Diuretics mainly exert their effect by inhibition of renal tubular reabsorption of sodium and water.

These may be classified according to their efficacy as

high ceiling(loop and osmotic diuretics),

medium ceiling(thiazides) and

low ceiling(carbonic anhydrase inhibitors and potassium sparing) diuretics

These are non-competitive but reversible inhibitors of carbonic anhydrase and act by inhibiting the reabsorption of sodium in the proximal tubular portion of the nephron

Luminal membrane of proximal tubules contain Na+-H+ antiporter which helps in the excretion of H+ in exchange with the reabsorption of Na+.

The net effect of carbonic anhydrase is to cause the absorption of sodium and bicarbonate

Inhibitors of this enzyme acetazolamide result in excretion of sodium and bicarbonate in the urine

acetazolamide, dichlorphenamide, and methazolamide

Due to urinary excretion of bicarbonate, metabolic acidosis and urinary alkalosis ensues that result in reduced filtration of HCO3- at the glomerulus

Therefore the action of carbonic anhydrase inhibitors are self-limiting

These agents also decrease the secretion of H+

Due to less reabsorption of sodium in the PT, more is delivered to the distal tubules

AT this site also known as cortical diluting segment, Na+ is exchanged with K+ and H+

Drugs that increase the delivery of Na+ to this site(thiazides, loop diuretics, CA inhibitors), will result in greater exchange and thus can cause hypokalemia

At equally natriuretic doses, K + excretion is maximum with CA inhibitors because Na+ delivered to the distal tubules is exchanged only with K+

because excretion of H+ is inhibited by these drugs

The major indication for carbonic anhydrase inhibitors is open-angle glaucoma

Two products developed specifically for this use are dorzolamide and brinzolamide, which are available only as ophthalmic drops

Orally administered acetazolamide is also used for the treatment of glaucoma and absence seizures

Acetazolamide can provide symptomatic relief
in patients with high-altitude illness or mountain sickness

Carbonic anhydrase inhibitors are also useful in patients with familial periodic paralysis

Dichlorphenamide is now approved for treating this syndrome

The mechanism for the beneficial effects of carbonic anhydrase inhibitors in altitude sickness and familial periodic paralysis may relate to the induction of a metabolic acidosis

Acetazolamide is a sulphonamide derivative and can result in bone marrow suppression and hypersensitivity reaction

Other adverse effects include metabolic acidosis(urinary alkalosis) and hypokalemia

Carbonic anhydrase inhibitors should not be used in the presence of liver disease due to the risk of precipitation of hepatic coma

In liver disease, NH3 is not converted to urea

and it is present in excess can cross the blood brain barrier resulting in encephalopathy.

It is excreted through kidney after conversion to NH4+ as it combines with H+ in the nephron

CA inhibitors decrease the excretion of H+ resulting in enhanced reabsorption of ammonia

because it is non-ionized form in the alkaline medium and thus more toxicity

Furosemide, bumetanide, torsemide and ethacrynic acid

They have greater maximal natriuretic effect than all other diuretics(high ceiling diuretics)

These drugs are faster acting with short duration of action

Loop diuretics and thiazides gain access to the tubular lumen through secretion by organic anion transporter in the PT

Loop of henle is responsible for maintaining the difference in osmotic pressure between cortex and medulla(corticomedullary osmotic gradient)

This gradient results from the absorption of water from the descending loop of henle(permeable to water)

and reabsorption of salt in the ascending limb (impermeable to water)

Loop diuretics abolish corticomedullary osmotic gradient

By inhibiting NA+K+2Cl- symporter, absorption of Na+ in loop of henle decreases

This unabsorbed 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

These drugs are also weak CA inhibitors(except ethacrynic acid, it doesn’t increase bicarbonate excretion in the urine)

Loop diuretics also change intrarenal hemodynamics resulting in decreased absorption of Na+ and water in the PT

these changes are mediated by the release of PGs(NSAIDS attenuate diuretic effect)

Since GFR not altered, 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 IV

Bumetanide is the most potent loop diuretic and

produces lesser adverse effects than furosemide

Ethacrynic acid is highly ototoxic with steep DRC

Mersalyl like organomercuicals are not used now due to the risk of kidney damage

Torsemide has longest half life

main use of loop diuretics is to remove the edema fluid in renal, hepatic or cardiac disease

These can be administered IV for prompt relief of acute pulmonary edema due to vasodilatory action

Thes drugs can cause excretion of ca2+ therefore can be used for the treatment of hypercalcemia

In patients with a drug overdose, loop diuretics can be used to induce forced diuresis to facilitate more rapid renal elimination of the offending drug

Loop diuretics combined with hypertonic saline are useful for the treatment of life-threatening hyponatremia

hypokalemia
hypomagnesemia
hyponatremia
alkalosis
hyperglycemia CI in diabetes mellitus
hyperuricemia CI in gout and
dyslipidemia

are seen with both thiazides as well as loop diuretics

But the effect on calcium excretion is opposite to thiazides( loop looses calcium)

Loop diuretics cause hypocalcemia by increasing the excretion of Ca2+

whereas thiazides cause hypercalcemia by decreasing its excretion

Ethacrynic acid can cause more ototoxicity more often than other loop diuretics.

Furosemide and bumetanide are sulphonamides in chemical structure

so they should be avoided in persons allergic to sulphonamides

mannitol, glycerol, urea and isosorbide are inert

drugs that can cause osmotic diuresis

Previously it was thought that osmotic diuretics act primarily in proximal tubules

but recent studies have suggested these drugs act both in PT as well as loop of henle

But the latter is the major site of action

When administered IV mannitol increases the osmotic pressure in the blood vessels

and the consequent removal of excess fluids from cells basis of its use in glaucoma and cerebral edema

results in expansion of extracellular fluid volume

Consequently renal blood flow and GFR increases

Further it is filtered at the glomerulus and reaches the proximal tubule(PT) and loop of henle

It inhibits the reabsorption in ascending loop of henle by decreasing medullary tonicity

Decreased medullary tonicity prevents the reabsorption of water from descending limb

that results in decreased absorption of solutes from ascending limb

Along with water, excretion of all the cations and anions increased

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

One use for mannitol is in the treatment of dialysis disequilibrium syndrome

A spray-dried form of mannitol is FDA approved for managing cystic fibrosis in adults; by hydrating airways,

mannitol improves mucus clearance.

Mannitol is also FDA approved for the diagnosis of bronchial hyperreactivity (by oral inhalation)

and for antihemolytic urologic irrigation during transurethral procedures

Mannitol is often used to treat or prevent acute kidney injury

It is contraindicated in acute renal failure because ECF volume increases but it cant be filtered

It is also contraindicated in cerebral haemorrhage(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

patients with heart failure or pulmonary congestion, this may cause frank pulmonary edema

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

These drugs reach the lumen of nephron by secretion through organic acid transporter system

Additional CA inhibitory action is also exhibited by thiazides

hyopkalemia more than loop diuretics

Thiazides are moderate efficacy diuretics with low ceiling effect(flat DRC)

natriuretic effect doesn’t increase appreciably with increase in dose

These drugs tend to reduce GFR, therefore are not indicated in renal failure patients

used for the treatment of edema associated with
diseases of the

heart (CHF)

liver (hepatic cirrhosis)

and kidney (nephrotic syndrome, chronic renal failure, and acute glomerulonephritis)

With the possible exceptions of metolazone and indapamide, most thiazide diuretics are ineffective when the GFR is less than 30 to 40 mL/min

Thiazide diuretics decrease blood pressure in hypertensive patients and

are used widely for the treatment of hypertension in combination with other antihypertensive drugs

Thiazide diuretics, which reduce urinary Ca2+ excretion, so

are employed to treat Ca2+ nephrolithiasis and

may be useful for treatment of osteoporosis

mainstay for treatment of nephrogenic diabetes insipidus (DI), reducing urine volume by up to 50%

Adverse effects of thiazides: these are similar to loop diuretics except the effect on Ca2+ excretion

Incidence of erectile dysfunction is greater with thiazides than with other antihypertensive drugs

Thiazides and loop diuretics enhance digitalis toxicity by causing hypokalemia and hypomagnesemia

Loop diuretics can enhance ototoxicity and nephrotoxicity of aminoglycosides

NSAIDs attenuate the actions of loop diuretics

Lithium toxicity can occur if used with diuretics

these diuretics act in the late DT and CD cells to preserve k+

Luminal membrane of these portions of renal tubule contain epithelial Na+ channels responsible for reabsorption of Na+

Due to decreased positive charge in the lumen, a transepithelial potential difference is generated(lumen negative)

Under this potential gradient K+ and H+ are secreted

These actions are promoted by aldosterone

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 are basic in nature and reach the lumen of PT by secretion through organic base secretory system

By travelling through the lumen, these drugs reach its site of action i.e late DT and CD

Important members of this group are triamterene and amiloride

Pentamidine and high dose trimethoprim used for pneumocystitis are also weak inhibitors of this channel

Amiloride is more potent and longer acting than triamterene

Triamterene is less often used because of incomplete absorption, photosensitivity and impairment of glucose tolerance

It is also associated with interstitial nephritis and renal stones

Lithium is absorbed through epithelial Na+ channels in CD cells and at toxic doses can cause diabetes insipidus

Amiloride is the drug of choice for this condition

It acts by blocking the entry of lithium through these channels

Aerosolized amiloride has been shown to improve mucociliary clearance in patients with cystic fibrosis

By inhibiting Na+ absorption from the surfaces of airway epithelial cells,

amiloride augments hydration of respiratory secretions and thereby improves mucociliary clearance

• Edema associated with congestive heart failure, liver cirrhosis, and chronic kidney disease

• Frequently combined with loop or thiazide diuretics to prevent hypokalemia and increase diuresis

• Risk of hyperkalemia in renal insufficiency or when combined with angiotensin converting enzyme inhibitors or angiotensin receptor blockers

Triamterene is a weak folic acid antagonist and can lead to megaloblastic anemia especially in cirrhotic patients

finerenone was FDA approved to reduce the risk of end-stage kidney disease, cardiovascular death, and heart failure in diabetic patients with CKD

spironolactone, eplerenone antagonize the action of aldosterone and produce effects similar to amiloride

These drugs act from interstial side 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

and are ineffective in its absence like addisons disease

Spironolactone is converted to canrenone and other active metabolites in the liver

• Edema associated with congestive heart failure, liver cirrhosis, chronic kidney disease

• Eplerenone and finerenone contraindicated with potent inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole)

• Spironolactone active metabolite has long half-life requiring slow dose adjustments (over days)

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

Spironolactone can cause gynaecomastia and impotence

Hyperkalemia, abdominal pain and aggravation of peptic ulcer

Hyperkalemia and GI disorders are the main adverse effects of eplerenone

The drugs that decrease urine volume are called antidiuretics

Primary indication of antidiuretics is the treatment of diabetes insipidus

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 ECF

• Use with extreme caution in patients with vascular disease

• Prevention of blood loss in patients with specific bleeding disorders like Von Willebrand disease and Hemophilia A

• Treatment of hypervolemic and euvolemic hyponatremia

• Risk of too rapid correction with serious consequences (osmotic demyelination syndrome)