Diuretics

                                                   An Overview : Diuretics

 

 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 arommonly 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

 re -absorption, 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 byosmosis. 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 intracranialpressure in patients with head injury, as well as lowering intraocular pressure in acuteglaucoma. 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 co -transporter 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 co-transporter acts in conjunction with back diffusion of potassium to create a positive lumen potentialthat drives re-absorption 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 co-transporter in the distal tubule, which reabsorbs about 5% of the sodium load, andare not as powerful as loop diuretics. However, thiazides also have a vasodilatione ffect by a still poorly understood mechanism. Thiazides are first-line drugs for uncomplicate dhypertension 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 re-absorption mediated by sodium/calcium exchanger located on the basolateral membrane. Other side effects are similar to those ofloop 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 negativelumen potential, which drives reabsorption of chloride and excretion of potassium and hydrogen. Both ENaC and sodium/potassium pump are inducedby 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 inhibitthe sodium/potassium pump, reducing potassium loss. Because the collecting duct reabsorbs onlya small amount of sodium, this class of drugs has only a mild diuretic effect. They are commonly used in conjunction withthiazide or loop diuretics to prevent hypokalemia. Side effects include hyperkalemia, metabolicacidosis, and effects associated with inhibition of aldosterone.