Diuretics, their classification, pharmacological characteristics. Prescription for dichlorothiazide. Diuretics that inhibit the reabsorption of sodium in the renal tubules

6-chloro-7-sulfamoyl-3,4-dihydro-2-H-l,2,4-benzothiadiazine-1,1-dioxide.

Synonyms: Hypothiazide, Dihydrochlorthiazid, Disalunil, Nefrix, Unazid, Urodiazin.

Release form. Tablets of 0.025 and 0.1 g.

Pharmacokinetics. Well absorbed (70-80%) from the digestive system. After oral administration 0.075 g maximum concentration in the blood plasma appears after 1.5-3 hours, in patients with heart failure - after 8 hours. Absorption from digestive tract increases when taken drug while eating. The half-life is 6-15 hours. Apparently, dichlorothiazide does not undergo biotransformation in the body and is excreted unchanged in the urine within 24 hours, however, in heart failure, excretion drug with urine it decreases to 21-63%. Renal clearance is normally 330 ml/min, and in case of heart failure - 10-187 ml/min, and there is a direct correlation with creatinine clearance. After ingestion a drug has a diuretic effect after 2-3 hours, maximum effect occurs in 3-6 hours, its duration is 6-12 hours or more, and in the first half of the period of action the saluretic effect predominates, and in the second - the diuretic effect. The maximum diuretic effect occurs when administered drug at midnight, minimum - at 8 am.

Pharmacodynamics. It is excreted from the body both by filtration and glomeruli, and by secretion in the proximal tubules. This is where its ability to inhibit tubular reabsorption of sodium mainly manifests itself. In addition to influencing the carbonic anhydrase enzyme, dichlorothiazide can inhibit the activity of sodium, potassium, ATPase, succinate dehydrogenase, as well as non-esterified oxidation enzymes. fatty acids and others. All this disrupts the energy supply of transporting mechanisms on the basement membrane. In addition, it has been shown that against the background of dichlothiazide, the permeability of the basal membrane for sodium changes, as a result of which energy consumption for its reabsorption increases. There are reports that thiazides in the distal tubules, without affecting the active transport of sodium, reduce electrical resistance, increasing the permeability to sodium chloride and facilitating the reverse current into the tubule of already reabsorbed sodium chloride.

The drug does not have a significant effect on the acid-base state, so it can be prescribed for both acidosis and alkalosis. Chlorides are released in ratios equivalent to sodium, and HCO 3 ions are released in physiological quantities. The excretion of potassium under its influence increases, so the development of hypokalemia is possible. This may be due to a blockade of potassium reabsorption in the proximal tubules of the nephron and a compensatory increase in its secretion in the distal tubules due to the greater loading of this part of the nephron with sodium.

Dichlorothiazide, secreted by the cells of the nephron tubules, can competitively inhibit the secretion uric acid and lead to an exacerbation of gout.

Hypotensive effect drug is caused not only by increased fluid loss and a decrease in the volume of intravascular fluid and a decrease in swelling vascular wall, but mainly by a decrease in the sensitivity of smooth muscles vessels to catecholamines.

The beneficial effect of dichlorothiazide in diabetes insipidus appears to depend on its ability to block thirst, directly acting on the thirst center, and by reducing stimulation of this center of high osmolarity of blood plasma. By increasing sodium excretion, a drug greatly reduces elevated osmotic pressure blood plasma accompanying this disease. By inhibiting the phosphodiesterase enzyme in the kidneys, it sensitizes the kidneys to endogenous vasopressin.

Application. With water retention in the body. Effective even if long-term use. For edema due to cardiovascular failure, liver cirrhosis, nephrotic syndrome, toxicosis of pregnancy, premenstrual syndrome, taking corticosteroids, obesity, hypothalamic pathology, as well as localized edema. Prescribed 0.025-0.1 g per day (in 1-2 doses), sometimes 0.2 g per day in the morning for 3-7 days with breaks of 3-4 days. When the daily dose is increased to more than 0.2 g, the diuretic effect increases. If long-term treatment prescribed 2-3 times a week.

During treatment it is necessary to prescribe a potassium diet or (if used in large doses, long-term use) combine dichlorothiazide with potassium supplements.

At hypertension And symptomatic hypertension dichlorothiazide is prescribed in slightly smaller doses doses(0.025-0.075 g), mainly in combination with antihypertensives and antispasmodics daily or every other day. In the absence of edema, the drug, without having a pronounced diuretic effect, reduces blood pressure due, as expected, to the redistribution of sodium in the cells of the vascular walls, a decrease in blood mass and the sensitivity of cells to catecholamines.

While taking dichlorothiazide arterial pressure decreases by the end of the 2nd day treatment due to a decrease in cardiac output (first phase of action), then the total peripheral resistance gradually decreases (second phase of action); clinical effect due to decreased tone vessels usually occurs after 2-3 weeks of treatment.

In patients with glaucoma, to lower intraocular pressure (usually in subcompensated forms), 0.025 g per day is prescribed. The effect occurs 24-48 hours after administration drug and against the background of miotic drugs lasts 1-6 days, after which a drug must be entered again.

In diabetes insipidus, dichlorothiazide reduces polyuria and thirst. Initially, 0.025 g is prescribed 1-2 times a day, then dose gradually increase until a therapeutic effect is achieved.

The drug may potentiate the effectiveness of anti-blastoma drugs.

Side effect. With long-term administration in large enough doses Hypokalemia and hypochloremic allkalosis are possible. Hypokalemia, as a rule, develops in patients with liver cirrhosis and nephrotic syndrome, hypochloremic alkalosis - with a salt-free diet and loss of chlorides due to vomiting and diarrhea.

In case of long-term use, exacerbation of gout, hyperglycemia and exacerbation of diabetes mellitus due to overstrain of the insular apparatus are possible. And big ones doses dichlorothiazide may cause general weakness, nausea, vomiting, diarrhea, and rare cases- dermatitis.

The decrease in glomerular filtration when dichlorothiazide is used can be explained, on the one hand, by a decrease in tubular reabsorption, an increase in intratubular pressure, resulting in a decrease in ultrafiltration into the nephron capsule, and on the other hand, by a decrease in the volume of extracellular fluid and a decrease in blood pressure.

Contraindications for use. Heavy liver failure, diabetic glomerulosclerosis, chronic diseases kidneys in the stage of chronic renal failure With hypoisosthenuria and azotemia, oliguria and anuria in the first 3 months of pregnancy. Conditionally contraindicated in patients with gout and diabetes. Should be used with caution in patients with reduced tolerance to carbohydrates.

Interaction with others medicines . A drug should be used with caution in combination with antihypertensive drugs due to the possibility of orthostatic hypotension due to potentiation of their effect. Combined use drug with cardiac glycosides is dangerous due to the hypokalemic effect of dichlorothiazide. Dichlorothiazide increases the ototoxicity of some antibiotics and reduces the sensitivity of body tissues to adrenergic agonists.

To enhance the diuretic effect, dichlorothiazide can be combined with drugs acting at the level of the apical membrane (spironolactone); this reduces the risk of hypokalemia and acid-base imbalances.

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Hydrochlorothiazide

Composition and release form of the drug

Pills white or almost white with a yellowish tint, round, flat-cylindrical, without marks, with a chamfer; Light marbling is allowed.

Excipients: lactose monohydrate - 70 mg, microcrystalline cellulose - 20 mg, potato starch - 13.7 mg, magnesium stearate - 1.3 mg.

7 pcs. - contour cell packaging (2) - cardboard packs.
7 pcs. - contour cell packaging (3) - cardboard packs.
7 pcs. - contour cell packaging (4) - cardboard packs.
10 pieces. - contour cellular packaging (1) - cardboard packs.
10 pieces. - contour cell packaging (2) - cardboard packs.
10 pieces. - contour cell packaging (3) - cardboard packs.
10 pieces. - contour cell packaging (4) - cardboard packs.
10 pieces. - contour cell packaging (5) - cardboard packs.

pharmachologic effect

Thiazide diuretic. Violates the reabsorption of sodium, chlorine and water ions in the distal tubules of the nephron. Increases the excretion of potassium, magnesium, bicarbonate ions; retains calcium ions in the body. The diuretic effect occurs after 2 hours, reaches a maximum after 4 hours and lasts up to 12 hours. It helps to reduce high blood pressure. In addition, it reduces polyuria in patients with diabetes insipidus (the mechanism of action has not been fully elucidated). In some cases it reduces intraocular pressure for glaucoma.

Pharmacokinetics

After oral administration, 60-80% of the dose is absorbed from the gastrointestinal tract. The time to reach Cmax is 1.5-3 hours. Hydrochlorothiazide accumulates in red blood cells. In the elimination phase, its concentration in erythrocytes is 3-9 times higher than in plasma. Plasma protein binding - 40-70%. Vd in the terminal elimination phase is 3-6 l/kg (equivalent to 210-420 l for a body weight of 70 kg).

Hydrochlorothiazide is metabolized to highly small degree. Its only metabolite found in trace amounts is 2-amino-4-chloro-M-benzene disulfonamide.

The removal of hydrochlorothiazide from plasma has a two-phase character: T1/2 in the initial phase is 2 hours, in the terminal phase - about 10 hours. In patients with normal function Kidney excretion is carried out almost exclusively by the kidneys. In general, 50-75% of an oral dose is excreted unchanged in the urine.

In elderly patients and with impaired renal function, the clearance of hydrochlorothiazide is significantly reduced, which leads to a significant increase in its concentration in the blood plasma. The decrease in clearance observed in elderly patients appears to be associated with worsening renal function. In patients with liver cirrhosis, no changes in the pharmacokinetics of hydrochlorothiazide are observed.

Indications

Arterial hypertension, edema syndrome various genesis (chronic failure, nephrotic syndrome, renal failure, fluid retention in obesity), Not diabetes, glaucoma (subcompensated forms).

Contraindications

Severe renal dysfunction, liver failure, severe forms gout and diabetes mellitus, increased sensitivity to sulfonamides.

Dosage

Installed individually. Single dose - 25-50 mg, daily dose- 25-100 mg. The frequency of administration depends on the indications and the patient's response to treatment.

Side effects

From the outside digestive system: nausea, vomiting, diarrhea; rarely - pancreatitis.

From the outside of cardio-vascular system: orthostatic hypotension, tachycardia.

From the side of metabolism: hypokalemia, hypomagnesemia, hyponatremia, hypochloremic alkalosis, hyperuricemia, hypercalcemia.

From the outside endocrine system: hyperglycemia.

From the hematopoietic system: rarely - neutropenia, thrombocytopenia.

From the side of the organ of vision: rarely - visual impairment.

From the central nervous system and peripheral nervous system: weakness, fatigue, dizziness, paresthesia.

Allergic reactions: rarely - allergic dermatitis.

Drug interactions

With the simultaneous use of antihypertensive drugs that do not depolarize, their effect is enhanced.

With the simultaneous use of barbiturates, diazepam, ethanol, the risk of developing orthostatic hypotension increases.

When used simultaneously with GCS, there is a risk of developing hypokalemia, as well as orthostatic hypotension.

When used simultaneously with ACE inhibitors(including captopril, enalapril) the antihypertensive effect is enhanced.

Possible pronounced arterial hypotension, especially after taking the first dose of hydrochlorothiazide, apparently due to hypovolemia, which leads to a transient increase in the hypotensive effect of the ACE inhibitor.

The risk of kidney dysfunction increases. The development of hypokalemia is not excluded.

With the simultaneous use of oral hypoglycemic drugs, their effectiveness decreases.

With the simultaneous use of calcium and / or D preparations in high doses possible hypercalcemia and the risk of developing metabolic acidosis due to a slowdown in the excretion of calcium in the urine under the influence of thiazide diuretics.

With simultaneous use with increases the risk of developing allergic reactions especially in patients with impaired renal function.

When used simultaneously with digoxin, the risk of developing glycoside intoxication may increase.

When used simultaneously with indomethacin, piroxicam, phenylbutazone, a slight reduction in the hypotensive effect is possible.

When used simultaneously with irbesartan, an additive hypotensive effect may develop.

When used simultaneously with carbamazepine, there are reports of the development of hyponatremia.

When used simultaneously with colestipol and cholestyramine, the absorption and diuretic effect of hydrochlorothiazide decreases.

When used simultaneously with lithium carbonate, the concentration of lithium salts in the blood may increase to a toxic level.

When used simultaneously with orlistat, the effectiveness of hydrochlorothiazide decreases, which can lead to a significant increase in blood pressure and the development of a hypertensive crisis.

When used simultaneously with sotalol, hypokalemia and the development of ventricular arrhythmia"pirouette" type.

special instructions

Use with caution in patients with gout and diabetes.

In patients with renal failure Systematic monitoring of plasma concentrations of electrolytes and CK is necessary.

If signs of potassium deficiency appear, as well as with the simultaneous use of cardiac glycosides, corticosteroids and ACTH, the prescription of potassium supplements or potassium-sparing diuretics is indicated.

At long-term use you should stick to a diet, rich in potassium.

Pregnancy and lactation

Adequate and well controlled clinical trials The safety of hydrochlorothiazide in pregnancy has not been studied.

IN experimental studies there were no signs of adverse effects on the fetus. Taking this into account, use during pregnancy is possible only for health reasons and only if the expected benefit to the mother outweighs the potential risk to the fetus.

Hydrochlorothiazide penetrates into breast milk. It is recommended to avoid the use of hydrochlorothiazide in the first month breastfeeding, since there are reports of suppression of lactation.

For impaired renal function

Contraindicated in cases of severe renal impairment. In patients with renal failure, systematic monitoring of plasma concentrations of electrolytes and CC is necessary.

For liver dysfunction

Contraindicated in liver failure.

Compound medicinal product Dichlorothiazide

The active substance is hydrochlorothiazide.

Dosage form

substance, tablets 25 mg, tablets 100 mg

Pharmacotherapeutic group

Thiazide and thiazide-like diuretics

Pharmacological properties

Diuretic, hypotensive. Reduces the reabsorption of sodium and chloride ions in the proximal tubules of the kidneys, the excretion of magnesium, calcium, and uric acid ions. Increases the concentration ability of the kidneys. Inhibits the susceptibility of the vascular wall to the exciting influences of mediators. Well absorbed from the gastrointestinal tract. Penetrates through the hematoplacental barrier and into breast milk. Excreted by the kidneys. The diuretic effect develops after 30-60 minutes, reaching a maximum after 8-12 hours.

Indications for use: Dichlorothiazide

Arterial hypertension, congestive heart failure, diabetes insipidus, liver cirrhosis with portal hypertension and edematous-ascitic syndrome, glaucoma, nephritis, nephrosis; rarely - toxicosis of pregnant women.

Contraindications

Hypersensitivity, diabetes mellitus, gout, lactation. Restrictions on use: severe dysfunction of the liver, kidneys, severe cerebral or coronary atherosclerosis, pregnancy.

Cautions for use

During long-term therapy, monitoring of the concentration of electrolytes in the blood plasma is necessary. Long-term treatment It is recommended to combine it with a diet rich in potassium. Use with caution when working for drivers Vehicle and people whose profession is associated with increased concentration.

Interactions with drugs

Reduces the effect oral contraceptives. Reduces the excretion of lithium salts. Increases the toxicity of cardiac glycosides, non-depolarizing muscle relaxants.

Side effects

Hypokalemia, hypochloremic alkalosis, dizziness, headache, weakness, nausea, vomiting, loss of appetite, diarrhea or constipation, thirst, paresthesia, orthostatic hypotension, tachycardia, cholestasis, pancreatitis, hemolysis, hypoplastic anemia, agranulocytosis, allergic reactions.

Overdose

Symptoms: dry mouth, weakness, drowsiness, tachycardia, hypotension, oliguria. Treatment: gastric lavage, reception activated carbon, symptomatic therapy.

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DIURETICS INHIBITED THE PROCESS OF SODIUM REVERSE ABSORPTION IN THE RENAL TUBULUS

The group of diuretic drugs that inhibit the reverse process of sodium absorption in the renal tubules includes mercury diuretics, cyclomethiazide, dichlorothiazide, furosemide, brinaldix, brinaldix.

Mercury diuretics (such as Mercusal, Novurite, Promeran) are essentially not found in medical practice its use due to high toxicity, despite the certainly strong diuretic effect.

DICHLOTHIAZIDE (pharmacological analogues:hypothiazide ) has a high diuretic activity and low toxicity. Diuretic effect begins after 30-40 minutes and lasts on average 8-10 hours. Dichlorothiazide reduces the reabsorption of chlorine and sodium ions in the renal tubules, and also reduces the reabsorption of other chemical substances, such as bicarbonate and potassium. This exposure to dichlorothiazide may result in hypokalemia, which must be corrected by administering potassium supplements, or special diet, rich in products containing potassium (prunes, dried apricots, potatoes, etc.). Side effects when using dichlorothiazide: weakness, dyspepsia, and delayed release of salts (urates) are sometimes observed. The latter can lead to gout or its exacerbation. Dichlorothiazide is contraindicated in case of exacerbation of gout or insufficient renal function. Release form of dichlorothiazide: tablets of 0.025 g and 0.1 g.

Example of a dichlorothiazide recipe in Latin:

Rep.: Tab. Dichlothiazidi 0.025 N. 20

D.S. 1-2 tablets per day (in severe cases the dose can be increased to 8 tablets in 2 doses).

Rep.: Tab. Hypothiazidi 0.1 N. 20

D.S. 1/2 each ~ 1 tablet per day (in severe cases - no more than 2 tablets per day).

CYCLOMETHIAZIDE- the drug according to its action, side effects, as well as contraindications for use are similar to dichlorothiazide. Release form of cyclomethiazide: tablets of 0.0005 g. List B.

Example of a cyclomethiazide recipe in Latin:

Rep.: Tab. Cyclomethiazidi 0.0005 N. 20

D.S. Po? - 1 tablet per day, in severe cases - no more than 4 tablets per day.

OXODOLIN (pharmacological analogues: hygroton ) - in its chemical action is very close to the drug dichlothiazide. Oxodoline has the same contraindications and side effects for use. The diuretic effect of oxodoline occurs on average after 2-4 hours and lasts up to 3 days. Oxodoline release form: tablets of 0.05 g. List B.

An example of an oxodoline recipe:

Rep.: Tab. Oxodolini 0.05 N. 50

D.S. Take 1 to 2 tablets per dose 2 times a day, when the effect is achieved - 1-2 tablets 1 time in 2-3 days.

FUROSEMIDE (pharmacological analogues:lasix, fruzix, furantril, furorese ) - inhibits the reabsorption of sodium and water ions, as well as potassium and chlorine. Furosemide can be administered intravenously (for poisoning, cerebral edema, etc.). Side effects when using furosemide: skin rashes, dyspepsia. Contraindications to the use of furosemide: impaired renal function, pregnancy. Furosemide release form: tablets of 0.04 g; ampoules of 2 ml of 1% solution. Furosemide is produced abroad in the form of preparations: Furoreze-250 (in 1 ampoule infusion solution contains 250 mg of furosemide) and “Furorese-500” (1 ampoule contains 500 mg of furosemide). List B.

Recipe example furosemide in Latin:

Rp.: Sol. Furosemidi (Lasicis) 1% 2 ml

D.t. d. N. 5 in ampull.

S. 1-4 ml intravenously or intramuscularly.