Thiazide diuretics[edit | edit code]
Hydrochlorothiazide
(dichlorothiazide, hypothiazide, nephrix); chemical structure of 6-chloro-7-sulfamoyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide. Like Diacarb, the drug contains a sulfonamide group.
Pharmacokinetics
. This thiazide diuretic is well absorbed from the intestine. It appears in the blood within 10 minutes. The maximum concentration after a single dose is 45-60 minutes, the duration of action is 4-6 hours. The half-life is 5.6-14.8 hours, depending on the dose. It is excreted by the kidneys by secretion in the proximal tubules similar to uric acid and, as a result of competition, inhibits its release from the body.
Cyclomethiazide
(cyclopenthiazide, Navidrex); chemical structure of 2-cyclopentylmethyl-6-chloro-7-sulfamoyl-3,4-dihydro-1,2,4-benzothi-adiazine-1,1-dioxide. As the name implies, cyclomethiazide is close in structure to hydrochlorothiazide, differing only in that one of the hydrogen atoms at the C3 position is replaced by a methylcyclopentyl radical.
Pharmacokinetics
. Well absorbed in the alimentary canal. The diuretic effect of this thiazide diuretic occurs after 2-4 hours, maximum after 3-6 hours and lasts 10-12 hours. It is excreted by the kidneys by secretion in the tubules.
Pharmacodynamics of thiazides
. The diuretic effect of thiazide diuretics is carried out, in contrast to diacarb, due to not only partial binding of carbonic anhydrase, but also inhibition of the activity of Na+,K-ATPase, succinate dehydrogenase, and enzymes for the oxidation of non-esterified fatty acids. The supply of energy to the sodium pump is disrupted and Na+ reabsorption is reduced, which contributes to an increase in natriuresis and diuresis. At the same time, the release of potassium, chlorides, hydrogen carbonates, magnesium ions, and phosphates increases. Thiazides in normal doses do not significantly disturb the acid-base balance. With prolonged administration, the drugs delay the excretion of calcium ions.
Cyclomethiazide is much more active than hydrochlorothiazide, is slowly eliminated by the kidneys and therefore has a longer effect.
Thiazide diuretics have an antihypertensive effect. The mechanism of action is that they reduce blood volume. The sodium and water content in the vascular wall also decreases, which leads to its thinning and an increase in the lumen of the vessels. The sensitivity of vascular adrenergic receptors to catecholamines decreases, which also contributes to vasodilation. With prolonged administration, thiazides reduce the excretion of uric acid.
In diabetes insipidus, thiazide diuretics exhibit a paradoxical effect - they significantly reduce diuresis. The mechanism of this action has not been precisely established; it is assumed that there is a decrease in thirst, an increase in the filtration capacity of the kidneys, and the sensitivity of vasopressin receptors to vasopressin in diabetes insipidus.
Side effects:
Thiazide diuretics cause hypokalemia with long-term use, so potassium intake should be increased; Secreted by the kidneys, according to the principle of competition, thiazides reduce the secretion of other substances, in particular uric acid. Therefore, taking thiazides by patients with gout leads to an exacerbation of the disease. In large doses, thiazides can cause hypochloremic alkalosis. In elderly people, thiazides provoke latent diabetes mellitus, causing hyperglycemia. Hypercholesterolemia and hypertriacyl-glycerolemia are also noted.
Thiazide diuretics in the treatment of arterial hypertension
Chlorothiazide, the first thiazide diuretic effective when taken orally, was created in 1956. In 1957, hydrochlorothiazide (HCT) was synthesized, which replaced chlorothiazide from clinical practice due to its higher effectiveness. In 1959, the thiazide-like diuretic chlorthalidone appeared, and indapamide in 1974. The most frequently used and, therefore, the most studied diuretics in clinical trials are chlorthalidone, HCTZ and indapamide (including indapamide retard form). In our country, the most popular diuretics are HCTZ and indapamide (indapamide retard). However, despite the recognition of the clinical value of this class of drugs, in recent years their leading position has been questioned, and this was primarily due to the discussion of their metabolic effects, with the results of the ACCOMPLISH study [7] and a new meta-analysis of the antihypertensive effects of HCTZ [8]. Metabolic effects of diuretics: myths and reality Negative metabolic effects on carbohydrate, lipid and purine metabolism, and electrolyte disturbances are used as arguments against the priority use of TDs as first-choice drugs. The most significant debate has developed in recent years around the “diabetogenic” effects of TD. A drug is considered a significant factor in the manifestation of diabetes mellitus (DM) if, firstly, the number of patients who developed diabetes mellitus while using this drug is greater than with the natural course of hypertension, and, secondly, the development of diabetes mellitus during therapy is accompanied by a worsening of clinical symptoms. outcomes. Available data allow discussion of differences between the main classes of drugs in relation to the development of new cases of diabetes. However, the significance of the existing evidence to date should be considered limited, primarily due to the fact that in none of the completed large controlled studies, the development of new diabetes was not the primary endpoint. An analysis of 27 randomized controlled trials involving 158,709 patients (of which 33,395 with diabetes), comparing the effect of the “old” and “new” antihypertensive therapy regimens on cardiovascular events and mortality in patients with hypertension depending on the presence of diabetes, did not reveal differences in reducing the risk of major cardiovascular events in patients with or without diabetes during therapy based on ACE inhibitors, AK, ARB II and TD/BB. Tighter BP control was accompanied by a significant reduction in major cardiovascular events in patients with diabetes compared with patients without diabetes [9]. Consequently, all modern classes of antihypertensive drugs, including TDs, can be used in the treatment of hypertension. In the ARIC cohort study (Atherosclerotic Risk in Community cohort, n=13877) - one of the most methodologically high-quality observations - when analyzing the subgroup with hypertension (3804 people), TD therapy compared with untreated patients was not accompanied by an increase in the incidence of diabetes (RR 0.91 , 95% CI 0.73–1.13), which was not significantly different from data for ACE inhibitors (RR 0.98, 95% CI 0.72–1.34) or OCs (RR 1.17, 95% CI 0.83–1.66) [10]. Only BB therapy led to a significant increase in new cases of diabetes (RR 1.28, 95% CI 1.04–1.57; p<0.05). In the EWPHE, STOP-Hypertension-2, INSIGHT, ALLHAT, LIFE, ASCOT-BPLA studies, a higher incidence of diabetes was indeed observed in the groups where TD was prescribed [11–16]. However, EWPHE, STOP-Hypertension-2, INSIGHT and ALLHAT did not reveal any advantages of other drugs over TD in terms of outcomes [12,13,14,16]. The LIFE study [15] found differences in the primary endpoint, and the ASCOT-BPLA study [11] found differences in secondary cardiovascular outcomes, but it should be remembered that in the latter two studies, TDs were not the main drugs. It seems important to note significant methodological differences when identifying new cases of diabetes. For example, in the EWPHE study, the assessment of new cases of diabetes was based on physician reports [12]. In summary, none of the completed studies considered new cases of diabetes as a primary endpoint. Inconsistent results regarding new cases of diabetes may be due to differences in study design and duration, sample sizes, comparison groups, patient populations, laboratory techniques, drugs, and dosages used. Data obtained from comparing two treatment regimens may equally reflect both the positive effect of one drug and the negative effect of the other. Despite the potentially negative effects of TD on glucose metabolism, therapy with this class of drugs leads to a decrease in cardiovascular morbidity and mortality in patients with hypertension. Any possible negative metabolic effects of TD therapy are offset by positive effects on other cardiovascular endpoints and overall mortality. Treatment with relatively high doses of TD during the first year may be accompanied by an increase in the level of total cholesterol and LDL cholesterol by 5–7% without a significant effect on HDL cholesterol; none of the long-term studies revealed an increase in the level of serum cholesterol during TD therapy compared with placebo [17]. The effectiveness of TD in relation to the incidence of strokes, coronary artery disease, and cardiovascular diseases did not depend on the initial cholesterol level in the SHEP study [18]. The adverse effects of TD on lipid metabolism are dose-dependent. At the present stage, HCTZ is used in low doses that are safe from the point of view of its effect on lipid metabolism, and indapamide retard has minimal effect on glucose and lipid metabolism. The effect of long-term TD therapy on cholesterol levels is minimal and may have limited clinical significance. Patients can receive TD regardless of baseline lipid levels, especially given the option of statin therapy. The risk of developing electrolyte disturbances (primarily hypokalemia) is determined by the initial potassium content in the body, the level of salt consumption during treatment, and the doses of diuretics. For a modern dose of HCTZ 12.5–25 mg/day. effects on serum potassium levels are minimal. To prevent hypokalemia induced by diuretics, it is recommended to use minimal doses of diuretics (HCTZ 12.5–25 mg/day, indapamide retard 1.5 mg/day), reducing sodium intake to 2.5 mg/day, increasing intake potassium, the use of diuretics as part of combination therapy. The development of hypokalemia when low doses of diuretics are prescribed is a factor requiring the exclusion of primary hyperaldosteronism [17]. An increase in the level of uric acid in the blood serum, associated with increased reabsorption in the proximal tubules, is also a dose-dependent effect of TD therapy [17]. One of the beneficial metabolic effects of TD that is largely undiscussed is its ability to increase bone density. Treatment with HCTZ is accompanied by an increase in calcium resorption by the renal tubules, a decrease in the activity of total and bone-specific alkaline phosphatase, and a beneficial effect on markers of bone formation (N-telopeptide and osteocalcin). Several RCTs have assessed whether HCTZ improves bone density and have explored possible mechanisms that might explain these effects [19–22]. For example, a randomized, double-blind, two-year study compared HCTZ 50 mg/day. versus placebo in 138 healthy postmenopausal women [19]. Significant effects were found in the active therapy group on the total bone density of the lower leg and forearm, with no effect on the spine or femoral neck. TDs were able to prevent fractures, which is especially important in elderly patients with osteoporosis (not a separate indication, but is considered as an additional positive metabolic effect). According to a cohort study of 7891 patients over 55 years of age (mean age 68.9 years), TD therapy for one year was associated with a statistically significant reduction in the risk of hip fractures (RR 0.46, 95% CI 0.21–0.96) according to compared with persons not receiving diuretic treatment. However, 4 months after cessation of TD therapy, the risk of fractures was similar to that before treatment [21]. Thus, adverse metabolic effects are minimal when diuretics are used in low doses and do not lead to undesirable clinical consequences, and the ability of TD to influence bone density and reduce the risk of osteoporosis deserves attention in a number of clinical situations. Have the results of the ACCOMPLISH trial changed the place of diuretics in the treatment of hypertension? The main result of the ACCOMPLISH study (Avoiding Cardiovascular Events in Combination therapy in Patients Living with Systolic Hypertension) [7] was a significant 20% reduction in the relative risk of cardiovascular morbidity and mortality (primary combined endpoint) in the group of patients with high-risk hypertension (n= 11506) receiving benazepril/amlodipine compared with those receiving benazepril/hydrochlorothiazide at 36 months. observations. To date, this is the only study to compare outcomes between two fixed combinations of antihypertensive drugs. Anticipating the main question in connection with the ACCOMPLISH results, whether the combination of an ACEI with a calcium antagonist should replace the combination of an ACEI with a thiazide diuretic, the authors emphasized that “the results of the study should not cast doubt on the ability of diuretics to reduce the risk of cardiovascular events in patients with hypertension” [7]. . To explain the results obtained, the characteristics of the observation group, the characteristics of the end point, the choice of diuretic, and the dose of amlodipine and hydrochlorothiazide were discussed. The observation group turned out to be a population with indications for the prescription of a calcium antagonist and relative contraindications for the prescription of a thiazide diuretic [3–5]: the average age of the patients was 68 years, 60% of them had a history of diabetes mellitus, 50% had obesity, 36% had coronary revascularization , 23% – myocardial infarction, 11% – history of unstable angina (patients with asymptomatic systolic dysfunction were not included). Thus, the ACCOMPLISH population was not representative and, therefore, its results cannot be extrapolated to all patients with hypertension. In addition, the tolerability of therapy with a combination that included HCTZ was better than that with a combination using amlodipine. The primary composite endpoint did not include hospitalization for heart failure (an event for which calcium antagonists are known to be inferior to other drugs, including thiazide diuretics)23,24, but did include coronary revascularization (usually a component of the secondary endpoint). . Moreover, revascularization accounted for more than 40% of events recorded as the primary endpoint. Thus, a number of features of the observation population and primary endpoint largely explain the differences observed. Another reason discussed was the choice of diuretic, with the assumption that HCTZ is less effective than chlorthalidone in reducing the risk of cardiovascular events. Hydrochlorothiazide and chlorthalidone differ in their pharmacokinetic characteristics. HCTZ begins to act 2 hours after administration, the peak of its effect occurs after 4–6 hours. With a single dose, the duration of action is about 12 hours. With long-term use, the duration of the antihypertensive effect increases and reaches 24 hours. Knowledge of the pharmacokinetics of HCTZ can protect you from a common mistake – premature change of treatment tactics. Unlike HCTZ, the peak effect of chlorthalidone occurs after 6 hours. Moreover, the drug has a very long half-life - about 42 hours. This is due to the fact that chlorthalidone accumulates in red blood cells and is slowly released from them into the plasma, providing a long-lasting therapeutic effect. The fact that the pharmacokinetic characteristics of HCTZ did not affect blood pressure control in the ACCOMPLISH study is evidenced by the results of a substudy using ABPM, which confirmed the comparability of blood pressure control [25]. A meta-analysis specifically comparing the results of studies using chlorthaladione or other TDs, including HCTZ (5 studies, 2 of which used chlorthalidone), did not reveal significant differences in the effect of chlorthaladione and other TDs on clinical outcomes [26]. . Therefore, there is currently no strong evidence to support the use of chlorthalidone instead of HCTZ. Available evidence suggests that one of these two drugs should be used to treat hypertension. The question of the advantages of one drug over another can only be resolved in a study with a direct comparison of them. The effectiveness of HCTZ was also criticized by a meta-analysis of studies that compared the antihypertensive effects of HCTZ with other drugs, with the conclusion that HCTZ is a “weak drug”, which is effective in modern doses of 12.5–25 mg/day. “has not been proven in any randomized controlled trial” and that it “should be excluded from first-line antihypertensive treatment” [8]. It should be noted that this meta-analysis included studies in which HCTZ in daily doses of 12.5 and 25 mg was used as monotherapy. Meta-analysis, as a methodological approach, has a number of known limitations, and in terms of its evidentiary power it is significantly inferior to double-blind randomized studies. A double-blind, randomized trial of indapamide retard, amlodipine, or hydrochlorothiazide (Hypothiazide) in elderly patients showed similar efficacy of the treatment regimens [27] (Fig. 1). From the point of view of modern recommendations on hypertension, it is obvious that it is not relevant to consider diuretic monotherapy as a strategy of preferential choice. The common position of all modern recommendations on hypertension is the emphasis on combination antihypertensive therapy, and from this point of view, the fact that HCTZ increases the effectiveness of all classes of antihypertensive drugs without exception when used in a combination regimen is very important. In addition, almost all representatives of the classes of ACE inhibitors, ARA II and some b-blockers are in the form of fixed combinations containing HCTZ at a dose of 12.5–25 mg. Moreover, it is HCTZ that is part of the first registered fixed three-component combination of APAII, AK and TD. All this puts HCT in the position of the most widely used TD throughout the world. The effectiveness of HCTZ as initial or adjunctive therapy on outcome has been well established in randomized controlled trials (Table 1). Use of the drug in low doses was associated with improved outcomes in a number of early and modern studies in the field of hypertension. Thus, in the placebo-controlled study EWPHE (European Working Party on High blood pressure in the Elderly trial) in patients over 60 years of age (average age 72 years) in the HCTZ therapy group 25 mg/day. and triamterene 50 mg/day. There was a significant decrease in cardiovascular mortality, mortality from myocardial infarction, and the number of non-fatal cerebrovascular complications [12]. According to the comparative study MRC Substudy (Medical Research Council trial of treatment hypertension in older adults), in the group of patients receiving diuretics (amiloride 2.5 mg/day + HCTZ 25 mg/day), the risk of developing strokes, cardiac events and all cardiovascular complications compared with the placebo group. In the atenolol group 50 mg/day. no significant reduction in the frequency of the above events was detected [28]. In the ANBP-2 study (Second Australian National Blood Pressure Study) in 6083 elderly patients with equally significant reductions in blood pressure, mixed results were obtained regarding the benefits of ACEIs over HCTZ. ACE inhibitors were more effective in preventing a combination of cardiovascular events (RR 0.89, 95% CI 0.79–1.00; p=0.05). Moreover, in the ACEI group, the risk of fatal stroke was almost twice as high as in the diuretic group (OR 1.91, 95% CI 1.04–3.5, p=0.01) [29]. Analysis of the results of the LIFE study, during which, of 9193 hypertensive patients with ECG-LVH, 70% received HCTZ in addition to the main therapy with losartan or atenolol during 4.8 years of follow-up [30], specifically addressed the question of how HCTZ administration affected outcomes. The results of the analysis showed that additional administration of HCTZ 12.5–25 mg/day. was associated with lower cardiovascular morbidity, cardiovascular and overall mortality, regardless of blood pressure reduction, regression of LVH and randomized therapy. In patients who received a diuretic, compared with those who did not receive it, the RR for the combined endpoint was 0.70 (0.62–0.80), cardiovascular death 0.58 (0.47–0.71), myocardial infarction 0 .64 (0.51–0.79), stroke 0.82 (0.68–0.99), death from any cause 0.55 (0.47–0.64). Thus, data from randomized controlled trials convincingly demonstrate the ability of HCTZ at a dosage of 12.5–25 mg/day. improve clinical outcomes in hypertension and the value of this drug in its treatment. The conclusion of thiazide diuretics still remain the cornerstone of modern antihypertension therapy and are an affordable effective class of antihypertensive drugs. This is one of the classes of antihypertensive drugs, which fully retained its value in the treatment of hypertension from the moment of its creation. Adverse metabolic effects are minimally expressed when using thiazide diuretics in low doses and do not lead to undesirable clinical consequences. Hydrochlorotiazide is one of the most studied diuretics, included in most fixed combinations of antihypertensive drugs and currently remains one of the most important drugs to reduce blood pressure, reliably reducing the risk of developing cardiovascular complications and reducing mortality from cardiovascular diseases.
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Reappraisal of European guidelines on hypertension management: a European Society of Hypertension Task Force document. J Hypertens 2009, 27:2121–2158 6. Williams B, Poulter NR, Brown MJ et al. British Hypertension Society guidelines for hypertension management 2004 (BHS–IV): summary. BMJ 2004;328:634–64 7. Jamerson K, Weber MA, Bakris GL, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med 2008;359:2417–28 8. Messerli FH et al. Hydrochlorothiazide is inappropriate for first–line antihypertensive therapy. ESH Meeting; June 12–16, 2009; Milan, Italy. Abstract LB1.3. 9. Blood Pressure Lowering Treatment Trialists' Collaboration. Effects of different blood pressure–lowering regimens on major cardiovascular events in individuals with and without diabetes mellitus designed: results of prospectively overviews of randomized trials. Arch Intern Med. 2005;165:1410–9. 10. Gress TW, Nieto FJ, Shahar E. et al. Hypertension and antihypertensive therapy as risk factors for type 2 diabetes mellitus. N Engl J Med 2000;342:905–912 11. Dahlof B, Sever PS, Poulter NR, et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo–Scandinavian Cardiac Outcomes Trial–Blood Pressure Lowering Arm (ASCOT–BPLA): a multicentre randomized controlled trial. Lancet 2005;366:895–906. 12. Fletcher A., Amery A., Birkenhager W. et al. Risks and benefits in the trial of the European Working Party on High Blood Pressure in the Elderly. J Hipertens 1991;9:225–2230 13. Hansson L, Lindholm LH, Ekbom T et al. Randomized trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity the Swedish Trial in Old Patients with Hypertension–2 study. Lancet 1999;354:1751–1756. 14. Mancia G., Broun M., Castaigne A. et al. 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Newspaper "News of Medicine and Pharmacy" 21 (301) 2009
Currently, we can talk about three generations of thiazide and thiazide-like diuretics: the first generation, typical representatives of which are hydrochlorothiazide and chlorthalidone; second generation, represented by xipamide; the third generation, which is represented by the regular and retard forms of indapamide.
Thiazide and thiazide-like diuretics act at the level of the distal convoluted tubules of the nephron. The greatest diuretic effect is achieved when relatively low doses of thiazide diuretics are prescribed.
The diuretic and antihypertensive effect of thiazide diuretics is significantly weakened in patients with renal failure (serum creatinine level more than 2.0 mg/dL; glomerular filtration rate less than 30 ml/min). For this reason, thiazide and thiazide-like diuretics are not recommended for the treatment of hypertension in patients with impaired renal function.
Thiazide diuretics (unlike loop and potassium-sparing diuretics) reduce the excretion of calcium ions in the urine. The calcium-sparing effect of thiazide and thiazide-like diuretics makes them especially useful in the treatment of arterial hypertension in patients with concomitant osteoporosis. According to some observations, bone fractures are much less likely to occur in patients with hypertension treated with thiazide diuretics compared to patients receiving other antihypertensive drugs.
Small doses of hydrochlorothiazide and thiazide-like diuretics do not affect carbohydrate, lipid and purine metabolism; in addition, a decrease in calcium excretion during long-term use of these drugs is a positive aspect in the treatment of women suffering from postmenopausal hypertension.
Along with the natriuretic effect, all thiazide diuretics increase the excretion of potassium and magnesium ions and at the same time reduce the excretion of uric acid. Therefore, thiazide diuretics are contraindicated in patients with hypokalemia (potassium level less than 3.5 mmol/l), gout and hyperuricemia (uric acid more than 8.5 mg/dl in men and more than 6.6 mg/dl in women).
Experience with the use of diuretics in long-term therapy of hypertension
In hypertension, the hemodynamic effects of hydrochlorothiazide and chlorthalidone, as well as indapamide, have been most well studied.
There are two phases in changes in hemodynamics in patients with hypertension during treatment with thiazide diuretics.
In the first 4–6 weeks of diuretic therapy, blood pressure decreases mainly due to a decrease in the volume of extracellular fluid by 10–15%. Cardiac output decreases at this time, as hypovolemia leads to a decrease in venous return to the heart. Total peripheral vascular resistance (TPVR) does not change or slightly increases. Body weight decreases at the beginning of diuretic therapy by approximately 1–1.5 kg. Plasma renin activity increases.
The mechanisms of the antihypertensive action of thiazide diuretics are not fully understood. Two different mechanisms of action are hypothesized:
1) antihypertensive effect, directly or indirectly associated with depletion of sodium (chloride) reserves; 2) antihypertensive effect associated with direct or indirect vascular effects of diuretics, independent of natriuresis.
Indapamide, unlike other thiazide and thiazide-like diuretics, has a direct vasodilator effect. When prescribing the drug at a dose of 2.5 mg/day, the total peripheral vascular resistance decreases by 10–18%. Vasodilating effect
indapamide is caused by blockade of calcium channels, stimulation of the synthesis of prostacyclin and prostaglandin E2, which have vasodilating properties and activation of potassium channels.
Thiazide and thiazide-like diuretics are first-line drugs for long-term treatment of patients with uncomplicated hypertension and patients with isolated systolic hypertension. Their location has been determined through numerous placebo-controlled studies.
Numerous controlled studies have shown that these diuretics not only effectively lower blood pressure, but also significantly reduce the risk of stroke in patients with hypertension by an average of 34–51% and congestive heart failure by 42–73%, as well as mortality from cardiovascular causes. by 22–24%.
In elderly patients, diuretics and β-blockers are equally effective in preventing the development of cerebrovascular complications. Diuretics prevent the development of coronary artery disease and reduce mortality from cardiovascular complications in elderly patients with hypertension. This gives grounds to consider diuretics as first-line drugs for the initial treatment of hypertension in elderly patients.
Before prescribing diuretics, it is necessary to determine the content of potassium, uric acid, glucose and creatinine in the blood. If hypokalemia, hyperuricemia, hyperglycemia and azotemia are detected, thiazide diuretics should not be used.
It is recommended to start diuretic therapy with low doses of drugs. The initial dose of hydrochlorothiazide is 12.5-25 mg, chlorthalidone - 12.5-25 mg, indapamide - 1.25-2.5 mg.
If there is no sufficient antihypertensive effect after 2–4 weeks of therapy, the initial doses of diuretics are increased. High doses of thiazide and thiazide-like diuretics should not be used unnecessarily - more than 50 mg of hydrochlorothiazide, more than 25 mg of chlorthalidone and more than 2.5 mg of indapamide per day.
For long-term treatment of patients with hypertension, preference should be given to low doses of diuretics in combination with other antihypertensive drugs. Combinations with β-blockers, ACE inhibitors or AII receptor blockers are recommended.
Use of indapamide in the treatment of patients with hypertension
Among the third generation thiazide diuretics, indapamide stands out first, which in its chemical structure is a chlorobenzamide derivative containing a methylindolinyl group.
At a dose of 2.5 mg/day, which is recommended for the treatment of hypertension, indapamide acts primarily as an arterial vasodilator. The daily volume of urine does not change significantly when treated with indapamide at a dose of 2.5 mg/day, but increases by 20% when the drug is prescribed at a dose of 5 mg/day. Therefore, according to the main mechanism of action, indapamide is a peripheral vasodilator, which, when administered in high doses, can have a diuretic effect.
Indapamide differs from other thiazide and thiazide-like diuretics in that it has minimal effects on potassium and uric acid levels.
When treated with indapamide, the plasma concentration of glucose practically does not change and the sensitivity of peripheral tissues to the action of insulin is not impaired, therefore it is the safest diuretic for the treatment of arterial hypertension in patients with diabetes mellitus.
Unlike other thiazide and thiazide-like diuretics, indapamide has a minimal effect on the levels of total cholesterol and triglycerides and slightly increases the level of high-density lipoprotein cholesterol in the blood (by an average of 5.5 ± 10.9%). The ability of indapamide to increase plasma levels of anti-atherogenic high-density lipoprotein cholesterol is unique among all diuretic drugs.
All these effects distinguish indapamide from other thiazide and thiazide-like diuretics and give reason to consider it the first representative of the third generation of this subclass of diuretics.
The retard form of indapamide, indapamide SR (sustained-release), provides controlled slow release and uniform delivery of the drug into the blood over 24 hours. Thanks to a special technology for retarding a small amount of the drug, a long-term antihypertensive effect is achieved. The T/P (trough-peak ratio) for indapamide retard 1.5 mg is 89% for systolic blood pressure (SBP) and 85% for diastolic blood pressure (DBP), indicating the stability of the antihypertensive effect over a 24-hour dosing interval . In addition, studies using a 32-hour period of ambulatory blood pressure monitoring (ABPM) showed that the T/P index 32 hours after the last dose of indapamide SR was 52% for SBP and 54% for DBP (according to the FDA criterion, T index /P of a single dose antihypertensive drug should be at least 50%).
Due to its improved pharmacokinetic profile, indapamide SR is better tolerated than the conventional dosage form of indapamide. The effectiveness and safety of the drug at a dose of 1.5 mg were studied in several large clinical studies - CTs, which showed the entire therapeutic spectrum of the drug, including the effect on target organs of hypertension in a subgroup of elderly patients.
Contraindications to the use of thiazide diuretics
Contraindications for long-term use of thiazide and thiazide-like diuretics in patients with hypertension are hypokalemia, gout, asymptomatic hyperuricemia, decompensated liver cirrhosis, intolerance to sulfonamide derivatives (diuretics, hypoglycemic and antibacterial drugs). In high doses, thiazide diuretics are contraindicated in diabetes mellitus, especially type 1. Diuretics should be prescribed with great caution to patients with ventricular arrhythmias or receiving cardiac glycosides or lithium salts.
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Thus, at present, thiazide and thiazide-like diuretics are effective, safe and the most accessible antihypertensive drugs that can be used to treat patients with hypertension, both as monotherapy and in combination with other drugs.
Prepared by Evgeniya Priymak
