Diuretics

Diuretics are drugs that work in the kidney to increase urine flow, and thus, decrease extracellular fluid (ECF) volume. Diuretics are used to treat disorders in which for various reasons, there is an unhelpful increase in extracellular fluid volume. Two important examples are heart failure and hypertension.

• Heart failure In heart failure, the heart does not pump enough blood, resulting in poor blood flow to the kidneys. Poor renal blood flow results in decreased GFR and decreased Na⁺ delivery to the distal tubule, thus activating the renin-angiotensin-aldosterone system. The result is increased ECF volume, causing edema and further stress to the heart.
• Hypertension Mean arterial pressure is the product of the cardiac output and the total peripheral resistance.  Hypertension can be due to an increase in cardiac output, which is related to an increase in the ECF volume.
  

The commonly used diuretics all work to block Na⁺ reabsorption at different sites along the nephron, as illustrated in the figure. Loop diuretics block the Na⁺/K⁺/2Cl^- cotransporter that is present in the loop of Henle. Examples are furosemide and bumetanide.

The thiazide diuretics are drugs that block Na⁺ reabsorption in the distal tubule by blocking the Na⁺/Cl^- cotransporter. These drugs are the diuretics that are most commonly prescribed to treat hypertension.

Amiloride blocks the epithelial Na⁺ channel (ENaC) that is present in the cortical collecting duct. Recall that Na⁺ reabsorption in this segment of the nephron is regulated by the hormone aldosterone. Thus, aldosterone receptor antagonists such as spironolactone and eplerenone also work as diuretics. Amiloride and the aldosterone receptor antagonists are considered potassium-sparing diuretics.

Effects on K⁺

A potential adverse effect in the use of diuretics is that they can cause imbalances in the potassium (K⁺) in the ECF. Changes in the K⁺ concentration in the ECF ([K⁺]_ECF) will affect the membrane potential of cells. Changes in the membrane potential will cause problems with electrical activity in the heart, nervous system, and muscles.

If Na⁺ reabsorption is blocked by either loop diuretics or thiazide diuretics, this increases Na⁺ delivery to the cortical collecting duct, and increases Na⁺ reabsorption in this segment of the nephron. Since Na⁺ reabsorption is coupled to K⁺ secretion in the cortical collecting duct, these drugs can lead to excessive K⁺ secretion and hypokalemia ([K⁺]_ECF too low). Loop diuretics and thiazide diuretics may be combined with potassium sparing diuretics to counteract this possibility.

Conversely, the use of potassium-sparing diuretics could cause hyperkalemia ([K⁺]_ECF too high). Drugs that interfere with the production or action of angiotensin II (ACE inhibitors, angiotensin II receptor blockers, or the direct renin inhibitor aliskiren) also have the potential to cause hyperkalemia, because they limit the production of aldosterone. Hyperkalemia is very rare when these drugs are used alone, but it is more likely when they are used in combination (for instance combining an ACE inhibitor with an angiotensin II receptor blocker).