Adrenocortical Antagonists

1 The potency of single doses of the aldosterone antagonist SC8109 relative to spironolactone in reversing the urinary electrolyte effects of fludrocortisone was examined in a double-blind, balanced, crossover study in six healthy volunteers. 2 For the urinary ratio log10 10 Na/K, the relative potency of SC8109: spironolactone on a weight basis was 0.08:1 (95% confidence limits 0.04-0.13:1). 3 The potency of SC8109 relative to spironolactone for natriuresis and antikaliuresis was 0.10:1 and 0.05:1, respectively. 4 The results show excellent agreement with clinical experience where SC8109 was considered to have one tenth the potency of spironolactone. We suggest that the human bioassay employed in this study provides quantitative information which should be predictive of the therapeutic potency of aldosterone antagonists.

Section: Discussionmentioning

confidence: 96%

Quantitative comparison of aldosterone antagonists in normal human subjects: prediction of therapeutic potency.

McInnes¹,

Harrison²,

Shelton³

et al. 1981

“…Continuous administration of aldosterone antagonists leads to increased endogenous aldosterone secretion so that activity after repeated dosing in the presence of fludrocortisone is a complex mixture of intrinsic pharmacological activity at renal level and the effect of the induced state of hyperaldosteronism. In contrast to earlier work (McInnes et al, 1981) for urinary loglo 10 Na/K, generally considered the best single index of renal mineralocorticoid (Johnson, 1954) or antimineralocorticoid activity (Gantt & Dyniewicz, 1963;Kagawa, 1964), this study allowed a precise estimate of relative potency (3.4, 95% confidence limits, 2.0-6.5). However, the urinary potassium findings and the similarity of this estimate with that for sodium excretion lead us to question the acceptance of this variable alone as an overall index of renal antimineralocorticoid activity.…”

Section: Discussionmentioning

confidence: 87%

Comparison of prorenoate potassium and spironolactone after repeated doses and steady state plasma levels of active metabolites.

McInnes¹,

Shelton²,

Harrison³

et al. 1982

1 After repeated single daily doses, the aldosterone antagonists prorenoate potassium and spironolactone were compared with regard to renal antimineralocorticoid activity, plasma potassium concentration and steady state plasma levels of their active metabolites, prorenone and canrenone respectively, in a balanced crossover study of twelve healthy subjects. 2 Following challenge with the mineralocorticoid, fludrocortisone, best estimates of the potency of prorenoate potassium relative to spironolactone were 3.6 (95% confidence limits 1.6-10.4) for urinary sodium excretion and 3.4 (95% confidence limits 2.0-6.5) for urinary log10 10 Na/K. Estimates with respect to urinary potassium excretion and plasma potassium concentration were imprecise, confirming the limitations of the fludrocortisone model in the evaluation of aldosterone antagonists at steady state.3 Both compounds exhibited directly proportional relationships between daily dose and steady state plasma levels of active metabolites. The approximate mean terminal elimination half-life of prorenone at steady state was 32.6 h (range 18-80 h).

“…In bioassay procedures, functions of this ratio have been accepted as the best index of activity (Johnson, 1954;Kagawa, 1964;Ramsay et al, 1975), and not infrequently have been used exclusively. The log1,( 10 Na/ K ratio may provide a useful index of overall response to aldosterone antagonists but the dose-response tends to follow that for sodium excretion in duration and in dose range, and fails to reflect the urinary potassium response.…”

Section: Discussionmentioning

confidence: 99%

Spironolactone dose‐response relationships in healthy subjects.

McInnes¹,

Perkins²,

Shelton³

et al. 1982

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.