JAWAHARLAL NEHRU TECHNOLOGICAL UNIVERSITY HYDERABAD Pharm. D III Year PHARMACOLOGY - II Previous Question Paper (July/August - 2021 - R08)

Diuretics are classified based on their primary site of action within the nephron:

1. Proximal Convoluted Tubule (PCT): Carbonic anhydrase inhibitors (e.g., Acetazolamide). They inhibit the enzyme carbonic anhydrase, reducing bicarbonate reabsorption and sodium-linked water transport.
2. Thick Ascending Limb of Loop of Henle: Loop diuretics (e.g., Furosemide, Bumetanide). They inhibit the Na+/K+/2Cl- symporter, disrupting the counter-current multiplier mechanism.
3. Distal Convoluted Tubule (DCT): Thiazides (e.g., Hydrochlorothiazide). They inhibit the Na+/Cl- symporter, leading to increased excretion of sodium, chloride, and water.
4. Collecting Duct: Potassium-sparing diuretics. These are subdivided into:
   • Aldosterone antagonists (e.g., Spironolactone): Competitively block aldosterone receptors, preventing the synthesis of sodium-potassium exchange proteins.
   • Epithelial sodium channel inhibitors (e.g., Amiloride, Triamterene): Directly block the ENaC channels, preventing sodium reabsorption.
5. Osmotic Diuretics (e.g., Mannitol): Act throughout the nephron, primarily in the PCT and descending limb of the Loop of Henle, by increasing the osmotic pressure of the tubular fluid, thereby preventing water reabsorption.

Loop diuretics are termed high-ceiling diuretics because they produce a dose-dependent, massive increase in sodium and water excretion, far exceeding the efficacy of other diuretic classes. This is due to their action on the thick ascending limb, which is responsible for reabsorbing approximately 25-30% of filtered sodium.

Therapeutic Applications:

• Congestive Heart Failure (CHF): Used to reduce pulmonary and peripheral edema by decreasing venous return and preload.
• Acute Pulmonary Edema: Rapid intravenous administration provides immediate venodilation and diuresis.
• Hypertension: Used specifically in patients with chronic kidney disease where thiazides are less effective.
• Hypercalcemia: They promote calcium excretion, making them useful in managing calcium overload.

Clinical Limitations:

• Hypokalemia: Increased sodium delivery to the collecting duct leads to compensatory potassium secretion.
• Ototoxicity: Dose-related hearing loss or tinnitus, particularly with rapid IV bolus administration.
• Hyperuricemia: Competition for organic acid transporters in the PCT can lead to gout.
• Hypovolemia and Hypotension: Excessive diuresis can lead to severe volume depletion and circulatory collapse.