Major classes of diuretic drugs: Class Carbonic anhydrase inhibitors Example Acetazolamide Comparison Less efficacious than the

thiazides and the loops Site of action Proximal tubular epithelial cells. Mechanism of action -Inhibits carbonic anhydrase (both luminal & intracellular CA) + - CA catalyses CO2+ H2O<-> H + HCO3 + -At DCT H ions are normally excreted in + exchange for Na + + - ability to exchange Na for H results in mild diuresis + - Only a weak effect on Na retention since the loop of Henle is able to reabsorb a large fraction of excess NaCl in the fluid leaving from the proximal tubule. Therapeutic uses i) Treatment of chronic glaucoma: -block CA in the ciliary body of eye decrease the production of aqueous humor  reduce the elevated intraocular pressure ii) Prophylaxis of acute mountain sickness: -given nightly 5 days before ascent above 10 000ft -prevents weakness, breathlessness, dizziness, nausea and cerebral & pulmonary edema i) Edematous state: reduce acute pulmonary edema of congestive heart failure (rapid onset, useful in emergency situations for rapid, intense diuresis) ii) Hypercalcemia: stimulate tubular Ca secretion, reducing Ca conc in blood iii) Severe traumatic brain injury: reduce intracranial pressure i) Hypertension: effective in reducing systolic & diastolic blood pressure for extended periods. After ~7 days, bp stabilises at lower level. ii) Mild/Moderate Congestive Heart Failure: reduce extracellular volume iii)Hypercalciuria: prevent recurrent kidney stone formation Pharmaco kinetics Adverse effects

Loop diuretics

Bumetanide Furosemide

Thiazides and related agents

Chlorothiazide Hydrochlorothia zide Chlorthalidone

Most effective of the diuretics (coz ascending limbs accounts for reabsorption of 2530% of filtered NaCl, downstream sites not able to compensate for Na excretion Most widely used diuretics

Ascending loop of Henle

-Inhibits Na /K /2Cl carrier in the luminal + membrane, therefore reabsorbtion of Na , + K ,Cl is decreasesd

+

+

-

-Administered orally @ parenterally -Duration of action relatively brief:1-6 hours

i) potassium depletion (hypokalemia) ii) Acute hypovolemia iii) Hyperuricemia iv) Oxtoxicity (rare)

Distal tube

- Binds to the Cl site of the Na+/Cl- cotransporter on the luminal membrane and inhibiting its action the reabsorption of Na -results in conc of Na&Cl in tubular fluid Chlorothiazide action: excretion of Na & Clloss of K+  decreased urinary calcium excretion (thiazide diuretics promote the reabsorption of Ca *contrasts with loop diuretics*) -continued usereduced peripheral vascular resistance,caused by relaxation of arteriolar smooth muscle.

-effective orally -take 1-3 weeks for stable reduction in bp -exhibit prolonged biological hallife(40hr)

Serious but rare i)Potassium depletion ii)Hyperuricaemia iii)Volume depletion iv)Hypercalcemia v)Hyperglycemia vi)Hypersensitivity

Potassium -Sparing Diuretics Spironolactone Amiloride Triamterene Major use in treatment of hypertension. canrenon. but cannot be reabsorbed -Inhibit Na+ reabsorption. -these mediator proteins normally stimulate Na-K exchange sites of distal tubuleprevent Na absorption and K & H secretion Amiloride & Triamterene -Act on the late DT and CD -Blocks luminal Na channels (act independently of aldosterone) inhibit Na+ reabsorption K+ and H+ secretion (may result in hyperkalemia) -Act indirectly by modifying the content of the filtrate by the osmolarity. preventing transcription and translation of mediator proteins. useful for retention of K+. plasma hal life of 16 hr i)Minimal hormonal activity ii) Hyperkalaemia iii)Nausea. To maintain osmotic balance. lethargy iv)Mental confusion Limited uses: i) Reducing intracranial pressure (mannitol increases blood osmolality relative to the brain— pulling water from the brain to restore osmolar balance) ii) Acute renal failure (maintains urine flow) . often in combination with a thiazide Distal / Collecting tubule Osmotic diuretics Mannitol. water is retained in the urine -Results in urinary output with little Na excretion Spironolactone: i) Diuretics: although low efficacy in mobilizing Na+ from body. K+ secretion and H+ secretion Spironolactone: -a synthetic aldosterone antagonist -used alone primarily when aldosterone in excess -competes with aldosterone for intracellular receptorsprevents translocation of receptor complex into nucleus. urea Pharmacologically inert substances Filtered in the glomerulus. Often given with thiazide or loop diuretic to prevent K+ loss ii) Secondary hyperaldosteronism: elevated levels of aldosterone Spironolactone: -completely absorbed orally -rapidly converted to active metabolite.