Drug Therapy in Renal Failure: Dosing Guidelines for Adults

Bennett, William M.; Muther, Richard S.; Parker, Richard; Feig, Peter U.; Morrison, Gail; Golper, Thomas A.; Singer, Irwin

doi:10.7326/0003-4819-93-1-62

Cited by 107 publications

(18 citation statements)

References 349 publications

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“…Amphotericin B is a large molecule and is in part eliminated by excretion into bile (10). Impaired elimination in patients with renal failure has not been observed (17), and dosage modifications in patients with renal failure are not advocated (4,16). It was therefore surprising to find that levels of amphotericin B in tissues were different between salt-depleted and salt-loaded rats in both the kidney and the liver, despite no evidence of accumulation in plasma.…”

Section: Discussionmentioning

confidence: 99%

Sodium status influences chronic amphotericin B nephrotoxicity in rats

Ohnishi

Stevenhead

et al. 1989

Antimicrob Agents Chemother

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The nephrotoxic potential of amphotericin B (5 mg/kg per day intraperitoneally for 3 weeks) has been investigated in salt-depleted, normal-salt, and salt-loaded rats. In salt-depleted rats, amphotericin B decreased creatinine clearance linearly with time, with an 85% reduction by week 3. In contrast, in normal-salt rats creatinine clearance was decreased but to a lesser extent at week 2 and 3, and in salt-loaded rats creatinine clearance did not change for 2 weeks and was decreased by 43% at week 3. All rats in the sodium-depleted group had histopathological evidence of patchy tubular cytoplasmic degeneration in tubules that was not observed in any normal-salt or salt-loaded rat. Concentrations of amphotericin B in plasma were not significantly different among the three groups at any time during the study. However, at the end of 3 weeks, amphotericin B levels in the kidneys and liver were significantly higher in salt-depleted and normal-salt rats than those in salt-loaded rats, with plasma/kidney ratios of 21, 14, and 8 in salt-depleted, normal-salt, and salt-loaded rats, respectively. In conclusion, reductions in creatinine clearance and renal amphotericin B accumulation after chronic amphotericin B administration were enhanced by salt depletion and attenuated by sodium loading in rats.Despite recent availability of newer antifungal drugs, amphotericin B remains the broad-spectrum antimycotic antibiotic of choice for the majority of systemic fungal infections. Unfortunately, amphotericin B also induces a variety of adverse effects, including fever, chills, nausea, vomiting, hypokalemia, hypomagnesemia, and phlebitis. The most restrictive adverse effect is its potential for inducing nephrotoxicity, which can occur in up to 80% of patients (6). The mechanism by which amphotericin B induces nephrotoxicity has not been clearly defined, although it is likely that this drug induces primary effects on the kidney, which can be modified by secondary renal responses. The initial renal toxic event may be due to the ability of amphotericin B to bind the sterols in membranes and alter membrane permeability (1, 2), possibly acting as an ionophore. It is unlikely, however, that this is the sole factor that determines the extent of change in renal function, since other factors have been shown to modify the renal response. The most notable of these is the salt status at the time of drug administration.There are observations in humans indicating that nephrotoxicity due to amphotericin B is enhanced when saltdepleted patients receive this drug and that salt supplementation can minimize this response (5, 15). It has also been shown that amphotericin B induces acute renal vasoconstriction in both dogs and rats (7,11,14) and that this response can be attenuated by salt loading (11). No direct evidence is available concerning whether salt loading is associated with maintenance of renal function during chronic administration in experimental animals. In one study, chronic supplements with sodium bicarbonate were shown to provide protec...

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Section: Discussionmentioning

confidence: 99%

Sodium status influences chronic amphotericin B nephrotoxicity in rats

Ohnishi

Stevenhead

et al. 1989

Antimicrob Agents Chemother

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“…More specifically, when amino glycoside dosages are increased above recommended doses in an attempt to assure optimal efficacy, can an increased risk of toxicity be excluded? The recommendation that patients with shorter drug half-lives receive larger doses at more frequent intervals cannot be supported by existing literature [12], although patients with longer drug half-lives that require less drug less frequently have been the major focus of clinical pharmacokinetics [21][22][23]. To further confuse the issue, observations in experimental animals have shown that intermittent administration of aminoglycoside doses results in less nephrotoxicity than continuous infusion of the same total dose, despite the fact that tissue levels were identical [24,25],…”

Section: Discussionmentioning

confidence: 88%

Aminoglycoside Dosage in Pediatric Patients: Considerations Regarding Pharmacokinetic-Based Dose Adjustment in Patients Requiring High versus Low Dose Therapy

Leff¹,

Roberts²

1981

Dev Pharmacol Ther

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Pharmacokinetic-based adjustment of individual aminoglycoside dosage regimens is currently being utilized in the clinical setting in an attempt to avoid toxicity and/or enhance efficacy. In this report, comparisons have been made between initial and adjusted aminoglycoside dosage employed in toddlers and older children with cystic fibrosis or leukemia (high daily dose) and neonates (low daily dose) with suspected or proven infection. The initial versus adjusted mean aminoglycoside dosage was 14.1 and 17.0 mg/kg/day, respectively, in toddlers and older children with cystic fibrosis, and 7.1 and 11.5 mg/kg/day, respectively, in toddlers and older children with leukemia. Neonates with suspected or proven infection had an initial mean total daily dose of 7.4 mg/kg/day and the adjusted mean daily dose was 5.4 mg/kg/day. The use of a single pharmacokinetic dosing model for all patients, irrespective of evidence of increased or decreased drug elimination, results in widely differing drug dosages. Important and serious questions must be considered regarding the balance between efficacy and toxicity resulting from the rigid manner by which dosage adjustment protocols are employed.

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“…Therefore, the elderly subjects may experience more side effects after administra tion of the recommended dosage of sulfisoxa zole for young adults. On the basis of our findings, the elderly subjects may benefit from a dosage adjustment of sulfisoxazole similar to that recommended in the therapy of patients with renal insufficiency [2].…”

Section: Discussionmentioning

confidence: 99%

“…Side effects of sulfisoxazole such as crystalluria [2] and gastrointestinal discom fort [11] are related to higher plasma levels of the drug. Therefore, the elderly subjects may experience more side effects after administra tion of the recommended dosage of sulfisoxa zole for young adults.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Sulfisoxazole in Young and Elderly Subjects

Boisvert¹,

Barbeau²,

Bélanger³

1984

Gerontology

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The pharmacokinetics of sulfisoxazole was studied in 6 elderly (age 63–75 years) and 7 young (age 22–37 years) healthy nonsmoking volunteers following the oral administration of 2 g of Gantrisin®. The plasma levels of sulñsoxazole obtained in the postabsorption phase were higher in the elderly subjects. There was no significant variation between the two groups of volunteers in the absorption rate constant, Cmax, bioavailability, the fraction of the dose of sulfisoxazole excreted unchanged, the area under the plasma curve of the N⁴-acetyl conjugate formed, and in the apparent volume of distribution of the drug. The t_max value and plasma half-life of sulfisoxazole were significantly longer, and the total body and renal clearances of the drug decreased in the elderly subjects. Diminished renal function as estimated by the creatinine clearance and urinary flow may explain the slower elimination of sulfisoxazole in the elderly subjects. Therefore, advancing age should be considered as a factor in the adjustment of sulfisoxazole dosage.

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Drug Therapy in Renal Failure: Dosing Guidelines for Adults

Cited by 107 publications

References 349 publications

Sodium status influences chronic amphotericin B nephrotoxicity in rats

Sodium status influences chronic amphotericin B nephrotoxicity in rats

Aminoglycoside Dosage in Pediatric Patients: Considerations Regarding Pharmacokinetic-Based Dose Adjustment in Patients Requiring High versus Low Dose Therapy

Pharmacokinetics of Sulfisoxazole in Young and Elderly Subjects

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