effect of sulfonamide drugs is associated with the stimulation of endogenous insulin secretion, suppression of glucagon production and a decrease in the intake of glucose from the liver into the bloodstream, as well as an increase in the sensitivity of insulin-dependent tissues to endogenous insulin due to stimulation of receptors binding to it or an increase in its post-receptor mechanism of action. There is evidence that with the simultaneous use of several sulfanilamide drugs, the effect on one or other of the listed pathogenetic factors is more effective. This explains the use of a combination of various sulfanilamide preparations in clinical practice. Most sulfonamide drugs are metabolized in the liver (except for chlorpropamide) and excreted by the kidneys. The prolongation of the sugar reduction effect inherent in certain sulfanilamide preparations is due either to the additional hypoglycemic effect of their metabolites (acetohexamide) or to binding to plasma proteins (chlorpropamide). Preparations that last for 6-8 hours are rapidly metabolized in the body. Essentially new sulfanilamide preparations are glycazide and glenororm. Gliklazid, in addition to the sugar reduction effect, has also an angioprotective effect, determined by a decrease in fibrin accumulation in the aorta, a decrease in aggregation of platelets and erythrocytes, and pressor action of catecholamines on peripheral vessels, contributing to improved microcirculation. The drug is metabolized in the liver and excreted by the kidneys. Gljurenorm differs from all sulfanilamide preparations in that 95% of it is excreted by the intestine and only 5% by the kidneys.

[1], [2], [3]

Characteristics of sulfanilamide preparations

Name		The content of the drug in 1 tablet, g	The highest daily dose, g	Duration of action, h	Manufacturer country
international	commercial
Preparations of the first generation
Tolbutamide	Butamid, orabet	0.5	3.0	6-12	Latvia,   Germany
Carbutamide	Bukarban, Oranil	0.5	3.0	6-12	Hungary, Germany
Chloropropamide	Chloropropamide, apochlorpropamide	0.1-0.25; 0.25	0.5	24	Poland, Canada
Preparations of the second and third generation
Glibenclamide	Antibet, dianti, apoglyburide, henglib, hylemal, 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 Dionil, manil Euglucon Antidiabe Glybenez Glipizide Minidiab	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, United States, France
Gliclazide	Glucotrol HL Diabetone Medoclaside Predian, glioral Gliclazide, dibrezide	0.005-0.01 0.08	0.32	8-12	France, Cyprus, Yugoslavia, Belgium, USA
Glikvidon	Gljurenorm	0.03	0.12	8-12	Germany
Glimipyride	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-glucocortic hyperglycemia. It should be noted that small doses of the drug have a pronounced therapeutic effect with the initial mild forms of diabetes mellitus. Patients with long-term moderate diabetes mellitus require a significant increase in the daily dose or combination with other sulfanilamide drugs.

Sulfanilamide preparations, as mentioned earlier, are used in the treatment of patients with type II diabetes, but only in those cases when diet therapy is not effective enough. The administration of sulfanilamide preparations to patients with this contingent usually causes a decrease in glycemia and an increase in tolerance to carbohydrates. Treatment should begin with minimal doses, increasing them under the control of the glycemic profile. If the selected sulfanilamide preparation is ineffective, it can be replaced by another or a complex of sulfanilamide preparations, including 2 or 3 drugs. Given the angioprotective effect of gliclazide (diamikrona, preiana, diabetone), it is desirable to include it as one of the components in a set of sulfanilamide preparations. A long-acting sulfanilamide agent, especially chlorpropamide, should be administered with caution in patients with grade I nephropathy, and patients in elderly and senile age due to the impossibility of cumulation and the appearance of hypoglycemic conditions in this regard. In the presence of diabetic nephropathy, glenorhorm is used in the form of monotherapy or in combination with insulin, regardless of its stage.

Long-term treatment with sulfanilamide drugs (more than 5 years) in 25-40% of patients causes a decrease in sensitivity (resistance), which is caused by a decrease in the binding of the sulfanilamide preparation to receptors of insulin-sensitive tissues, a violation of the post-receptor mechanism, or a decrease in the 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 blood content of the C-peptide in 30 adult patients, translated after several years of treatment with sulfanilamide preparation for insulin, found a significant decrease in the level of the first in 10% of patients. In other cases, its content was at or above the norm, which allowed again to prescribe to patients oral sugar reducing drugs. In many cases, resistance to the sulfanilamide drug is eliminated after 1-2 months of treatment with insulin, and sensitivity to the sulfanilamide drug is fully restored. However, in a number of cases, especially after hepatitis, against a background of severe hyperlipidemia, despite the high level of C-peptide, it is not possible to compensate the course of diabetes without the use of insulin preparations. The dosage of the sulfanilamide preparation should not exceed 3-4 tablets per day in 2 divided doses (for chlorpropamide - no more than 2 tablets), as increasing their dose, without leading to an improvement in the hypoglycemic effect, only increases the risk of side effects of the drugs. First and foremost, the undesirable effect of the sulfanilamide drug is expressed in the appearance of hypoglycemic conditions in case of drug overdose or against untimely food intake in combination with exercise or alcohol use; in the complex use of sulfanilamide preparation with certain drugs that enhance their sugar reduction effect (salicylic acid, phenylbutazole, PASK, ethionamide, sulfafenogol). The consequence of the use of sulfonamide drugs may be allergic or toxic reactions (skin itching, urticaria, Quincke's edema, leukopenia, granulocytopenia, thrombocytopenia, hypochromic anemia), less often - dyspepsia (nausea, pain in the epigastric region, vomiting). Sometimes there is a dysfunction of the liver in the form of jaundice caused by cholestasis. Against the background of the use of chlorpropamide, fluid retention is likely as a consequence of potentiating the effect of antidiuretic hormone. Absolute contraindication for the use of sulfonamide drugs are ketoacidosis, pregnancy, childbirth, lactation, diabetic nephropathy (except for gljurenorma), blood diseases accompanied by leukopenia and thrombocytopenia, cavitary operations, acute liver diseases.

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

Elimination of post-glycerol hyperglycemia. Despite the presence of a large set of sulfanilamide preparations used in the treatment of diabetes, most patients develop post-acute hyperglycemia, which occurs 1-2 hours after a meal, which prevents good compensation for diabetes mellitus.

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

1. reception of the drug novonorm;
2. taking other sulfanilamide preparations 1 hour before meals to create a sufficiently high concentration of the drug, coinciding with the increase in blood sugar;
3. reception before meals acarbose (glucobai) or guarem, blocking the absorption of glucose in the intestine;
4. use of food rich in fiber (including bran).

Biguanides are derivatives of guanidine:

1. dimethyl biguanides (glucophag, metformin, gliiformin, diformin);
2. Butyl biguanides (adebit, silin, buformin).

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

[4], [5], [6], [7], [8], [9], [10], [11]

Characteristics of biguanides

Name		The content of the drug in 1 tablet, mg	The highest daily dose, mg	Duration of action, h	Manufacturer country
International	Commercial
Metformin Buformin	Gliiformin Glicon, 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 sugar-reducing effect is due to increased utilization of glucose by muscle tissue by enhancing anaerobic glycolysis in the presence of endogenous or exogenous insulin. In contrast to sulfanilamide preparations, biguanides do not exert a stimulating effect on insulin secretion, but have the ability to shadow its effect at the receptor and postreceptor levels. In addition, the mechanism of their action is associated with inhibition of gluconeogenesis and the release of glucose from the liver and in part - with a decrease in glucose absorption in the intestine. An increase in anaerobic glycolysis causes excessive accumulation in the blood and tissues of lactic acid, which is the final product of glycolysis. A decrease in the activity of pyruvate dehydrogenase reduces the rate of conversion of lactic acid into pyruvate and the metabolism of lactic acid in the Krebs cycle. This leads to accumulation of lactic acid and a shift in pH to the acid side, which in turn causes or exacerbates tissue hypoxia. Preparations of the butyl-biguanide group have a smaller ability to cause lactic acidosis. Metformin and its analogs practically do not cause the accumulation of lactic acid. Biguanides, in addition to the hypoglycemic effect, have anorexigenic (contributing to weight loss of up to 4 kg per year), lipid-lowering and fibrinolytic effect. Treatment begins with small doses, increasing them if necessary, depending on the glycemia and glucosuria. More often biguanides are combined with various sulfanilamide preparations at insufficient efficiency of the latter. The indication for the use of biguanides is diabetes mellitus type II in combination with obesity. Given the possibility of lactic acidosis, caution should be applied to their patients with concomitant changes in the liver, myocardium, lungs and other organs, since in these diseases there is an increase in the concentration of lactic acid in the blood and without the use of biguanides. It is desirable in all cases before appointment of biguanides to patients with diabetes mellitus in the presence of pathology of internal organs, use the ratio lactate / pyruvate and start treatment only if there is no excess of the norms of this indicator (12: 1). Conducted at the Department of Endocrinology of the Russian Medical Academy of Postgraduate Education (RMAPO), clinical trials of metformin and its domestic analogue - glyformin showed that accumulation of lactic acid in the blood and an increase in the ratio of lactate / pyruvate in patients with diabetes mellitus does not occur. With the use of preparations of the adebit group, as well as in the treatment with only sulfanilamide preparations (in patients with concomitant diseases of the internal organs), some tended to increase the lactate / pyruvate ratio, which was eliminated by adding dipromonium at doses of 0,08-0,12 g / preparation of a metabolic action promoting the activation of pyruvate dehydrogenase. Absolute contraindication for the use of biguanides is the condition of ketoacidosis, pregnancy, lactation, acute inflammatory diseases, surgical interventions, stage II-III nephropathy, chronic diseases accompanied by tissue hypoxia. 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.

[12], [13], [14], [15], [16], [17], [18], [19]