Furosemide Cisplatin

Nephrotoxins (N) orototoxins (0) (eg., amphotericin B (N), cisplatin (N/0), cyclosporine (N), furosemide (0), NSAIDs (N), radio contrast (N), vancomycin (N) Additive adverse effects Monitor aminoglycoside SDC and renal function... 

Uses Edema, HTN, CHF, h atic cirrhosis Action Loop diuretic -1- reabsorption of Na Cr in ascending loop of Henle distal tubule Dose 5-20 mg/d PO or IV 200 mg/d max Caution [B, ] Contra Sulfonylurea sensitivity Disp Tabs, inj SE Orthostatic -1- BP, HA, dizziness, photosens, electrolyte imbalance, blurred vision, renal impair Notes 20 mg torsemide = 40 mg furosemide Interactions t Risk of ototox W/ aminoglycosides, cisplatin t effects W/ thiazides t effects OF anticoagulants, antih5rpCTtensives, Li, salicylates X effects IT/barbiturates, carbamaz ine, cholestyramine, NSAIDs, phenytoin, phenobarbital, probenecid, dandehon EMS t Effects of anticoagulants monitor for S/Sxs tinnitus, monitor ECG for hypokalemia (flattened T waves) OD May cause HA, hypotension, hypovolemia, and hypokalemia give IV fluids symptomatic and supportive... 

The severity of aminoglycoside nephrotoxicity is additive with that of vancomycin, polymixin, gallium, furosemide, enflurane, cisplatin, and cephalosporins. Aminoglycoside nephrotoxicity is synergistic with that of amphotericin B and cyclosporine. 

Ototoxicity Ototoxicity (vestibular and cochlear) is directly related to high peak plasma levels and duration of treatment. Deafness may be irreversible and has been known to affect fetuses in utero. Patients simultaneously receiving another ototoxic drug such as the loop diuretics furosemide, bumetanide, ethacrynic acid (see p. 227) or cisplatin (see p. 396), are particulary at risk. Vertigo and loss of balance may also occur because these drugs affect the vestibular apparatus. 

Beta-lactam induced renal toxicity can results from their use in monotherapy or when used in combination with other nephrotoxic drugs such as aminoglycosides, amphotericin B, cisplatin, cyclosporine, furosemide, ifosfamide, vancomycin and nephrotoxic p-lactams. While the risk of nephrotoxic injury from monotherapy with p-lactams is relatively low, this risk is substantially increased when multiple drug combinations are required. 

While several experimental reports have suggested that diuretics [mannitol and furosemide] decrease cisplatin nephrotoxicity [36, 41] others have shown that they may aggravate it [43]. Further, in humans, there is no convincing evidence than diuretics may attenuate cisplatin nephrotoxicity as shown in a randomized study by Alsarraf et al. [44] hydration + cisplatin was compared to hydration + mannitol + cisplatin. 

Since the above ototoxins have other targets than cochlear/ vestibular hair cells, the requirements of in vitro models for these drugs differ from models for permanent hair cell loss by cisplatin and AGs. Consequently, in vitro models for furosemide and quinine ototoxicity require the experimental assessment of the lateral wall, not so much of the organ of Corti or the vestibular organs. The action of salicylate may be studied in organ of Corti explants that allow for analysis of hair cells. 

Mannitol and furosemide reduce the concentration of platinum in the urine, suggesting that these agents might attenuate cisplatin nephrotoxicity [40,41]. However, plasma and renal platinum content were unchanged and the degree of cellular necrosis did not improve with use of these diuretics [41]. Platinum does not appear to undergo tubular reabsorption based on the nearly complete urinary recovery of microinjected platinum [13]. Hence, renal platinum content is independent of its luminal concentration. 

Conclusions regarding the renoprotective action of mannitol and furosemide to decrease experimentally induced cisplatin nephrotoxicity are conflicting [36,41, 43]. However, in humans, a randomized study hy Alsarraf et al. [44] comparing hydration + cisplatin to hydration + mannitol + cisplatin concluded that mannitol did not attenuate cisplatin nephrotoxidly. 

Heidemann HTH, Gerkens JF, Jackson EK, Branch RA. Attenuation of cisplatin-induced nephrotoxicity in the rat by high salt diet, furosemide and acetazolamide. Naunyn-Schmiedeberg s Arch Pharmacol 1985 329 201-205. 

Vancomycin is both potentially nephrotoxic and ototoxic, and its manufacturers therefore suggest that it should be used with particular care, or avoided in patients with renal impairment or deafiiess. They also advise the avoidance of other drugs that have nephrotoxic potential, because the effects could be additive. They list amphotericin B, aminoglycosides, bacitracin, colistin, poymyxin B, viomycin and cisplatin. They also list etacrynic acid and furosemide as potentially aggravating ototoxicity. 

A single report describes the development of renal failure in a patient treated with furosemide and other antihypertensives during cisplatin therapy. However, note that furosemide can be used to promote diuresis during cisplatin therapy to reduce the risk of nephrotoxicity. Although animal studies show that the damaging effects of cisplatin on the ear can be markedly increased by the concurrent use of etacrynic acid or furosemide a retrospective analysis in patients did not find this effect. 

Three hours after receiving intravenous cisplatin 70 mg/m a patient experienced severe nausea and vomiting and his blood pressure rose from 150/90 to 248/140 mmHg. This was managed with furosemide 40 mg intravenously, hydralazine 10 mg intramuscularly, diazoxide 300 mg intravenously and propranolol 20 mg orally twice daily for 2 days. Nine days later the patient showed evidence of renal impairment (creatinine raised from about 88 micromol/L to 283 micromol/L), which resolved within 3 weeks. The patient was subsequently similarly treated on two occasions with cisplatin and again developed hypertension, but no treatment was given and there was no evidence of renal impairment. The reasons for the renal impairment are not known, but a study in rats indicate that kidney damage may possibly be related to the concentrations of cisplatin, and that furosemide can increase cisplatin levels in the kidney. However, another study in patients found that there was no difference in the toxicity or pharmacokinetics of cisplatin when furosemide was used to induce diuresis, compared with mannitol. Two other studies have also found that furosemide does not alter cisplatin pharmacokinetics. Another study showed that sodium chloride solution with or without furosemide was associated with less cisplatin nephrotoxicity than sodium chloride solution with mannitol. ... 

Ostrow S, Egorin MJ, Hahn D, Markus S, Aisner J, Chang P, LeRoy A, Bachur NR, Wiemik PH. High-dose cisplatin tiierapy using mannitol versus furosemide diuresis comparative pharmacokinetics and toxicity. Cancer Treat Rep (1981) 65, 73-8. 

Santoso JT, Lucci JA, Coleman RL, Schafer I, Hannigan EV. Saline, mannitol, and furosemide hydration in acute cisplatin nephrotoxicity a randomised trial. Cancer Chemother Phar-macol(2003) 52,13-18. 

Laurell G, Engstrom B. The combined effect of cisplatin and furosemide on hearing function in guinea pigs. HearRes( 9S9) 38,19-26. 

Other diuretics such as furosemide may be used [17] and administration in hypertonic saline was also shown to limit the nephrotoxicity [18, 19] and allow higher doses. The rationale in the latter case was that high chloride concentration would inhibit hydrolysis and the complex would pass through the kidneys in the unreactive chloride form. However, the mechanism by which hydration protects the kidneys is not fully understood and may be due to a lesser concentration of cisplatin and a shorter exposure in the renal tubules [20]. 

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