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Diuretics (saluretics) elicit increased production of urine (diuresis). In the strict sense, the term is applied to drugs with a direct renal action. The predominant action of such agents is to augment urine excretion by inhibiting the reabsorption of NaCl and water.

Indications for Diuretics

Mobilization of edemas

In edema there is swelling of tissues due to accumulation of fluid, chiefly in the extracellular (interstitial) space. When a diuretic is given, increased renal excretion of Na+ and H2O causes a reduction in plasma volume with hemoconcentration. As a result, plasma protein concentration rises along with oncotic pressure.

As the latter operates to attract water, fluid will shift from interstitium into the capillary bed. The fluid content of tissues thus falls and the edemas recede. The decrease in plasma volume and interstitial volume means a diminution of the extracellular fluid volume (EFV). Depending on the condition, use is made of: thiazides, loop diuretics, aldosterone antagonists, and osmotic diuretics.

Antihypertensive therapy

Diuretics have long been used as drugs of first choice for lowering elevated blood pressure. Even at low dosage, they decrease peripheral resistance (without significantly reducing EFV) and thereby normalize blood pressure.

Therapy of congestive heart failure

By lowering peripheral resistance, diuretics aid the heart in ejecting blood (reduction in afterload); cardiac output and exercise tolerance are increased. Due to the increased excretion of fluid, EFV and venous return decrease (reduction in preload). Symptoms of venous congestion, such as ankle edema and hepatic enlargement, subside.

The drugs principally used are thiazides (possibly combined with K+-sparing diuretics) and loop diuretics.

Prophylaxis of renal failure

In circulatory failure (shock), e.g., secondary to massive hemorrhage, renal production of urine may cease (anuria). By means of diuretics an attempt is made to maintain urinary flow. Use of either osmotic or loop diuretics is indicated.

Osmotic Diuretics

Agents: mannitol, sorbitol.

Site of action of Osmotic Diuretics: mainly the proximal tubules.

Mode of action of Osmotic Diuretics

Since NaCl and H2O are reabsorbed together in the proximal tubules, Na+ concentration in the tubular fluid does not change despite the extensive reabsorption of Na+ and H2O. Body cells lack transport mechanisms for polyhydric alcohols such as mannitol and sorbitol, which are thus prevented from penetrating cell membranes. Therefore, they need to be given by intravenous infusion.

They also cannot be reabsorbed from the tubular fluid after glomerular filtration. These agents bind water osmotically and retain it in the tubular lumen. When Na ions are taken up into the tubule cell, water cannot follow in the usual amount. The fall in urine Na+ concentration reduces Na+ reabsorption, in part because the reduced concentration gradient towards the interior of tubule cells means a reduced driving force for Na+ influx. The result of osmotic diuresis is a large volume of dilute urine.

• Indications for Osmotic Diuretics:
  • prophylaxis of renal hypovolemic failure
  • mobilization of brain edema
  • acute glaucoma

Diuretics of the Sulfonamide Type

These drugs contain the sulfonamide group -SO2NH2. They are suitable for oral administration. In addition to being filtered at the glomerulus, they are subject to tubular secretion. Their concentration in urine is higher than in blood. They act on the luminal membrane of the tubule cells.

• Loop diuretics have the highest efficacy.
• Thiazides are most frequently used.
• Carbonic anhydrase inhibitors are now restricted to special indications.

Carbonic anhydrase (CAH) inhibitors

Carbonic anhydrase (CAH) inhibitors include:

• acetazolamide
• methazolamide
• brinzolamide
• dorzolamide
• sulthiame

They act predominantly in the proximal tubules. CAH catalyzes CO2 hydration/ dehydration reactions: H + HCO3– ↔ H2CO3 ↔ H20 + CO2. The enzyme is used in tubule cells to generate H+, which is secreted into the tubular fluid in exchange for Na+. There, H+ captures HCO3 –, leading to formation of CO2 via the unstable carbonic acid.

Membrane-permeable CO2 is taken up into the tubule cell and used to regenerate H+ and HCO3 –. When the enzyme is inhibited, these reactions are slowed, so that less Na+, HCO3 – and water are reabsorbed from the fast-flowing tubular fluid. Loss of HCO3 – leads to acidosis.

The diuretic effectiveness of CAH inhibitors decreases with prolonged use. CAH is also involved in the production of ocular aqueous humor.

• Indication for Carbonic anhydrase (CAH) inhibitors:
  • acute glaucoma (Dorzolamide can be applied topically to the eye to lower intraocular pressure in glaucoma)
  • acute mountain sickness
  • epilepsy

Loop Diuretics

Loop diuretics include:

• furosemide (frusemide)
• torsemide
• ethacrynic acid (not a sulfonamide)
• piretanide
• bumetanide

With oral administration, a strong diuresis occurs within 1 h but persists for only about 4 h. The effect is rapid, intense, and brief (high-ceiling diuresis).

The site of action of these agents is the thick portion of the ascending limb of Henle’s loop, where they inhibit Na+/K+/2Cl– cotransport. As a result, these electrolytes, together with water, are excreted in larger amounts. Excretion of Ca2+ and Mg2+ also increases.

Special toxic effects include: (reversible) hearing loss, enhanced sensitivity to renotoxic agents.

• Indications for Loop Diuretics:
  • pulmonary edema (added advantage of i.v. injection in left ventricular failure: immediate dilation of venous capacitance vessels
    preload reduction)
  • refractoriness to thiazide diuretics, e.g., in renal hypovolemic failure with creatinine clearance reduction (<30 mL/min)
  • prophylaxis of acute renal hypovolemic failure
  • hypercalcemia

Thiazide Diuretics (benzothiadiazines)

Thiazide Diuretics (benzothiadiazines) include:

• hydrochlorothiazide
• indapamide
• benzthiazide
• trichlormethiazide
• cyclothiazide
• chlorthalidone (long-acting analogue)

These drugs affect the intermediate segment of the distal tubules, where they inhibit a Na+/Cl– cotransport. Thus, reabsorption of NaCl and water is inhibited. Renal excretion of Ca2+ decreases, that of Mg2+ increases.

• Indications for Thiazide Diuretics
  • hypertension
  • cardiac failure
  • mobilization of edema
  • urolithiasis
  • nephrogenic diabetes insipidus

Potassium-Sparing Diuretics

These agents act in the distal portion of the distal tubule and the proximal part of the collecting ducts where Na+ is reabsorbed in exchange for K+ or H+. Their diuretic effectiveness is relatively minor.

In contrast to sulfonamide diuretics, there is no increase in K+ secretion; rather, there is a risk of hyperkalemia. These drugs are suitable for oral administration.

Triamterene and Amiloride

Triamterene and amiloride, in addition to glomerular filtration, undergo secretion in the proximal tubule. They act on the luminal membrane of tubule cells. Both inhibit the entry of Na+, hence its exchange for K+ and H+.

They are mostly used in combination with thiazide diuretics, e.g., hydrochlorothiazide, because the opposing effects on K+ excretion cancel each other, while the effects on secretion of NaCl complement each other.

Aldosterone antagonists (Spironolactone)

The mineralocorticoid aldosterone promotes the reabsorption of Na+ (Cl– and H2O follow) in exchange for K+. Its hormonal effect on protein synthesis leads to augmentation of the reabsorptive capacity of tubule cells. Spironolactone, as well as its metabolite canrenone, are antagonists at the aldosterone receptor and attenuate the effect of the hormone.

The diuretic effect of spironolactone develops fully only with continuous administration for several days. Two possible explanations are:

1. the conversion of spironolactone into and accumulation of the more slowly eliminated metabolite canrenone
2. an inhibition of aldosterone-stimulated protein synthesis would become noticeable only if existing proteins had become nonfunctional and needed to be replaced by de novo synthesis.

A particular adverse effect results from interference with gonadal hormones, as evidenced by the development of gynecomastia (enlargement of male breast).

• Clinical uses of Spironolactone include:
  • conditions of increased aldosterone secretion, e.g., liver cirrhosis with ascites
  • congestive heart failure