Spironolactone dose‐response relationships in healthy subjects.

Abstract

I The effect of single oral doses of spironolactone 25 mg, 50 mg, 100 mg, 200 mg, 400 mg, and placebo in reversing the urinary electrolyte changes induced by fludrocortisone between 2-10 h and 12-16 h after treatment was examined in healthy subjects. 2 In the two collection periods, there were statistically significant log linear dose-response relationships for sodium excretion (P < 0.001), potassium excretion (P <0.001 and P < 0.025 respectively) and logl0 10 Na/K (P < 0.001).3 However, there was evidence that the log spironolactone dose-urinary sodium responses did not increase monotonically, while the relationship for urinary potassium appeared to enter the lower 'plateau' at doses between 100 mg and 200 mg, and when compared to placebo values, potassium excretion was not significantly depressed 12-16 h after treatment (P > 0.1). Thus, sodium and potassium responses were dissociated in dose producing maximal effect and in duration of activity, reinforcing the view that functions of the urinary sodium/potassium ratio alone cannot be considered an adequate description of renal antimineralocorticoid activity. 4 Dose-response relationships for all urinary electrolyte variables seem consistently steep and linear between 25 mg and 100 mg of spironolactone, suggesting that, in studies employing this model, the doses of spironolactone should be restricted to this range.

PF-03882845, a non-steroidal mineralocorticoid receptor antagonist, prevents renal injury with reduced risk of hyperkalemia in an animal model of nephropathy

“…PK-PD modeling demonstrated that PF-03882845 and eplerenone were equipotent for increasing serum K + levels relative to the vehicle + aldosterone group and for increasing the urinary Na + /K + ratio following single doses in normal SD rats. Effects of MR antagonists on urinary Na + /K + ratio have been well-characterized in rodents as well as humans (McInnes et al, 1982). Early on, Kagawa demonstrated blockade of mineralocorticoid activity in adrenalectomized rats by measuring urinary Na + /K + ratio (Kagawa, 1960).…”

The Effect of Spironolactone on the Incidence of Contrast-Induced Nephropathy in Patients Undergoing Cardiac Catheterization: Study Design and Rationale

“…Nevertheless, we will measure the effect of this moderate dose on serum potassium (S.K+) after 6 h in all patients and possibly after 3 days in randomly selected patients. Many studies reported the safety of moderate acute (single or few days) dose on serum potassium levels and chronic follow-up of such levels were unnecessary [ 22 – 24 ]. If hyperkalemia were to be found, it will be reported to the treating physician immediately for follow-up and treatment according local guidelines.…”

First-in-Man Demonstration of Direct Endothelin-Mediated Natriuresis and Diuresis

“…As hypothesized, big ET-1 infusion led to a significant natriuresis as shown by the increases in both UNaV and FeNa of ~40% from baseline. If this were maintained over a 24-hour period it would amount to ~60mmol of sodium excreted in the urine and is broadly equivalent to the natriuresis elicited by a single 25mg dose of spironolactone 42. Our subjects were healthy and relatively sodium restricted (with a sodium intake of ~90mmol Na or ~5g NaCl per day, around 50% of that contained in a standard Western); it is unclear whether the natriuretic effect of ET-1 would be different on a high salt diet, or in patient populations in which there is activation of the renin-angiotensin-aldosterone system (RAAS), such as in congestive heart failure, CKD or liver cirrhosis.…”