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Hydrochlorothiazide, Ramipril

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Clinical Pharmacology

Ramipril / hydrochlorothiazide pills have antihypertensive and diuretic effects. Ramipril and hydrochlorothiazide are used alone or together in the treatment of high blood pressure (BP). The antihypertensive effects of both components complement each other, are almost additive, and the hypokalemic effect of hydrochlorothiazide is reduced by ramipril.
Ramiprilat, the active metabolite of ramipril, inhibits the enzyme dipeptidylcarboxypeptidase I (synonyms: angiotensin-converting enzyme, kininase II). This enzyme catalyzes the conversion of angiotensin I by the tissues to the active vasoconstrictor angiotensin II, as well as the breakdown of the active vasodilator bradykinin. Reducing the amount of angiotensin II and suppressing the breakdown of bradykinin leads to the expansion of blood vessels.
Since angiotensin II also stimulates the release of aldosterone, ramiprilat leads to a decrease in the release of aldosterone.
The use of ramipril leads to a marked decrease in peripheral vascular resistance. Significant changes in renal blood flow and glomerular filtration are not usually observed.
Taking ramipril pills by patients with arterial hypertension lowers blood pressure while standing and lying without a compensatory increase in heart rate (HR). In most patients, the antihypertensive effect appears 1-2 hours after taking a single dose. The severity of the effect reaches a maximum after 3-6 hours after administration. As a rule, the antihypertensive effect of a single dose is maintained for 24 hours. With prolonged treatment with ramipril, the maximum antihypertensive effect is usually achieved in 2-4 weeks. It has been shown that with long-term therapy, the antihypertensive effect can be maintained for 2 years. Abrupt discontinuation of ramipril does not lead to a rapid and excessive increase in blood pressure.
Hydrochlorothiazide - thiazide diuretic. Suppresses the reabsorption of sodium ions and chlorine in the distal nephron. Enhanced renal excretion of these ions is accompanied by increased urination (due to osmotic binding of water). The excretion of potassium and magnesium ions increases, while uric acid is delayed. High doses lead to increased bicarbonate excretion, and long-term use delays the excretion of calcium ions. Possible mechanisms of antihypertensive action include: changing the sodium balance, reducing the volume of extracellular fluid and plasma, changing the resistance of the renal vessels or reducing the reactions to norepinephrine and angiotensin II.
Removal of electrolytes and water begins approximately 2 hours after ingestion, the maximum effect is achieved within 3-6 hours and lasts for 6-12 hours. Antihypertensive effect is achieved within 3-4 days of treatment and lasts for 1 week after completion of the drug. With long-term treatment, a decrease in blood pressure is achieved by using smaller doses than are necessary for the diuretic effect. Reduction of blood pressure is accompanied by a slight increase in glomerular filtration rate, vascular resistance of the renal bed and renin activity in the blood plasma.
Acceptance of single high doses of hydrochlorothiazide leads to a decrease in plasma volume, glomerular filtration rate, renal blood flow, and mean blood pressure. With long-term intake of small doses, the volume of blood plasma remains reduced, while the minute volume and glomerular filtration rate return to the initial level preceding the start of treatment. Mean blood pressure and systemic vascular resistance remain reduced. Thiazide diuretics may interfere with the production of breast milk.


Arterial hypertension (for patients who are recommended combination therapy).


Each tablet containsactive substances: 5 mg ramipril and 25 mg hydrochlorothiazide, respectively.
Excipients:lactose monohydrate, hypromellose, crospovidone, microcrystalline cellulose, sodium stearyl fumarate.

Hydrochlorothiazide, Ramipril is marketed under different brands and generic names, and comes in different dosage forms:

Brand nameManufacturerCountryDosage form
Hartil-d Egis Hungary pills
Amprilan ND Krka dd Novo mesto AO Slovenia pills
Amprilan NL Krka dd Novo mesto AO Slovenia pills

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Hydrochlorothiazide, Ramipril

Dosage and Administration

Hartil-D should be taken once daily in the morning, drinking plenty of fluids. The drug can be taken regardless of the meal. pills are not intended to be divided into parts.
It is recommended to prescribe the combined drug Hartil-D only after individual selection of doses of each of the components. The dose can be increased with an interval of at least 3 weeks. The usual starting dose is 2.5 mg ramipril and 12.5 mg hydrochlorothiazide. The usual maintenance dose is 2.5 mg ramipril and 12.5 mg hydrochlorothiazide or 5 mg ramipril and 25 mg hydrochlorothiazide. The recommended maximum daily dose is 5 mg ramipril and 25 mg hydrochlorothiazide.
Elderly patients and patients with impaired renal function
For elderly patients and patients with QA from 30 to 60 ml / min. Individual doses of each of the components (ramipril and hydrochlorothiazide) must be carefully selected before switching to the combined drug Hartil-D.
The dose of the drug Hartil-D should be as low as possible. The recommended maximum daily dose is 5 mg ramipril and 25 mg hydrochlorothiazide.
Hartil-D is contraindicated in patients with severely impaired renal function, that is, when CC is less than 30 ml / min / 1.73 m2
Liver dysfunction
Before switching to Hartil-D, patients with mild or moderately impaired liver function should be given a dose of ramipril.
Hartil-D is not allowed to be taken by patients with severely impaired liver function and / or cholestasis (see section Contraindications).
Children and teenagers (under the age of 18)
Charter-D is not recommended for children and adolescents (under the age of 18 years) due to the lack of safety and efficacy data for this age group.

Adverse reactions

A number of adverse reactions have been noted while taking ACE inhibitors, ramipril or hydrochlorothiazide.
Severe arterial hypotension was observed at the beginning of the course of treatment and after increasing the dose. This effect is especially characteristic of some risk groups. Symptoms such as dizziness, general weakness, blurred vision, sometimes in combination with loss of consciousness (fainting) may occur. Individual cases of tachycardia, palpitations, arrhythmias, angina pectoris, myocardial infarction, severe arterial hypertension and shock, dynamic cerebrovascular accident, cerebral hemorrhage and ischemic stroke were observed while taking ACE inhibitors against arterial hypotension. Frequency is defined as follows: often (> 1/100, 1/1000, 1/10000, Disruption of the blood and lymph systems:rarely: decrease in hemoglobin and hematocrit, leukopenia, thrombocytopenia, very rarely: agranulocytosis, pancytopenia, eosinophilia, hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency
Metabolism and nutrition disorders:often: hypokalemia, increased levels of uric acid, urea and creatinine in the blood, hyperglycemia, gout, infrequently: hyperkalemia, hyponatremia, hypomagnesemia, hyperchloraemia, hypercalcemia, rarely: impairment of water and electrolyte balance (especially in patients with kidney disease), hypochloremia, disfunction alkalosis, very rare: an increase in the level of trigitseridov in the blood serum, hypercholesterolemia, increased serum amylase, decompensation of diabetes.
Mental Disorders:infrequently: apathy, nervousness, rarely: feeling of fear, confusion, sleep disturbance.
Nervous system disorders:often: dizziness, fatigue, headache, weakness, infrequently: drowsiness, rarely: anxiety, disturbance of smell, imbalance, paresthesia.
Violations by the organ of vision:infrequently: conjunctivitis, blepharitis, rarely: transient myopia, blurred vision.
Violations of the organ of hearing:rarely: tinnitus.
Violations of the cardiovascular system:marked reduction of blood pressure Uncommon: swelling of the ankles, rarely, fainting, thromboembolic complications are very rare: angina pectoris, myocardial infarction, arrhythmia, palpitations, tachycardia, dynamic stroke, brain hemorrhage, exacerbation of Raynaud's disease, vasculitis, venous diseases, thrombosis embolism.
Respiratory disorders:dry cough, bronchitis, rarely: dyspnea, sinusitis, rhinitis, pharyngitis, glossitis, bronchospasm, allergic interstitial pneumonia, very rarely: angioedema with lethal obstruction of the respiratory tract1)pulmonary edema due to increased sensitivity to hydrochlorothiazide
Disorders of the digestive system:nausea, abdominal pain, vomiting, dyspepsia, infrequently: epigastric cramps, thirst, constipation, diarrhea, loss of appetite, rarely: dry mouth, vomiting, taste disturbances, inflammation of the mucous membranes of the mouth and tongue, sialadenitis, glossitis, very rare : intestinal obstruction, (hemorrhagic) pancreatitis
Liver disorders:rarely: increased activity of liver enzymes and / or bilirubin2)very rare: cholestatic jaundice2), hepatitis, cholecystitis (with gallstone disease), liver necrosis
Violations of the skin and subcutaneous fat3): infrequently: photosensitization, pruritus, urticaria, rarely: blood flushes to the skin of the face, sweating, peripheral edema, very rarely: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, skin reactions of psoriatic or pemphigoid type, systemic red lupus, alopecia, exacerbation of psoriasis, onycholysis.
Disorders of the musculoskeletal system and connective tissue:seldom: muscular spasm, myalgia, arthralgia, muscular weakness, arthritis, very rarely: paralysis.
Violations of the urinary system:infrequently: proteinuria, rarely: impaired renal function, increased residual nitrogen and serum creatinine, dehydration, very rarely: (acute) renal failure, nephrotic syndrome, interstitial nephritis, oliguria
Disturbances from the reproductive organs and mammary glands:infrequently: decreased libido, rarely: impotence
General violations:very rare: anaphylactic reactions, angioedema1)
1) Angioedema often occurs in individuals with dark skin. In a small group of patients, the occurrence of angioedema of the face and oropharyngeal region is associated with the use of ACE inhibitors.
2) In case of jaundice or increased activity of liver enzymes, the patient should be taken under medical supervision.
3) If skin reactions are pronounced, urgent consultation with a doctor is necessary.
It has been reported that taking this drug can lead to the appearance of a symptom complex represented by at least one of the following components: fever, vasculitis, myalgia, arthralgia / arthritis, a positive reaction to anti-nuclear antibodies, an increase in erythrocyte sedimentation rate (ESR), eosinophilia and leukocytosis, rash, photosensitization (other skin manifestations are also possible).


Carefully:severe lesions of the coronary and cerebral arteries (risk of reducing blood flow with an excessive decrease in blood pressure), unstable angina, severe ventricular arrhythmias, chronic heart failure stage IV, decompensated pulmonary heart, conditions accompanied by a decrease in circulating blood volume (including diarrhea, vomiting), systemic connective tissue diseases, diabetes mellitus, oppression of bone marrow hematopoiesis, advanced age, aortic and mitral stenosis, hypertrophic obstructions massive cardiomyopathy, bilateral renal artery stenosis or single kidney artery stenosis, gout, hyperkalemia, hyponatremia (including while taking diuretics and salt-restricted diets), hypokalemia, hypercalcemia, coronary heart disease, renal and / or liver failure, cirrhosis the liver.

Drug interactions

The following lists the interaction of the components of the drug Hartil-D with other inhibitors
APF and preparations containing hydrochlorothiazide.
Assigning a diuretic to a patient taking ramipril usually results in the summation of the antihypertensive effect.
In patients who are already taking diuretics, especially those to whom diuretics have been prescribed recently, the addition of ramipril can sometimes cause an excessive decrease in blood pressure. The likelihood of symptoms of arterial hypotension under the influence of ramipril is reduced if you stop taking a diuretic before starting treatment with ramipril (see Special Instructions section).
Tricyclic antidepressants / antipsychotics (neuroleptics) / anesthetics
Acceptance of some anesthetics, tricyclic antidepressants, and antipsychotics against the background of ACE inhibitors can increase arterial hypotension (see the Special Instructions section).
Sympathomimetics can weaken the hypotensive effect of ACE inhibitors, so patients need careful monitoring.
Hypoglycemic agents
Epidemiological studies have shown that the simultaneous use of ACE inhibitors and hypoglycemic agents (insulin and hypoglycemic agents for oral administration) may enhance the effect of the latter, up to the development of hypoglycemia. The likelihood of such events is especially high during the first weeks of combined treatment of patients, as well as in violation of renal function.
Thrombolytic and / or beta-blockers
Ramipril can be used on the background of taking trombolitikov beta-blockers.
Other antihypertensive drugs
Simultaneous intake of nitroglycerin and other organic nitrates or vasodilators may enhance the hypotensive effect of ramipril.
Nonsteroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid (3 g / day)
Ramipril can be used while taking acetylsalicylic acid (in small doses under medical supervision). Long-term use of NSAIDs can weaken the hypotensive effect of ACE inhibitors. The effects of NSAIDs and ACE inhibitors on the increase in serum potassium levels are summarized, which can lead to impaired renal function. These effects are usually reversible. In rare cases, acute renal failure may occur, especially in cases of impaired renal function, for example, in elderly or dehydrated patients.
Simultaneous treatment with an ACE inhibitor and allopurinol increases the risk of renal failure and may lead to an increased risk of leukopenia.
The simultaneous use of ACE inhibitors and cyclosporine increases the risk of renal failure and hyperkalemia.
The simultaneous use of ACE inhibitors and lovastatin increases the risk of hyperkalemia.
Procainamide, cytostatics and immunosuppressants
Taking these drugs simultaneously with ACE inhibitors may increase the risk of leukopenia.
Hartil-D is not indicated for patients whose condition requires dialysis, since the use of ACE inhibitors against dialysis using membranes that provide high current intensity is often accompanied by anaphylactoid reactions. This combination is not allowed.
Amphotericin B (parenteral), carbenoxolone, corticosteroids, corticotropin (ACTH) or stimulatory laxatives
Hydrochlorothiazide can cause electrolyte imbalances, especially hypokalemia.
Calcium salts
While taking these drugs with thiazide diuretics, a decrease in calcium ion excretion may increase the level of calcium in blood serum.
Cardiac glycosides
The risk of poisoning with digitalis and thiazide hypokalemia increases.
Cholestyramine resin and colestipol
These drugs may reduce or slow down the absorption of hydrochlorothiazide. Therefore, sulfonamide diuretics should be taken at least one hour before or 4-6 hours after taking the resin.
Non-polarizing muscle relaxants (i.e., tubocurarine chloride)
Hydrochlorothiazide may enhance the effect of these medicines.
Drugs that cause tachycardia type "pirouette"
The risk of hypokalemia necessitates caution while taking hydrochlorothiazide and drugs that cause tachycardia such as "pirouette", for example, some antipsychotic and other drugs.
Against the background of thiazide hypokalemia, the risk of arrhythmia due to sotalol increases.
Ramipril / hydrochlorothiazide
Potassium-containing dietary supplements, potassium-saving diuretics, or potassium-containing salt substitutes
Although serum potassium levels during clinical trials of ACE inhibitors usually remained within the normal range, some patients still developed hyperkalemia.
The risk of hyperkalemia is associated with a number of factors, including renal failure, diabetes mellitus and simultaneous intake of potassium-saving diuretics (for example, spironolactone, triamterene, or amiloride), as well as potassium-containing food additives or salt substitutes. The use of potassium-containing dietary supplements, potassium-sparing diuretics, or potassium-containing salt substitutes may lead to a significant increase in serum potassium, especially in patients with impaired renal function.
While taking ramipril on the background of potassium-diuretic diuretics, the hypokalemia caused by their intake may be weakened.
At the same time taking lithium and ACE inhibitors reversibly increases the level of lithium in the blood serum and develop toxic effects. The use of thiazide diuretics may increase the risk of lithium intoxication and increase lithium intoxication if it is already caused by the simultaneous use of ACE inhibitors. It is not recommended to use ramipril at the same time as lithium, but in cases where such a combination is necessary, careful monitoring of the level of lithium in the blood serum should be carried out (see Special Instructions section).
Taking ACE inhibitors and thiazides simultaneously with trimethoprim increases the risk of hyperkalemia.
Oral hypoglycemic agents (for example, sulfomurea derivatives and biguanides, such as metformin) and insulin
Perhaps hydrochlorothiazide weakens the hypoglycemic effect of these agents, while ramipril potentiates it.
Sodium chloride
The weakening of the antihypertensive effect of a fixed combination of ramipril and hydrochlorothiazide.
Treatment with high doses of salicylates (> 3 g / day)
Hydrochlorothiazide may enhance the toxic effects of salicylates on the central nervous system.

Pregnancy and Lactation

Hartil-D is not recommended during the first trimester of pregnancy. In the case of a planned or confirmed pregnancy, it is necessary to switch to another therapy as soon as possible. Controlled studies on the use of ACE inhibitors during pregnancy were not conducted.
Hartil-D is contraindicated during the second and third trimesters of pregnancy. Long-term use during the second and third trimesters may cause signs of intoxication in the fetus (depression of renal function, oligohydramnios, delayed ossification of the skull) and the newborn (renal failure of the newborn, hypotension, hyperkalemia).
Prolonged use of hydrochlorothiazide during the third trimester of pregnancy may cause ischemia of the fetus and placenta, the risk of stunting. Moreover, in some cases, admission shortly before birth can cause hypoglycemia and thrombocytopenia in newborns. Hydrochlorothiazide may decrease plasma volume and decrease uteroplacental blood flow.
Women who took Hartil-D during pregnancy (starting from the second trimester) need to undergo an ultrasound examination to check the condition of the kidneys and skull of the fetus.
Lactation period
Hartil-D is contraindicated during lactation. Both ramipril and hydrochlorothiazide are secreted into breast milk. The decrease and cessation of milk secretion is associated with the admission of thiazides during breastfeeding. Hypersensitivity reactions to sulfonamide drugs, hyperkalemia and nuclear jaundice may occur. Because of the potential for serious side effects in infants, it is necessary to consider stopping breastfeeding.

Special instructions

Symptoms of arterial hypotension
In patients with uncomplicated arterial hypertension, symptoms of arterial hypotension are rarely observed. In patients with arterial hypertension who take ramipril, the likelihood of arterial hypotension increases with a decrease in circulating blood volume (for example, as a result of diuretic treatment, restriction of salt intake, dialysis, diarrhea or vomiting), as well as in severe forms of renin-dependent arterial hypertension . Symptoms of arterial hypotension were observed in patients with heart failure, regardless of whether it is combined with renal failure. This is most often observed in patients with more severe heart failure, who are forced to take high doses of "loop" diuretics, in whom hyponatremia or functional renal failure is observed. Patients with an increased risk of arterial hypotension require close observation in the initial period of treatment and in the selection of the dose. This also applies to patients with coronary heart disease or vascular disease of the brain, in which a significant drop in blood pressure can lead to myocardial infarction or impaired cerebral circulation. In case of arterial hypotension, the patient should be placed on his back, his legs raised and, if necessary, intravenous infusion of sodium chloride solution. Transient hypotensive reaction is not a contraindication for subsequent administration of the drug. In some heart failure patients with normal or low BP, ramipril may cause an additional decrease in systolic BP. This effect can be foreseen, so it is usually not a reason to stop treatment. If arterial hypotension presents with symptoms, it may be necessary to reduce the dose or discontinue treatment.
Aortic and mitral stenosis / hypertrophic cardiomyopathy
Like other ACE inhibitors, ramipril requires caution when prescribing to patients with aortic stenosis or difficulty in ejection from the left ventricle (for example, in aortic stenosis or hypertrophic cardiomyopathy). In some cases, the hemodynamic picture may make inadmissible reception of a fixed combination of ramipril and hydrochlorothiazide.
Primary aldosteronism (Conn's disease)
The use of fixed combinations of ramipril and hydrochlorothiazide is contraindicated, since patients with primary aldosteronism are not sensitive to antihypertensive drugs, which are based on the suppression of the renin-angiotensin system.
Renal dysfunction
Patients with heart failure at the beginning of treatment with ACE inhibitors may experience renal impairment. In such situations, described cases of acute renal failure, usually transient.
In some patients with narrowing of both renal arteries or with stenosis of the artery of a single kidney, ACE inhibitors increase the level of urea in the blood and creatinine in the blood serum; usually, these changes disappear after stopping the medication. The likelihood of this is especially high in renal failure. In the presence of renovascular hypertension, the risk of severe arterial hypotension and renal failure is high.In such patients, treatment should begin under close medical supervision with small doses, which should be carefully selected. Since diuretics can contribute to the clinical dynamics described above, they should be discontinued during the first weeks of ramipril treatment, and renal function needs careful monitoring.
In some patients with arterial hypertension without obvious kidney disease, taking ramipril, especially against the background of diuretics, causes an increase in blood urea and creatinine in serum; these changes are usually minor and transient. The probability of their occurrence is higher in patients already suffering from renal dysfunction. In such cases, it may be necessary to reduce the dose and / or stop taking diuretic and / or ramipril.
Condition after kidney transplantation
Due to the lack of experience with the use of ramipril in patients who recently underwent kidney transplantation, ramipril is not recommended for such patients.
Increased sensitivity / angioedema
Angioedema of the face, extremities, lips, tongue, vocal cords and / or larynx rarely develops in patients receiving ACE inhibitors, including ramipril. During treatment, angioedema can develop at any time. In this case, the reception of ramipril should be immediately discontinued, an appropriate treatment should be carried out and patient monitoring established; Before releasing the patient, make sure that all symptoms of the edema are eliminated. Even in cases where the edema is limited only to the tongue and there are no signs of impaired breathing, patients may need long-term follow-up, since treatment with angistamines and corticosteroids may be insufficient. In rare cases, death of patients due to angioedema of the larynx or tongue has been recorded.
If the edema spreads to the tongue, vocal cords or larynx, it is very likely that the airways overlap, especially in patients who have previously undergone respiratory surgery. In such cases, it is necessary to take emergency treatment measures (see section Overdose). It may include the administration of epinephrine (adrenaline) and / or the maintenance of the airway. The patient must be under close medical supervision until the symptoms disappear completely and permanently.
In patients with a history of angioedema, not associated with taking an ACE inhibitor, the risk of developing angioedema in response to taking an ACE inhibitor may be increased.
Anaphylactoid Reactions in Hemodialysis Patients
There are reports of anaphylactoid reactions in patients on hemodialysis using membranes with high hydraulic permeability (for example, AN 69) with simultaneous use of ACE inhibitors. In such cases, you should consider using a different type of membrane or antihypertensive drugs of another class.
Anaphylactoid reactions in the apheresis of low-density lipoprotein (LDL)
In rare cases, patients taking an ACE inhibitor during low-density lipoprotein (LDL) apheresis with dextran sulfate develop life-threatening anaphylactoid reactions. Such reactions can be avoided if you temporarily refrain from taking an ACE inhibitor before each apheresis procedure.
Long-term anaphylactoid reactions develop in patients taking ACE inhibitors during desensitization therapy (for example, hymenoptera poison). If such patients refrained from taking ACE inhibitors for the duration of desensitization, no reactions were observed, however, the accidental administration of ACE provoked an anaphylactoid reaction.
Liver failure
The development of a rare syndrome, which begins with cholestatic jaundice or hepatitis and is converted into transient necrosis of the liver, is sometimes associated with the use of ACE inhibitors and sometimes transforms into transient necrosis of the liver, sometimes with a fatal outcome. The mechanism for the development of this syndrome is not clear. If patients taking ramipril develop jaundice or significantly increase the activity of liver enzymes, the drug should be discontinued, leaving the patient under medical supervision until the symptoms disappear.
Neutropenia / Agranulocytosis
It has been reported that patients taking ACE inhibitors may develop neutropenia / agranulocytosis, thrombocytopenia and anemia. With normal kidney function and in the absence of complications, neutropenia rarely develops. Neutropenia and agranulocytosis are reversible and disappear after discontinuation of the ACE inhibitor. Extreme caution should be exercised when prescribing ramipril to patients suffering from connective tissue diseases with vascular manifestations, undergoing treatment with antidepressants, taking allopurinol or procainamide, as well as combining these factors, especially against the background of renal dysfunction. Some of these patients develop severe infections that are not always amenable to intensive antibiotic therapy. If ramipril is used in the treatment of such patients, it is recommended to periodically check the number of leukocytes, and patients should be warned to report any signs of infection.
ACE inhibitors more often cause the development of angioedema in patients of the Negroid race compared with patients of a different race.
Like other ACE inhibitors, ramipril may be less effective in lowering blood pressure in black patients than in other races, possibly due to a higher incidence of people with low renin levels in a population of black patients with arterial hypertension.
It has been reported that taking ACE inhibitors may be accompanied by cough. Characteristically, the cough is dry and persistent; It passes after drug withdrawal. The fact that a cough is caused by taking an ACE inhibitor should be considered a differential diagnostic sign.
Surgical intervention / general anesthesia
In patients undergoing surgery or general anesthesia with drugs that reduce blood pressure, ramipril can block the increase in the formation of angiotensin II under the influence of compensatory renin release. If it is assumed that arterial hypotension develops by this mechanism, it can be adjusted by increasing the circulating blood volume.
Some patients taking ACE inhibitors, including ramipril, have an increase in serum potassium. At risk of developing hyperkalemia include patients suffering from renal failure or diabetes, taking potassium-sparing diuretics, or potassium-containing salt substitutes, as well as those who take other drugs that increase the level of serum potassium (eg, heparin). If taking the drugs listed above against the background of treatment with an ACE inhibitor is deemed necessary, regular monitoring of the level of potassium in the blood serum is recommended (see Interaction section).
Patients with diabetes
In patients with diabetes mellitus, taking hypoglycemic agents for oral administration or insulin, it is necessary to carefully monitor blood sugar levels during the first month of treatment with an ACE inhibitor (see the Interaction section).
It is usually not recommended to combine lithium and ramipril intake (see the Interaction section).
Potassium-containing dietary supplements, potassium-saving diuretics, or potassium-containing salt substitutes
Although serum potassium levels during clinical trials of ACE inhibitors usually remained within the normal range, some patients still developed hyperkalemia. The risk of developing hyperkalemia is associated with a number of factors, including renal failure, diabetes mellitus and simultaneous intake of potassium-saving diuretics (for example, spironolactone, triamterene, or amiloride), as well as potassium-containing food additives or salt substitutes. The use of potassium-containing dietary supplements, potassium-sparing diuretics, or potassium-containing salt substitutes can lead to a significant increase in serum potassium, especially in patients with impaired renal function.
While taking ramipril on the background of potassium-diuretic diuretics, the hypokalemia caused by their intake may be weakened.
Renal dysfunction
In patients with kidney disease, thiazides may cause azotemia. Taking medication on the background of renal dysfunction can lead to cumulative effects. If renal failure progresses, characterized by an increase in non-protein nitrogen, the need for therapy should be carefully assessed and the possibility of discontinuing diuretics should be considered.
Liver dysfunction
Patients with impaired or progressive liver dysfunction should be prescribed thiazides with caution, since even minor fluctuations in water and electrolyte balance can cause hepatic coma.
Metabolic and endocrine effects
Thiazide therapy may decrease glucose tolerance. In diabetes mellitus, it may be necessary to adjust the dose of insulin or oral hypoglycemic agents.
Thiazide therapy may cause latent diabetes.
Thiazide diuretic therapy is associated with an increase in cholesterol and triglyceride levels. Some patients receiving thiazide diuretics may experience an increase in uric acid levels or manifestations of gout.
In some patients, thiazide therapy may increase uric acid levels and / or cause gout. However, ramipril can increase the excretion of uric acid, thus weakening the degree of increase in the level of uric acid under the influence of hydrochlorothiazide.
Disorders of water and electrolyte balance
Any patient receiving diuretic treatment should periodically determine the content of electrolytes in the blood serum.
Thiazides, including hydrochlorothiazide, can cause a disturbance of water and electrolyte balance (hypokalemia, hyponatremia, and hypochloraemic alkalosis). Precursors to water or electrolyte imbalance are dry mouth, thirst, weakness, lethargy, drowsiness, anxiety, myalgia or muscle spasms, muscle fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disorders such as nausea and vomiting.
Although the use of thiazide diuretics can lead to the development of hypokalemia, while taking ramipril, it is possible to reduce the severity of hypokalemia caused by diuretics. The probability of development of hypokalemia is highest with liver cirrhosis, in patients with elevated diuresis, with inadequate oral electrolyte intake, and also during treatment with corticosteroids and ACTH (see the Interaction section). In hot weather, hyponatremia may develop in patients with peripheral edema. The lack of chlorides is usually insignificant and does not require treatment. Thiazides can reduce the excretion of calcium ions in the urine, leading to a slight periodic increase in the level of calcium in the blood, even in the absence of obvious violations of calcium metabolism. Explicit hypercalcemia may indicate latent hyperparathyroidism.Reception of thiazides should be stopped until the results of the study of the function of the parathyroid glands are obtained. It has been shown that thiazides increase the renal excretion of magnesium, which can lead to a decrease in the level of magnesium in the blood.
Neutropenia / Agranulocytosis
You should stop taking a combination of fixed doses of ramipril and hydrochlorothiazide in case of or suspected neutropenia (the number of neutrophils less than 1000 / mm3). 
Anti doping tests
Hydrochlorothiazide, which is part of this drug, can give a positive reaction with anti-doping control.
Regardless of the history of allergies or asthma, hypersensitivity reactions may develop in patients. It was reported about the possibility of exacerbation of systemic lupus erythematosus.
Lactose intolerance
This drug contains lactose monohydrate.
It should not be prescribed to patients with a rare inherited disorder of galactose tolerance, hereditary lactose deficiency, or glucose-galactose absorption disorder syndrome.

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