Mechanism of action of loop diuretics ( Source: Bertram Katzung, Basic and Clinical Pharmacology, Mc Graw Hill Medical, 2007):
These drugs inhibit NKCC2, the luminal Na+/K+/2Cl– transporter in the thick ascending limb of Henle’s loop. By inhibiting this transporter, the loop diuretics reduce the reabsorption of NaCl and also diminish the lumen-positive potential that comes from K+ recycling (Figure 15-3). This positive potential normally drives divalent cation reabsorption in the loop (Figure 15-3), and by reducing this potential, loop diuretics cause an increase in Mg2+ and Ca2+ excretion. Prolonged use can cause significant hypomagnesemia in some patients. Since vitamin D-induced intestinal absorption of Ca2+ can be increased and Ca2+ is actively reabsorbed in the DCT, loop diuretics do not generally cause hypocalcemia. However, in disorders that cause hypercalcemia, Ca2+ excretion can be usefully enhanced by treatment with loop diuretics combined with saline infusions.
Loop diuretics induce synthesis of renal prostaglandins, which participate in the renal actions of these diuretics. NSAIDs (eg, indomethacin) can interfere with the actions of the loop diuretics by reducing prostaglandin synthesis in the kidney. This interference is minimal in otherwise normal subjects but may be significant in patients with nephrotic syndrome or hepatic cirrhosis.
In addition to their diuretic activity, loop agents have direct effects on blood flow through several vascular beds. Furosemide increases renal blood flow. Both furosemide and ethacrynic acid have also been shown to reduce pulmonary congestion and left ventricular filling pressures in heart failure before a measurable increase in urinary output occurs, and in anephric patients.
Mechanism of action of tiazide diuretics ( Source: Bertram Katzung, Basic and Clinical Pharmacology, Mc Graw Hill Medical, 2007):
Thiazides inhibit NaCl reabsorption from the luminal side of epithelial cells in the DCT by blocking the Na+/Cl– transporter (NCC). In contrast to the situation in the TAL, where loop diuretics inhibit Ca2+ reabsorption, thiazides actually enhance Ca2+ reabsorption. This enhancement has been postulated to result from effects in both the proximal and distal convoluted tubules. In the proximal tubule, thiazide-induced volume depletion leads to enhanced Na+ and passive Ca2+ reabsorption. In the DCT, lowering of intracellular Na+ by thiazide-induced blockade of Na+ entry enhances Na+/Ca2+ exchange in the basolateral membrane (Figure 15-4), and increases overall reabsorption of Ca2+. While thiazides rarely cause hypercalcemia as the result of this enhanced reabsorption, they can unmask hypercalcemia due to other causes (eg, hyperparathyroidism, carcinoma, sarcoidosis). Thiazides are useful in the treatment of kidney stones caused by hypercalciuria.
The action of thiazides depends in part on renal prostaglandin production. As described above for the loop diuretics, the actions of thiazides can also be inhibited by NSAIDs under certain conditions.
Mechanism of action of potasium sparing diuretics ( Source: Bertram Katzung, Basic and Clinical Pharmacology, Mc Graw Hill Medical, 2007):
Potassium-sparing diuretics reduce Na+ absorption in the collecting tubules and ducts. Na+ absorption (and K+ secretion) at this site is regulated by aldosterone, as described above. Aldosterone antagonists interfere with this process. Similar effects are observed with respect to H+ handling by the intercalated cells of the collecting tubule, in part explaining the metabolic acidosis seen with aldosterone antagonists (Table 15-2).
Spironolactone and eplerenone bind to aldosterone receptors and may also reduce the intracellular formation of active metabolites of aldosterone. Amiloride and triamterene do not block the aldosterone receptor but instead directly interfere with Na+ entry through the epithelial sodium ion channels (ENaC) in the apical membrane of the collecting tubule. Since K+ secretion is coupled with Na+ entry in this segment, these agents are also effective potassium-sparing diuretics.
The actions of the aldosterone antagonists depend on renal prostaglandin production. As described above for loop diuretics and thiazides, the actions of K+-sparing diuretics can be inhibited by NSAIDs under certain conditions.
Mechanism of action of osmotic diuretics ( Source: Bertram Katzung, Basic and Clinical Pharmacology, Mc Graw Hill Medical, 2007):
Osmotic diuretics have their major effect in the proximal tubule and the descending limb of Henle’s loop. Through osmotic effects, they also oppose the action of ADH in the collecting tubule. The presence of a nonreabsorbable solute such as mannitol prevents the normal absorption of water by interposing a countervailing osmotic force. As a result, urine volume increases. The increase in urine flow rate decreases the contact time between fluid and the tubular epithelium, thus reducing Na+ as well as water reabsorption. The resulting natriuresis is of lesser magnitude than the water diuresis, leading eventually to excessive water loss and hypernatremia.