Administration Of Potassium Canrenoate Research Articles

Potassium canrenoate treatment in paediatric patients

To characterize the population pharmacokinetics of canrenone following administration of potassium canrenoate (K-canrenoate) in paediatric patients. Data were collected prospectively from 37 paediatric patients (median weight 2.9 kg, age range 2 days-0.85 years) who received intravenous K-canrenoate for management of retained fluids, for example in heart failure and chronic lung disease. Dried blood spot (DBS) samples (n=213) from these were analysed for canrenone content and the data subjected to pharmacokinetic analysis using nonlinear mixed-effects modelling. Another group of patients (n=16) who had 71 matching plasma and DBS samples was analysed separately to compare canrenone pharmacokinetic parameters obtained using the two different matrices. A one-compartment model best described the DBS data. Significant covariates were weight, postmenstrual age (PMA) and gestational age. The final population models for canrenone clearance (CL/F) and volume of distribution (V/F) in DBS were CL/F (l/h) = 12.86 × (WT/70.0) × e [0.066 × (PMA - 40]) and V/F (l) = 603.30 × (WT/70) × (GA/40) where weight is in kilograms. The corresponding values of CL/F and V/F in a patient with a median weight of 2.9 kg are 1.11 l/h and 20.48 l, respectively. Estimated half-life of canrenone based on DBS concentrations was similar to that based on matched plasma concentrations (19.99 and 19.37 h, respectively, in 70 kg patient). The range of estimated CL/F in DBS for the study population was 0.12-9.62 l/h; hence, bodyweight-based dosage adjustment of K-canrenoate appears necessary. However, a dosing scheme that takes into consideration both weight and age (PMA/gestational age) of paediatric patients seems more appropriate.

Displacement of Cortisol From Human Heart by Acute Administration of a Mineralocorticoid Receptor Antagonist

Mineralocorticoid receptor (MR) antagonists have beneficial effects in patients with heart failure and myocardial infarction, often attributed to blocking aldosterone action in the myocardium. However, binding of aldosterone to MR requires local activity of the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which inactivates cortisol to cortisone and thereby prevents receptor occupancy by cortisol. In vivo activity of 11β-HSD2 and potential occupancy of MR by cortisol in human heart have not been quantified. This study aimed to measure in vivo activity of 11β-HSD2 and to establish whether cortisol binds MR in human heart. Nine patients without heart failure undergoing diagnostic coronary angiography were infused to steady state with the stable isotope tracers 9,11,12,12-[(2)H]4-cortisol and 1,2-[(2)H]2-cortisone to quantify cortisol and cortisone production. Samples were obtained from the femoral artery and coronary sinus before and for 40 minutes after bolus iv administration of an MR antagonist, potassium canrenoate. Coronary sinus blood flow was measured by venography and Doppler flow wire. There was no detectable production of cortisol or cortisone across the myocardium. After potassium canrenoate administration, plasma aldosterone concentrations increased substantially but aldosterone was not detectably released from the myocardium. In contrast, plasma cortisol concentrations did not change in the systemic circulation but tissue-bound cortisol was released transiently from the myocardium after potassium canrenoate administration. Human cardiac 11β-HSD2 activity appears too low to inactivate cortisol to cortisone. Cortisol is displaced acutely from the myocardium by MR antagonists and may contribute to adverse MR activation in human heart.

TIME-COURSE REDUCTION OF RENAL FUNCTION IN RATS ON HIGH SODIUM INTAKE: ACUTE REVERSAL BY POTASSIUM CANRENOATE

1. Time course of renal alterations associated with long-term (since weaning) administration of a high sodium (HS, 8% NaCl) diet was assessed in Sprague-Dawley rats. Reversal by acute administration of the mineralocorticoid receptor antagonist, potassium canrenoate (40 mg/kg, i.p.) or the type 1 angiotensin II receptor antagonist, losartan (10 mg/kg, i.v.), was evaluated at the age of 5 months (i.e. after 21 weeks of HS feeding). 2. High sodium intake had no detectable effect on blood pressure; however, albuminuria was always higher in the HS than control group. Glomerular filtration rate, renal plasma flow and filtration fraction decreased significantly after 12 weeks of HS diet by approximately 50, 30 and 20%, respectively. Canrenoate was effective and markedly reversed the renal hypofiltration associated with HS feeding without change in systemic blood pressure. In contrast, losartan reduced blood pressure and it was devoid of a beneficial effect on renal function. 3. The present observations indicate that hypofiltration and hypoperfusion of the kidney occurred progressively and require a long period of exposure to a high sodium intake. Albuminuria, which increased before detectable changes in renal function, may represent an early marker of renal dysfunction. The beneficial effect of acute administration of potassium canrenoate favours the participation of aldosterone, at least partially, in the sustained deterioration of renal function after 21 weeks of high sodium feeding.

Effects of the aldosterone receptor antagonist potassium canrenoate on renal blood flow and urinary output during prolonged increased intraabdominal pressure (IAP) in pigs

Increased intraabdominal pressure can be found after major abdominal trauma and necrotizing pancreatitis and is used during laparoscopic surgery. The purpose of this study was to investigate the effect of the aldosterone receptor antagonist (potassium canrenoate) on renal hemodynamics and urinary output in pigs during increased intraabdominal pressure (IAP). The IAP was kept at 30 mmHg for 3 h by instillation of Ringer's solution into the peritoneal cavity. Eight animals were treated with potassium canrenoate and eight animals served as controls. Renal blood flow, hormones in femoral artery blood, and the urinary output were measured. The administration of potassium canrenoate was followed by increased aldosterone concentrations in arterial blood, increased blood concentration of potassium, and increased concentration of sodium in the urine, indicating satisfactory inhibition of aldosterone. Potassium canrenoate did not cause changes in cardiac output and arterial pressure. It did not affect the renal vascular resistance that increased at an IAP of 30 mmHg, or the renal blood flow that remained constant during the experiments. The group treated with potassium canrenoate had higher mean urinary output than the controls, but the difference was not significant. Increased IAP in pigs is associated with markedly reduced urinary output and increased serum concentrations of aldosterone. Although the urinary output did not increase significantly, the increased sodium concentration in the urine of canrenoate-treated animals suggests that the high blood level of aldosterone contributes to the oliguria under increased IAP.

Acute aldosterone antagonism improves cardiac vagal control in humans

ObjectivesWe have examined the acute effects (<45 min) of aldosterone antagonism on heart rate variability and baroreflex sensitivity, markers of cardiac vagal control, in 13 healthy subjects. BackgroundEvidence for the beneficial effects of aldosterone antagonists comes from studies showing increased survival rates following their addition to standard heart failure therapy. Many mechanisms have been suggested for this action, including effects upon the autonomic nervous system. MethodsHeart rate variability and baroreflex sensitivity were examined 30 min following the administration of potassium canrenoate (intravenous) (aldosterone antagonist) or saline (control). ResultsActive treatment reduced resting heart rate (−6 ± 1 beats/min [mean ± standard error mean]) compared to control (0 ± 1 beat/min) (p < 0.001) and increased measures of high frequency (HF) heart rate variability. Root mean square of successive RR interval differences increased by 21 ± 5 ms versus −6 ± 5 ms control (p < 0.001); HF power increased by 1,369 ± 674 ms2with aldosterone antagonism compared to −255 ± 431 ms2following saline infusion (p < 0.01). Baroreflex sensitivity (alpha-HF) was increased after active treatment (+4 ± 2 ms/mm Hg vs. 0 ± 1 ms/mm Hg control [p < 0.05]). No changes in plasma potassium levels were observed. ConclusionsThese results provide evidence that aldosterone antagonists acutely improve cardiac vagal control, irrespective of any diuretic effects, and may in part explain their beneficial effects in treatment of heart failure.

The Antihypertensive and Renal Activities of Potassium Canrenoate are Associated with Increased Renal Prostaglandin Excretion

1. In a double-blind, randomized, cross-over study the effects of potassium canrenoate administration (100 mg twice daily for 10 days orally) on renal prostaglandin synthesis (prostaglandin E2 and prostaglandin F2 alpha) were evaluated in 10 normotensive females and in 10 females with essential hypertension. 2. When compared with normotensive subjects, hypertensive patients in baseline conditions showed a reduced excretion of urinary prostaglandin E2 associated with an excessive prostaglandin F2 alpha production. 3. Potassium canrenoate significantly reduced mean blood pressure in hypertensive patients [from 118.9 +/- 8.7 mmHg (1.62 +/- 0.12 kPa) to a peak minimum value of 104.7 +/- 9.8 mmHg (1.42 +/- 0.13 kPa) on the seventh day of treatment; P less than 0.01 for the whole period] but not in control subjects [from 88 +/- 9.4 mmHg (1.20 +/- 0.13 kPa) to 84.3 +/- 8.3 mmHg (1.15 +/- 0.11 kPa) on the eighth day, NS] even though potassium canrenoate significantly increased sodium excretion in both groups. Renal prostaglandin excretion was affected differently in the two groups: in control subjects excretion of both prostaglandin E2 and prostaglandin F2 alpha was increased after drug administration, whereas in hypertensive patients only prostaglandin E2 excretion was enhanced.

Acute effect of potassium canrenoate administration on renin-angiotensin, kallikrein-kinin and prostaglandin systems

Abstracto1.To investigate the possible effects of potassium canrenoate (PC) on plasma renin activity (PRA) and on renal prostaglandins (PGS) and kinins under elevated sodium and/or potassium intakes, a single dose of PC was administered to four groups of Wistar male rats.2.They were fed a normal diet (C), a diet supplemented with 4% of NaCl, (Na), with 1% of KCl: (K) or both supplements (NaK).3.PRA and urinary PGS excretion did not show changes after PC administration, but total urinary kinins showed higher values after the treatment in all groups.4.A diuretic but not natriuretic effect was observed only in C animals.5.In conclusion, the single dose of PC was able to stimulate urinary kinins and to spare potassiumindependently of dietary electrolyte supplements that were able to block the diuretic effect of the drug. To investigate the possible effects of potassium canrenoate (PC) on plasma renin activity (PRA) and on renal prostaglandins (PGS) and kinins under elevated sodium and/or potassium intakes, a single dose of PC was administered to four groups of Wistar male rats. They were fed a normal diet (C), a diet supplemented with 4% of NaCl, (Na), with 1% of KCl: (K) or both supplements (NaK). PRA and urinary PGS excretion did not show changes after PC administration, but total urinary kinins showed higher values after the treatment in all groups. A diuretic but not natriuretic effect was observed only in C animals. In conclusion, the single dose of PC was able to stimulate urinary kinins and to spare potassiumindependently of dietary electrolyte supplements that were able to block the diuretic effect of the drug.

EFFECTS OF POTASSIUM CANRENOATE ON PLASMA MAGNESIUM CONCENTRATION IN ABDOMINAL SURGERY

Plasma magnesium (Mg) concentrations were measured before and after operations in 51 patients undergoing abdominal surgery. Twenty-four patients were administered potassium canrenoate 8 mg/kg immediately after induction of anesthesia, and the other 27 served as controls. The mean plasma Mg concentrations in the control group were 1.74±0.37 mg/100 ml prior to surgery, 1.50±0.36 on the first postoperative day and 1.57±0.33 on the second postoperative day. Postoperative values remained significantly lower than the preoperative value. In the administration group, in contrast, plasma Mg concentrations were 1.77±0.28 preoperatively, 1.66±0.25 on the first postoperative day and 1.77±0.27 on the second postoperative day. Although the first postoperative value in this group was significantly lower than the preoperative value, it was restored to the control level on the second postoperative day. These results suggest that plasma Mg concentration was decreased after abdominal surgery and that administration of potassium canrenoate is useful in order to prevent the decrease in plasma Mg concentrations.

Acute effect of potassium canrenoate administration on renin-angiotensin, kallikrein-kinin and prostaglandin systems

1. To investigate the possible effects of potassium canrenoate (PC) on plasma renin activity (PRA) and on renal prostaglandins (PGS) and kinins under elevated sodium and/or potassium intakes, a single dose of PC was administered to four groups of Wistar male rats. 2. They were fed a normal diet (C), a diet supplemented with 4% of NaCl, (Na), with 1% of KCl: (K) or both supplements (NaK). 3. PRA and urinary PGS excretion did not show changes after PC administration, but total urinary kinins showed higher values after the treatment in all groups. 4. A diuretic but not natriuretic effect was observed only in C animals. 5. In conclusion, the single dose of PC was able to stimulate urinary kinins and to spare potassium independently of dietary electrolyte supplements that were able to block the diuretic effect of the drug.

Potassium canrenoate in the treatment of long-term digoxin-induced arrhythmias in conscious dogs

The effects of potassium canrenoate on arrhythmias induced by longterm progressive digoxin toxicity were studied in eight conscious beagle dogs. Sinus bradycardia and sinoatrial block, as well as atrioventricular (A-V) conduction disturbances, were consistently alleviated by administration of potassium canrenoate. Premature supraventricular (including junctional) and ventricular depolarizations as well as ventricular tachycardias were also suppressed. Although potassium canrenoate always terminated the digitalis-induced arrhythmias, it usually converted the rhythm to sinus arrhythmia rather than to normal sinus rhythm. Equimolar sodium canrenoate, but not potassium chloride, had similar reversal effects on arrhythmias induced by long-term digoxin intoxication. These data indicate that canrenoate, a diuretic agent with reported positive inotropic effects, may be useful in the treatment of digitalis-induced arrhythmias in man.

Inability of potassium canrenoate to convert experimentally induced ouabain arrhythmias in the canine heart.

The antiarrhythmic effects of potassium canrenoate were examined in 20 closed-chest, pentobarbital-anesthetized dogs with ouabain-induced ventricular tachycardia. In a group of 8 dogs, a mean dose of ouabain of 64.4 ± 3.7 µg/kg induced sustained ventricular tachycardia. Subsequent administration of potassium canrenoate (30 mg/kg, iv) caused ventricular fibrillation in 1 dog and sinus tachycardia in 3 dogs. Stimulation of the distal end of the cut right vagus in the latter 3 dogs slowed the sinus rhythm enough to permit the ventricular focus to become the dominant pacemaker. In the other 4 dogs, potassium canrenoate did not alter the ouabain-induced ventricular tachycardia. In a second group of 12 dogs, ventricular tachycardia was also induced by administering a toxic dose of ouabain (65.5 ± 2.9 µg/kg, iv). After ouabain intoxication, atrial overdrive suppression of the ventricular rhythm was initiated by electrically pacing the right atrium at a mean frequency of 184.5 ± 7.9 beats/min. Subsequent administration of potassium canrenoate (30 mg/kg, iv) to these dogs restored sinus rhythm in 4 of the dogs; however, stimulation of the distal end of the cut right vagus caused a reappearance of the ventricular ectopic focus. After potassium canrenoate administration, the minimum atrial pacing rate required to capture the ventricular rhythm was 160.9 ± 9.4 beats/min. This rate represents a significant reduction ( P &lt; 0.005) in the rate of the ouabain-induced ventricular ectopic focus, but in no instance was the focus directly suppressed by potassium canrenoate. Propranolol, in contrast to potassium canrenoate, restored normal sinus rhythm in all 20 ouabain-intoxicated dogs and suppressed the ouabain-induced ectopic pacemaker during the period of vagally induced sinoatrial arrest. The results of this study show that potassium canrenoate fails to exert an antiarrhythmic effect against digitalis-induced arrhythmias and that any apparent restoration of sinus rhythm in response to potassium canrenoate is due to overdrive suppression of the ouabain-induced ventricular ectopic pacemaker.