Thiazide diuretics in the era of new drugs: how effective and safe it is to treat arterial hypertension with them

Arterial hypertension is classified as a modifiable cardiovascular risk factor, as it can be effectively treated with non-drug and drug measures (diet, physical activity, antihypertensive drugs) to reduce the risk of heart and blood vessel damage. Resistant (refractory) hypertension occurs in no more than 5–10% of cases. Clinical studies have shown that elevated blood pressure significantly increases the risk of stroke, ischemic heart disease, heart failure, and chronic kidney disease, but by controlling blood pressure with antihypertensive drugs, this risk can be significantly reduced. Lowering blood pressure is beneficial to protect target organs, although there is no clear direct link between blood pressure and the risk, morbidity, and mortality of cardiovascular disease. The benefits of antihypertensive treatment depend on many factors: blood pressure reduction, additional beneficial properties of the drugs used, control of comorbidities, and others. The guidelines prepared by the European cardiologists and the European Hypertension Societies list 5 classes of antihypertensive drugs: beta-blockers, diuretics, ACE inhibitors, angiotensin receptor blockers (ARBs), and calcium channel blockers. Any class of drug can be chosen as the first-line treatment for hypertension based on individual patient needs, disease severity, comorbidities, drug tolerance, and other circumstances. Thiazide diuretics are among the oldest and most widely used antihypertensive drugs. Thiazide diuretics can be prescribed as a first-line antihypertensive drug for many patients because they reliably reduce the risk of death, stroke, and heart attacks.

Mechanism of action of thiazide diuretics

In clinical practice, the most commonly used 6 thiazide diuretics are hydrochlorothiazide (HCT), indapamide, bendroflumethiazide, chlorthalidone, cyclopenthiazide, and metolazone. Thiazide diuretics were synthesized in the 1950s from sulfonamide carbonic anhydrase inhibitors. The aim was to create a drug that would promote diuresis by increasing the excretion of sodium chloride and decreasing the excretion of sodium bicarbonate. Thiazide diuretics are derivatives of benzothiazine. Other drugs that affect kidney function similarly but have a different chemical structure than thiazide diuretics are called thiazide-like diuretics – these include indapamide, chlorthalidone, and metolazone. Metolazone and indapamide act on the same kidney cotransporters as thiazide diuretics, so they are classified in the same group of drugs.

Physiological studies show that at the beginning of treatment, diuretics reduce blood volume, plasma volume, and cardiac output by reducing intracellular volume, while peripheral resistance remains unchanged. After a few weeks of treatment, cardiac output increases and returns to normal, and peripheral resistance decreases. In the kidneys, thiazide diuretics block the Na+Cl- cotransporters in the distal tubules sensitive to thiazide diuretics, thereby inhibiting the reabsorption of sodium and chloride ions.

Analysis of the effects of thiazide diuretics

Clinical studies have shown that low doses of thiazide diuretics significantly reduce the incidence of cardiovascular disease and mortality, but there is insufficient data on whether the antihypertensive effect of thiazide diuretics depends on the dose. In clinical trials, thiazide diuretics were administered in low doses (

It is now well established that treatment with low doses of thiazide diuretics significantly reduces the incidence of cardiovascular disease and mortality. The use of very high doses of thiazide diuretics can be risky due to possible side effects: hypokalemia, hyponatremia, and other metabolic disorders. On the other hand, prescribing very high doses of thiazide diuretics is not clinically justified because blood pressure does not decrease significantly.

V. M. Musini and colleagues, based on data from the COCHRANE statistical database, conducted an analysis with the main goal of determining how the systolic and (or) diastolic blood pressure-lowering effect of thiazide diuretics in treating primary hypertension depends on the dose and comparing it with the placebo effect. Secondary outcomes were also evaluated: dose-dependent adverse effects of thiazide diuretics leading to discontinuation of diuretic use, undesirable biochemical effects on serum potassium, uric acid, glucose, creatinine, and lipid concentrations. The analysis selected highly reliable double-blind randomized placebo-controlled trials in which adults with primary hypertension (blood pressure not less than 140/90 mm Hg) were treated for 3–12 weeks. Individuals with severe kidney failure (creatinine concentration>1.5 k. above the norm). A total of 60 clinical trials (conducted between 1946 and 2014) were screened, including data from 11,282 patients with AH (average age - 55 years, initial BP - 158/99 mm Hg). On average, these patients received monotherapy with one of these thiazide or thiazide-like diuretics for 8 weeks: bendroflumethiazide (1.25–10 mg/day), butiazide, chlorthalidone (12.5–75 mg/day), chlorothiazide, clopamide, clorexolone, cyclopenthiazide (50–500 μg/day), cyclothiazide, diazoxide, fenquizone, hydrochlorothiazide (3–100 mg/day), hydroflumethiazide, indapamide (1–5 mg/day), isothiazide, mefruside, metolazone (0.5–2.0 mg/day), polythiazide, quinethazone, trichlormethiazide, xipamide.

Antihypertensive effect

Hydrochlorothiazide. The most data on the clinical effects and adverse reactions of HCT were collected (35 studies, 6,725 patients), therefore the conclusions regarding the dose-dependent antihypertensive action of HCT are the most reliable. A clear relationship was established between HCT doses of 6.25–12.5–25 mg/day and reduced systolic BP. Higher HCT doses more effectively reduced systolic BP than lower doses. The reduction in diastolic BP depended less on the dose of HCT taken, meaning the effect on diastolic BP varied less between high and low HCT doses. When each HCT dose was doubled (from 6.25 to 50 mg/day), systolic BP decreased on average by an additional 2 mm Hg. Similarly, BP decreases when adding HCT to another antihypertensive drug already being taken. In summary, higher HCT doses more effectively reduced systolic BP than lower doses typically used in clinical practice: 6.25 mg/day - 4 mm Hg, 12.5 mg/day - 6 mm Hg, 25 mg/day - 8 mm Hg.

The different effects on systolic and diastolic BP led to a reduction in pulse pressure by 2–6 mm Hg with HCT doses of 6.25–50 mg/day. The maximum 50 mg/day HCT dose reduced pulse pressure by an average of 5.5 mm Hg, whereas according to other studies, ACE inhibitors, ARBs, and renin inhibitors reduce pulse pressure by an average of 3 mm Hg, and non-selective beta-blockers by 2 mm Hg. Indapamide. According to the analyzed data, indapamide was the second most used diuretic. The lowest dose of indapamide (1.25 mg/day) reduced BP by an average of 7.4/3.6 mm Hg, all other evaluated doses reduced BP by an average of 9/4 mm Hg. The lowest indapamide dose (1.25 mg/day) reduced BP similarly to 25 mg/day HCT. Higher doses of indapamide did not significantly further reduce BP. Therefore, 1–2 mg/day of indapamide has the greatest effect on BP reduction, making treatment with higher doses unwarranted. Chlorthalidone. Similar to indapamide, the antihypertensive effect of chlorthalidone was almost independent of the dose. The lowest chlorthalidone doses (12.5 mg/day) had the greatest reduction in BP. The antihypertensive effect of chlorthalidone did not differ statistically from HCT and indapamide, although clinical practice shows that chlorthalidone reduces BP more than HCT (12.5 mg of chlorthalidone is equivalent to 50 mg of HCT). This is due to the pharmacokinetic differences between these drugs: the half-life of HCT is 8–15 hours, while that of chlorthalidone is 45–60 hours. The serum concentration after taking 100 mg/day of chlorthalidone is only twice as high as after taking 25 mg/day, resulting in a flat curve of serum concentrations of this drug. However, a longer elimination time does not mean that chlorthalidone is a superior antihypertensive drug to HCT. Other thiazide diuretics. There was insufficient data on the dose-dependent antihypertensive effects of other thiazide diuretics to formulate reliable conclusions.

Undesirable metabolic effects

According to COCHRANE analysis, no patient using thiazide diuretics discontinued treatment due to adverse reactions, but concerns are often raised about the possible side effects of thiazide diuretics: hypokalemia, hyperuricemia, increased cholesterol and triglyceride concentrations. The analysis found that treatment with thiazide diuretics (including thiazide-like diuretics such as indapamide) significantly reduced potassium and increased urine acid, total cholesterol, and triglyceride concentrations in the serum. The undesirable metabolic effect was stronger with higher doses of thiazide diuretics than with lower doses. HCT had the weakest effect on metabolism compared to other thiazide diuretics. All evaluated thiazide diuretics, except for chlorthalidone, did not have a significant impact on glucose concentration.

Summary

• The antihypertensive effect of hydrochlorothiazide depends on the daily dose: 6.25 mg reduced BP by 4/2 mm Hg, 12.5 mg by 6/3 mm Hg, 25 mg by 8/3 mm Hg. The dose-dependent antihypertensive effect of other thiazide diuretics was not established.
• Thiazide diuretics more significantly reduced systolic BP than diastolic, resulting in a significant decrease in pulse pressure (4–6 mm Hg) when used for treatment.
• Based on short-term study data, no patient discontinued thiazide diuretic treatment due to adverse effects.
• • All thiazide diuretics (hydrochlorothiazide (HCT), indapamide, bendroflumethiazide, chlorthalidone, cyclopenthiazide, and metolazone) reduced potassium and sodium, increased uric acid, total cholesterol, and triglyceride concentrations in serum.
  • The undesired metabolic effect of thiazide diuretics depended on the dose, with hydrochlorothiazide being the least metabolically active.
  • Only chlorthalidone increased glucose concentration in serum.

  LT/Zof/2014/09 Article reprinted from the publication "Lietuvos gydytojo žurnalas" The bibliography is in the editorial office.