Diuretics and diuretic combinations

Fixed combinations of a thiazide diuretic and a potassium-sparing drug are commonly used as initial therapy for the treatment of hypertension. In the USA, there are three such fixed combinations available (Figure 11). Of note, triamterene and amiloride have relatively little diuretic or antihypertensive effect, whereas spironolactone and eplerenone act synergistically on BP.

Fixed-dose diuretic combinations

Amiloride 5 or 2.5 mg/HCTZ 50 mg Spironolactone 25 or 50 mg/HCTZ 50 or 25 mg Triamterene 37.5, 50, or 75 mg/HCTZ 25 or 50 mg Triameterene 50 mg/benzthiazide 25 mg

Figure 11 Fixed-dose diuretic combinations. HCTZ, hydrochlorothiazide.

These compounds serve mainly to retain the potassium that is excessively excreted with thiazide diuretics. In contrast, spironolactone, an aldosterone antagonist, has been shown to lower BP and also to exert some diuretic effects. The prevention of hypokalemia with thiazide diuretics is important because, as shown in the SHEP study [12], hypokalemia may remove the benefits con ferred by the decrease in BP. In addition, the risk of sudden death has been shown to rise with increasing doses of thiazide diuretics and to be reduced with the addition of a potassium-sparing compound. In general, fixed diuretic combinations are well tolerated and have remarkably few adverse effects. In combinations containing high doses of ACE inhibitors or ARBs hyperkalemia is of concern in susceptible patients, such as patients with diabetes or chronic renal failure. In rare instances, triamterene has been associated with kidney stones. Spironolactone is known to cause gynecomastia, impotence, menstrual irregularities, and, rarely, agranulocytosis. However, these endocrine adverse effects usually occur at higher doses (above 25 mg/day) only. In the Randomized Aldactone Evaluation Study (RALES) [38], spironolactone was shown to decrease morbidity and mortality when added to standard triple therapy in patients with heart failure. A novel aldosterone antagonist (eplerenone) is available that, while sharing the antihypertensive efficacy of spironolactone, seems to cause less hyperkalemia and few, if any, endocrine abnormalities, such as gynecomastia and menstrual irregularities. Eplerenone seems to be particularly effective in reducing target organ damage, such as left ventricular hypertrophy (LVH) and microproteinuria.

Loop diuretics, such as furosemide and torsemide, can also be combined with potassium-sparing compounds, although no fixed combinations are available. Adverse effects and precautions are similar to those used in combination with the thiazide diuretics.

Occasionally, in therapy-resistant edematous states, the combination of a loop diuretic with a thiazide, such as metolazone, is useful. However, volume depletion and hypokalemia are common adverse effects of this combination and patients need to be monitored closely.

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