Thiazide Diuretics

Thiazide diuretics are a group of urine producing medicines also called as diuretics belonging to the chemical group of benzothiadiazines. They are used for urine production if the urine output decreases.

Benzothiadiazines

Introduction of thiazide diuretics revolutionized the oral diuretic therapy, since before chlorothiazide, no effective and reliable oral diuretic was available. Synthesis of thiazides stems from the original observation by South worth (1937) that sulfanilamide, an antibacterial drug, possesses a mild diuretic activity. This was later shown to be related to its carbonic anhydrase inhibiting action. Interestingly, chlorothiazide, synthesized as one of the carbonic anhydrase inhibitor, revealed marked diuretic activity in doses that did not significantly inhibit the enzyme carbonic anhydrase. Since then, many thiazide-like diuretics have been introduced.

Thiazide

Benzothiadiazine nucleus

Thiazide diuretics Pharmacological actions

On Kidney and electrolytes:

Like acetazolamide, these drugs are secreted into the tubular fluid and block the electro neutral sodium and chloride transport (symport) in the distal convoluted tubule by competing with Na+ and CI” for the binding sites.

How does a thiazide diuretic work?

They primarily act on the site proximal to the sodium and potassium exchange region in the distal tubule (site III). Hence, they are sometimes known as early distal diuretics. The GFR is not affected.

Thiazides increase Na+ and CI- excretion but as almost 90% of the filtered load of sodium is reabsorbed before reaching the distal tubules, they exert only a moderate diuretic effect.

Thiazide Diuretics

Chlorothiazide has a weak carbonic anhydrase inhibitory activity and hence it can cause some loss of bicarbonate. The newer thiazides, however, do not significantly increase the bicarbonate loss.

Because of the marked inhibitory action on sodium re absorption, a large amount of sodium is made available to the distal segment where exchange of K+ with Na takes place. This causes increased potassium loss, particularly in the presence of excessive aldosterone which stimulates this exchange mechanism.

Excessive renal loss of sodium and chloride may cause hyponatremia and hypochloremia; excessive potassium loss can cause hypokalemia, thus leading to hypokalemic hypochloremic alkalosis. Long term use causes hypomagnesaemia.

Initially, the drug causes a diminution in sodium re absorption in the distal tubule and a gradual reduction in the ECF volume. When the ECF volume falls to slightly below normal, the re absorption of sodium from the proximal tubule is stimulated, resulting in diminished amount of sodium delivered into the distal tubule. This decreases its diuretic activity and causes resistance. Thiazides are less effective when GFR falls below 30-40 ml/min.

Thiazide diuretics Antihypertensive action

Thiazides produce a mild antihypertensive effect partly due to their action on sodium metabolism and partly due to their direct action on blood vessels .

ThiazideThiazide diuretics Metabolic actions

Thiazide diuretic may cause:

  1. Hyperglycemia
  2. Hyperuricemia
  3. Hypercalcemia
  4. Hyperlipidemia

The mechanism by which thiazides cause hyperglycemia is not known. Catecholamine release, secondary to volume depletion, a direct inhibition of insulin release and hypokalemia are the possible mechanisms. These drugs can unmask or aggravate the pre-existing diabetes mellitus. Diazoxide, a thiazide diuretic derivative with potent hyperglycemic action, has been used in the treatment of hypoglycemia.

Thiazides

However, during long-term therapy of hypertension, thiazides do not significantly increase the incidence of diabetes mellitus.

Thiazides also decrease the excretion of uric acid, thus raising plasma uric acid level. Usually, this is asymptomatic but, occasionally, it can precipitate attacks of gouty arthritis.

Unlike loop diuretics, thiazides reduces urinary calcium loss and promote calcium retention; they are useful in treating idiopathic hypercalciuria.

Serum cholesterol and triglycerides may increase slightly; however, this has hardly any significance as the elevation is not persistent beyond 6-12 months of treatment.

In patients with diabetes insipidus, especially the nephrogenic type, thiazides decrease urinary volume. This is discussed later.

Thiazide diuretics – Absorption, fate and excretion

Thiazide Diuretic

Thiazides are well absorbed from the intestine and the effect starts within one hour. They are distributed throughout the ECF and arc relatively concentrated in the kidney. They can cross the placental barrier.

Like other organic acids, thiazides are secreted into the tubules and excreted in urine. The excretion rate varies with the individual thiazide diuretic drug. The slowly excreted compounds like polythiazide and bendro- flumethiazide have prolonged action.

The long acting thiazides are long acting because of their greater plasma protein binding and greater lipid solubility.

Bendroflumethiazide, polythiazide and indapamide are primarily metabolized in the liver; whereas chlorothiazide, hydro-chlorothiazide, hydroflumethiazide and chlorthalidone are excreted in the urine. Plasma half-life of thiazides is sufficient to permit their use once or twice daily.

Adverse reactions: Apart from electrolyte disturbances such as hypokalemic and hypo­chloremic alkalosis, these drugs have remarkably few serious toxic effects.

Hypokalemia increases the risk of fatal toxicity of certain arrhythmias and drugs like digoxin. Because of structural similarity, they may rarely cause sulfonamide-like allergic reactions such as dermatitis and thrombocytopenia.

In the presence of renal and hepatic insufficiency, these drugs may precipitate renal failure or hepatic coma. This is attributed to the development of hypokalemia and alkalosis.