Aldosterone antagonists dosing

Epierenone (Inspra) [Anrihyperfensive/Seled ive Aldosterone Receptor Antagonist] Uses HTN HF following Ml Action Selective aldosterone antagonist Dose Adults. 50 rag PO daily-bid, doses >100 rag/d no benefit w/ T K" X to 25 rag PO daily if giving w/ CYP3A4 inhibitors (Table VI-8) Caution [B, +/-] monitor w/ ACE inhibitor, ARBs, NSAIDs, K -spai ing diiu etics grapefruit juice, St. John s wort Contra >5.5 mEq/L NIDDM w/... 

Antihypertensive drug name and dose is associated with compelling indications which are based on benefits from outcome studies or clinical guidelines. For example, the drug class aldosterone antagonists have eplerenone dosed at 25-50 mg per day which is indicated for heart failure patients after an Ml and supported by the EPHESUS trial. 

In patients without contraindications, spironolactone is initiated at a dose of 12.5 to 25 mg daily, or occasionally on alternate days for patients with baseline renal insufficiency. Eplerenone is used at a dose of 25 mg daily, with the option to titrate up to 50 mg daily. Doses should be halved or switched to alternate-day dosing if creatinine clearance falls below 50 mL/minute. Potassium supplementation is often decreased or stopped after aldosterone antagonists are initiated, and patients should be counseled to avoid high-potassium foods. At anytime after initiation of therapy, if potassium concentrations exceed... 

Based on clinical trial results demonstrating reduced mortality, low-dose aldosterone antagonists may be appropriate for (1) patients with moderately severe to severe HF who are receiving standard therapy and (2) those with LV dysfunction early after MI. 

Hepatic cirrhosis-The usual initial dose is 5 or 10 mg once daily oral or IV, administered together with an aldosterone antagonist or a potassium-sparing diuretic. If the diuretic response is inadequate, titrate the dose upward by approximately doubling until the desired diuretic response is obtained. Single doses greater than 40 mg have not been adequately studied. 

Hepatic cirrhosis PO, IV Initially, 5 mg/day given with aldosterone antagonist orpo-tassium-sparing diuretic. May increase by approximately doubling dose until desired therapeutic effect is attained. Doses greater than 40 mg have not been adequately studied. 

Adrenalectomized rats treated with DOCA or aldosterone can be utilized to test aldosterone antagonists. Spironolactone has no effect in the absence of a min-eralocorticoid, but reverses in a dose-related manner the effect of DOCA on the Na+/K+ ratio in the urine (Kagawa et al. 1957 Bicking et al. 1965). 

Spironolactone, an aldosterone antagonist, is the drug of choice since secondary hyperaldosteronism often coexists in patients with hepatic ascites. Aldosterone is usually metabolised by the liver and is highly protein bound, therefore the free aldosterone levels are raised in cirrhosis. Spironolactone competes with aldosterone for receptor sites in the distal tubule, resulting in potassium retention and sodium and water loss. The initial dose of spironolactone is 100-200 mg and can be slowly increased according to response. There is a lag of 3-5 days between the beginning of spironolactone treatment and the onset of the natriuretic effect. 

Intravenous application of sodium-free albumin and/or 10% mannitol can be successful, possibly with the additional administration of low-dose diuretics (such as xipamide, torasemide), whereby due attention should be paid to renal function. Diuretics or aldosterone antagonists may only be used if the indication is precise and all risks have been considered. 

Thiazides are the preferred type of diuretic for treating hypertension. In patients with adequate kidney function (estimated GER > 30 mL/min), thiazides are the most effective diuretics for lowering BR As kidney fnnction declines, a more potent diuretic is needed to counteract the associated increase in sodinm and water retention. In this case, a loop dinretic (e.g., furosemide dosed twice daily) should be considered. Dinretics ideally should be dosed in the morning if given once daily and in the morning and afternoon if dosed twice daily to minimize the risk of nocturnal diuresis. However, with chronic use, thiazides, potassium-sparing diuretics, and aldosterone antagonists rarely cause a pronounced diuresis. 

Aldosterone antagonism with low-dose spironolactone has been shown to reduce mortality in patients with New York Heart Association (NYHA) class III and IV heartfailure and thus should be strongly considered in these patients. Given its low cost and safety profile at the doses studied, it may be reasonable to consider in other patients with symptomatic heart failure, especially those taking potassium supplementation, in whom the aldosterone antagonist might allow dose reduction or discontinuation of the potassium supplement, and should be considered strongly in patients with severe heart failure. 

The benefits of aldosterone antagonists in heart failure appear to be due largely to their neurohormonal inhibition, namely, inhibition of aldosterone s actions in the heart. Specifically, the benefits are believed to be due to the ability of these agents to inhibit aldosterone-mediated cardiac fibrosis and thus ventricular remodeling. And while spironolactone historically has been viewed as a diuretic, this is believed to contribute little to its benefits in heart failure in part because the doses used have minimal diuretic effect. Thus, as with ACE inhibitors and /S-blockers, the data on aldosterone antagonists also support the neurohormonal model of heart failure. 

Hyperkalaemia with ACE inhibitors and potassium-sparing diuretics, and particularly the aldosterone antagonist spironolactone, is well documented and well established. If it occurs it can be serious and potentially life threatening. Its incidence depends on the presence of other risk factors, and clinically important hyperkalaemia usually only appears to develop if one or more of these are also present, particularly renal impairment. Other risk factors in patients with heart failure include advanced age and diabetes" (hyperkalaemia has been found to be relatively common in both non-insulin-dependent and insulin-dependent diabetics). In addition, doses of spironolactone greater than 25 mg daily increase the risk of hyperkalaemia. 

Li JS, Flynn JT, Portman R, Davis I, Ogawa M, Shi H, Pressler ML. The efficacy and safety of the novel aldosterone antagonist eplerenone in children with hypertension a randomized, double-blind, dose-response study. J Pediatr 2010 157(2) 282-7. 

Aliskiren is the most advanced of these and the first to be approved for the treatment of hypertension. In healthy subjects, aliskiren produces a dose-dependent reduction in plasma renin activity and Ang I and II and aldosterone concentrations. In patients with hypertension, many of whom have elevated plasma renin levels, aliskiren suppresses plasma renin activity and causes dose-related reductions in blood pressure similar to those produced by ACE inhibitors (Figure 17-3). The safety and tolerability of aliskiren appear to be comparable to angiotensin antagonists and placebo. 

Although troublesome, these adverse effects are reversible and dose-related. The advent of selective aldosterone receptor antagonists, such as eplerenone, should reduce these adverse effects and thereby improve patient compliance. In EPHESUS there was no increase in the incidence of gynecomastia, breast pain, or impotence in men or menstrual irregularities in women who took eplerenone. 

Pitt B, Roniker B. Epierenone a novel selective aldosterone receptor antagonist (SARA) dose finding study in patients with heart failure. J Am CoU Cardiol 1999 33(Suppl A) A188-9. 

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