Diuretic drugs

Diuretics

Diuretic drugs are agents that increase the salt and water excretion by an action on the kidneys. Diuretics effective for the treatment of edema have been available since the 16th century and mercurous chloride was known by Paracelsus to be diuretic.

In 1930, Swartz discovered that the antimicrobial sulfanilamide could be used to treat edema in patients with congestive heart failure due to an increase in renal excretion of Na+.

Most modern diuretics were developed when side effects of antibacterial drugs were noted, which included changes in urine composition and output.

Except for spironolactone, diuretics were developed empirically, without knowledge of specific transport pathways in the nephron. They are used mainly in cases of cardiac failure, edema and hypertension.

Physiological diuresis

Physiological diuresis is occasionally desirable to provoke diuresis in order to increase urinary flow or volume as in the case of treatment of cystitis or to prevent crystalluria with sulphonamide therapy, rather than with the intention of reducing body fluid volume. In such cases increased water intake is sufficient.

Classification of diuretic drugs

Based on their action on the kidneys diuretics are classified as-

  1. Diuretics acting directly on the cells of the nephron
    • Agents acting on the ascending loop of Henle – Ethacrynic acid, frusemide
    • Agents acting on the early distal tubules – Thiazides like chlorthiazide
    • Agents acting on the Collecting tubules and ducts – Triamterene, amiloride
  2. Diuretics modifying the contents of the filtrate
    • Osmotic diuretics – Mannitol
    • Carbonic anhydrase inhibitors – Acetazolamide

Based on their mode of action diuretics are classified as-

  1. Osmotic diuretic drugs – Glycerine, mannitol, urea, isosorbide
  2. Inhibitors of carbonic anhydrase – Acetazolamide, dichlorphenamidine
  3. Inhibitors of Na+-K+-2Cl– symport (High ceiling loop diuretics) – Frusemide, Ethacrynic acid, Bumetanide
  4. Inhibitors of Na+-Cl– symport – Thiazide and thiazide like drugs
  5. Potassium sparing diuretics
    • Inhibitors of epithelial sodium channels – Triamterene, amiloride
    • Antagonists of aldosterone – Spironolactone
  6. Xanthine diuretics – Theophylline

Diuretics also can be classified as

  1. Cardiac diuretics – Xanthines
  2. Osmotic diuretics – Mannitol, Isosorbide, Urea
  3. Natriuretics – Mercurials, Thiazides, Acetazolamide
Diuretic drugs - Site of action of Diuretics
Diuretic drugs – Site of action of Diuretics

Osmotic diuretics

Osmotic diuretics are inert substances filtered into the glomerulus. their main effect is exerted in the proximal tubule, descending limb of Henle and the collecting duct which are freely permeable to water. By remaining in the tubular lumen, these agents cause an increase in colloid osmotic pressure in the tubular lumen causing suction of water into the tubular lumen. There is also reduced water reabsorption due to renal medullary hyperemia. and there is impairment of Na+ reabsorption because the diluted solution in the lumen reduces the Na+ concentration gradient, making it harder for Na+ to be reabsorbed.

Osmotic diuretics are not useful in treating conditions with sodium retention. These drugs are useful in acutely raised intracranial pressure or intraocular pressure. They are also useful in prevention of acute renal failure.

Unwanted effects include transient expansion of extracellular fluid volume and hyponatraemia, headache and vomiting.

Mannitol is commonly used as an osmotic diuretic and has to be administered intravenously. Isosorbide has the advantage of being absorbed after oral administration in monogastric species.

Carbonic anhydrase inhibitor diuretics

Bicarbonates penetrate the luminal membrane only very slowly, and its absorption in the proximal tubule is heavily dependent on the presence of an enzyme ‘carbonic anhydrase’. This is a zinc containing enzyme whose function is to speed up the attainment of equilibrium of the reaction:

CO2 + H2O → H2CO3

Role of carbonic anhydrase in diuresis is that it is capable of accelerating this reaction in either direction. This enzyme is found within the proximal tubule cells and in association with their luminal brush border.

Role of carbonic anhydrase in diuresis - Diuretic drugs
Role of carbonic anhydrase in diuresis – Diuretic drugs

The activating step in the process of bicarbonate absorption is the secretion of H+ into the tubule lumen, which is largely responsible for the favourable electrical gradient down which Nadiffuses into the cell.

This His derived from the dissociation of carbonic acid, whose supply is facilitated by the presence of carbonic anhydrase.

The carbonic anhydrase inhibitors interfere with the absorption of bicarbonate from the proximal tubule, by reducing the supply of Hto the membrane pump and by reducing the rate of absorption of carbonic acid from the lumen.

Filtered bicarbonate is thus trapped in the urine together with an electrically equal amount of Na+ and an osmotically equivalent amount of water.

These drugs cause an increased excretion of bicarbonate with accompanying sodium, potassium and water excretion resulting in an increased flow of alkaline urine and mild metabolic acidosis.

Carbonic anhydrase inhibitor diuretics are poor diuretics because there is compensatory reabsorption of Na+ is the segments further down the nephron. These drugs are used in glaucoma and in some types of epilepsy.

Their action results in a depletion of extracellular bicarbonate and their effect is self limiting as the blood bicarbonate level falls.

Side effects are drowsiness, numbness and tingling of the face and extremities (due to metabolic acidosis) and disturbances of vision.

Carbonic anhydrase inhibitor diuretics group of drug is rarely used as diuretics. Acetazolamide used as a carbonic anhydrase inhibitor is a derivative of a sulphonamide but does not possess any antibacterial action. Acetazolamide is a non-competitive, irreversible inhibitor of carbonic anhydrase.

Loop diuretics (High ceiling diuretics)

Loop diuretics ( High ceiling diuretics) are the most effective diuretics A fairly high proportion of Na+ is also reabsorbed in the loop of Henle (22%). They are inhibitors of Na+, K+ Cl symport.

Main effect of this group of diuretics is inhibition of chloride pumping throughout the whole length of the thick ascending limb of Henle, thus paralysing the kidney’s ability to concentrate and to dilute the urine.

Loop diuretics effect is from the luminal surface of the loop cells. These drugs are extensively bound to plasma proteins and relatively little is filtered in the glomerulus.

They are actively secreted by the organic anion transporters at the site of action. Substances, like probenecid which block this mechanism , can reduce their efficacy.

Examples of Loop diuretics are Frusemide, Bumetanide and Ethacrynic acid. Frusemide and bumetamide are sulphonamide derivatives while ethacrynic acid is not a sulphonamide derivative.

Ethacrynic acid may produce clinical dehydration and acute circulatory collapse as it produces severe diuresis after administration. Frusemide produces rapid diuresis and hence is useful in emergency cases. It is easier to control the degree of diuresis with this drug by varying the dose rate. There is an increase in the excretion of calcium and magnesium and a decreased excretion of uric acid.

The effect on calcium is made use of in the treatment of hypercalcaemia. The loop diuretics are readily absorbed from the gastrointestinal tract and can also be administered parenterally.

Administration of Loop diuretics

  • Orally or intravenously at 1-5 mg/kg in dogs.
  • This can be doubled with successive doses until an effect is obtained.
  • Duration of action is 4-6 hours.
  • In horses the drug is given at the rate of 0.5 mg/kg to reduce incidence of epistaxis.
  • In cattle given orally at 0.5-1 mg/kg, 12-24 hourly. Loop diuretics are useful in patients with salt and water overload due to acute pulmonary oedema, chronic heart failure, hepatic cirrhosis complicated by ascites, nephrotic syndrome etc.
  • Hypertension especially if accompanied by renal impairment.
  • Acute treatment of hypercalcaemia.
  • Untoward effects include potassium loss, metabolic alkalosis, depletion of calcium and magnesium, hypovolaemia and hypotension.
  • Local irritation of the gastronintestinal tract and competition with other drugs like digitalis are noticed.
  • As with other potent diuretics, hyponatraemia can occur, but deafness is an adverse effect peculiar to loop diuretics.
  • Hence concurrent dosing with aminoglycosides is contraindicated.

Thiazide diuretics

Thiazide diuretics group includes chlorthiazide, hydrochlorthiazide, bendrofluazide, cyclopenthiazide. These drugs are more potent than carbonic anhydrase (CA) inhibitors. Most thiazides are weak inhibitors of CA, but this is not the basis of their action.

Site of action of thiazide diuretic is at the distal tubule (hence they are medium acting diuretics) where there is only a small amount of reabsorption of sodium since most of the Na+ is already absorbed in the earlier parts of the nephron. In the distal tubule, Na+ is reabsorbed via a Na+ Cl co-transport.

Thiazides inhibit this co-transport mechanism, thus preventing Na+ from being reabsorbed. this drugs may also inhibit the Na+ K+ ATPase indirectly.

Due to Na+ K+ counter exchange at the collecting tubule, potassium loss may be induced by these drugs leading to serious hypokalemia.

The thiazides are active by mouth as well as by parenteral administration. Their effects are fairly slow in onset.

Thiazides are used in the treatment of oedema in cardiac failure. In hepatic cirrhosis, much K+ loss is not appreciable. Hence thiazides are given in conjunction with Ktablets or with a K+ sparing diuretic.

Thiazides are secreted in the kidney via the organic acid secretary system.

Side effects of Thiazide diuretic

  1. Hypokalemia
  2. Increase in blood sugar (hyperglycemia), especially in diabetics,
  3. Reduced insulin also causes increased glycogenolysis and reduced glycogenesis.
  4. Thiazides may cause a reduced excretion of uric acid, leading to gout. The thiazides are sulphonamides, and so share cross reactivity with other drugs of this group.
  5. Therefore, if a patient is allergic to a sulphonamide, chances are that the patient will also be allergic to thiazides.
  6. Photosensitivity and haemolytic anaemia may occur.

Potassium sparing diuretics

There are 2 groups of drugs in this category. The only thing, they have in common is their site of action (late distal tubule and collecting duct). However their mechanism of action is quite different. these drugs functions by Inhibition of aldosterone – Spiranolactone and Inhibition of the Na+ K+ exchange in the collecting duct – Triamterene, Amiloride.

Aldosterone antagonists

  • Aldosterone (a steroid hormone) enters tubular cells and binds to a mineralocorticoid receptor in the cytoplasm.
  • This hormone receptor complex binds to a response element on the DNA.
  • Binding results in the expression of aldosterone induced proteins leading to activation of silent Na+ channels/pumps, alteration of the cycling of the channels and pumps, increased expression of channels and pumps and altered permeability of the tight junction (zonula occludens).
  • All the above effects result in an increase in Na+ conductance (reabsorption) and secretion of K+ (One of the complications of excess aldosterone secretion is hypokalemia).
  • Spiranolactone binds to the mineralocorticoid receptor and prevents aldosterone from binding.
  • Spiranolactone a true competitive antagonist of aldosterone enhances direct reabsorption of sodium in more proximal areas of the distal tubules.
  • This drug has a very slow onset of action, which is not dose dependent.
  • It may exert oestrogen like activity
  • It is used in combination with thiazide diuretics.
  • Spiranolactone is not effective in the presence of low levels of aldosterone.
  • It is available only for oral administration.
  • If hyperkalemia occurs as a result of spiranolactone toxicity, thiazide diuretics can be administered.

Triamterene and amiloride

  • These drugs have a limited diuretic efficacy.
  • They act on the collecting tubules and collecting ducts, inhibiting sodium reabsorption and decreasing potassium excretion.
  • Triamterene inhibits aldosterone specific ATPase.
  • But, is not dependent on aldosterone levels.
  • Amiloride blocks Na+ channels in the luminal membrane affecting Napermeability.
  • Both the drugs promote excretion of uric acid.
  • The main importance of these drugs lies in their potassium-sparing ability.
  • They can be given with potassium-losing diuretics like thiazides to maintain potassium balance.
  • They are useful in conditions where K+ loss cannot be tolerated (often used in conjunction with thiazides)
  • In hypertension and congestive heart failure – If a person is being treated with digoxin for their heart failure, loss of K+ can enhance the toxicity of digoxin (cardiac glycoside).
  • If K+ is reduced, the actions of digoxin are enhanced because normally, digoxin must compete with Kfor the Na+ K+ ATPase.
  • By using the drugs in combination, there is an enhanced diuretic effect and the added benefit of not losing K+.
  • Spironolactone is used in primary hyperaldosteronism (tumor of the adrenals) or secondary hyperaldosteronism (cardiac failure, hepatic cirrhosis).

Side effects of Potassium sparing diuretic

  1. Hyperkalemia
  2. Metabolic acidosis
  3. Gynecomastia
  4. Impotence
  5. Decreased libido
  6. Hirsutism
  7. Gastric upsets

Xanthines diuretics

Xanthines diuretic drugs stimulate cardiac functions. Their diuretic activity may stem from the resultant increase in renal blood flow and thereby an increase in glomerular filtration rate. They also exert a direct action on the renal tubule. Renal response is manifested by an increase in levels of sodium and chloride in urine.

There is no significant change in the urine pH and potassium excretion appears to be relatively unaffected. Examples of xanthine diuretics are Caffeine, Theophylline

Mercurials diuretics

Diuretic action of mercurials is associated with sulphydryl groups and so they inactivate the sodium transport mechanism of the nephron.

For clinical use, mercurials are obsolete.

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