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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
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
-Inhibits Na /K /2Cl carrier in the luminal + membrane, therefore reabsorbtion of Na , + K ,Cl is decreasesd
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 & Clloss of K+ decreased urinary calcium excretion (thiazide diuretics promote the reabsorption of Ca *contrasts with loop diuretics*) -continued usereduced 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
Osmotic diuretics
Mannitol, urea
-Inhibit Na+ reabsorption, K+ secretion and H+ secretion Spironolactone: -a synthetic aldosterone antagonist -used alone primarily when aldosterone in excess -competes with aldosterone for intracellular receptorsprevents translocation of receptor complex into nucleus, preventing transcription and translation of mediator proteins. -these mediator proteins normally stimulate Na-K exchange sites of distal tubuleprevent 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. To maintain osmotic balance, 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, useful for retention of K+. 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, canrenon, plasma hal life of 16 hr
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)