Diuretics – Mechanism of Action of Different Classes of Diuretics, Animation

Diuretics – Mechanism of Action of Different Classes of Diuretics, Animation


Diuretics are substances that increase production
of urine. Most diuretics act to increase excretion of
sodium, which is followed by water. Because increased urine production results
in reduced blood volume, diuretics are commonly used to treat primary hypertension and edema. Changes in body fluid and electrolytes induced
by diuretics can also be therapeutic for some other conditions. Sodium and water are filtered in the glomerular
capsule of nephrons, then reabsorbed back to the blood at various sites along the renal
tubule. Different classes of diuretics prevent sodium
reabsorption, and thus increase sodium loss, at different sites, by different mechanisms. Carbonic anhydrase inhibitors inhibit the
enzyme carbonic anhydrase, which is required for reabsorption of bicarbonate in the proximal
tubule. This leads to greater sodium loss, in the
form of sodium bicarbonate, and subsequently greater water loss in the urine. These inhibitors have the weakest diuretic
effect because most of sodium lost at this early stage is reclaimed further down the
renal tubule. Increased delivery of sodium to the collecting
duct increases its reabsorption at this site through epithelial sodium channels, in exchange
for a greater potassium loss, and may cause hypokalemia. Loss of bicarbonate also affects acid-base
balance, producing metabolic acidosis. Carbonic anhydrase inhibitors are rarely prescribed
for cardiovascular diseases; they are mainly used in the treatment of glaucoma. Osmotic diuretics, such as mannitol, promote
water loss directly through osmosis. Being filtered without subsequent reabsorption,
mannitol stays in the renal tubule, creating a higher osmolality which attracts water by
osmosis. It produces a greater loss of water compared
to sodium and potassium. Mannitol is not usually used to treat edema
because its initial presence in the circulation may actually further increase fluid volume
to a dangerous level. It is however effective in lowering intracranial
pressure in patients with head injury, as well as lowering intraocular pressure in acute
glaucoma. Osmotic diuretics act on the entire renal
tubule, with predominant effect on the proximal tubule and the descending loop of Henle. Loop diuretics inhibit the sodium/potassium/chloride
cotransporter in the thick ascending limb of the loop of Henle. These are very powerful diuretics because
this transporter not only reabsorbs a large share of sodium, but is also responsible for
the osmolarity gradient in the medulla that enables the collecting duct to concentrate
urine. As the loop diuretics cause the salinity gradient
to diminish, the collecting duct loses less water, more water is excreted in urine. Because the sodium/potassium/chloride cotransporter
acts in conjunction with back diffusion of potassium to create a positive lumen potential
that drives reabsorption of other positive ions, its inhibition by loop diuretics also
induces a greater loss of these ions. Side effects include electrolyte imbalances,
metabolic alkalosis, hypovolemia due to excessive loss of water, loss of hearing due to inhibition
of a similar transporter in the inner ear, and gout due to interference with transporters
involved in urate secretion. Thiazide diuretics inhibit the sodium/chloride
cotransporter in the distal tubule, which reabsorbs about 5% of the sodium load, and
are not as powerful as loop diuretics. However, thiazides also have a vasodilation
effect by a still poorly understood mechanism. Thiazides are first-line drugs for uncomplicated
hypertension and most effective for heart failure prevention. Unlike loop diuretics, thiazides reduce calcium
loss in urine and can be used to prevent formation of new calcium kidney stones. This is because lower intracellular sodium
induced by thiazides leads to higher calcium reabsorption mediated by sodium/calcium exchanger
located on the basolateral membrane. Other side effects are similar to those of
loop diuretics and include hypokalemia, metabolic alkalosis and hyperuricemia. Potassium-sparing diuretics act mainly in
the collecting duct. Here, sodium reabsorbs through epithelial
sodium channels, ENaC, then sodium/potassium pump, in exchange for potassium loss. Sodium influx into cells creates a negative
lumen potential, which drives reabsorption of chloride and excretion of potassium and
hydrogen. Both ENaC and sodium/potassium pump are induced
by aldosterone. Potassium-sparing diuretics include aldosterone
receptor antagonists and direct ENaC inhibitors. They are called potassium-sparing because
they do not increase potassium loss, unlike all other diuretics acting upstream. Instead, they reduce potassium loss because
reduced sodium reabsorption decreases the electrogenic exchange for potassium. Aldosterone antagonists also directly inhibit
the sodium/potassium pump, reducing potassium loss. Because the collecting duct reabsorbs only
a small amount of sodium, this class of drugs has only a mild diuretic effect. They are commonly used in conjunction with
thiazide or loop diuretics to prevent hypokalemia. Side effects include hyperkalemia, metabolic
acidosis, and effects associated with inhibition of aldosterone.

3 Replies to “Diuretics – Mechanism of Action of Different Classes of Diuretics, Animation”

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