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Mechanism of Action of Diuretics in Human Body

Categories: HumanHypertension

Diuretics cause an effect on the kidneys, to increase the excretion of salt and water. They are used in the treatment of heart failure and oedema (the accumulation of extracellular fluid), but also are used to treat hypertension.

General Mechanism of Action

Diuretics cause a net loss of water from the body by an action on the kidney, normally associated with a loss of sodium. The effect of causing increased water loss is achieved by decreasing the reabsorption of sodium and chloride from the filtrate.

There are two methods of achieving this

  1. A direct action on the cells of the nephron
  2. Indirectly modifying the content of the filtrate

As the glomerulus filters such a large volume of water per day, a small decrease in reabsorption can result in a large increase in excretion of water.

Diuretics Acting on the Cells of the Nephron

To cause a net loss of salt by acting on cells, the diuretics must affect the parts of the nephron where the majority of the active and selective solute reabsorption occurs.

These are

  1. The ascending loop of Henle
  2. The early distal tubule
  3. The collecting tubules and ducts

Loop Diuretics

These drugs include

  • Frusemide
  • Bumetanide
  • Piretanide

and are the most powerful of the diuretics causing 15 to 25 % of the sodium in the filtrate to be excreted. They act primarily on the ascending loop of Henle, inhibiting the Na+/K+/2Cl- carrier on the apical membrane, and thus inhibiting the transport of sodium chloride out of the tubule into the interstitial fluid.

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Frusemide, bumetanide, torasemide, and piretanide directly inhibit the chloride binding site, whilst ethacrynic acid forms a complex with cysteine. This complex is then the active form of the drug.

Solute reabsorption creates a hypertonic interstitial area in the medulla, which then provides the osmotic force by which water is absorbed from the collecting tubules under the influence of the antidiuretic hormone. More solute is delivered to the distal portion of the nephron, under the influence of diuretics, where its osmotic pressure further reduces water absorption. Some of the solute which would normally pass out of the medullary interstitium, drawing water out of the collecting ducts now remains in the tubular fluid, therefore holding water with it. The normal loss of glomerular filtrate is about 1%, but as much as 25% may pass out of the nephron, having a large diuretic effect.

Associated Responses

Loop diuretics also have a venodilator effect via the release of a renal factor. They also cause significant potassium loss, and produce an alkalosis. This occurs because potassium depletion and loss of sodium and chloride stimulates hydrogen ion secretion and bicarbonate generation. Depletion of magnesium and calcium is also common, and hypotension can occur due to a sudden loss of extracellular fluid volume.

Early Distal Tubule Diuretics

Diuretics acting at this site include the thiazides and related drugs, with the main example being bendrofluazide. They have a moderate action compared to the loop diuretics.

  • Control
  • Hydrochlorothiazide
  • Frusemide

The thiazides decrease active reabsorption of sodium and chloride by binding to the chloride site of the Na+/Cl- co-transport system, but they do not have an effect on the thick ascending loop of Henle. Potassium loss is significant, and can be serious, leading to ventricular fibrillations.

Extra-renal actions include vasodilation and hyperglycaemia. When thiazides are used as treatment for hypertension, whilst the initial fall in blood pressure is due to decreased blood volume from diuresis, the later phase seems to be due to a direct action on the blood vessels. Diazoxide is a non-diuretic thiazide, and it has powerful vasodilator effects and increases blood sugar by opening membrane K+ channels.

Spironolactone

This is an antagonist of aldosterone, attaching to intracellular aldosterone receptors in the distal tubule cells. The complex does not then attach to the DNA, so transcription, translation and production of mediator proteins do not occur. This means that the sodium-retaining action of aldosterone is lost, and with it the potassium secreting effect. Spironolactone also has action in decreasing hydrogen ion secretion.

Triamterene and Amiloride

These inhibit sodium reabsorption and potassium excretion by acting on the distal tubules and collecting ducts. Amiloride blocks the luminal sodium channels, so less sodium is available for transport across the basolateral membrane. They also reduce Na+/H+ exchange, inhibiting H+ excretion, so there is some alkalinisation of the urine. The main importance of these diuretics is that they are potassium sparing. As diuretics are often given to people with heart failure, and loss of potassium can lead to ventricular fibrillations, then diuretics that promote loss of potassium can often exacerbate the situation.

Diuretics acting by Modifying the Content of the Filtrate

Diuretics modifying the content of the filtrate increase either the osmolarity or the sodium load.

Osmotic Diuretics

An example of this is mannitol, and they are pharmacologically inert substances that are filtered in the glomerulus, but are incompletely reabsorbed, or not absorbed at all by the nephron. If given in large enough amounts, they can constitute a large fraction of the plasma osmolarity. The proximal tubule, the descending limb of the loop of Henle and the collecting duct are freely permeable to water, and this is where the main the effect is exerted. Water reabsorption is a passive process due to osmosis, so it is reduced by the presence of more solute in the tubule. The presence of osmotic diuretics also reduces sodium reabsorption, as the sodium concentration in the tubule is lower than if the diuretic was not there, and this alters the electrochemical gradient for reabsorption.

Therefore, the main effect of osmotic diuretics is to increase the amount of water excreted, with an associated slight decrease in sodium reabsorption. They cannot be used to treat conditions associated with sodium retention, but are used to treat acutely raised intracranial pressure, and prevent acute renal failure. Acute renal failure involves reduction in glomerular filtration rate, with almost complete reabsorption of salts and water in the proximal tubule. Distal parts of the nephron virtually dry up, and urine flow ceases, but osmotic diuretics limit these effects.

The reduction of raised intracranial pressure is associated with an increase in plasma osmolarity by solutes that do not enter the brain or eye, resulting in extraction of water from the cranium. The effect is lost as soon as the diuretics are excreted in the urine, as the effects have nothing to do with the kidney.

Diuretics Acting on the Proximal Tubule

Increased excretion of bicarbonate can be caused by carbonic anhydrase inhibitors, and these drugs also cause increased excretion of sodium, potassium and water. This results in alkaline urine with an increased flow, and a mild metabolic acidosis. They are not used as diuretics any longer, but may be used to treat glaucoma by reducing the formation of aqueous humor, and also to treat altitude sickness by increasing the rate of breathing.

Carbonic anhydrase catalyses the formation of carbonic acid from carbon dioxide and water in the proximal tubule cells. The carbonic anhydrase then dissociates, with the bicarbonate ion passing into the plasma, and the hydrogen ion being secreted into the lumen. The secretion of hydrogen is balanced by antiport sodium transport, driven by the electrochemical gradient for sodium. In the lumen, the hydrogen ions combine with bicarbonate ions to form carbonic acid, this is then catalysed back to water and carbon dioxide by carbonic anhydrase. This carbon dioxide then diffuses back into the cell with the net effect of bicarbonate reabsorption in the proximal tubule. Carbonic anhydrase inhibitors increase urine flow by preventing bicarbonate reabsorption, and depleting extra cellular bicarbonate. The effect is self-limiting as the concentration of bicarbonate falls.

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Mechanism of Action of Diuretics in Human Body. (2020, Jun 01). Retrieved from http://studymoose.com/mechanism-of-action-of-diuretics-in-human-body-essay

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