Showing papers on "Spironolactone published in 1983"

Effects of antihypertensive therapy on serum lipoproteins.

Abstract: Several drugs used for standard antihypertensive therapy may also interact with the lipoprotein metabolism. The following has been observed after 1 to 12 months of treatment. Various thiazide-type diuretics may significantly increase the potentially atherogenic serum low-density-lipoprotein cholesterol (LDL-C) and/or very-LDL-C-fractions, while the antiatherogenic high-density-lipoprotein cholesterol (HDL-C) is largely unchanged. Certain loop-diuretics also increase the LDL-C/HDL-C ratio and both types of diuretics elevated serum triglycerides (Tg) in some but not all studies. LDL-C was increased in diuretic-treated men and in chlorthalidone-treated postmenopausal women, but not in chlorthalidone-treated premenopausal women. The latter may be protected from this effect. Only two diuretics evaluated, namely indapamide and spironolactone, had no apparent influence on lipoproteins. Beta-blocker monotherapy may often increase Tg and slightly decrease HDL-C. The magnitude of these changes did not distinctly differ between highly cardioselective and nonselective beta-blockers, but it was less pronounced on beta-blockers than on those without intrinsic sympatholytic activity. Other sympatholytics such as reserpine, methyldopa, clonidine, debrisoquine, the alpha-beta-blocker labetalol, or the postsynaptic alpha-blocker, prazosin, did not affect or even slightly decrease Tg or total C, LDL-C, and very-LDL-C values. With combinations, a tendency for increased Tg and lower HDL-C was also apparent during thiazide-type diuretic-beta-blocker therapy. However, diuretic-induced increases in LDL-C were prevented or reversed by concomitant beta-blockade, but not by reserpine, methyldopa, or clonidine. Monotherapy with the potent direct vasodilator, carprazidil, improved blood pressure and significantly increased HDL-C. Prospective long-term studies are needed to clarify the course and the pathogenic and prognostic relevance of lipoprotein changes induced by certain diuretics or beta-blockers.

Metabolic and Blood Pressure Responses to Hydrocortisone in the Syndrome of Apparent Mineralocorticoid Excess

Abstract: A syndrome of low renin hypertension in childhood with apparent mineralocorticoid excess associated with a defect in the peripheral metabolism of cortisol has been described previously in 2 patients. In these patients, decreased secretion rates of glucocorticoids, mineralocorticoids, and sex steroids have been demonstrated. In a 1010/12-yr-old girl with this disorder, continuous iv administration of hydrocortisone in doses of 5, 10, 15, and 20 mg/day resulted in an increase in blood pressure and a decrease in serum potassium concentration. The addition of spironolactone during the continued administration of 20 mg/day hydrocortisone did not result in a decrease in blood pressure. Withdrawal of hydrocortisone and continued administration of spironolactone alone resulted in a decrease in blood pressure, a rise in serum potassium concentration, and a fall in serum sodium concentrations. These studies suggest that an abnormality in cortisol action or metabolism causing cortisol to behave as a potent mineraloc...

Negative effects of diuretic drugs on metabolic risk factors for coronary heart disease: Possible alternative drug therapies

Abstract: The results of 8 major hypertension treatment trials, all using diuretics as first-line therapy, show a clear-cut reduction in stroke and congestive heart failure, but coronary heart disease (CHD) is not consistently benefited. It is unclear why CHD is not controlled, but diuretics can subtly upset metabolic risk factors for CHD, among which are lipid and glucose concentrations. Although these metabolic disturbances appear clinically unimpressive, risk table analysis reveals that they can offset or even reverse the benefits of reducing blood pressure. A link between glucose intolerance and increased serum lipid concentrations during diuretic-based therapy is suggested by multiple correlations between them. Replacement of diuretics as first-line therapy for mild and moderate hypertension should therefore be considered. Spironolactone seems to counter the adverse metabolic effects, but its effect on lipoproteins needs more study. A drug that does not disturb glucose and lipid metabolism would seem preferable. Thus prazosin is a promising candidate.

Interaction of diuretics and non-steroidal anti-inflammatory drugs in man

Abstract: 1. The influence of four diuretics on renal prostaglandins was investigated in a study designed in two parts (A and B): A, 24 normal subjects on a constant sodium intake received frusemide (80 mg daily), or hydrochlorothiazide (100 mg), or triamterene (200 mg) or spironolactone (300 mg); B, the same subjects were pretreated for 3 days with indomethacin (150 mg daily), which was continued during the 3 day administration of the respective diuretics and during a 2 day post-diuretic period. 2. In study A, only triamterene provoked a rise in urinary prostaglandins E2 and F2 alpha (+ 474 +/- SEM 92%, P less than 0.01, and + 192 +/- 7%, P less than 0.01). In study B, prostaglandins were significantly inhibited in all subjects. After indomethacin, the natriuretic effect of frusemide and spironolactone was reduced by 80 +/- 12% (P less than 0.01) and 54 +/- 11% (P less than 0.001), whereas the natriuresis induced by hydrochlorothiazide and triamterene was unchanged. No correlation was found between urinary PGE2 and F2 alpha and natriuresis. 3. When triamterene was associated with indomethacin, two subjects developed reversible acute renal failure. 4. Plasma renin activity and urinary aldosterone were stimulated by the four diuretics in study A, but their response was blunted in study B. Urinary antidiuretic hormone was not modified by diuretics but was suppressed by indomethacin. 5. Diflunisal, a structurally unrelated nonsteroidal anti-inflammatory drug, given to 12 of the subjects provoked similar interactions with frusemide, hydrochlorothiazide and spironolactone. 6. The results suggest that prostaglandins contribute to the natriuretic effects of frusemide and spironolactone, but not to those of hydrochlorothiazide and triamterene.

Interactions between digoxin and potassium-sparing diuretics.

Abstract: A kinetic and hemodynamic study of digoxin was performed in six healthy subjects and similar studies were performed during digoxin with spironolactone and with triamterene. Spironolactone reduced renal tubular secretion of digoxin and attenuated its positive inotropic effect (evaluated by systolic time intervals and echocardiography) and triamterene reduced the extrarenal elimination of digoxin, but induced no changes in digoxin-elicited inotrophy. It is suggested that the renal handling of digoxin is influenced by the intracellular potassium concentration in the renal tubular cell. The results indicate a drug-receptor interaction between spironolactone metabolites and digoxin at the hypothetical inotropic digitalis receptor. Amiloride has been reported to suppress digoxin inotropism, whereas spironolactone induces minor inhibition and triamterene does not affect digoxin inotropism.

Relation of blood pressure with body and plasma electrolytes in Conn's syndrome.

Abstract: Thirty-four patients with untreated Conn's syndrome were studied in a metabolic ward. The final diagnosis in each case was based on the finding and removal of an adrenal cortical adenoma with histological features typical of the disorder. Compared with 34 age and sex-matched normal controls the untreated patients had increased plasma aldosterone concentration, increased blood pressure (183/112 mmHg), increased exchangeable sodium (116.7% of normal), hypokalaemia and increased plasma sodium concentration. Exchangeable potassium was lower than normal and plasma concentrations of active renin, total renin and angiotensin II were lower than normal mean values. Arterial pressure correlated significantly and positively with plasma and exchangeable sodium and there was a significant negative correlation with plasma potassium concentration. Partial regression analysis showed that the relation of exchangeable sodium with blood pressure did not depend on age or renal function but that the relation of blood pressure and plasma potassium could be attributed to the correlation of exchangeable sodium and blood pressure. Multiple regression analysis suggested that exchangeable and plasma sodium were the most important determinants of blood pressure in untreated patients. Spironolactone, amiloride and surgical removal of the adenoma corrected the electrolyte abnormality and usually lowered blood pressure. The fall in exchangeable sodium was related to the fall in blood pressure. The pattern of correlation found by multiple regression analysis in postoperative patients was similar to that in normal subjects. The findings are relevant to some of the mechanisms proposed for the hypertension of mineralocorticoid excess.

The effect of spironolactone in hypertensive patients on regular haemodialysis and after renal allotransplantation.

Abstract: To determine the role of the renin-angiotensin-aldosterone system in the maintenance of hypertension in patients with end stage renal disease, twenty four hypertensive patients were studied on regular haemodialysis treatment (RDT) and after successful kidney transplantation. The first group consisted of nine patients on RDT with their own kidneys in situ, and the second group consisted of nine kidney transplants. All 18 patients were given spironolactone 300 mg daily for three weeks following a control period of the same duration. In addition, three anephric patients on RDT were studied with the above protocol and three other patients on RDT were given the same dose for only six days. Blood pressure (BP), body weight, plasma K-Na, aldosterone and renin activity in all patients, and Na and aldosterone in urine in the second group were measured. In the first group of patients on RDT plasma potassium and renin activity increased significantly but BP remained unchanged. In the second group of transplanted patients plasma potassium, renin activity, and aldosterone were increased and BP diminished significantly. In the group of three anephric patients plasma potassium increased but plasma renin activity remained very low. Finally, in the patients on dialysis who received spironolactone for only six days there was a parallel increase of serum potassium and plasma renin activity. These findings suggest that in patients on RDT spironolactone stimulates renin secretion and potassium retention possibly by an effect on the remaining nephrons and/or the intestinal wall. On the contrary, in the transplanted patients the effect of spironolactone on the renal tubule is capable of producing sodium depletion and fall in BP.

Modern diuretic treatment.

Abstract: Thiazide diuretics form the mainstay of treatment for numerous conditions characterised by oedema, most notably congestive heart failure when there is a reduced glomerular filtration rate, increased aldosterone production, and increased sodium reabsorption from the renal tubules. Longstanding heart failure no longer responsive to a thiazide often responds dramatically to a loop diuretic, and a loop diuretic also rapidly relieves acute pulmonary oedema secondary to left ventricular failure. Resistant oedema, on the other hand, may respond favourably when diuretics that act on different parts of the renal tubule are given together?for example, thiazide plus a loop diuretic with or without the addition of an aldosterone antagonist. A thiazide or loop diuretic is prescribed together with spiro nolactone in the nephrotic syndrome and in cirrhosis of the liver complicated by ascites, both conditions being almost invariably associated with secondary hyperaldosteronism. Thiazides and spironolactone are often prescribed, too, in some cases of recurrent, idiopathic cyclical oedema, particularly of the ankles, associated with water retention. In this disorder, which is most often seen in premenopausal women and especially at menstruation, diuretics may have an initial cosmetic effect, but long term benefit is hard to establish. Thiazides are also often inappropriately prescribed in managing chronic lymph oedema or chronic ankle oedema associated with varicose veins and poor venous return. Only in a few of these patients is the oedema easier to control as a result of using diuretics; adequate elastic support is more appropriate. The requirement for diuretic treatment in managing oedema needs to be regularly reassessed in order not to exceed the necessary minimum dose of the least powerful diuretic that will suffice. When clinical judgment does not suffice, a useful means of measuring the loss of sodium and water is to observe the rate and extent of weight loss. Provided that the serum sodium concentration remains normal, 1 kg of water loss corresponds to 140-150 mmol(mEq) of associated sodium loss. Another useful assessment is to measure the 24 hour urinary sodium excretion: if this is below 10-20 mmol the diuretic treatment is inadequate, but if it is quite high (above 100 mmol) and body weight is not decreasing sodium excretion is satisfactory but sodium intake needs to be reduced. On the other hand, some patients are at risk of developing saline depletion with loss of tissue turgor, postural hypotension, and a rising serum urea concentration because of loss of interstitial fluid and a fall in plasma volume with poor renal perfusion. The diuretic dose in such patients may best be adjusted to allow mild ankle oedema in the evening, which will clear during the night in bed. Excessive diuresis will othe wise produce undue shrinkage of the plasma volume with resu tant secondary hyperaldosteronism and hypokalaemia. Excessively rapid clearance of oedema also causes malaise.

The interaction of canrenone with oestrogen and progesterone receptors in human uterine cytosol.

Abstract: 1 Canrenone, the major active metabolite of spironolactone, decreased [3H]-progesterone binding to isolated uterine cytosolic progesterone receptors. The inhibition was concentration-dependent. 2 Canrenone did not alter [3H]-oestradiol binding to isolated uterine cytosolic oestrogen receptors. 3 Canrenone inhibition of progesterone binding to isolated cytosolic receptors was strictly competitive: Kd (apparent dissociation constant for progesterone binding) was increased in a concentration-dependent manner by canrenone, whereas Bmax (maximal number of progesterone binding sites/mg cytosolic protein) was unaltered. There was marked cooperativity in progesterone binding at high canrenone and low progesterone concentrations. The implication is that canrenone alters the subunit interaction of the receptor protein. 4 Kd for progesterone was 3.2 X 10(-9)M. Ki (the inhibition constant for canrenone with respect to progesterone binding) was 300 X 10(-9)M. Reports in the literature suggest that, following spironolactone administration, canrenone may rise to concentrations sufficiently high to inhibit progesterone binding. This action may contribute to the effect of spironolactone in inducing menstrual disturbances in female patients.

Aldosterone-binding globulin-induced hypertension in the rat. A new experimental model.

Abstract: A thermostable urinary homologue of the plasma aldosterone-binding globulin (ABG), designated ABG-TsU, was isolated and purified by differential ultrafiltration, ion exchange chromatography, and gel filtration to electrophoretic homogeneity. Scatchard plot analysis using highly purified ABG-TsU demonstrated reversible high-affinity low-capacity binding at separate sites for aldosterone and dehydroepiandrosterone sulfate (DHEA-SO4). ABG-TsU injected intraperitoneally (i.p.) in male rats resulted in sustained hypertension after 5 to 8 days, characterized after 12 days by no changes in plasma Na+ K+, aldosterone, or plasma renin activity (PRA). No histological changes could be detected in the kidneys, brains, or hearts, nor evidence of adrenocortical hyperplasia. This hypertension appears to be aldosterone-dependent since it is prevented by bilateral adrenalectomy or administration of a spironolactone, but not by adrenalectomy when aldosterone is given concomitantly with ABG-TsU. Hemodynamic characterization of this hypertension was carried out in rats after treatment with ABG-TsU or saline i.p. for 14 days. Cardiac output (CO) was measured using the reference sample microsphere method. ABG-TsU-treated rats had significantly higher mean arterial pressure (MAP), systolic blood pressure (SBP), diastolic blood pressure (DBP), and CO, while no difference in total peripheral resistance (TPR) was detected. This new animal model of borderline essential hypertension (EH) induced by ABG-TsU, which has a reversible high-affinity binding for aldosterone, results in adrenal-dependent hypertension due at this early phase to an increase in CO without any change in TPR, which remains inappropriately normal.

Comparison of chlorthalidone and spironolactone in low--renin essential hypertension

Abstract: Nineteen patients with uncomplicated essential hypertension and low activity of plasma renin in response to a change from recumbency to an upright posture along with furosemide administration were given spironolactone, 400 mg/d, or chlorthalidone, 100mg/d, in a double-blind, random-sequence, crossover trial. The sequence of treatments was placebo for 2 months, one active drug for 2 months, placebo again for 1 month and the other active drug for 2 months. With both active treatments the average systolic, diastolic and mean arterial pressures decreased significantly. The two agents were equally efficacious in lowering the blood pressure regardless of the severity of hypertension during placebo treatment. Body weight, 24--hour urinary excretion of sodium, the plasma renin activity and the plasma aldosterone level at the end of the initial placebo period did not allow us to predict the response to either drug. Both drugs reduced the body weight and increased the stimulated plasma renin level activity. Chlorthalidone significantly increased the serum uric acid level and significantly reduced the serum potassium level. Three patients experienced orthostatic dizziness during spironolactone therapy, but no adverse symptoms were observed with chlorthalidone therapy. Thus, spironolactone is an effective alternative to thiazide-type drugs in patients with low-renin essential hypertension.

Dose‐response relationships for spironolactone in combination with a potassium‐wasting diuretic

Abstract: The plasma and urine electrolyte responses to repeated doses of spironolactone, 25, 50, and 100 mg, in combination with metolazone, 2.5, 5.0, and 10 mg, were examined in 18 healthy subjects (six at each dose of metolazone). During the period of pharmacologic steady state, there were log linear spironolactone dose-response relationships for plasma potassium, sodium, and bicarbonate (P less than 0.001 in each case) with no contraindication to parallelism between the metolazone groups. In the absence of mineralocorticoid challenge, spironolactone dose-urine electrolyte responses could not be demonstrated. However, after fludrocortisone, spironolactone log dose-response trends were linear with respect to natriuresis (P = 0.027), antikaliuresis (P = 0.020), and log 10 Na/K (P = 0.001), which is usually considered the best single index of renal antimineralocorticoid activity, and exhibited parallelism between the metolazone doses. These observations suggest that a convenient bioassay for aldosterone antagonists in normal men may be provided by the electrolyte responses to repeated doses of such drugs in combination with potassium-wasting diuretics. In view of the limitations of other methods, this approach may have particular relevance to the evaluation of potassium-sparing properties.

[Spironolactone in idiopathic hirsutism, clinical and biological evaluation of treatment].

Abstract: Ten midly hirsute women with normal serum levels of testosterone were treated with spironolactone (100 mg die), and the effectiveness of this dose-schedule regimen was evaluated after six months of therapy. Hirsutism subsided partly in all women. We estimated however, that in 6 of the 10 women, the clinical benefit was out weighed by the side effects and other drawbacks of a long term therapy and their medication was then stopped 6 months after its initiation. The changes induced on the pituitary function were evaluated by measuring basal serum T3 T4 and basal and stimulated (TRH-LHRH) TSH, PRL, FSH and LH, prior to and after one month of therapy. Spironolactone induced a greater response of TSH to TRH (p less than .025) but no change in T3 T4, PRL, FSH and LH. These data suggest that changes in TSH response are not explained by the speculated intrinsic oestrogenic activity of spironolactone but rather by a selective interaction with TSH secreting cells. We conclude that spironolactone therapy should not be recommended for the large category of normal women complaining of slight increase of facial hair.

Influence of food intake on antihypertensive drugs: spironolactone

Abstract: A series of studies has been initiated to examine the influence of concomitant food intake on the effects of antihypertensive drugs during long-term therapy. In the present study, the therapeutic effect of spironolactone and the steady-state concentrations of its major, active metabolite canrenone were compared in 10 hypertensive patients after two 60-day periods of spironolactone treatment, 100 mg once daily, prescribed to be ingested before and together with breakfast, respectively. There was no significant difference in the blood pressure and heart rate values during the two treatment periods, and the canrenone levels were similar. As spironolactone can cause gastric irritation, the present findings support the recommendation that spironolactone always be prescribed for once-daily intake together with breakfast.

Spironolactone in Essential Hypertension: Effects on Kidney Function and Plasma Electrolytes in Relation to Salt Intake

Abstract: The antihypertensive action of spironolactone has been ascribed to both a nonspecific diuretic and an antimineralocorticoid effect. By inhibiting the action of aldosterone in the distal nephron, spironolactone blocks the reabsorption of Na+ ions by the luminal membrane in the cortical collecting ducts. This is the basis of its natriuretic and diuretic efficiency. Through this salt and water excretory capacity, spironolactone leads to volume depletion and, thereby, to a lowering of the blood pressure. When high blood pressure is caused by overproduction of mineralocorticoids, such as aldosterone, the blood-pressure-lowering effect of spironolactone is considerable. In fact earlier, we, as well as others, reported that the lowering of blood pressure by spironolactone even in essential hypertension is greater the more aldosterone is secreted [1, 2].

Polycystic ovary syndrome

Abstract: Objective: To investigate whether the administration of an oral contraceptive containing the new antiandrogenic drospirenone is associated with reduced adrenal androgen synthesis in hyperandrogenic women with diagnosis of polycystic ovary syndrome. Drospirenone, an analogue of spironolactone and aldosterone antagonist, is a novel progestin under clinical development that is similar to the natural hormone progesterone, combining potent progestogenic with antimineralocorticoid and antiandrogenic activities. Design: Prospective study. Setting: Healthy volunteers in University Department of Obstetrics and Gynecology. Patient(s): Fifteen women ages 18 to 28 years with the diagnosis of polycystic ovary syndrome. Intervention(s): Three months of contraceptive use (30 mcg ethinylestradiol, 3 mg drospirenone). Main Outcome Measure(s): An adrenocorticotropic hormone test was performed before and after the study. Result(s): Adrenal production of cortisol was unchanged after therapy with oral contraceptives. An interesting observation was reduced basal concentrations of androgens such as androstenedione, dehydroepiandrosterone sulfate, testosterone, and free testosterone during therapy. The ratios of the areas of substrates to products before and after oral contraceptive administration were compared for differences in 17 -hydroxylase (17-hydroxyprogesterone/progesterone) and 17,20-lyase (androstenedione/17-hydroxyprogesterone); activities were significantly reduced, indicating a reduction in the activities of these enzymes. Conclusion(s): The present results show for the first time that oral contraceptives containing drospirenone affect adrenal steroidogenesis by reducing synthesis and release of androgens in response to adrenocorticotropic hormone, leaving adrenal production of cortisol unchanged. (Fertil Steril 2007;88:113–7. ©2007 by American Society for Reproductive Medicine.)

The Relative Potency of Competitive and Non-competitive Mineralocorticoid Antagonists in Man

Abstract: Mineralocorticoid antagonists are used clinically in conditions of primary mineralocorticoid excess, such as primary hyperaldosteronism, and in disease states characterised by secondary aldosteronism, for example, chronic liver disease and the nephrotic syndrome. They also find wide use in the treatment of essential hypertension, cardiac failure, and diuretic-induced hypokalaemia, although mineralocorticoid excess has not been demonstrated convincingly in these conditions. The mineralocorticoid antagonists available are the specific competitive aldosterone antagonists, among which spironolactone is the standard drug [1], and the non-competitive physiological antagonists, amiloride and triamterene. The latter drugs have a direct membrane action, principally on the distal renal tubule, and do not require the presence of aldosterone or other mineralocorticoids, whereas spironolactone is pharmacologically inactive in the absence of mineralocorticoids.

Factors affecting the frequency of occurrence of spironolactone bodies in aldosteronomas and

Abstract: Summary Histological sections taken from aldosterone-producingadenomas and from non-tumorous adrenal cortex of 18 patients treated for primary aldosteronism by unilateral adrenalectomy were examined for spironolactone inclusion bodies. Typical inclusions were found in 10 of the 13 patients who received spironolactone up to within 24 h of surgery. They were present in the tumours of 7 patients, and their frequency correlated positively with the percentage of glomerulosa type cells in the tumours. In tumours containing 50% or more glomerulosa-type cells, their frequency correlated negatively with duration of treatment. They were present in the non-tumorous cortex of 4 of these 7 patients, and in the cortex of 3 others whose tumours did not contain them. In the cortex, they were found only in glomerulosa cells, and their presence appeared unrelated to dosage or duration of treatment. No spironolactone inclusion bodies were seen in either the tumour or the non-tumorous cortex of 3 patients who had discontinued spironolactone 19 to 97 d before surgery, or of 2 patients who had never received spironolactone.