Info

Site 3

Cortical diluting segment

Reduction of Na+ reabsorption (leads to K+ loss at site 4)

Thiazides, chlorthalidone, metolazone, clopamide, mefruside, xipamide

Site 4

Distal tubule

Inhibition of Na+ exchange with K+ H+ (K+ retention); aldosterone antagonism; aldosterone independent

Spironolactone, triamterene, amiloride

Site 2

Ascending limb of Henle's loop

Reduction of Na+ reabsorption (leads to K+ loss at site 4}; reduction of medullary hypertonicity

Frusemide Bumetanide

Site 4

Distal tubule

Inhibition of Na+ exchange with K+ H+ (K+ retention); aldosterone antagonism; aldosterone independent

Spironolactone, triamterene, amiloride

Fig. 26.1 Sites of action of diuretic drugs receptor is inhibited by the competitive receptor antagonist spironolactone, whilst the sodium channel is inhibited by amiloride and triamterene. All three of these diuretics are potassium sparing because potassium is normally transported into the tubular lumen down the electrochemical gradient created by sodium reabsorption. All other diuretics, acting proximal to site 4, are potassium losing, because an increased sodium load is presented to ENaC, and sodium/potassium exchange is therefore increased. The potassium sparing diuretics are normally considered weak diuretics because site 4 is normally responsible for 'only' 5% of sodium reabsorption, and they usually cause less sodium loss than thiazides or loop diuretics. Patients with genetic abnormalities of ENaC develop severe salt wasting or hypertension, depending on whether the mutation causes loss or gain, respectively, of channel activity. Although ENaC clearly does not have the capacity to compensate for large sodium losses, e.g. during loop diuretic usage, it is the main site of physiological control (via aldosterone) over sodium losses. The reason why amiloride and triamterene are weak diuretics is partly that they compete with sodium for binding to ENaC, and are effective therefore only when sodium intake is low.

The collecting duct then travels back down into the medulla to reach the papilla; in doing so it passes through a gradient of increasing osmotic pressure which tends to draw water out of tubular fluid. This final concentration of urine is under the influence of antidiuretic hormone (ADH) whose action is to make the collecting duct permeable to water, and in its absence water remains in the collecting duct; ethanol causes diuresis by inhibiting the release of ADH from the posterior pituitary gland.

Diuresis may also be achieved by extrarenal mechanisms, by raising the cardiac output and increasing renal blood flow, e.g. with dobutamine and dopamine.

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