Casarc® [Hydrochlorothiazide, candesartan]

Pharmacological properties

candesartan cilexetil is a prodrug that quickly turns into an active substance - candesartan - by ester hydrolysis during absorption from the digestive tract. candesartan is a selective antagonist of angiotensin ii at1 receptors with strong binding and slow dissociation with them. he does not show agonist activity. candesartan is not inhibited by apf, which converts angiotensin i to angiotensin ii and destroys bradykinin. there is no effect on apf and potentiation of bradykinin or substance p. when comparing candesartan with apf inhibitors, cough development was less common in patients receiving candesartan.

Candesartan does not bind to receptors of other hormones and does not block the ion channels, which are known to play a role in cardiovascular regulation. AT antagonism₁ receptors leads to a dose-dependent increase in plasma renin, angiotensin I and angiotensin II, as well as a decrease in plasma aldosterone.

The effect of candesartan cilexetil at a dose of 16 mg once a day on the incidence and mortality from cardiovascular diseases was studied in a randomized clinical trial in elderly patients with mild or moderate hypertension. Patients took candesartan or placebo with other antihypertensive drugs if necessary. Blood pressure decreased from 166/90 to 145/80 mm Hg. Art. in the candesartan group, and from 167/90 to 149/82 mm RT. Art. in the control group. No statistically significant differences in the number of significant cardiovascular events were detected.

Hydrochlorothiazide blocks sodium reabsorption, mainly in the distal renal tubules, and promotes the excretion of sodium, chlorides, and water. Renal excretion of potassium and magnesium increases depending on the dose of the drug, while calcium is reabsorbed to a greater extent. Hydrochlorothiazide reduces plasma and extracellular fluid volume and reduces cardiac output and blood pressure. With prolonged therapy, reduced peripheral resistance helps lower blood pressure.

Candesartan and hydrochlorothiazide exhibit an additive antihypertensive effect. In patients with hypertension, Casark HD leads to a dose-dependent and long-term decrease in blood pressure. Antihypertensive activity is predetermined by a decrease in systemic peripheral resistance without a reflex increase in heart rate. There is no information regarding severe or excessive arterial hypotension after taking the first dose or withdrawal syndrome.

After taking a single dose of Casarca HD, the onset of the antihypertensive effect usually occurs within 2 hours. With constant treatment, the maximum decrease in blood pressure with any dose is usually achieved within 4 weeks and is maintained with prolonged treatment.

Casarc HD when taken once a day provides an effective and uniform decrease in blood pressure over 24 hours, with a small difference between the maximum and minimum effect during the dosing interval. Casark HD is equally effective in patients regardless of age and gender.

There are currently no data on the use of candesartan cilexetil / hydrochlorothiazide in patients with kidney disease / nephropathy, decreased left ventricular function / congestive heart failure, and the condition after myocardial infarction.

Pharmacokinetics Absorption and distribution

Candesartan Cilexetil. Candesartan cilexetil is excreted mainly in an unchanged state with urine and bile, and only in a small amount is metabolized by the liver (CYP 2C9). Existing interaction studies indicate no effect on CYP 2C9 and CYP 3A4. Based on in vitro data, in vivo interaction is not expected with drugs whose metabolism depends on the isoenzymes CYP 1A2, CYP 2A6, CYP 2C9, CYP 2C19, CYP 2D6, CYP 2E1 or CYP 3A4 cytochrome P450.

T_½ candesartan is about 9 hours. Cumulation of the drug after repeated repeated use does not occur. T_½ candesartan after taking candesartan cilexetil in combination with hydrochlorothiazide does not change. Marked increase in AUC (15-18%) and C_max (23-24%) of candesartan when used in combination with hydrochlorothiazide, but this does not have clinical significance. In addition, before switching to the use of Casarc N, separate titration of the components of the drug is recommended. Additional cumulation of candesartan after taking repeated doses of this combination compared with monotherapy was not noted.

The total plasma clearance of candesartan is about 0.37 ml / min / kg, and the renal clearance is about 0.19 ml / min / kg. Candesartan is excreted by the kidneys by glomerular filtration and active tubular secretion. After ingestion ¹⁴With C-labeled candesartan cilexetil, about 26% of the dose is excreted in the urine as candesartan and 7% as an inactive metabolite, while 56% of the dose is detected in feces as candesartan and 10% as an inactive metabolite.

Hydrochlorothiazide. Hydrochlorothiazide is rapidly absorbed in the digestive tract with an absolute bioavailability of 70%. Eating improves the absorption of hydrochlorothiazide by approximately 15%. Bioavailability may decrease in patients with heart failure and severe edema. The binding of hydrochlorothiazide to plasma proteins is about 60%. The apparent volume of distribution is about 0.8 l / kg body weight.

Metabolism and excretion

Candesartan Cilexetil. Candesartan is mainly excreted in the urine and bile unchanged and, to a small extent, through hepatic metabolism. T_½ candesartan is about 9 hours. After taking multiple doses of cumulation of the drug in the body is not detected. The total plasma clearance of candesartan is about 0.37 ml / min / kg, and the renal clearance is about 0.19 ml / min / kg. Renal excretion of candesartan is carried out by both glomerular filtration and active tubular secretion. After taking an oral dose ¹⁴About 26% of C-labeled candesartan cilexetil is excreted in the urine as candesartan and 7% as an inactive metabolite, although about 56% of the dose is determined in feces as candesartan and 10% as an inactive metabolite.

Hydrochlorothiazide. Hydrochlorothiazide is not metabolized and is excreted mainly unchanged by glomerular filtration and active tubular secretion. Final t_½ is 8 hours. About 70% of the dose taken orally is excreted in the urine for 48 hours. T_½ hydrochlorothiazide remains unchanged when combined with candesartan cilexetil. Additional cumulation of hydrochlorothiazide after repeated administration of the combination compared with monotherapy was not noted.

Pharmacokinetics in special categories of patients

Candesartan Cilexetil. In elderly patients (over 65 years old)_max and candesartan AUC increased by approximately 50 and 80%, respectively, compared with younger patients. However, the reaction of blood pressure and the incidence of side effects are the same after taking the prescribed dose of candesartan in young and old patients.

In patients with mild to moderate renal failure, compared with patients with normal renal function, C_max and AUC of candesartan increase after repeated doses of approximately 50 and 70%, respectively, while T_½ the drug remains unchanged. The corresponding changes in patients with severe renal failure are about 50 and 110%, and T_½ the drug increases 2 times. Candesartan AUC in hemodialysis patients is similar to that in patients with severe renal failure.

Patients with mild to moderate hepatic insufficiency showed an increase in AUC of candesartan by 23% in one study and by 80% in another study. There is no experience with the use of the drug in patients with severely impaired liver function.

Hydrochlorothiazide. Final t_½ hydrochlorothiazide is increased in patients with renal failure.

Indications

Essential hypertension in cases when monotherapy of candesartan with cilexetil or hydrochlorothiazide is not enough.

Application

Dosage. the recommended initial and usual maintenance dose of Casarc nd is 16 mg / 12.5 mg (½ tablets of Casarc nd or 1 tablet of Casarc n) once a day. if sufficient control of hell is not achieved after 4 weeks of treatment, the dose of 16 mg / 12.5 mg once a day can be increased to 32 mg / 25 mg (1 tablet Casarc nd) 1 time per day. if sufficient control of hell is not achieved after 4 weeks of treatment at a dose of 12.5 mg once a day, then the dose can be increased to 25 mg once a day. therapy must be corrected in accordance with the reaction of hell. maximum antihypertensive effect is achieved within 4 weeks from the start of treatment. before transferring a patient to Casarc hd, the dose of candesartan cilexetil should be titrated taking into account hell. with clinical feasibility, you can consider a direct transition from single drugs to the combination drug Casarc hd. if sufficient control of hell is not achieved with the use of hd Casarca at a dose of 32/25 mg once a day, the appropriateness of alternative treatments should be considered.

Application. Casarc HD should be taken 1 time per day, regardless of food intake.

Elderly patients. Correction of the initial dose in elderly patients is not required.

Use in patients with a decrease in bcc. For patients at risk of arterial hypotension, for example, with a possible decrease in BCC, an initial dose of 4 mg candesartan cilexetil should be considered. Such patients are not recommended to prescribe a combined drug in a dose of 16 / 12.5 or 32/25 mg. They are prescribed a single drug of candesartan cilexetil (Casarc) at a dose of 4 or 8 mg, depending on the severity and tolerance, with the addition of an appropriate dose of hydrochlorothiazide if necessary.

Application for renal failure. In this category of patients, it is desirable to use loopback rather than thiazide diuretics. Casarc HD should not be used to treat patients with severe renal failure (creatinine clearance 30 ml / min / 1.73 m² body surface area). Titration of a dose of candesartan cilexetil is recommended for patients with renal failure whose creatinine clearance is ≥30 ml / min / 1.73 m² body surface area before starting treatment with Casark HD (for patients with mild to moderate renal failure, the recommended initial dose of candesartan cilexetil is 4 mg).

Use for liver failure. Titration of a dose of candesartan cilexetil is recommended for patients with mild to moderate hepatic insufficiency prior to initiation of treatment with Casark HD (the recommended initial dose of candesartan cilexetil for such patients is 2 mg). The dose can be adjusted taking into account blood pressure. Casark HD should not be used to treat patients with severe liver failure and / or cholestasis.

Contraindications

Hypersensitivity to the active substances or to any of the excipients of the drug. severe renal failure (creatinine clearance 30 ml / min / 1.73 m2 of body surface area), severe liver failure and / or bile congestion (cholestasis), persistent hypokalemia or hypercalcemia, gout, pregnancy and lactation, children under 18 years of age .patients with diabetes mellitus or impaired renal function (SCF 60 ml / min / 1.73 m2) are contraindicated in the simultaneous use of Casarc hd with drugs containing aliskiren (see interactions).

Side effects

According to controlled clinical trials, the use of the combination of candesartan cilexetil / hydrochlorothiazide side reactions were mild and temporary. discontinuation of therapy during the study due to side effects was similar when using the combination of candesartan cilexetil / hydrochlorothiazide (2.3–3.3%) and placebo (2.7–4.3%).

According to clinical studies, when using the combined drug candesartan cilexetil / hydrochlorothiazide, the adverse reactions were the same as when using candesartan cilexetil and / or hydrochlorothiazide.

The frequency of adverse reactions is as follows: very often (≥ 1/10), often (≥ 1/100 to 1/10), infrequently (≥1 / 1000 to 1/100), rarely (≥1 / 10,000 to 1/1000) , very rarely (1/10 000) and unknown (it is impossible to estimate from the available data).

Candesartan Cilexetil / Hydrochlorothiazide

From the nervous system: often - dizziness / vertigo, headache.

Candesartan cilexetil

Infections and infestations: often - respiratory tract infections;

on the part of the blood system and lymphatic system: very rarely - leukopenia, neutropenia and agranulocytosis;

from the vessels: very rarely - arterial hypotension;

from the respiratory system, organs of the chest cavity and mediastinum: very rarely - cough;

from the nervous system: often - dizziness, headache;

from the gastrointestinal tract: very rarely - nausea;

on the part of the skin and subcutaneous tissue: very rarely - angioedema, rash, urticaria, itching;

from the musculoskeletal system: very rarely - back pain, arthralgia, myalgia;

from the urinary system: very rarely - impaired renal function, including renal failure in susceptible patients;

from the hepatobiliary system: very rarely - an increase in the level of liver enzymes, impaired liver function or hepatitis;

metabolic changes and eating disorders: very rarely - hyperkalemia, hyponatremia.

Hydrochlorothiazide

From the blood and lymphatic systems: rarely - leukopenia, neutropenia / agranulocytosis, thrombocytopenia, aplastic anemia, inhibition of bone marrow function, hemolytic anemia;

from the immune system: rarely - anaphylactic reactions;

metabolic and nutritional disorders: often - hyperglycemia, hyperuricemia, electrolyte imbalance (including hyponatremia and hypokalemia);

mental disorders: rarely - sleep disturbances, depression, anxiety;

from the nervous system: often - dizziness, vertigo; rarely - paresthesia;

on the part of the organ of vision: rarely - temporary blurred vision, acute myopia, acute angle-closure glaucoma;

from the cardiovascular system: infrequently - postural hypotension; rarely - cardiac arrhythmia; necrotizing angiitis (vasculitis, skin vasculitis);

from the respiratory system, chest and mediastinal organs: rarely - respiratory failure (including pneumonitis and pulmonary edema);

from the digestive system: infrequently - anorexia, loss of appetite, irritation of the gastric mucosa, diarrhea, constipation; rarely - pancreatitis;

hepatobiliary disorders: rarely - jaundice (intrahepatic cholestatic jaundice);

on the part of the skin and subcutaneous tissue: infrequently - rash, urticaria, photosensitivity reactions; rarely - toxic epidermal necrolysis, skin reactions similar to systemic lupus erythematosus, reactivation of the skin form of systemic lupus erythematosus;

from the musculoskeletal system: rarely - muscle spasm;

from the urinary system: often - glucosuria; rarely, renal dysfunction and interstitial nephritis;

general disorders and changes at the injection site: often - weakness; rarely fever;

changes in laboratory parameters and instrumental research data: often - increased levels of cholesterol and TG; infrequently - increased blood urea nitrogen and creatinine levels in blood plasma; data were obtained on cases of increasing levels of uric acid, glucose and ALAT in blood plasma, a slight decrease in hemoglobin and an increase in AcAT, an increase in creatinine, urea or potassium and a decrease in sodium levels.

special instructions

Double blockade of the renin-angiotensin-aldosterone system (raas). There is evidence that the simultaneous use of APF inhibitors, angiotensin ii receptor antagonists or aliskiren increases the risk of hypotension, hyperkalemia and decreased kidney function (including IDF). as a result, a double blockade of raas occurs, so the combined use of apf inhibitors, angiotensin ii receptor blockers or aliskiren is not recommended (see interactions).

If the use of double blockade is absolutely necessary, it should be carried out only under the supervision of a specialist and subject to frequent close monitoring of kidney function, electrolyte levels and blood pressure. Patients with diabetic nephropathy should not use ACE inhibitors and angiotensin II receptor blockers at the same time.

Pregnancy. There have been no special studies of Casarc HD during pregnancy and lactation. The effect is associated with the effects of individual components of the drug.

Angiotensin II receptor antagonists should not begin treatment during pregnancy. Except in cases where long-term treatment with angiotensin II receptor antagonists is considered necessary, patients planning a pregnancy should switch to alternative antihypertensive drugs, the use of which is safe during pregnancy. When pregnancy is established, discontinue use of the drug immediately and, if necessary, begin alternative treatment (see CONTRAINDICATIONS and Use during pregnancy and lactation).

The use of angiotensin II receptor antagonists is contraindicated during pregnancy. When pregnancy is established, the drug should be stopped immediately. If necessary, alternative therapy should be prescribed (see Use during pregnancy and lactation).

Other antihypertensive drugs. The effect of lowering blood pressure when using Casarc ND can be enhanced by the combined use of other antihypertensive drugs.

Renal failure. In such patients, loop diuretics rather than thiazides are desirable. When using Casarc HD in patients with renal failure, periodic monitoring of plasma levels of potassium, creatinine and uric acid is recommended.

Kidney transplantation. There is no experience with Casarca HD in patients who have recently undergone kidney transplantation.

Renal artery stenosis. Medicines that affect RAAS, such as ACE, can increase blood urea and creatinine levels in patients with bilateral or monolateral renal artery stenosis. A similar effect can be expected with angiotensin II receptor antagonists.

Decrease in bcc. In patients with a decrease in BCC and / or hyponatremia, symptomatic hypotension may occur, as with other agents that affect RAAS. Therefore, it is not recommended to use Casarc HD until the BCC is corrected.

Anesthesia and surgery.In patients receiving treatment with angiotensin II receptor antagonists, arterial hypotension may develop during anesthesia and surgery due to RAAS blockade. In some cases, arterial hypotension can be so severe that it may require the use of IV fluids and / or vasopressors.

Liver failure. Thiazides should be used with caution in patients with liver failure or with progressive liver diseases, since minor changes in the water-electrolyte balance can provoke hepatic coma. There is no clinical experience with Casarc HD in patients with liver failure.

Stenosis of the aorta or mitral valve, obstructive hypertrophic cardiomyopathy. As with other vasodilators, special care must be taken when treating patients with hemodynamically significant stenosis of the aorta or mitral valve or obstructive hypertrophic cardiomyopathy.

Primary hyperaldosteronism. Patients with primary hyperaldosteronism usually do not respond to antihypertensive drugs that act by inhibiting RAAS. Therefore, it is not recommended to use the drug in such patients.

Electrolyte imbalance. As with any patient receiving diuretic therapy, plasma levels should be determined through appropriate periods. Thiazides, including hydrochlorothiazide, can cause water or electrolyte imbalance (hypercalcemia, hypokalemia, hyponatremia, hypomagnesemia and hypochloremic alkalosis). Thiazide diuretics can reduce urinary calcium excretion and cause a transient and slight increase in plasma calcium concentration. Severe hypercalcemia may be a sign of latent hyperparathyroidism. Before monitoring the function of the parathyroid gland, the use of thiazides should be discontinued. Hydrochlorothiazide dose-dependently enhances the excretion of potassium in the urine, which can lead to hypokalemia. This effect of hydrochlorothiazide is less pronounced when used in combination with candesartan cilexetil. The risk of hypokalemia may be increased in patients with cirrhosis, increased diuresis, inadequate oral administration of electrolytes, and in patients receiving concomitant therapy with corticosteroids or ACTH. Based on the experience of using other drugs that affect the renin-angiotensin-aldosterone system, the simultaneous use of Casarca HD and potassium-sparing diuretics, potassium supplements or salt substitutes, or other drugs that can increase the level of potassium in the blood plasma (for example, heparin), can lead to increased levels of potassium in blood plasma. Treatment with ACE inhibitors or angiotensin II receptor antagonists can cause hyperkalemia, especially in the presence of heart and / or kidney failure. Thiazides increase urinary excretion of magnesium, which can lead to hypomagnesemia.

Effect on metabolism and endocrine system. Treatment with thiazide diuretics may interfere with glucose tolerance. A dose adjustment of antidiabetic agents, including insulin, may be necessary. Latent diabetes mellitus may occur during thiazide therapy. An increase in cholesterol and triglyceride levels was associated with thiazide diuretic therapy. However, with a dose of 12.5 mg hydrochlorothiazide, side effects are minimal or none. Thiazide diuretics increase the concentration of uric acid in blood plasma and can provoke gout in patients prone to it.

Photosensitivity. During therapy with thiazide diuretics, cases of the appearance of photosensitivity reactions were noted. If photosensitivity reactions occur, it is recommended to discontinue treatment.If there is a need to prescribe diuretics again, it is recommended to protect vulnerable areas from exposure to the sun or sources of artificial ultraviolet radiation.

General information. In patients whose vascular tone and renal function mainly depend on RAAS activity (for example, patients with severe congestive heart failure or with kidney diseases, including renal artery stenosis), treatment with other drugs that affect this system has been associated with acute arterial hypotension, azotemia, oliguria, or, in rare cases, with acute renal failure. The possibility of such effects cannot be excluded with the use of angiotensin II receptor antagonists. As with any other antihypertensive drug, an excessive decrease in blood pressure in patients with ischemic cardiomyopathy or ischemic cerebrovascular disease can lead to myocardial infarction or stroke.

Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without allergies, or a history of AD, but are more likely in patients with such diseases. An exacerbation or activation of systemic lupus erythematosus with the use of thiazide diuretics is possible.

The drug contains lactose as an auxiliary substance, therefore, it should not be taken by patients with rare hereditary diseases of galactose intolerance, Lapp lactase deficiency or malabsorption of glucose-galactose.

The drug contains tartrazine, therefore, it can cause allergic reactions.

Use during pregnancy and lactation. Pregnancy. Angiotensin II receptor antagonists. Casarc ND is contraindicated for pregnant women or women planning a pregnancy. If pregnancy is confirmed during treatment, its use must be stopped immediately and replaced with another drug approved for use by pregnant women.

Hydrochlorothiazide. The experience of using hydrochlorothiazide during pregnancy, especially in the first trimester, is limited. The results of animal experiments are insufficient.

Hydrochlorothiazide crosses the placental barrier. Based on the pharmacological mechanism of action of hydrochlorothiazide, its use in the II and III trimester of pregnancy can disrupt fetoplacental circulation and cause fetal and neonatal complications such as jaundice, electrolyte imbalance and thrombocytopenia.

Hydrochlorothiazide should not be used for gestational edema, gestational hypertension in pregnant women or preeclampsia due to the risk of a decrease in blood plasma volume and the development of placental hypoperfusion and the absence of any positive effects on the course of the disease.

Hydrochlorothiazide should not be used for essential hypertension in pregnant women, except in rare cases when there is no other alternative treatment for such patients.

Lactation. Angiotensin II receptor antagonists. You should switch to alternative means, the use of which is safe during breastfeeding, especially for newborns and premature babies.

Hydrochlorothiazide. Hydrochlorothiazide in small amounts passes into breast milk. Thiazides in high doses, causing increased diuresis, can reduce the amount of breast milk.

Children. The safety and effectiveness of Casarc HD in children has not been established, so it is not prescribed for patients of this age category.

The ability to influence the reaction rate when driving vehicles or working with other mechanisms. The effect of the drug on the ability to drive vehicles or work with other mechanisms has not been studied, however, given the pharmacodynamic properties of candesartan, it is unlikely that he possessed this ability.When driving vehicles or working with other mechanisms, the possibility of arterial hypotension during treatment with Casark HD, which may be accompanied by dizziness and increased fatigue, should be taken into account.

Interactions

No clinically significant drug interaction of candesartan with hydrochlorothiazide, warfarin, digoxin, oral contraceptives such as ethinyl estradiol / levonorgestrel, glibenclamide and nifedipine has been detected.

Other antihypertensive agents may enhance the antihypertensive effect of Casarka HD with these drugs. It can be expected that the decrease in potassium levels, which is typical for hydrochlorothiazide, is enhanced by other drugs that are associated with potassium loss and hypokalemia (for example, other potassium-sparing diuretics, laxatives, amphotericin, carbenoxolone, penicillin G sodium, salicylic acid derivatives). Experience with other drugs that affect RAAS suggests that the simultaneous use of Casark HD with potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, or other drugs that can increase potassium levels (such as heparin) can lead to increased levels potassium in blood plasma.

Hypokalemia caused by diuretics and hypomagnesemia contribute to the potential cardiotoxic effects of digitalis glycosides and antiarrhythmic drugs. With the simultaneous use of Casarc HD with these drugs, it is recommended to periodically monitor the level of potassium in the blood plasma.

It is recommended to monitor the level of potassium in the blood plasma if Casarc HD is prescribed simultaneously with such drugs, as well as with the following drugs that can cause torsades de pointes (paroxysmal ventricular tachycardia like pirouette):

• class Ia antiarrhythmic drugs (e.g. quinidine, hydroquinidine, disopyramide);
• class III antiarrhythmic drugs (e.g. amiodarone, sotalol, dofetilide, ibutilide);
• certain antipsychotic drugs (for example, thioridazine, chlorpromazine, levomepromazine, trifluoroorazine, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperiodol);
• other drugs (e.g. bepridil, cisapride, diphemanil, erythromycin for iv use, halofantrine, ketanserin, misolastine, pentamidine, sparfloxacin, terfenadine, vincamine for iv use).

Perhaps a reversible increase in the concentration of lithium in blood plasma and its toxicity during the simultaneous use of lithium with ACE inhibitors or hydrochlorothiazide. A similar effect can occur with angiotensin II receptor antagonists, therefore, with simultaneous use, careful monitoring of the level of lithium in blood plasma is recommended.

With the simultaneous use of ARA II with NSAIDs, for example, selective COX-2 inhibitors, acetylsalicylic acid (3 g / day) and non-selective NSAIDs), a hypotensive effect can be weakened.

As with the use of ACE inhibitors, the simultaneous use of angiotensin II receptor antagonists with NSAIDs may increase the risk of developing renal failure, including acute renal failure, as well as an increase in plasma potassium levels, especially in patients with a history of impaired renal function. This combination should be used with caution, especially in elderly patients. Patients should receive a sufficient amount of fluid, and the need to monitor renal function after the initiation of concomitant therapy and periodic monitoring subsequently should be considered.

NSAIDs reduce the severity of the diuretic, natriuretic and antihypertensive effect of hydrochlorothiazide.

Colestipol or colestyramine reduces the absorption of hydrochlorothiazide.

Hydrochlorothiazide can potentiate the effect of non-polarizing skeletal muscle relaxants (e.g. tubocurarine).

Thiazide diuretics can increase plasma calcium levels due to its reduced excretion. When prescribing calcium supplements or vitamin D, it is necessary to control the level of calcium in the blood plasma and adjust the dose accordingly.

Thiazides can enhance the hyperglycemic effect of β-adrenergic receptor blockers and diazoxide.

Anticholinergics (such as atropine, biperiden) can increase the bioavailability of thiazide-type diuretics, reducing gastrointestinal motility and gastric emptying rate.

Thiazides may increase the risk of side effects caused by amantadine.

Thiazides can reduce the excretion of cytotoxic drugs (such as cyclophosphamide, methotrexate) by the kidneys and potentiate their myelosuppressive effects.

It can be expected that the decrease in potassium levels characteristic of hydrochlorothiazide is exacerbated by other drugs that are associated with potassium loss and hypokalemia (e.g., steroids, ACTH).

Concomitant use of alcohol, barbiturates or anesthetics can cause postural hypotension.

Treatment with thiazide diuretics may impair glucose tolerance. There may be a need for dose adjustment of antidiabetic agents, including insulin.

Metformin should be prescribed with caution, given the risk of developing lactic acidosis caused by possible functional renal failure associated with hydrochlorothiazide.

Hydrochlorothiazide can cause a decrease in arterial response to pressor amines (such as epinephrine), but this is not enough to exclude the pressor effect.

Hydro