Indapamide
Indapamide is a thiazide-like diuretic that also has vasodilatory properties. Used to treat arterial hypertension. Thiazide and thiazide-like diuretics are still at the forefront of antihypertensive therapy. They are used as first-line drugs both in monotherapy and as part of combination treatment, and their inclusion in the pharmacotherapeutic antihypertensive course significantly improves the overall cardiovascular prognosis.
The mechanism of action of indapamide is close to that of thiazides, which is not surprising, because both drug groups are sulfonamide derivatives. The drug acts in the initial sections of the distal tubules, where under normal conditions the reabsorption of 5–10% of sodium and chlorine ions filtered into the primary urine occurs, suppressing this very absorption. Despite ongoing discussions about the advantages and disadvantages of thiazide and thiazide-like diuretics in comparison with each other, thiazide-like drugs have recently come to the fore, supporting their breakthrough with the results of numerous clinical studies. For example, British experts already today recommend giving preference to thiazide-like diuretics when treating patients with arterial hypertension.
Due to some unique properties, indapamide stands out even within its pharmacological subgroup. It has been reliably confirmed that it has a vasodilating effect, which contributes a considerable amount to the overall antihypertensive effect. The vasodilator activity of the drug is due to the normalization of the increased sensitivity of blood vessels to the action of a number of vasopressor factors (norepinephrine, angiotensin II, thromboxane A2) and a decrease in the concentration of free radicals, which occurs incl.
h due to inhibition of peroxidation of “bad” cholesterol. Indapamide also has some calcium channel blocker properties. Another distinctive feature of the drug, which makes it stand out among thiazide and thiazide-like diuretics, is the peculiar separation of its antihypertensive activity and diuretic effect, a clear indication of which is the preservation of the antihypertensive effect at the same level in patients with chronic kidney disease. The lipophilicity (ability to dissolve in fats) of indapamil is an order of magnitude higher than that of other thiazides, which gives it the ability to accumulate in smooth muscle vascular cells.
At the end of the last century, clear requirements for an ideal antihypertensive agent were formulated: the duration of the effect is at least 24 hours (subject to a single dose) and the uniformity of the antihypertensive effect, supported by the absence of significant fluctuations in the concentration of the active substance in the blood. To solve (at least partially) this problem, sustained-release dosage forms of indapamide (so-called retard forms) were developed. The process of its absorption in the digestive tract is essential to ensure the uniformity of the drug's action. The antihypertensive agent should not be absorbed all at once, because in this case, a sharp decrease in blood pressure will occur. The retard form avoids pronounced changes in the concentration of the drug in the blood and instability of the pharmacological effect over time. Indapamide in this release form can be found in pharmacies under the name “indapamide retard”.
Perindopril + Indapamide 2.5 mg + 8 mg 30 pcs ➤ instructions for use
Common to perindopril and indapamide Lithium preparations
The simultaneous use of Perindopril PLUS Indapamide with lithium preparations is usually not recommended (see section “Interaction with other drugs”).
Renal dysfunction
Therapy with the drug Perindopril PLUS Indapamide is contraindicated in patients with severe renal failure (creatinine clearance less than 30 ml/min). In some patients with arterial hypertension without previous obvious renal impairment, laboratory signs of functional renal failure may appear during therapy. In this case, treatment with Perindopril PLUS Indapamide should be discontinued. In the future, you can resume combination therapy using low doses of a combination of perindopril and indapamide, or use only one of the drugs.
Such patients require regular monitoring of the content of potassium and creatine ions in the blood serum - 2 weeks after the start of therapy and then every 2 months. Renal failure occurs more often in patients with severe chronic heart failure or underlying renal impairment, including renal artery stenosis.
The drug Perindopril PLUS Indapamide is not recommended for use in cases of bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney.
Arterial hypotension and water-electrolyte imbalance
In the case of initial hyponatremia, there is a risk of sudden development of arterial hypotension (especially in patients with renal artery stenosis). Therefore, when monitoring patients, attention should be paid to possible symptoms of dehydration and decreased plasma electrolytes, for example, after diarrhea or vomiting. Such patients require regular monitoring of blood plasma electrolyte levels.
In case of severe arterial hypotension, intravenous administration of 0.9% sodium chloride solution may be required.
Transient arterial hypotension is not a contraindication for continued therapy. After restoration of blood volume and blood pressure, therapy can be resumed using low doses of a combination of perindopril and indapamide, or only one of the drugs.
Potassium content
The combined use of perindopril and indapamide does not prevent the development of hypokalemia, especially in patients with diabetes mellitus or renal failure. As with the use of other antihypertensive drugs in combination with a diuretic, regular monitoring of the content of potassium ions in the blood plasma is necessary.
Childhood
The drug Perindopril PLUS Indapamide should not be prescribed to children and adolescents under the age of 18 years due to the lack of data on the effectiveness and safety of the use of perindopril and indapamide both in monotherapy and in combination use in patients of this age group
Indapamide
Hepatic encephalopathy
In the presence of liver dysfunction, taking thiazide and thiazide-like diuretics can lead to the development of hepatic encephalopathy. In such a situation, you should immediately stop taking the diuretic.
Photosensitivity
Cases of photosensitivity reactions have been reported with thiazide and thiazide-like diuretics (see section “Side Effects”). If a photosensitivity reaction develops while taking the drug, treatment should be discontinued. If it is necessary to continue diuretic therapy, it is recommended to protect the skin from exposure to sunlight or artificial ultraviolet rays.
Water and electrolyte balance
Content of sodium ions in blood plasma
The content of sodium ions in the blood plasma must be determined before starting treatment, and then regularly monitored while taking the drug. Hyponatremia at the initial stage may not be accompanied by clinical symptoms, so regular laboratory monitoring is necessary. More frequent monitoring of sodium ion levels is indicated for patients with liver cirrhosis and elderly patients (see sections “Side effects” and “Overdose”). Treatment with any diuretics can cause hyponatremia, sometimes with very serious consequences. Hyponatremia accompanied by hypovolemia can lead to dehydration and orthostatic hypotension. A simultaneous decrease in the content of chloride ions can lead to the development of secondary compensatory metabolic alkalosis: the frequency of its occurrence and severity are insignificant.
Content of potassium ions in blood plasma
Therapy with thiazide and thiazide-like diuretics is associated with a high risk of developing hypokalemia. Hypokalemia (less than 3.4 mmol/L) should be avoided in the following high-risk patients: elderly patients, malnourished patients (both those receiving and not receiving concomitant drug therapy), patients with cirrhosis (with edema and ascites) , coronary heart disease, chronic heart failure. Hypokalemia in these patients increases the toxic effect of cardiac glycosides and increases the risk of developing arrhythmia.
Patients with a prolonged QT interval, either congenital or drug-induced, are also at increased risk.
Hypokalemia, like bradycardia, contributes to the development of severe cardiac arrhythmias, especially arrhythmias, which can be fatal. In all the cases described above, more frequent monitoring of the content of potassium ions in the blood plasma is necessary. The first measurement of potassium ion content should be carried out within the first week from the start of therapy.
If hypokalemia is detected, appropriate correction should be made.
Content of calcium ions in blood plasma
Thiazide and thiazide-like diuretics can reduce the excretion of calcium ions by the kidneys, leading to a slight and temporary increase in the content of calcium ions in the blood plasma. Severe hypercalcemia may be a consequence of previously undiagnosed hyperparathyroidism. Before studying the function of the parathyroid glands, you should stop taking diuretics.
Plasma glucose concentration
It is necessary to monitor blood glucose concentrations in patients with diabetes mellitus, especially in the presence of hypokalemia.
Uric acid
When the concentration of uric acid in the blood plasma increases during therapy, the frequency of gout attacks may increase.
Diuretics and kidney function
Thiazide and thiazide-like diuretics are fully effective only in patients with normal or slightly impaired renal function (plasma creatinine clearance in adult patients below 25 mg/l or 220 µmol/l). In elderly patients, plasma creatinine levels should be assessed taking into account age, weight and gender according to the Cockroft formula:
CC = (140 – age) × weight/0.814 × plasma creatinine concentration,
where: age – in years, weight – in kg, plasma creatinine concentration – in µmol/l.
The formula is suitable for elderly men; for elderly women, the result should be multiplied by a factor of 0.85.
At the beginning of treatment with diuretics, patients due to hypovolemia (due to the excretion of water and sodium ions) may experience a temporary decrease in glomerular filtration rate and an increase in the concentration of urea and creatinine in the blood plasma. This transient functional renal failure is not dangerous for patients with normal renal function, but its severity may increase in patients with renal failure.
Athletes
Indapamide may give a positive reaction during doping control.
Acute myopia and secondary angle-closure glaucoma
Sulfonamides and their derivatives can cause the development of idiosyncratic reactions leading to temporary (transient) myopia and acute angle-closure glaucoma. Without proper treatment, acute angle-closure glaucoma can lead to vision loss. The first step is to stop taking the drug as soon as possible. If intraocular pressure continues to be high, immediate medical or surgical treatment may be required. Risk factors that may lead to the development of acute angle-closure glaucoma include a history of allergies to sulfonamides or penicillin.
Perindopril
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
There is evidence of an increased risk of arterial hypotension, hyperkalemia and renal dysfunction (including acute renal failure) when ACE inhibitors are used simultaneously with ARB II or aliskiren. Therefore, double blockade of the RAAS by combining an ACE inhibitor with ARA II or aliskiren is not recommended (see sections “Interaction with other drugs” and “Pharmacodynamics”). If a double blockade is absolutely necessary, it should be performed under the strict supervision of a specialist with regular monitoring of renal function, plasma electrolytes and blood pressure.
The use of ACE inhibitors in combination with ARA II receptor antagonists is contraindicated in patients with diabetic nephropathy and is not recommended in other patients (see section "Contraindications").
Potassium-sparing diuretics, potassium supplements, potassium-containing table salt substitutes and food supplements
The simultaneous use of perindopril and potassium-sparing diuretics, as well as potassium preparations, potassium-containing table salt substitutes and food additives is not recommended (see section “Interaction with other drugs”).
Neutropenia/agranulocytosis/thrombocytopenia
There are reports of the development of neutropenia/agranulocytosis, thrombocytopenia and anemia while taking ACE inhibitors. In patients with normal renal function and without concomitant risk factors, neutropenia rarely occurs. Perindopril should be used with extreme caution against the background of systemic connective tissue diseases (including systemic lupus erythematosus, scleroderma), as well as while taking immunosuppressants, allopurinol, procainamide, or a combination of these factors, especially in patients with initially impaired renal function.
Some patients developed severe infectious diseases, in some cases resistant to intensive antibiotic therapy. When prescribing perindopril to such patients, it is recommended to periodically monitor the number of leukocytes in the blood. Patients should tell their doctor about any signs of infectious diseases (for example, sore throat, fever) (see sections "Interaction with other drugs" and "Side effects").
Anemia
Anemia may develop in patients after kidney transplantation or in patients undergoing hemodialysis. In this case, the decrease in hemoglobin is greater, the higher its initial value. This effect does not appear to be dose-dependent, but may be related to the mechanism of action of ACE inhibitors.
A slight decrease in hemoglobin occurs during the first 6 months, then it remains stable and is completely restored after discontinuation of the drug. In such patients, treatment can be continued, but hematological tests should be carried out regularly.
Hypersensitivity/angioedema
When taking ACE inhibitors, including perindopril, in rare cases, the development of angioedema of the face, extremities, lips, tongue, vocal folds and/or larynx may occur (see section “Side effects”). This can happen at any time during therapy. If symptoms occur, Perindopril PLUS Indapamide should be discontinued immediately and the patient should be observed until signs of swelling have completely resolved. If the swelling affects only the face and lips, it usually goes away on its own, although antihistamines can be used as symptomatic therapy.
Angioedema, accompanied by swelling of the larynx, can be fatal. Swelling of the tongue, vocal folds, or larynx can lead to airway obstruction. If such symptoms appear, appropriate therapy should be started immediately, for example, epinephrine (adrenaline) administered subcutaneously at a dilution of 1:1000 (0.3 or 0.5 ml) and/or ensure airway patency.
A higher risk of developing angioedema has been reported in black patients.
Patients with a history of angioedema not associated with taking ACE inhibitors may have an increased risk of developing it when taking drugs of this group (see section “Contraindications”).
In rare cases, angioedema of the intestine develops during therapy with ACE inhibitors. In this case, patients experience abdominal pain as an isolated symptom or in combination with nausea and vomiting, in some cases without previous angioedema of the face and with normal activity of the C-1 esterase enzyme. The diagnosis is made using computed tomography of the abdominal cavity, ultrasound, or at the time of surgery. Symptoms disappear after stopping ACE inhibitors. In patients with abdominal pain receiving ACE inhibitors, when carrying out differential diagnosis, it is necessary to take into account the possibility of developing angioedema of the intestine.
mTOR (mammalian Target of Rapamycin) inhibitors (eg, temsirolimus, sirolimus, everolimus)
In patients receiving concomitant therapy with mTOR inhibitors, the risk of developing angioedema (including swelling of the airways or tongue with or without impairment of respiratory function) may be increased (see section "Interaction with other drugs").
Anaphylactoid reactions during desensitization
There are isolated reports of the development of prolonged, life-threatening anaphylactoid reactions in patients receiving ACE inhibitors during desensitizing therapy with hymenoptera venom (bees, wasps). ACE inhibitors should be used with caution in patients with a history of allergies or a tendency to allergic reactions undergoing desensitization procedures. The use of an ACE inhibitor should be avoided in patients receiving immunotherapy with hymenoptera venom. However, an anaphylactoid reaction can be avoided by temporarily discontinuing the ACE inhibitor at least 24 hours before the start of the desensitization procedure.
Anaphylactoid reactions during LDL apheresis
In rare cases, life-threatening anaphylactoid reactions have developed in patients receiving ACE inhibitors during LDL apheresis using dextran sulfate. To prevent an anaphylactoid reaction, ACE inhibitor therapy should be temporarily discontinued before each apheresis procedure.
Hemodialysis
Anaphylactoid reactions have been reported in patients receiving ACE inhibitors during hemodialysis using high-flux membranes (eg, AN69®). Therefore, it is advisable to use a different type of membrane or use an antihypertensive agent of a different pharmacotherapeutic group.
Cough
During therapy with an ACE inhibitor, a dry persistent cough may occur. The cough persists for a long time while taking drugs of this group and disappears after their discontinuation. If a patient develops a dry cough, one should be aware of the possible iatrogenic nature of this symptom. If the doctor believes that ACE inhibitor therapy is necessary for the patient, the drug may be continued.
Risk of arterial hypotension and/or renal failure (in patients with chronic heart failure, fluid and electrolyte imbalance, etc.)
In some pathological conditions, significant activation of the RAAS may be observed, especially with severe hypovolemia and a decrease in the content of electrolytes in the blood plasma (due to a salt-free diet or long-term use of diuretics), in patients with initially low blood pressure, renal artery stenosis, chronic heart failure or cirrhosis of the liver with edema and ascites.
The use of ACE inhibitors causes blockade of the RAAS and therefore may be accompanied by a sharp decrease in blood pressure and/or an increase in plasma creatinine clearance, indicating the development of functional renal failure. These phenomena are more often observed when taking the first dose of the drug and during the first two weeks of therapy. In rare cases, these conditions develop acutely and during other periods of therapy. In such cases, it is recommended to restart therapy at a lower dose and then gradually increase the dose.
Elderly age
Before starting to take perindopril, it is necessary to assess the functional activity of the kidneys and the content of potassium ions in the blood plasma. At the beginning of therapy, the dose of the drug is selected taking into account the degree of reduction in blood pressure, especially in the case of a decrease in blood volume and loss of electrolytes. Such measures help to avoid a sharp decrease in blood pressure.
Atherosclerosis
The risk of arterial hypotension exists in all patients, however, special care should be taken when using the drug in patients with coronary heart disease and cerebrovascular insufficiency. In such patients, treatment should begin with low doses of the drug.
Renovascular hypertension
The treatment method for renovascular hypertension is revascularization. However, the use of ACE inhibitors may have a beneficial effect in patients both awaiting surgery and in cases where surgery is not possible.
Treatment with the drug Perindopril PLUS Indapamide is not indicated in patients with diagnosed or suspected renal artery stenosis, because Therapy should be started in a hospital setting with lower doses of the combination of perindopril and indapamide.
Heart failure/severe heart failure
In patients with chronic heart failure (functional class IV according to the NYHA classification), treatment with the drug Perindopril PLUS Indapamide is not indicated, because Therapy should begin with lower doses of the combination of perindopril and indapamide under close medical supervision.
Patients with arterial hypertension and coronary heart disease should not stop taking beta-blockers: an ACE inhibitor should be added to beta-blocker therapy.
Diabetes
In patients with type 1 diabetes mellitus, a spontaneous increase in potassium levels in the blood is possible. Treatment of such patients with the drug Perindopril PLUS Indapamide is not indicated, because it should start with minimal doses and be under constant medical supervision. Patients receiving oral hypoglycemic agents or insulin require regular monitoring of plasma glucose concentrations during the first month of therapy with ACE inhibitors (see section “Interaction with other drugs”).
Ethnic differences
Perindopril, like other ACE inhibitors, have a clearly less pronounced antihypertensive effect in patients of the Negroid race compared to representatives of other races. This difference may be due to the fact that black patients with arterial hypertension are more likely to have low renin activity.
Surgery/general anesthesia
Carrying out general anesthesia while taking ACE inhibitors can lead to a significant decrease in blood pressure, especially when using general anesthesia agents that have an antihypertensive effect. It is recommended, if possible, to stop taking long-acting ACE inhibitors, including perindopril, the day before surgery. It is necessary to warn the anesthesiologist that the patient is taking an ACE inhibitor.
Aortic or mitral stenosis/hypertrophic obstructive cardiomyopathy
ACE inhibitors should be prescribed with caution to patients with left ventricular outflow tract obstruction.
Liver failure
In rare cases, cholestatic jaundice occurs while taking ACE inhibitors. As this syndrome progresses, fulminant liver necrosis develops, sometimes with death. The mechanism of development of this syndrome is unclear. If jaundice appears or if there is a significant increase in the activity of liver enzymes while taking ACE inhibitors, the patient should stop taking the ACE inhibitor and consult a doctor (see section “Side Effects”).
Hyperkalemia
Hyperkalemia may develop during treatment with ACE inhibitors, including perindopril. Risk factors for hyperkalemia are renal failure, impaired renal function, advanced age over 70 years, diabetes mellitus, some concomitant conditions (dehydration, acute cardiac decompensation, metabolic acidosis), concomitant use of potassium-sparing diuretics (such as spironolactone and its derivative eplerenone, triamterene, amiloride), as well as potassium preparations or potassium-containing substitutes for table salt, as well as the use of other drugs that help increase the content of potassium ions in the blood plasma (for example, heparins, AFP inhibitors, angiotensin II receptor antagonists, acetylsalicylic acid at a dose of 3 g/day or more , COX-2 inhibitors and non-selective NSAIDs, immunosuppressants such as cyclosporine or tacrolimus, and trimethoprim). The use of potassium supplements, potassium-sparing diuretics, and potassium-containing table salt substitutes can lead to a significant increase in potassium levels in the blood, especially in patients with reduced renal function. Hyperkalemia can lead to serious, sometimes fatal, heart rhythm disturbances. If combined use of the above drugs is necessary, treatment should be carried out with caution, against the background of regular monitoring of the content of potassium ions in the blood serum (see section “Interaction with other drugs”).
Impact on the ability to drive vehicles and machinery
Care must be taken when driving vehicles and other technical devices that require increased attention and speed of psychomotor reactions (risk of dizziness and fainting).
Efficacy and tolerability of enalapril and indapamide in the correction of arterial hypertension
A
Hypertension (AH) is a non-infectious pandemic that determines the structure of disability and mortality due to cardiovascular diseases in a socially significant group of the population. The development of primary hypertension is determined by many interacting factors: from genetic predisposition to social environmental conditions. Hypertension, which begins as a functional disorder, in most cases, sequentially, through various pathophysiological mechanisms, leads to specific damage to target organs (central nervous system, heart, kidneys), transforming from a risk factor into a disease.
According to various authors, hypertension in 80% or more cases is combined with various types of metabolic disorders, which are included in world clinical practice under the term “metabolic syndrome”, including dyslipidemia, impaired carbohydrate metabolism and insulin resistance (IR), abdominal obesity [1,3, 5.15].
From the standpoint of the modern understanding of the mechanisms of formation of high blood pressure numbers, prescribed antihypertensive drugs should have the following properties:
1. Effectively reduce blood pressure (achieving the target blood pressure level);
2. Prevent (reduce) damage to target organs;
3. Do not cause metabolic disorders;
4. Be safe to use and have no side effects;
5. Have a prolonged hypotensive effect (reduce the frequency of administration) [9].
According to modern WHO recommendations (1999), at the first stage of treatment of hypertension, the use of diuretics, b-blockers and angiotensin-converting enzyme inhibitors is recommended
(ACE inhibitors) with metabolically neutral properties [4,9,10].
Thiazide and thiazide-like diuretics can be divided into two generations: the first generation - derivatives of benzothiadiazine (hydrochlorothiazide, etc.) and benzenesulfonamide (chlorthalidone, etc.); second generation - chlorobenzamide derivatives (indapamide, xipamide, etc.) containing a methylindoline group.
The hemodynamic effect of indapamide-like diuretics is due to their pharmacological action: inhibition of the reabsorption of Na+, Cl–, H+ and, to a lesser extent, K+ and Mg2+ in the proximal and distal tubules of the short segment of the nephron. At the same time, the discussed diuretics eliminate the excess content of Na+ ions in the vascular wall (due to their high lipophilicity), increase the synthesis of prostaglandins E2 and prostacyclin I2, inhibit the influx of Ca2+ ions into the smooth muscle cells of the vascular wall, which causes dilatation of blood vessels and reduces their sensitivity to pressor agents (catecholamines, thromboxanes). The total hemodynamic effect of indapamide is manifested as:
1. Vasodilation;
2. Decrease in total peripheral vascular resistance (TPVR);
3. Decrease in blood pressure;
4. Changes in the viscosity properties of blood due to inhibition of platelet aggregation activity.
The use of indapamide in a daily dose of 2.5 mg has a hypotensive effect without a significant effect on diuresis.
In its hypotensive activity, indapamide is 30 times superior to the action of spironolactones, 100 times superior to furosemide, and 300 times superior to chlorthalidone when used in comparable doses.
The therapeutic efficacy of indapamide diuretics has been demonstrated in a number of large randomized studies [6,11,14]. Their ability to prevent the development of coronary artery disease by reducing myocardial mass in hypertension has been noted. This property, atypical for other classes of diuretics, makes indapamide a unique drug with cardioprotective effects.
, the severity of which is not inferior to b-blockers and ACE inhibitors.
Particular attention is drawn to the fact that indapamide-like diuretics do not have a withdrawal syndrome and do not cause adverse metabolic disorders: they do not have a negative effect on glucose metabolism and the level of atherogenic blood lipids. In recent years, studies have shown that indapamide helps normalize glucose levels in type II diabetics, preventing diabetic nephropathy [10,15]. Indapamide, improving microcirculation in the kidney, eliminates microalbuminuria, which is a marker of generalized vascular damage and a predictor of cardiovascular complications. A similar pattern was noted when studying the metabolism of cholesterol (C) and triglycerides (TG) in patients with dyslipoproteinemia. Indapamide reduces the level of atherogenic low-density lipoprotein cholesterol (LDL) and TG, while increasing the concentration of high-density lipoprotein (HDL).
Thus, indapamide
, combining all the positive pharmacodynamic, pharmacokinetic and economic advantages, in the absence of side effects of other diuretics,
is a first-line drug for the treatment of patients with hypertension and chronic heart failure
.
Currently, ACE inhibitors, despite their large number, according to the chemical structure responsible for the binding of systemic and tissue ACE, comprise three groups:
1. Containing a sulfhydryl group (captopril);
2. Containing a carboxyl group - carboxyalkyl dipeptides ( Enalapril
, quinapril, lisinopril, ramipril, perindopril, celazapril, benazapril);
3. Containing a phosphyl group (fosinopril).
Captopril acts as an active drug and is excreted by the kidneys, which limits its use in cases of impaired renal function and requires a minimum of twice daily use.
Enalapril
is metabolized in the body and acts due to its active metabolites, surpasses captopril in duration and potency of action, which allows its single daily use and in smaller doses compared to captopril, it is excreted through the kidneys.
Fosinopril acts through metabolites, is used once a day and has two routes of elimination - the kidneys and the gastrointestinal tract.
All ACE inhibitors have cardio-, vaso-, nephro-protective and metabolic effects:
1. Cardioprotective effects:
restoring the balance between the need and supply of myocardium O2, reducing pre- and afterload on the LV, reducing LV volume and mass, slowing down LV remodeling, reducing sympathetic stimulation, antiarrhythmic effect;
2. Vasoprotective effects:
direct antiatherogenic effect, antiproliferative and antimigration effect on smooth muscle cells, neutrophils and monocytes; improvement and restoration of endothelial function; antiplatelet effect, increased endogenous fibrinolysis, improved arterial compliance and decreased tone;
3. Nephroprotective effects:
decrease in intraglomerular hypertension, increase in glomerular filtration rate, increase in Na+-cut and decrease in K+-cut, decrease in proteinuria, increase in diuresis;
4. Metabolic effects:
increased breakdown of very low density lipoproteins and decreased TG synthesis, increased HDL synthesis, increased sensitivity of cellular receptors to insulin and increased glucose consumption.
Summarizing the above, it can be argued that today ACEIs are a promising group of drugs in the treatment of hypertension; their multidisciplinary action allows them to be called the “gold standard in the treatment of cardiovascular diseases.”
.
The purpose of this work is to study the effectiveness and tolerability of the thiazide diuretic, indapamide, and the ACE inhibitor, enalapril, in patients with hypertension.
Materials and research methods
We examined 51 patients with stage 1–2 hypertension. according to WHO classification [4]: 10 men and 41 women aged 60–78 years (mean age 66.1±3.7 years). Criteria for inclusion in the study of patients with hypertension: systolic blood pressure from 140 to 180 mm Hg, diastolic blood pressure from 90 to 110 mm Hg. The average duration of hypertension for the entire group of patients was 12.3±4.5 years.
All patients before treatment and 24 weeks after treatment underwent 24-hour blood pressure monitoring (ABPM) on the AVRM-04 complex (Hungary), registration of a standard ECG on a six-channel electrocardiograph "Kenz" (Japan), echocardiography in M and V modes on a Toshiba device – 104A” (Japan) with calculation of LV myocardial mass (LVMM) according to the formula proposed by Devereux R. and Reichek N. [8] and the LVMM index: LVMI = LVMM/body surface area. At the same time, a study of serum electrolytes (Na, K, Ca) and biochemical blood parameters was carried out: glucose content and glucose tolerance according to the standard method by collecting blood 120 minutes after a 75 g glucose load; lipid level (total cholesterol - TC, TG, HDL).
Depending on the treatment program, patients with hypertension were randomly divided into two groups: A – 26 patients received indapamide in a dosage of 1.5 to 3 mg/day; group B – 25 patients whose basic antihypertensive therapy was Enalapril
from 10 to 40 mg/day.
At the beginning of the study, patients with hypertension were prescribed one of the 2 study drugs as monotherapy in a minimal dose once a day in the morning. After the first dose of drugs, patients were under medical supervision for 2–4 hours for timely recognition of “first dose hypotension.” A control study was carried out after 4 weeks. If, according to ABPM, blood pressure reached normal values (average daily blood pressure 140/90 mm Hg or less, and average night blood pressure 125/80 mm Hg or less), the dose of the drug remained unchanged until the end of the study, i.e. up to 24 weeks. If after 4 weeks, according to ABPM results, blood pressure remained elevated (average daily blood pressure > 140/90 mm Hg and/or average night blood pressure > 125/80 mm Hg), the dose of the drug was increased. At the same time, with an average daily blood pressure equal to or more than 140/90 mm Hg, and an average night blood pressure of 125/80 mm Hg. and increased the morning dose less. When the average nightly blood pressure was 125/80 or more, regardless of the level of the average daytime blood pressure, a second (evening) dose of the drug was added. If ABPM did not show normalization of blood pressure both during the day and at night, the dose of the drug was increased again. The final dose was considered to be the maximum dose of the drug, when taken by the patient no side effects occurred, or the dose of the drug at which normal blood pressure was achieved (average daily blood pressure 140/90 mm Hg or less, and average night blood pressure 125/80 mm Hg. Art. or less). Once the final dose of the drug was reached, it remained unchanged until the end of the study, i.e. until the 24th week of treatment. At the 24th week of the study, during the last visit of the patient, ABPM and laboratory tests were repeated.
Statistical processing of the obtained data was performed using the Microsoft Excel spreadsheet software package. To establish the relationship between signs, multivariate correlation analysis was used using Pearson and Spearman tests. When processing the results and identifying correlations, the significance (probability) of deviations p<0.05 or less was used.
Treatment results
Criteria for assessing antihypertensive effectiveness
were assessed according to the following parameters:
good
– with normalization of the average blood pressure level: a decrease in SBP below 140 mm Hg.
during the day and 125 mm Hg. at night, DBP below 90 mmHg. during the day and 75 mm Hg. at night; satisfactory
– with a decrease in average blood pressure by more than 10 mm Hg.
from the initial level without its normalization; unsatisfactory
- with a decrease in average blood pressure by less than 10 mmHg.
without normalizing it. Side effects were recorded at all stages of the study. Tolerability of treatment
was assessed according to the following criteria: absence of side effects – “
excellent
”, mild side effects that do not require dose adjustment – “
good
”, side effects that resolve after dose adjustment – “
satisfactory
” and severe side effects requiring discontinuation of the drug – “
unsatisfactory
."
Figure 1 shows the results of antihypertensive effectiveness at the end of the study program in patients with hypertension, depending on the treatment program.
Rice. 1. Diagrams of the effectiveness of treatment of patients with hypertension
In group A, good effectiveness of the prescribed therapy was in 16 patients (61.5%), satisfactory – in 6 patients (23%), unsatisfactory – in 4 patients (15%); in group B, good treatment effectiveness was recorded in 14 patients (56%), satisfactory – in 9 patients (36%), unsatisfactory – in 3 patients (12%).
Table 1 shows the dynamics of the blood pressure profile, which characterizes the circadian rhythm, disturbances of which are most often found in patients with type II diabetes mellitus, with carbohydrate tolerance, with symptomatic hypertension (pheochromacytoma, hypertension of renal origin, chronic renal failure), and in the elderly.
As can be seen from the table, in group A, where indapamide was included in the treatment program, before treatment,
non-dippers
and
night-peakers
totaled 53.8%, and in group B (enalapril treatment) - 61%, respectively.
The presence of pathological non-dipper
and
night-peaker
types of daily blood pressure profile in patients suffering from hypertension can be considered an unfavorable prognostic sign.
It is well known that a “monotonic” daily rhythm of blood pressure often occurs in patients with impaired carbohydrate metabolism and is considered as one of the manifestations of insulin resistance syndrome (IR) [2]. The similar nature of disturbances in the biphasic rhythm of blood pressure in patients of the two groups suggests that these changes are markers of carbohydrate metabolism disorders. As a result of treatment with indapamide and enalapril, after 24 weeks in both groups, the number of patients with nocturnal hypertension ( night-peakers
) and insufficient nocturnal reduction in blood pressure (
non-dippers
) decreased and in group A amounted to 34.6% (almost doubled), in group B – 44%, respectively (p<0.01).
When analyzing the results of EchoCG (Table 2), after 24 weeks of treatment with enalapril, a significant decrease in the LVMM index (on average by 19%), a decrease in the thickness of the walls of the left ventricle (by an average of 12.3%) was established. Studying the Echo-CG indicators after 24 weeks of treatment with indapamide, a significant decrease in the LVMM index (on average by 29%), a decrease in the thickness of the walls of the left ventricle (by an average of 15%) was established. The differences compared to the original data are significant according to the second threshold of the probability of error-free predictions (p<0.01).
Thus, in patients receiving indapamide and enalapril, the degree of reduction in LV wall thickness was comparable. However, during therapy with indapamide, the decrease in the LVMM index was more pronounced (almost 30%), which exceeded the corresponding values (about 19.1%) for enalapril. The data obtained on the regression of LV myocardial hypertrophy coincide with the conclusions of other authors [14,16,17]. One of the possible explanations for this fact may be a progressive decrease in the number of functioning nephrons with age, due to glomerulosclerosis, with a decrease in the number of cells of the juxtaglomerular apparatus that produces circulating renin, which is a substrate for the synthesis of angiotensin, i.e. reducing the contribution of the renin-angiotensin-aldosterone system (the point of application for ACE inhibitors) in the formation of high blood pressure numbers and in the development of LVMH [7].
When analyzing the ECG, no significant changes in the PQ and QRS intervals were detected after 24 weeks of treatment with indapamide and enalapril.
According to biochemical blood parameters (Table 3), during treatment with indapamide and enalapril, a statistically unreliable moderate increase in plasma glucose was noted by an average of 2.3% (p>0.05). According to various authors, non-thiazide diuretics and ACE inhibitors do not increase the likelihood of developing type II diabetes mellitus (DM) [2,12,15].
During treatment with indapamide and enalapril, there were also no statistically significant dynamics (of different directions) in the blood lipid spectrum (p>0.05 for all indicators). The cholesterol level during indapamide therapy increased insignificantly by 0.75% (from 5.35±0.39 mmol/l to 5.39±0.49 mmol/l). As a result of treatment with enalapril, there was an unreliable but clear trend towards a decrease in total cholesterol by 5.51% (from 5.26±0.75 mmol/l to 4.97±0.52 mmol/l). Similar data were obtained when assessing influence of drugs on plasma TG. Thus, indapamide reduced the TG level by 2.4% (from 1.499±0.41 mmol/l to 1.463±0.35 mmol/l), while enalapril by 2.86% (from 1.40±0.33 mmol /l to 1.36±0.32 mmol/l), however, these changes were not significant (p>0.05). The absence of a negative effect of indapamide and enalapril on lipid metabolism has been noted in a number of studies [2,13,14,15,17,18].
The level of uric acid (UA) increased during treatment with indapamide by 2.51% (from 234.00±29.09 µmol/l to 239.88±35.95 µmol/l) and decreased by 0.89% (from 224 .30±35.93 µmol/l to 222.30±25.07 µmol/l) during treatment with enalapril. However, these changes were unreliable. In some studies [6], the level of sUA increased significantly when taking indapamide; however, P. Weidmann [18] revealed an increase in sUA with short-term therapy, and with prolonged use, the amount of sUA in the blood decreases to initial values. According to a number of authors [7], enalapril can increase the level of sUA in the blood, however, there are reports of a neutral effect of the drug [12,13]. In addition, indapamide decreased the level of urea by 3.83%, while enalapril increased it by 3.04%, but these changes were not significant (p>0.05).
During a 24-week cycle of therapy with both drugs (indapamide and enalapril), along with a decrease in blood pressure, all patients noted a noticeable improvement in their general condition, manifested by a decrease or disappearance of headache, tinnitus, and dizziness. The majority of patients improved their ability to work and tolerate daily physical activity. Of the 26 patients in the indapamide group, all patients completed the full course of treatment. Among patients in this group, 22% of patients reported no side effects - excellent tolerability. Good tolerability was found in more than half of the patients (59%). Severe side effects requiring discontinuation of the drug (poor tolerability) were not identified. The most common were dry mouth - in 8 people (30.8%), orthostatic hypotension and dizziness - in 4 people (15.4%), headaches and constipation - in 2 patients (7.7%), itching and parasthesia - in 2 people (7.7%), nausea, skin rash, lack of coordination were noted in isolated cases (3.8%).
In the enalapril group, approximately a quarter of patients (21%) reported no side effects - excellent tolerability. Good tolerability was found in more than half of the patients (52%). Severe side effects (severe dry cough) requiring discontinuation of the drug (unsatisfactory tolerability) were recorded in 4 people (16%), myalgia, dizziness, skin rash were noted in isolated cases (4%).
The discussion of the results
As is known, the level of blood pressure in the body is determined by two physiological parameters: MO (minute volume) and total peripheral vascular resistance (TPVR). This dependence can be represented as the following formula:
BP = MO x OPSS
With a sudden increase in blood pressure (increased activity of the sympathetic nervous system), the body, through the functioning of the baroreflex compensatory mechanism, reduces peripheral vascular resistance, “quenches” the effect of the increased blood pressure and helps maintain blood pressure within normal limits.
However, some individuals experience inadequate baroreflex control, which will make it difficult for the body to adequately respond to blood pressure fluctuations and contribute to the “stabilization” of high blood pressure numbers.
Thus, the main pathophysiological essence of hypertension is determined by the imbalance of vasodilating and vasoconstrictor systems
, which is aggravated by impaired metabolism of glucose and lipoproteins responsible for atherogenesis.
Figure 2 shows a diagram of the main vasoconstrictor systems and their relationship with the surface of the smooth muscle cell of the vascular bed and the sympathetic nerve ending.
Rice. 2. Scheme of the main vasoconstrictor systems and the site of action of ACE inhibitors
Norepinephrine (NA) released from the terminal endings of the neuron through postsynaptic a2-adrenergic receptors located on the surface of the muscle cell causes vasoconstriction by acting on calcium channels and increasing the concentration of ionized Ca2+ on contractile intracellular structures (actin-myosin) of smooth muscle. At the same time, released NA limits its release through stimulation of the presynaptic α2-adrenergic receptor, limiting the prolongation of the vasoconstrictor effect.
Angiotensin II (AT II), which is formed as a result of the activity of the circulating and local (tissue) RAAS, exerts its vasoconstrictor effect through several mechanisms:
– direct effect on AT1 receptors located on the surface of the muscle cell (postsynaptic receptors);
– increased release of NA from the neuron through stimulation of AT1 receptors (presynaptic) located at the nerve endings;
– increased secretion by endothelial cells of another powerful vasoconstrictor – endothelin-1;
– an increase in the entry of ionized Ca2+ into the cell (opening of slow calcium channels).
ACE inhibitors, by blocking the activity of the RAAS, reduce the versatility of the constrictor effect of hypertension II, which underlies the protective effect of ACE inhibitors for the heart, blood vessels and kidneys. By indirectly reducing the production of NA and the entry of Ca2+ into the cell (the main intracellular component of contraction), ACE inhibitors repeat the mechanism of action of such antihypertensive drugs as Ca antagonists and a2-blockers.
Indapamide-like diuretics (in particular indapamide
) the hypotensive effect is realized through the removal of Na+ from the vascular wall (reduced sensitivity of smooth muscle to the sympathetic impulse), a decrease in the concentration of Ca2+ in the myoplasm of the executive cell, a decrease in the aggregation activity of platelets and the production of thromboxane (a powerful vasoconstrictor) through the calcium mechanism, maintaining a normal level of Mg2+ concentration inside the cell – a natural, physiological antagonist of Ca.
The hypotensive effect of indapamide and enalapril in combination with metabolic neutrality (does not have a negative effect on the metabolism of glucose and lipids), confirmed by data from our studies and other authors [6,11,14,16,17], distinguishes them favorably from other antihypertensive drugs (thiazide diuretics, beta-blockers of the first and second generation) and are placed in the first line of the treatment program for hypertension.
Thus, the drugs indapamide and enalapril (ACEIs), having good antihypertensive effectiveness in combination with metabolic neutrality of glucose and lipid metabolism, have a low percentage of side effects compared to other antihypertensive drugs, they can be recommended as first-line drugs in the treatment of hypertension.
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