D. Craig Brater

Effects of Nonsteroidal Anti-Inflammatory Drugs on Renal Function: Focus on Cyclooxygenase -2- Selective Inhibition

Nonsteroidal anti-inflammatory drugs (NSAIDs) can affect renal function in a variety of ways. The most important clinical effects are decreased sodium excretion, decreased potassium excretion, and declines in renal perfusion. Decreased sodium excretion can result in weight gain, peripheral edema, attenuation of the effects of antihypertensive agents, and rarely precipitation of chronic heart failure. Hyperkalemia can occur to a degree sufficient to cause cardiac arrhythmias. Renal function can decline sufficiently enough to cause acute renal failure. Risk factors for all of these effects have been identified, allowing prospective identification of patients at risk with institution of appropriate precautionary measure. All NSAIDs seem to share these adverse effects. Preliminary data from cyclooxygenase-2-selective inhibitors suggest that they also affect renal prostaglandins. Therefore, the same cautions should be exercised with their use as with traditional NSAIDs.

Renal Effects of COX-2-Selective Inhibitors

Although nonsteroidal anti-inflammatory drugs (NSAIDs) effectively treat a variety of inflammatory diseases, these agents may cause deleterious effects on kidney function, especially with respect to solute homeostasis and maintenance of renal perfusion and glomerular filtration. NSAIDs act by reducing prostaglandin biosynthesis through inhibition of cyclooxygenase (COX) which exists as two isoforms (COX-1 and COX-2). NSAID-induced gastrointestinal toxicity is generally believed to occur through blockade of COX-1 activity, whereas the anti-inflammatory effects of NSAIDs are thought to occur primarily through inhibition of the inducible isoform, COX-2. However, the situation in the kidney may be somewhat different. Recent studies have demonstrated that COX-2 is constitutively expressed in renal tissues of all species; this isoform may, therefore, be intimately involved in prostaglandin-dependent renal homeostatic processes. Drugs that selectively inhibit COX-2 might, therefore, be expected to produce effects on renal function similar to nonselective NSAIDs which inhibit both COX-1 and COX-2. This assertion is borne out by recent clinical studies showing that the COX-2 inhibitors rofecoxib and celecoxib procedure qualitative changes in urinary prostaglandin excretion, glomerular filtration rate, sodium retention, and their consequences similar to nonselective NSAIDs. It, therefore, seems unlikely that these COX-2 inhibitors (and perhaps their successors) will offer renal safety benefits over nonselective NSAID therapies, and, at this juncture, it is reasonable to assume that all NSAIDs, including COX-2-selective inhibitors, share a similar risk for adverse renal effects.

A conceptual framework to study medication adherence in older adults.

BACKGROUND Adults aged > or =50 years often have multiple chronic diseases requiring multiple medications. However, even drugs with well-documented benefits are often not taken as prescribed, for a variety of reasons. OBJECTIVE The objective of this article was to provide background information about medication adherence and its measurement, the development of the conceptual model for use in adherence research, and supportive intervention strategies such as pharmaceutical care by pharmacists to improve chronic medication use in older adults. METHODS English-language literature published from 1990 to 2000 was searched on MEDLINE, International Pharmaceutical Abstracts, and AARP Ageline using the terms aged, heart failure, CHF, adherence, chronic heart failure, compliance, and related terms. The authors used their personal files and libraries to obtain seminal literature and textbooks published before 1990. RESULTS Although the cognitive processes needed to manage and take medications decline with aging, the number of prescription and nonprescription medications consumed increases. Other factors such as vision, hearing, health literacy, disability, and social and financial resources may all complicate the ability of older adults to adhere to the pharmacologic prescription. CONCLUSIONS Many factors are associated with medication adherence and related health outcomes in older adults. Therefore, strategies to improve adherence will need to be multidimensional, including improvements in pharmacy services that consider age-related factors (eg, declining cognitive and physical functions) as well as a variety of environmental and social factors.

Bioavailability, pharmacokinetics, and pharmacodynamics of torsemide and furosemide in patients with congestive heart failure

The bioavailability, pharmacokinetics, and pharmacodynamics of torsemide (10 mg orally and intravenously) and furosemide (40 mg orally and 20 mg intravenously) were determined in a randomized crossover clinical trial in 16 patients with compensated congestive heart failure. Torsemide (time to reach maximum concentration [tmax], 1.1 ± 0.9 hour) was more rapidly absorbed than furosemide (tmax, 2.4 ± 2.5 hours), the absorption of which was delayed compared with that in healthy volunteers. Bioavailability of torsemide was also greater and less variable than that of furosemide. All four treatments yielded comparable changes from baseline in 24‐hour electrolyte excretion. Based on the relationships between sodium excretion rate and fractional sodium and urinary drug excretion rate, response to both diuretic agents at the level of the nephron was decreased compared with previous studies with healthy subjects. Assessment of the clinical relevance, if any, of the difference in the variability of absorption warrants further study.

The interaction of diltiazem with lovastatin and pravastatin

Lovastatin is oxidized by cytochrome P4503A to active metabolites but pravastatin is active alone and is not metabolized by cytochrome P450. Diltiazem, a substrate and a potent inhibitor of cytochrome P4503A enzymes, is commonly coadministered with cholesterol‐lowering agents.

LOOP DIURETICS FOR CHRONIC RENAL INSUFFICIENCY. A CONTINUOUS INFUSION IS MORE EFFICACIOUS THAN BOLUS THERAPY

OBJECTIVE To test the hypothesis that a continuous, low-dose infusion of a loop diuretic is more efficacious and better tolerated than conventional intermittent bolus therapy in patients with severe chronic renal insufficiency (CRI). DESIGN Randomized, crossover clinical trial with subjects serving as their own controls. SETTING The General Clinical Research Center of Indiana University Hospital, Indianapolis, Indiana. PATIENTS Eight adult volunteers with severe stable CRI (mean creatinine clearance, 0.28 mL/s; range, 0.15 to 0.47 mL/s) were recruited from the outpatient nephrology clinics of Indiana University Medical Center. INTERVENTIONS On admission, diuretic drugs were withdrawn and patients were equilibrated on an 80 mmol/d sodium, 60 mmol/d potassium metabolic diet. Patients were randomized to receive a 12-mg intravenous dose of bumetanide given either as two 6-mg bolus doses separated by 6 hours or as the same total dose administered as a 12-hour continuous infusion. When sodium balance was re-established, each patient was crossed over to the alternative study limb. All patients completed both phases of the study. MEASUREMENTS AND RESULTS Comparable amounts of bumetanide appeared in the urine during the study period (infusion, 912 +/- 428 micrograms; bolus, 944 +/- 421 micrograms; difference, 32 micrograms; 95% CI, -16 micrograms to 80 micrograms, P = 0.16). The continuous infusion resulted in significantly greater net sodium excretion (infusion, 236 +/- 77 mmol; bolus, 188 +/- 50 mmol; difference, 48 mmol; CI, 16 mmol to 80 mmol, P = 0.01). No patient had episodes of drug-induced myalgias during the continuous infusion compared with 3 of 8 patients with bolus therapy. CONCLUSIONS In patients with severe CRI, a continuous intravenous infusion of bumetanide is more effective and less toxic than conventional intermittent bolus therapy. Continuous administration will probably be useful in patients with severe CRI who have not achieved an adequate natriuresis or who show evidence of drug toxicity with standard diuretic dosing regimens. A similar benefit may occur in selected diuretic-resistant patients with cardiac or hepatic disease, and studies in these patients seem warranted.

Open-label randomized trial of torsemide compared with furosemide therapy for patients with heart failure

PURPOSE Because the bioavailability of oral furosemide is erratic and often incomplete, we tested the hypothesis that patients with heart failure who were treated with torsemide, a predictably absorbed diuretic, would have more favorable clinical outcomes than would those treated with furosemide. PATIENTS AND METHODS We conducted an open-label trial of 234 patients with chronic heart failure (mean [+/- SD] age, 64 +/- 11 years) from an urban public health care system. Patients received oral torsemide (n = 113) or furosemide (n = 121) for 1 year. The primary endpoint was readmission to the hospital for heart failure. Secondary endpoints included readmission for all cardiovascular causes and for all causes, numbers of hospital days, and health-related quality of life. RESULTS Compared with furosemide-treated patients, torsemide-treated patients were less likely to need readmission for heart failure (39 [32%] vs. 19 [17%], P <0.01) or for all cardiovascular causes (71 [59%] vs. 50 [44%], P = 0.03). There was no difference in the rate of admissions for all causes (92 [76%] vs. 80 [71%], P = 0.36). Patients treated with torsemide had significantly fewer hospital days for heart failure (106 vs. 296 days, P = 0.02). Improvements in dyspnea and fatigue scores from baseline were greater among patients treated with torsemide, but the differences were statistically significant only for fatigue scores at months 2, 8, and 12. CONCLUSIONS Compared with furosemide-treated patients, torsemide-treated patients were less likely to be readmitted for heart failure and for all cardiovascular causes, and were less fatigued. If our results are confirmed by blinded trials, torsemide may be the preferred loop diuretic for patients with chronic heart failure.

The interaction of diltiazem with simvastatin

Simvastatin is an inhibitor of 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase that is used as a cholesterol‐lowering agent and is metabolized by cytochrome P450 3A (CYP3A) enzymes. Diltiazem is a substrate and an inhibitor of CYP3A enzymes and is commonly coadministered with cholesterol‐lowering agents such as simvastatin. The objective of this study was to quantify the effect of diltiazem on the pharmacokinetics of simvastatin.

Resistance to Loop Diuretics

SummaryResistance to loop diuretics is often encountered clinically. Studies in healthy subjects have shown that overall response to loop diuretics depends upon the interplay between the total amount of drug reaching the urine, the time course of its entry into urine and the pharmacodynamics of response to diuretic in the urine. The mechanism by which diuretic resistance occurs has been elucidated in several clinical conditions. Treatment with inhibitors of prostaglandin synthesis has no effect on diuretic appearance in urine but blunts response by blocking the increase in renal blood flow produced by loop diuretics. In the elderly and in patients with moderate renal insufficiency, the mechanism of resistance appears to be purely pharmacokinetic, involving altered access of diuretic into the urine. In contrast, patients with nephrotic syndrome and hepatic cirrhosis manifest a purely pharmacodynamic form of resistance: in nephrosis, diuretic may bind to protein in the urine; in cirrhosis the mechanism of resistance is unclear. Lastly, in patients with congestive heart failure, with intravenous administration, resistance represents a pharmacodynamic phenomenon. With oral administration, however, the time course but not the extent of absorption is altered; consequently, in this setting, both pharmacokinetic and pharmacodynamic changes may contribute to the subnormal response.Strategies for overcoming resistance to loop diuretics in patients receiving NSAIDs orthose with renal disease, hepatic cirrhosis or congestive heart failure include one or more of: increasing the dose size; administering frequent ‘small’ (but effective) doses; continuous intravenous infusion of the diuretic; tor concomitant administration of another diuretic such as metolazone or hydrochlorolhiazide.

Pharmacology of diuretics.

The diuretics in our therapeutic armamentarium have predictable effects based on their nephron sites of action. All but spironolactone must reach the lumen or urinary side of the nephron to exert their effects. Thus, in settings of decreased renal function, doses must be increased to deliver more diuretic into the urine. In other edematous disorders, such as congestive heart failure (CHF) and cirrhosis, adequate amounts of diuretic reach the site of action if renal function is satisfactory. Diminished response in these conditions is caused by a decrease in the sensitivity of the nephron to the diuretic, the mechanism of which is unknown. Rather than using large single doses of diuretic in CHF and cirrhosis, multiple doses and/or combinations of diuretics should be used. Therefore, thiazide diuretics coupled with loop diuretics are most logical because they affect different nephron sites and the thiazide counteracts distal nephron hypertrophy that may occur with loop diuretics alone. Ample studies have shown that such combinations can result in a truly synergistic response. Using pharmacokinetics and pharmacodynamics of diuretics, we can design therapeutic regimens in which satisfactory control of fluid and electrolyte homeostasis can be achieved in the vast majority of patients.