Thiazide diuretics

Drug classification

This group unites drugs that visually differ in their heterocyclic ring structure but have a similar pharmacological effect. Two main subgroups are distinguished:

1. Thiazide diuretics (benzothiadiazine derivatives):
2. Hydrochlorothiazide (Hypothiazide);
3. Cyclopenthiazide.

1. Thiazide-like diuretics (representatives of various chemical groups):
2. Indapamide;
3. Chlortalidone (Oxodoline);
4. Clopamide.

All these drugs are well absorbed from the gastrointestinal tract upon oral administration, and their efficacy is maintained regardless of the blood acid-base status (in both acidosis and alkalosis). They are excreted from the body by the kidneys and intestines.

Mechanism of action and urine ionogram

The site of action of thiazides is the renal tubular epithelium, specifically the initial segment of the distal convoluted tubule.

The drugs block the $Na^+$-$Cl^-$-cotransporter (NCC system) on the luminal (apical) membrane of cells. This disrupts the transport system responsible for the reabsorption of sodium and chloride ions. As a result of the inhibition of the reabsorption of these electrolytes, water follows them according to the laws of osmosis, which increases diuresis.

Changes in the urine ionogram:

• $Na^+$ and $Cl^-$: excretion significantly increases (this is the primary, main effect).
• $K^+$: excretion increases secondarily, as a consequence of sodium reabsorption blockade.
• $Ca^{2+}$: excretion decreases. The drugs activate TRPV5 calcium channels on the luminal membrane, leading to calcium retention in the body.

Clinical application

Thiazides are highly effective and widely used in clinical practice. The main indications include:

• Hypertension. These are first-line drugs with high antihypertensive efficacy. The mechanism of blood pressure reduction is twofold: first, the diuretic effect itself reduces the circulating blood volume (CBV); second, there is an additional vasodilating effect. It is believed to be associated with a decrease in sodium content in the vascular wall, which reduces its reactivity.
• Edematous syndrome. Prescribed for chronic heart failure (CHF), as well as liver and kidney diseases.
• Nephrolithiasis (kidney stone disease). Due to their ability to reduce urinary calcium excretion, thiazides are used to prevent the formation of insoluble calcium stones in idiopathic hypercalciuria.
• Diabetes insipidus. In this condition, the drugs produce a paradoxical effect — they reduce the volume of urine output.
• Glaucoma. Used in a number of specific cases.

Characteristics of individual agents

Hydrochlorothiazide The reference drug of the group. Well absorbed from the GI tract. Action begins in 30–60 minutes, peaks in 2 hours, and lasts 8–12 hours. Administered once daily. It is a first-line drug in the treatment of arterial hypertension and can be used as monotherapy. Side effects: nausea, weakness, hypokalemia, hypomagnesemia, hyperuricemia (elevated uric acid levels), and hyperglycemia.

Cyclopenthiazide Structurally similar to hydrochlorothiazide, but 50 times more potent, therefore used in smaller doses. The latent period is 2–4 hours, peak effect is in 3–6 hours, and average duration of action is 10–12 hours.

Indapamide An effective diuretic with an independent antihypertensive effect, the exact mechanism of which is not directly related to diuresis. The half-life ($T_{1/2}$) is 18 hours. Specific side effect: orthostatic hypotension is possible.

Long-acting drugs

• Chlortalidone: characterized by the longest duration of effect (up to 72 hours), therefore the dosing regimen is 2–3 times a week.
• Clopamide: has high potency, acts for up to 18 hours, and is administered once daily.

Class and exam questions

What else to study on this topic

• Mechanism of the vasodilating action of thiazides in arterial hypertension
• The role of TRPV5 calcium channels in the mechanism of calcium retention
• Pathogenesis of hyperuricemia and hyperglycemia development during hydrochlorothiazide therapy
• Comparative pharmacokinetics of thiazide-like diuretics (indapamide, chlortalidone, clopamide)

Other topics in the section "Diuretics"

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