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decline in renal perfusion and function26. Consequently, the clinical progression of HF is characterized by the need for increasing doses of diuretics.

Patients may become unresponsive to high doses of diuretic drugs if they consume large amounts of dietary sodium, and/or take agents that can block the effects of diuretics (e.g., nonsteroidal anti-inflammatory drugs, including cyclooxygenase-2 inhibitors)27,28 and/or have a significant impairment of renal function or perfusion29. Diuretic resistance can generally be overcome by the intravenous administration of diuretics (including the use of continuous infusions), the use of 2 or more diuretics in combination (e.g., furosemide and metolazone)30, or the use of diuretics together with drugs that increase renal blood flow (e.g., positive inotropic agents)31.

Risks of treatment

The principal adverse effects of diuretics include electrolyte depletion as well as hypotension and azotemia. Diuretics may also cause rashes and hearing difficulties, but these are generally idiosyncratic or are seen with the use of very large doses, respectively.

Diuretics can cause the depletion of important cations (potassium and magnesium), which can predispose patients to serious cardiac arrhythmias, particularly in the presence of digitalis therapy32. The risk of electrolyte depletion is markedly enhanced when 2 diuretics are used in combination.

The loss of electrolytes is related to enhanced delivery of sodium to distal sites in the renal tubules and the exchange of sodium for other cations, a process that is potentiated by activation of the renin-angiotensin-aldosterone system. Potassium deficits can be corrected by short-term treatment with potassium supplements, or if severe, by the addition of magnesium supplements33.

26 Vargo DL, Kramer WG, Black PK, Smith WB, Serpas T, Brater DC. Bioavailability, pharmacokinetics, and pharmacodynamics of torsemide and furosemide in patients with congestive heart failure. Clin Pharmacol Ther 1995;57:601-9.

27 Herchuelz A, Derenne F, Deger F, et al. Interaction between nonsteroidal anti-inflammatory drugs and loop diuretics: modulation by sodium balance. J Pharmacol Exp Ther 1989;248:1175-81.

28 Brater DC, Harris C, Redfern JS, Gertz BJ. Renal effects of cox-2-selective inhibitors. Am J Nephrol 2001;21:1-15.

29 Risler T, Schwab A, Kramer B, Braun N, Erley C. Comparative pharmacokinetics and pharmacodynamics of loop diuretics in renal failure. Cardiology 1994;84 Suppl 2:155-61:155-61.

30 Ellison DH. The physiologic basis of diuretic synergism: its role in treating diuretic resistance. Ann Intern Med 1991;114:886-94.

31 Oster JR, Epstein M, Smoller S. Combined therapy with thiazide-type and loop diuretic agents for resistant sodium retention. Ann Intern Med 1983;99:405-6.

32 Steiness E, Olesen KH. Cardiac arrhythmias induced by hypokalaemia and potassium loss during maintenance digoxin therapy. Br Heart J 1976;38:167-72.

33 Solomon R. The relationship between disorders of K+ and Mg+ homeostasis. Semin Nephrol 1987;7:253-62.

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