DIURETICS

Diuretics mainly exert their effect by the inhibition of renal tubular reabsorption of sodium
and water and increases urine volume. OR. Diuretics (natriuretics) are drugs which cause a
net loss of Na+ and water in urine
CLASSIFICATION
Carbonic anhydrase inhibitors-Acetazolamide, dichlorphenamide and methazolamide
Loop diuretics (Inhibitors of Na+-K+-2Cl¯ cotransport)-Furosemide, Bumetanide, Torasemide
Thiazides (Medium efficacy diuretics) (Inhibitors of Na+-Cl¯ symport)
Benzothiadiazines (thiazides) Hydrochlorothiazide, Benzthiazide, Hydroflumethiazide,
Bendroflumethiazide
Thiazide like (related heterocyclics) Chlorthalidone, Metolazone, Xipamide, Indapamide, Clopamide
Potassium sparing diuretics
(i) Aldosterone antagonist: Spironolactone, Eplerenone
(ii) Inhibitors of renal epithelial Na+ channel: Triamterene, Amiloride.
(c) Osmotic diuretics-Mannitol, Isosorbide, Glycerol

Carbonic Anhydrase (CA) Inhibitors

Luminal membrane of proximal tubules contain Na+–H+ antiporter which helps in the excretion of
H+ in exchange with the reabsorption of Na+. The H+ is formed inside the tubular cells due to the
action of carbonic anhydrase according to the reaction:

–
The secreted H+ combines with HCO3– in the lumen of PT with the help of carbonic anhydrase to
form carbonic acid (H2CO3), which is converted to H2O and CO2. Latter are absorbed in the tubular
cell and again converted to HCO3 – and H+. Thus, the net effect of carbonic anhydrase is to cause the
absorption of sodium and bicarbonate. Inhibitors of this enzyme (acetazolamide, dichlorphenamide
and methazolamide) result in the excretion of sodium and bicarbonate in the urine. Due to urinary
excretion of bicarbonate, metabolic acidosis (and urinary alkalosis)
Dorzolamide and brinzolamide are topically acting CA inhibitors for use in glaucoma as eye drops.
Acetazolamide is a sulfonamide derivative and can result in bone marrow suppression and
hypersensitivity reactions. Other adverse effects include metabolic acidosis (urinary alkalosis) and
hypokalemia
Inhibitors of Na+-K+-ATPase
These are also known as loop diuretics and act by causing inhibition of Na+ K+ 2Cl– symporter
present at the luminal membrane of the ascending limb of loop of Henle By inhibiting Na+ K + 2Cl–
symporter, absorption of Na+ in loop of Henle decreases. Thismunabsorbed Na+ reaches DT, where it
is exchanged with K+ and H+ resulting in hypokalemia and alkalosis. At equivalent doses, loop
diuretics cause less hypokalemia than thiazides loop diuretics are the diuretics of choice in presence
of moderate to severe renal failure Furosemide possesses vasodilatory action which is responsible
for the quick relief in LVF and pulmonary edema (used i.v.).
• Bumetanide is the most potent loop diuretic and produces less adverse effects than furosemide.
• Ethacrynic acid is highly ototoxic
Uses
Main use of loop diuretics is to remove the edema fluid in renal, hepatic or cardiac diseases. These
can be administered i.v. for prompt relief of acute pulmonary edema (due to vasodilatory action).
These drugs cause excretion of Ca++, therefore can be used for the treatment of hypercalcemia
Adverse Effects
Hypokalemia, hypomagnesemia, hyponatremia, alkalosis, hyperglycemia (C/I in DM),
hyperuricemia (C/I in gout) and dyslipidemia are seen with both thiazides as well as loop
diuretics
Osmotic Diuretics
Mannitol, glycerol, urea and isosorbide are inert drugs that can cause osmotic diuresis.
When administered i.v., mannitol increases the osmotic pressure in the blood vessels and the
consequent removal of excess fluid from the cells (basis of its use in glaucoma and cerebral edema)
results in the expansion of extracellular fluid volume. Consequently, renal blood flow and GFR
increases Properties for a substance to act as an ideal osmotic diuretic are:
• It should exert osmotic effect.
• It should be pharmacologically inert.
• It should be freely filtered at the glomerulus.
• It should not be reabsorbed.
Mannitol is a low molecular weight compound possessing all these properties. It is used i.v. for the
treatment of glaucoma and cerebral edema. It can also be used to maintain GFR in the impending
renal failure. It is contraindicated in acute renal failure because ECF volume increases but it cannot be
filtered. It is also contraindicated in cerebral hemorrhage (active bleeding) because in this
situation, mannitol can leak from ruptured cerebral blood vessels resulting in the increased ICT (more
fluid retention due to its osmotic effect in the cells). If given orally, mannitol can result in osmotic
diarrhea. Isosorbide and glycerol can be used orally for the treatment of glaucoma and cerebral
edema.
Thiazides
These drugs act by inhibiting Na+-Cl– symporter at the luminal membrane of early DT. This part of
DT is impermeable to water and absorbs only solutes. By increasing excretion of solutes, thiazides
make the urine concentrated Decreased absorption of Na+ results in its greater delivery to late DT and
CD that is responsible for hypokalemia (more than loop diuretics). Chlorthiazide has minimum
potency and efficacy These drugs tend to reduce GFR, therefore are not indicated in renal
failure patients.
• Polythiazide and trichloromethiazide are most potent thiazides.
• Chlorthalidone is the longest acting thiazide.
• Metolazone is useful even in severe renal failure.
• Indapamide has no CA inhibitory action. It has vasodilatory property because of which, its
antihypertensive effect precedes the natriuretic effect.
Uses
Thiazides are used as first line antihypertensive drugs. These are also used to mobilize the edema fluid
in mild to moderate heart failure. Paradoxically, these drugs decrease urine output in diabetes
insipidus. Thiazides reduce the excretion of Ca++ in the kidney, so can be used for the treatment of
patients with hypercalciurea and recurrent Ca++ stones in the kidney.
Adverse effects
These are similar to loop diuretics except the effect on Ca++ excretion. Incidence of erectile
dysfunction is greater with thiazides than with other antihypertensive drugs (like β blockers,
CCBs, ACE inhibitors and α blockers)

Potassium Sparing Diuretics

These diuretics act in the late DT and CD cells to preserve K+. Luminal membrane of these portions
of renal tubule contains epithelial Na+ channels responsible for reabsorption of Na+. Drugs that
inhibit the epithelial Na+ channels or the actions of aldosterone can decrease the reabsorption of Na+
(diuretic effect) and excretion of K+ (potassium sparing effect) and H+. these drugs reach its site of
action i.e. late DT and CD. Important members of this group are amiloride and triamterene
Amiloride is more potent and longer acting than triamterene
Triameterene is a weak folic acid antagonist and can lead to megaloblastic anemia
especially in cirrhotic persons.
• Amiloride decreases Mg++ and Ca++ excretion and increases urate excretion

Aldosterone antagonists
Spironolactone, canrenone, potassium canreonate and epleronone antagonize the action of
aldosterone and produce effects similar to amiloride. These drugs act from the interstitial
site of tubular cell (all other diuretics act from luminal side). These agents have maximum effect
when aldosterone levels are high (e.g. hepatic cirrhosis, CHF, nephrotic syndrome etc.) and are
ineffective in its absence (e.g. Addison’s disease). Spironolactone increases Ca++ excretion
whereas amiloride decreases it. Spironolactone is converted to canrenone and other active
metabolites in the liver
Uses: These are weak diuretics and are used only in combination with thiazides or loop
diuretics to counteract K+ loss. These can be used for CHF (decrease mortality), hypertension and
cirrhotic edema (diuretic of choice is spironolactone) Spironolactone can be used for the treatment of
hirsutism because of its anti-androgenic action. (Its structure is similar to testosterone and thus it acts
as a competitive antagonist at testosterone receptors.
Adverse effects and interactions: Spironolactone can cause gynaecomastia and impotence.
Hyperkalemia, abdominal pain and aggravation of peptic ulcer can also occur. ACE inhibitors
and potassium supplements increase the risk of hyperkalemia, if used along with these agents.
Hyperkalemia and GI disorders are the main adverse effects of epleronone. It is metabolized
by microsomal enzymes; therefore, is prone to drug interactions

ANTI-DIURETICS
The drugs that decrease urine volume are called antidiuretics. Primary indication of antidiuretics is the
treatment of diabetes insipidus (DI)
Anti-Diuretic Hormone (ADH)
Physiological antidiuretic is vasopressin (antidiuretic hormone or ADH) that is synthesized
in the hypothalamus and secreted by the posterior pituitary. It is secreted in response to increased
plasma osmolality or decreased volume of extracellular fluid (ECF). ADH acts via 3 receptors V1,
V2 and V3.
Actions of ADH
• In the absence of ADH, collecting ducts (CD) of the nephron are impermeable to water. ADH
increases the permeability of CD by its action on V2 receptors. Stimulation of these receptors elevates
cAMP levels that increase aquaporins on the apical membrane of CD (by decreasing endocytosis and
increasing exocytosis).V2 receptor activation also increases permeability of CD to urea by stimulating
the urea transporter.
• Vasopressin (ADH) as the name suggests is a potent pressor of blood vessels ADH is also involved
in the release of vWF and factor VIII from the endothelium. This action is also mediated by V2
receptors.
• V3 receptors (previously known as V1b receptors) are involved in the release of ACTH Use of ADH
(arginine vasopressin) for this indication is limited due to two reasons; its short half life (require
frequent daily dosing) and non-specific action on V1 and V2 receptors (V1 mediated vasoconstriction
can result in increased BP). Both of these shortcomings have been overcome in desmopressin. It is
longer acting and V2 selective analogue of vasopressin and is the drug of choice for the treatment of
central DI. It can be administered orally or intranasally.
• Desmopressin (oral) is also the drug of choice for nocturnal enuresis and bed wetting in children.
Intranasal desmopressin is not used for this indication now because of risk of dilutional hyponatremia
• Another V2 receptor mediated use of desmopressin is to check bleeding in patients with
hemophilia and von Willebrand’s disease. It acts by releasing factor VIII and vWF from the
endothelium.
• Arginine vasopressin (AVP) has vasoconstrictor action that can be utilized to stop bleeding in
esophageal varices. Lypressin has longer duration of action but is non-specific (action on both V1
and V2). Terlipressin (prodrug of vasopressin) is the preferred agent for this indication.
• Felypressin can also be used along with local anaesthetics to prolong their duration of action (like
adrenaline).
Adverse Efects and Contra-indications
Intranasal desmopressin can cause nasal irritation and rhinitis. AVP can cause hypertension and
precipitation of angina, so it is contra-indicated in the patients with ischemic heart disease and
hypertension