Copyright © 1992 by the European Society of Cardiology.
© 1992 The European Society of Cardiology
Clinical pharmacology of loop diuretics in health and disease
Department of Medicine, Indiana University School of Medicine U.S.A.
Correspondence: D. Craig Brater, MD, Wishard Memorial Hospital, West Outpatient Building, Room 320, 1001 West 10th Street, Indianapolis, IN 46202, U.S.A.
There are differences in metabolism and excretion of the loop diuretics which extrapolate to differences in pharmcokinetic behaviour in different disease states. For example, furosemide is eliminated in equal portions by renal and non-renal routes; the non-renal route involves primarily glucuronidation. Both renal and non-renal pathways are impaired during renal insufficiency, such that the elimination half-life is prolonged considerably in this disease state. In contrast, there seems to be little change in disposition in patients with liver disease. Bumetanide and torasemide have non-renal elimination pathways via the hepatic cytochrome system. In patients with renal insufficiency these non-renal pathways of elimination are left intact so that there is little prolongation of half-life in such patients. In contrast, in patients with liver disease or with congestive hepatopathy, there is impairment in non-renal elimination so that relatively more drug appears in the urine.
With all loop diuretics, response is governed by the amount of drug appearing in the urine. By assessing the relationship between urinary excretion rates of the diuretic and sodium excretion rate, a maximal response which amounts to a fractional excretion of sodium of approximately 20% can be defined. Thus it is possible to define a maximal dose as the amount of drug necessary to attain a fractional excretion of sodium of 20%. Studies in different disease states using escalating doses can thereby use this relationship to define a dose above which little is to be gained in terms of therapeutic efficacy.
Analysing the relationship between amount of diuretic in the urine and response also allows assessment of different mechanisms by which resistance to diuretics occurs in different disease states. For example, in patients with renal insufficiency, the primary mechanism for resistance is diminished delivery of drug to the site of action. As such, administration of large doses of drug to deliver ‘normal’ amounts of diuretic into the urine result in the same response as occurs in subjects with normal renal function. However, this response is in terms of the fractional excretion of sodium meaning that the total amount of sodium eliminated in the urine is still diminished as a result of decreased filtered sodium.
In contrast, in patients with liver disease or with congestive heart failure even when normal amounts of diuretic reach the urinary site of action there is diminished response which may be accounted for by either increased proximal or increased distal tubular reabsorption of sodium. In such syndromes, frequent administration of drug is needed to attain the desired cumulative response and, in addition, combination drug therapy can be helpful by inhibiting sodium reabsorption at several distinct sites of the nephron. This latter strategy can be particularly helpful in subjects who have received long-term loop diuretic therapy who likely have hypertrophy of distal nephrons which are thereby able to reabsorb more sodium and diminish overall response. These distal nephron sites can be inhibited by thiazide diuretics accounting for the synergistic response that often occurs with a combination of loop and thiazide diuretics.
Key Words: Diuretics • comparative pharmacokinetics • comparative pharmacodynamics • renal failure • liver failure
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  N. Takamura, T. Maruyama, and M. Otagiri Effects of uremic toxins and fatty acids on serum protein binding of furosemide: possible mechanism of the binding defect in uremia Clin. Chem., December 1, 1997; 43(12): 2274 - 2280. [Abstract] [Full Text] [PDF]
|
|