- Potassium-sparing Diuretics refer to a class of compounds that interfere with sodium resorption within Principal Cells of the late distal tubule and collecting duct (See: Late Distal Tubule and Collecting Duct Transport). Because only a small fraction of urinary sodium is absorbed at this segment, potassium-sparing diuretics are rather weak in terms of their sodium diuresis capacity. However, interference with sodium resorption at this segment yields a significant increase in urinary potassium resorption and so these compounds are largely used to reduce urinary potassium excretion. Clinically they are most frequently utilized to reduce the potassium-wasting properties of thiazide and loop diuretics. Predictably, their primary adverse effect is hyperkalemia. Spirinolactone and triamterene are the prototype drugs of this class and operate using distinct mechanisms.
- Triamterene specifically inhibits the Na-channel present on the luminal membrane of Principal Cells of the late distal tubule and collecting duct (See: Late Distal Tubule and Collecting Duct Transport). This inhibits sodium resorption at this segment. However, as mentioned above, since the vast majority of sodium has already been resorbed by the time tubular fluid arrives at this segment, the effect of triamterene on decreasing sodium resorption is very mild.
- In contrast, the majority of tubular fluid potassium modulation occurs at this segment. Principal Cells are responsible for potassium secretion and this is achieved via luminal K+-specific channels as described in External Potassium Balance. The rate of potassium secretion is governed by the luminal electrochemical gradient for potassium in principal cells. Blockage of the luminal sodium channel by triamterene inhibits sodium resorption and thus depolarizes the luminal membrane, reducing the electrochemical gradient for potassium secretion.
- Spirinolactone and Eplerenone
- Spironolactone is a steroid hormone-mimetic that is similar in structure to aldosterone and competitively inhibits the binding of aldosterone to its nuclear receptor (Mineralocorticoid Receptor). As a result, aldosterone's physiologic action on the Principal Cells of the late distal tubule and collecting duct is blocked. As discussed in Aldosterone Physiology the binding of aldosterone to Mineralocorticoid Receptor results in the synthesis of basolateral NaK ATPase and luminal potassium channels. Together these changes primarily result in an increased electrochemical gradient for potassium secretion and a mild increase in the electrochemical gradient for sodium resorption. By blocking these activities, spironolactone inhibit potassium secretion and reduces sodium resorption.
- Because spironolactone functions by blocking aldosterone action, it is clinically efficacious only in situations where excess aldosterone levels are present and contributing to the pathophysiology. This primarily occurs in situations of hyperaldosteronism either due to an aldosterone-secreting tumor (Primary Hyperaldosteronism) or due to excess Renin-Angiontensin-Aldosterone System activation (Secondary Hyperaldosteronism) as might occur in heart failure.
- The most concerning adverse effect of all potassium-sparing diuretics is hyperkalemia that can rapidly become fatal as potassium levels rise.
- Because of its steroid hormone-like structure, spironolactone can mildly activate the nuclear receptors for testosterone and progesterone leading to gynecomastia and impotence in men as well as menstrual irregularities in women.