Spironolactone and furosemide

Fuller, R.K., Khambatta, P.B., Gobezie, G.C. An optimal diuretic regimen for cirrhotic ascites. A controlled trial evaluating safety and efficacy of spironolactone and furosemide. J. Amer. Med. Ass. 1977 237 972-975... 

The combination of spironolactone and furosemide is now the recommended initial diuretic therapy for patients with ascites. 

The AASLD practice guidelines recommend that diuretic therapy be initiated with the combination of spironolactone and furosemide. Spironolactone alone was commonly recommended for initial therapy, but clinical trials have demonstrated a 14-day delay in the onset of action, as well as the development hyperkalemia when spironolactone is used alone. Administering spironolactone in single daily doses is justified based on its pharmacokinetics and helps to improve patient compliance. If tense ascites is present, paracentesis... 

Adult patients admitted to the hospital with new-onset ascites should have an abdominal paracentesis performed to establish the serum-ascites albumin gradient, the ascitic fluid PMN count, and to obtain ascitic fluid cultures. Patients who drink alcohol should be strongly discouraged from further alcohol use. Sodium restriction to 2000 mg/ day, together with spironolactone and furosemide, is the main-... 

Figure 55. Direct optical evaluation of spironolactone and furosemide from the contents of a capsule measured by the TLC Scanner II (CAMAG) at 254 nm...

A particularly impressive example of an improved result after development in a saturated N-chamber is shown by the chromatogram of the separation of spironolactone and furosemide on normal silica gel 60, where without chamber saturation the spironolactone is in the front and the furosemide is slightly below this (Fig. 60a,b). However, in this example the development is performed with a CHC-containing solvent system, and an alternative system for separating these two substances is therefore given in Table 15. Other information on the conditions is also given. 

Figure 60. Influence of chamber saturation in the separation of spironolactone and furosemide...

Diuretic therapy should be initiated with single morning doses of spironolactone, 100 mg, and furosemide, 40 mg, with a goal of 0.5-kg maximum daily weight loss. The dose of each can be increased together, maintaining the 100 40 mg ratio, to a maximum daily dose of 400 mg spironolactone and 160 mg furosemide. 

A 37-year old man with a dilated cardiomyopathy was given furosemide, spironolactone, and candesartan. After 1 year carvedilol was introduced in a maintenance dose of 10 mg/day. HbAic was 5.1% at the beginning of carvedilol treatment. After 9 months of treatment, he started to feel extremely thirsty and lost 10 kg in 3 months. No viral infections or pancreatitis were detected. The HbAic concentration increased to 17%, the blood glucose concentration was 31 mmol/1 (557 mg/dl). Furosemide was withdrawn and the blood glucose concentration fell within a week to 8.9 mmol/1 (160 mg/dl). Carvedilol was then replaced by metopro-lol and after 2 further weeks the fasting blood glucose concentration fell to 5.9 mmol/1 (106 mg/dl). The patient was stable thereafter. 

Both drugs are gastric irritants and should probably be avoided in patients with varices or a history of variceal bleeding or coagulopathy, or a risk thereof. Niacin can also cause thrombocytopenia. This patient has a varix and would be at risk of a variceal bleed if decompensation occurred. Niacin and acipimox also commonly cause pruritus. They are also vasodilators and may potentiate the effect of drugs that lower blood pressure (spironolactone, propranolol, furosemide), which are used to treat ascites and portal hypertension. 

Flomeida M, Roberts C, Branch RA. Influence of probenecid and spironolactone on furosemide kinetics in man. Clin Pharmacol Ther 1977 22 402-409. 

The loop diuretics, bumetanide, furosemide and torasemide, the potassium-sparing diuretic spironolactone, and the thiazides chlortalidone and chlorothiazide, have all been shown either not to interact or to cause only a small reduction in the effects of the coumarin anticoagulants of minimal or no clinical importance. The lack of reports of clinically relevant interactions su ests that, in general, diuretics do not interact with anticoagulants. The possible exception is etacrynic acid, which on rare occasions has caused a marked increase in the effects of warfarin. 

A study in 4 healthy subjects found that indometacin 150 mg daily given with triamterene 200 mg daily over a 3-day period reduced the creatinine clearance in 2 subjects by 62% and 72%, respectively. Renal function returned to normal after a month. Indometacin alone caused an average 10% fall in creatinine clearance, but triamterene alone caused no consistent change in renal function. No adverse reactions were seen in 18 other subjects treated in the same way with indometacin and furosemide, hydrochlorothiazide or spironolactone. Five patients are reported to have rapidly developed acute renal failure after receiving indometacin and triamterene, either concurrently or sequentially. " ... 

Diuretic activity of a chloroform extract of horsetail was observed in mice. The effect of 50 mg/kg of horsetail was greater than that of the drugs hydrochlorothiazide, spironolactone, or furosemide (all 25 mg/kg) in relation to the urine output and excretion of sodium, potassium, and chloride (Perez Gutierrez et al. 1985). 

Chromatograms of (a) urine matrix, (b) urine matrix spiked with a mixture of 1 pg/mL of each diuretic and (c) an aqueous solution of the diuretics, all eluted with a 0.042 M SDS-4% 1-propanol mobile phase in phosphate buffer at pH 4.5. Compounds (1) furosemide, (2) chlorthalidone, (3) ethacrynic acid, (4) bendroflumethiazide, (5) probenecid, (6) bumetanide, (7) amiloride, (8) xipamide, (9) spironolactone and (10) triamterene. Reprinted from Ref 23 with permission of Elsevier. 

Electrolyte balance Hypernatremia has been reported in a 44-year-old woman with normal renal function who was given too much sodium polystyrene sulfonate she was also taking furosemide, spironolactone, and lisinopril [39 ]. The authors attributed this to net intestinal water loss because of profuse osmotic diarrhea. 

A potential case of an interaction between quinidine and flucloxacillin was demonstrated in a 63-year-old patient with recently diagnosed dilated cardiomyopathy who was admitted to the hospital with polymorphic ventricular tachycardia and ventricular fibrillation episodes induced by bradycardia. The patient was on a heart failure regimen of furosemide, spironolactone and perindopril, and was initiated on oral quinidine in the hospital for the prevention of ventricular arrhythmias. The patient s temporary pacemaker lead was removed and an implantable cardioverter-defibrillator was placed due to continued ventricular fibrillation. The next day, the patient became febrile. Culture of pacemaker lead tip and blood cultures were positive for S. aureus. Flucloxacillin and rifampin were initiated, but rifampin was discontinued due to the development of renal insufficiency and liver test abnormalities. These were normalised after rifampin was discontinued. The patient required continuous pacing to prevent ventricular tachycardia episodes, and quinidine was increased to 2800 mg per day (maximum daily dose). Quinidine plasma levels were subtherapeutic at 1.1 mg/L. The authors speculate that this interaction was due to quinidine being a substrate of Pgp and CYP3A4, and flucloxacillin s ability to induce these enzymes. While this may be a potential mechanism, the authors do not comment on how long the patient received rifampin. Rifampin is also a CYP3A4 inducer and could have been parf of fhe reason for fhe decrease in quinidine level [46 ]. 

Ascites. Patients with cirrhosis, especially fiver cirrhosis, very often develop ascites, ie, accumulation of fluid in the peritoneal cavity. This is the final event resulting from the hemodynamic disturbances in the systemic and splanchnic circulations that lead to sodium and water retention. When therapy with a low sodium diet fails, the dmg of choice for the treatment of ascites is furosemide, a high ceiling (loop) diuretic, or spironolactone, an aldosterone receptor antagonist/potassium-sparing diuretic. 

In order to correct potassium losses and the consequent diuretic-induced hypokalemia, spironolactone or triamterene can be successfully combined with the thiazide, metolazone, chlorthalidone, furosemide or ethacrynic acid. 

Hypertension therapy suggests wide use of diuretics, including thiazide diuretics, drugs related to them, such as metolazone (21.3.20) and indapamide (21.3.26), furosemide (21.4.11), loop diuretics, as well as potassium sparing diuretics—spironolactone (21.5.8), triamterene (21.5.13), and amyloride (21.5.18). 

Diuretics and their mechanisms of action will be discussed in detail in Chapter 21. Loop diuretics, such as furosemide (Lasix), block the Na" -K" -2CLsymporter in the ascending limb of the loop of Henle.The resultant effect is delivery of more Na" to the distal tubule and enhanced urinary loss of Na" and water. Unfortunately, the resultant increase in urinary excretion of and K+ can lead to arrhythmias. The potential for arrhythmias is exacerbated by the loss of Mg++ and Ca++ and an underlying vulnerability of the myocardium in CHF. However, loop diuretics are still part of the mainstay of therapy for CHF despite these potential problems and the absence of well-controlled multicenter clinical trials. The rationale for their use is so compelling that placebo-controlled studies appear unethical. Moreover, furosemide was accepted as the standard of care in all of the clinical trials that form the basis for recommended therapy for CHF. The use of the potassiumsparing diuretic spironolactone has been shown to improve survival and is discussed below. 

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