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Furosemide Tables:

Pharmacokinetics

Bioavailability Peak plasma

level

Plasma half-

life

Active

metabolites

Elimination

variable* 50% (30-80%)

1 hour 1 to 2 hours none predominantlyrenal

*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 theplasma level.

Dose

Indication Administration Initial loadingdose

Dose Interval

Maintenance dose

Dose* Interval

edemas associated with heartfailure

oral 20-40 mg 24 hours 20-80mg

8 to 24hours

emergency therapy i.v. 20-40 mg 2 hours** - -

*In consideration of the adverse reactions, higher doses - for refractory edema - of up to 2500 mg/dayand 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 fewerhypokalemias (in average 5% of thetreated subjects). However, electrolyte imbalances (also hyponatremia, hypomagnesemia,

hypochloremic alkalosis) aredose related. Hypokalemia and hypomagnesemia increase the risk ofdangerous arrhythmias! Hypotensive reactions and syncopes occur.

Gastrointestinal ailments (e.g. nausea/vomiting), impaired glucose tolerance, hyperuricemia, skinrashes and other allergic reactions, pancreatitis, thrombocytopenia, agranulocytosis are not asfrequent. High furosemide doses also have a (mostly reversible) ototoxic effect.

Furosemide: Interactions

The risk ofototoxicityis increased when furosemide is used together with aminoglycosides orcefaloridine. Hypokalemia induced by furosemide increases the risk of toxicity of digitalis. Like otherdiuretics furosemide also increases the lithium level. The antihypertensive effect of furosemide is notinhibited by non-steroidal anti-infalammatory agents.

Contraindications

Pronounced hyponatremia or hypovolemia and anuria.

Furosemide: Cautions

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

Risk Groups

Pregnant women:Furosemide may reduce placental blood circulation. Only administer for very urgentindications!

Nursing mothers:No adverse effects are known in the child. However, it is excreted in breast milk and mayinhibit 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 orelectrolyte imbalances.

Renal failure:High and very high doses are often necessary for renal failure. Usual oral doses 80-120mg/day. Higher doses for refractory edemas.

Liver insufficiency:In combination with spironolactone the usual dose is 20-120 mg/day. Apply with greatcaution (electrolyte problems!).

References

Ponto LL, Schoenwald RD. Furosemide (frusemide). A pharmacokinetic/pharmacodynamicreview, 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 Peak plasmalevel

Plasma half-life

Activemetabolites

Elimination

variable about70%

about 2 hours 10 to 20 hours* several predominantlyhepatic

*Under consideration of the active metabolites. These are partially sulphur-free (canrenone) andpartially sulphur-containing. The latter are now considered more relevant for the efficacy.

Dose

Indication Administration Initial loading dose Maintenance dose

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Dose Interval Dose Interval

ascites with hepatic cirrhosis oral* 100 mg 24 hours 50-400 mg 24 hours

cardiac edema oral 50 mg 24 hours 25-100 mg 24 hours

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.

IndicationsSpironolactone is considered the drug of choice forcirrhotic ascites if there is no renal failure. In 40-75% of the cases of hepatic cirrhosis with ascites, spironolactone is sufficiently effective as a diureticin single drug therapy. For other mainfestations ofsecondary hyperaldosteronism (heart failure withedema) its effect is also well documented. Forprimary hyperaldosteronism (Conn's syndrome) it canbe 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 becombined with the latter. (In Great Britain it is notrecommended as an antihypertensive agent astumours 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 iseven less established for the treatment of acne and premenstrual syndrome.

Adverse ReactionsSpironolactone has a dose-dependent effect on the function of the sexual hormones: in the longrun gynecomastiaoccurs in more than 10% (in more than half with doses of 150 mg/day) of the treatedmen. 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 areimpaired, 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) andpotassium salts, as well as ACE inhibitors, can cause dangerous hyperkalemia.

References

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Jeunemaitre X, Chatellier G, Kreft-Jais C et al. Efficacy and tolerance of spironolactone inessential 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