Paradoxical potassium excretion in response to aldosterone antagonists

Ramsay, L. E.; Harrison, I. R.; Shelton, J. R.; Tidd, M. J.

doi:10.1007/bf00562899

Cited by 8 publications

(5 citation statements)

References 15 publications

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“…As in studies using the dose ratio approach (McInnes et al, 1981;Ramsay et al, 1977a), an acceptable estimate of relative potency for potassium excretion was precluded although a statistically valid estimate was possible for urinary potassium concen- (Ramsay et al, . 1977b.…”

Section: Discussionmentioning

confidence: 99%

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

McInnes¹,

Shelton²,

Harrison³

et al. 1982

Brit J Clinical Pharma

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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).

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Section: Discussionmentioning

confidence: 99%

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

McInnes¹,

Shelton²,

Harrison³

et al. 1982

Brit J Clinical Pharma

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“…If the urine flow rate does affect potassium excretion we must assume that spironolactone, function ally, affects the tubule proximal to the potassium excre tory site. A consequence of the theory of Ramsey et al [12] is that calculated proximal sodium reabsorption in our patients might be slightly underestimated. We conclude from our observations on CH20 /D D and on 24-hour potassium excretion that spironolactone inhibits sodium reabsorption at a site situated proximal to the localiza tion of the sodium/potassium and/or potassium excre tory site.…”

Section: Discussionmentioning

confidence: 99%

“…Ramsay et al [12] examined healthy subjects, who were pretreated with fludrocortisone, during aldosterone antagonists. They suggested that the initial kaliuretic effect was urine flow rate-and not natriuresis-dependent.…”

Section: Discussionmentioning

confidence: 99%

Intrarenal Sodium Handling during Chronic Spironolactone Treatment

Roos¹,

Mees²,

Koomans³

et al. 1984

Nephron

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Intrarenal sodium handling was studied in 8 patients with essential hypertension before spironolactone treatment (200 mg/day), on the 4th day of treatment, and after 3 months of treatment. The results were compared with similar studies with chlorthalidone (50 mg/day). Renal sodium handling was assessed by simultaneous determination of the glomerular filtration rate, sodium, and potassium excretion, and maximal free-water clearance (CH₂O). We took CH₂O as an index of’distal’ sodium chloride reabsorption from which the proximal sodium reabsorption was calculated. During the first days of spironolactone treatment a natriuresis and increase in urinary flow rate was found. It resulted in a decrease of the extracellular fluid volume amounting to 0.9 liters and a 2.5-fold increase in the plasma renin activity. Potassium excretion showed a small but significant rise. After 3 months, virtually the same degree of volume depletion was found, which was comparable to that obtained after 3 months of chlorthalidone treatment. CH₂O, as a fraction of glomerular filtration rate, decreased by 24% both after 3 days and 3 months, whereas proximal sodium reabsorption increased from 87.8 to 90.4% of the filtered load. CH₂O, corrected for the ‘distal’ delivery of sodium, decreased from 85.3 to 80.7%. These changes were nearly the same as those found after 3 months of chlorthalidone treatment. It is concluded from these calculated values that spironolactone inhibits sodium chloride reabsorption in the diluting segment of the nephron and that the resulting increase in sodium delivery or urinary flow to the potassium excretory site partly counteracts the blocking effect of spironolactone on this part of the nephron, thus increasing potassium excretion during the acute administration of this drug.

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“…Synthesis of the title compounds is outlined in Scheme I. Dibenzothiophene-l-carboxylic acid (4) was prepared from 2-allylbenzo [6]thiophene and ethyl di-chloroethoxyacetate3 according to published methods. 4 It was converted to the acid chloride and reacted with 2amino-2-methylpropanol, yielding an hydroxyamide. Cyclization with thionyl chloride produced the oxazoline 5.…”

Section: Methodsmentioning

confidence: 99%

Structure-activity relationship study of spirolactones. Contribution of the cyclopropane ring to antimineralocorticoid activity

Chinn¹,

Salamon²,

Desai³

1981

J. Med. Chem.

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A series of spirolactones containing a cyclopropane ring in the molecule was examined for its effects on the mineralocorticoid receptor. The results were compared with those of a similar series of spirolactones in which the cyclopropane ring was replaced by a double bond. Insertion of a double bond or an alpha-cyclopropane ring into the 1,2 or the 6,7 position leads to a reduction in the binding affinity. The pi-bonding system of the beta-cyclopropane ring at C-6 and C-7 does not promote binding to the receptor. The presence of the 6 beta, 7 beta-cyclopropane ring may deter metabolic activation to account for the enhanced in vivo activity.

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Paradoxical potassium excretion in response to aldosterone antagonists

Cited by 8 publications

References 15 publications

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

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

Intrarenal Sodium Handling during Chronic Spironolactone Treatment

Structure-activity relationship study of spirolactones. Contribution of the cyclopropane ring to antimineralocorticoid activity

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