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Furosemide Tables:

Pharmacokinetics Bioavailability variable* 50% (3080%) Peak plasma level 1 hour Plasma halflife 1 to 2 hours Active metabolites none Elimination predominantly renal

*The variability of the bioavailability is based on the discrepancies of the gastrointestinal absorption (no presystemic metabolism). The urine concentration is more important for the efficacy than the plasma level. Dose Indication Administration Initial loading dose Dose Interval 20-40 mg 20-40 mg Maintenance dose Dose* Interval 8 to 24 hours -

edemas associated with heart failure emergency therapy

oral i.v.

24 hours 20-80 mg 2 hours** -

*In consideration of the adverse reactions, higher doses - for refractory edema - of up to 2500 mg/day and longer intervals of administration are possible for long-term treatment. **The slow i.v. injection can be repeated already after 30 minutes to 1 hour for pulmonary edema. Compared to thiazides, furosemide seems to cause slightly fewer hypokalemias (in average 5% of the treated subjects). However, electrolyte imbalances (also hyponatremia, hypomagnesemia, hypochloremic alkalosis) aredose related. Hypokalemia and hypomagnesemia increase the risk of dangerous arrhythmias! Hypotensive reactions and syncopes occur. Gastrointestinal ailments (e.g. nausea/vomiting), impaired glucose tolerance, hyperuricemia, skin rashes and other allergic reactions, pancreatitis, thrombocytopenia, agranulocytosis are not as frequent. High furosemide doses also have a (mostly reversible) ototoxic effect.

Furosemide: Interactions
The risk of ototoxicity is increased when furosemide is used together with aminoglycosides or cefaloridine. Hypokalemia induced by furosemide increases the risk of toxicity of digitalis. Like other diuretics furosemide also increases the lithium level. The antihypertensive effect of furosemide is not inhibited by non-steroidal anti-infalammatory agents.

Contraindications
Pronounced hyponatremia or hypovolemia and anuria.

Furosemide: Cautions

Caution when there are losses of potassium (vomiting, diarrhea)! A pronounced hypokalemia demands to be treated (potassium sparing diuretics, potassium substitution). For men with prostate hyperplasia there is a risk of urinary retention.

Risk Groups
Pregnant women: Furosemide may reduce placental blood circulation. Only administer for very urgent indications! Nursing mothers: No adverse effects are known in the child. However, it is excreted in breast milk and may inhibit lactation.The manufacturers recommend weaning. Children: Oral single dose: 2 mg/kg, 3 times daily if necessary. Intravenous: initially 1 mg/kg, maximum of 6 mg/kg/dose. Elderly people: Cautious dosing! There is a possibility of hypovolemia with orthostatic hypotension or electrolyte imbalances. Renal failure: High and very high doses are often necessary for renal failure. Usual oral doses 80-120 mg/day. Higher doses for refractory edemas. Liver insufficiency: In combination with spironolactone the usual dose is 20-120 mg/day. Apply with great caution (electrolyte problems!).

References
Ponto LL, Schoenwald RD. Furosemide (frusemide). A pharmacokinetic/pharmacodynamic review, Part I and II. Clin Pharmacokin 1990; 18: 381-408 und 460-71 Rocco VK, Ware AJ. Cirrhotic ascites. Ann Int Med 1986; 105: 573-85

Spironolactone Tables:
Pharmacokinetics Bioavailability variable about 70% Peak plasma level about 2 hours Plasma halflife Active metabolites Elimination predominantly hepatic

10 to 20 hours* several

*Under consideration of the active metabolites. These are partially sulphur-free (canrenone) and partially sulphur-containing. The latter are now considered more relevant for the efficacy. Dose Indication Administration Initial loading dose Maintenance dose

Dose ascites with hepatic cirrhosis cardiac edema oral* oral 100 mg 50 mg

Interval

Dose

Interval 24 hours 24 hours

24 hours 50-400 mg 24 hours 25-100 mg

Bioavailability is better if spironolactone is taken with a meal. *Potassium canrenoate, a metabolite, is available if a parenteral administration is necessary.

Spironolactone is a synthetic steroid with an aldosterone-like structure; it acts as a competitive antagonist at aldosterone receptors. The most important of these receptors are situated in the distal portion of the renal tubules. Spironolactone thus inhibits sodium and water reabsorption while sparing the potassium and magnesium metabolism. The optimal effect is dependent on a sufficient sodium supply in the distal portion of the renal tubules, as it can be observed in thiazide treatments. Immediate inhibitory effect on aldosterone synthesis is of secondary importance. Spironolactone is also an anti-androgen.

Indications
Spironolactone is considered the drug of choice for cirrhotic ascites if there is no renal failure. In 4075% of the cases of hepatic cirrhosis with ascites, spironolactone is sufficiently effective as a diuretic in single drug therapy. For other mainfestations of secondary hyperaldosteronism (heart failure with edema) its effect is also well documented. For primary hyperaldosteronism (Conn's syndrome) it can be used for the diagnosis or (if surgery is not feasible) for long-term treatment. Spironolactone has a similar antihypertensive action on hypertension as thiazides and it can easily be combined with the latter. (In Great Britain it is not recommended as an antihypertensive agent as tumours have been observed in animal experiments.) Further recognized indications include hypokalemia, idiopathic edema, and nephrotic syndrome. Its use against hirsutism has yet to be documented in controlled studies. The use of spironolactone is even less established for the treatment of acne and premenstrual syndrome.

Adverse Reactions
Spironolactone has a dose-dependent effect on the function of the sexual hormones: in the long run gynecomastiaoccurs in more than 10% (in more than half with doses of 150 mg/day) of the treated men. Impotence, loss of libido and menstrual irregularities are not uncommon. In more than 5% of the treated subjects a hyperkalemia develops (especially if renal functions are impaired, in diabetics, and the elderly). Hyponatremia, reduced renal functions and skin reactions (e.g. urticaria) are rare. Hematologic anomalies, gastric ulcers and hepatitis are rare as well.

Interactions
Concomitant administration of other potassium-sparing diuretics (amiloride, triamterene) and potassium salts, as well as ACE inhibitors, can cause dangerous hyperkalemia.

References

Jeunemaitre X, Chatellier G, Kreft-Jais C et al. Efficacy and tolerance of spironolactone in essential hypertension. Am J Card 1987; 60: 820-5 Rocco VK et al. Cirrhotic ascites. Ann Int Med 1986; 105: 573-85 Skluth HA, Gums JG. Spironolactone: a re-examination. Drug Intell Clin Pharm 1990; 24: 52-9