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NSAIDs: Kidney Damage Possible
NSAIDs: Kidney Damage Possible At the Consensus Development Conference on Analgesic-Related Kidney Disease (see American Pharmacy May 1984, p. 15), the potential for renal damage from nonprescription products was covered in close detail and the results, although based mainly on uncontrolled epidemiological studies, were fairly conclusive. But the consensus panel sidestepped the issue of whether similar-or worse-damage might accrue from the use of the closely related prescription analgesics, the nonsteroidal anti-inflammatory drugs (NSAIDs). It was claimed that insufficient data were available to make any judgment on the potential for harm from this class of drugs. Perhaps. But several recent articles in the medical literature (for example, New England journal of Medicine, 310, 563, 1984) have addressed precisely this topic. One general conclusion is that any renal toxicity caused by NSAIDs is probably a result of their special mechanism of action, specifically on prostaglandin synthesis within the kidney. Prostaglandins secreted locally within the kidney are an integral part of renal physiologyincluding regulation of blood flow, modulation of renin release, tubular ion transport, and water metabolism. It seems reasonable, then, that diminished prostaglandin synthesis might be the initiating event in the process of NSAID-associated renal dysfunction and eventual damage.
Toxic Reactions How does this effect come about? In normal animals and humans, renal blood flow is not impaired after treatment with an NSAID like indomethacin. But when certain special physiologic conditions prevail, for instance, when patients are depleted of sodium and so have suffered a generalized decrease in fluid volume, the body's pressor mechanisms (both adrenergic and renin-angiote~sin systems) become
American Pharmacy Vol. NS24, No. 6, June 1984/339
activated. Both norepinephrine and angiotensin II then act so as to constrict the renal blood vessels. At the same time, though, prostaglandins will be secreted as well, and these serve to mitigate the effects of both norepinephrine and angiotensin, by inducing a countervailing vasodilation. When prostaglandin synthesis is blocked by NSAID action, therefore, both~ renal blood flow and glomerular filtration rate will be dim inished. And if vasoconstriction becomes severe enough, kidney tissue may fail to receive its vital supply of oxygen; temporary-and sometimes permanent-damage to functional kidney cells will result. On the basis of this explanation, patients with certain conditions would seem to be especially at risk for toxic reactions in the kidney due to NSAIDs, particularly after chronic administration: • Volume depletion; • · Shock; • Septicemia; • Congestive heart failure; • Cirrhosis. Patients with chronic renal disease and the elderly may also be at some risk.
Water Balance Prostaglandins also serve to regulate the maintenance of water balance in animals and humans. Therefore, when renal prostaglandin- synthesis is blocked by an NSAID, major disturbances in the concentration of body fluids may occur. Both water and sodium will be retained, and a highly concentrated urine will be formed. Edema and a decrease in the effectiveness of diuretic drugs like furosemide may result as well. This action may be independent of the effect of NSAIDS on renal blood flow. Or the decrease in renal blood flow may in turn decrease the filtered load of sodium chloride, resulting in salt retention. However, both actions-sodium retention and increased vasocon-
striction-make it possible that NSAIDs may act to aggravate hypertension, so these drugs should be used with caution in patients with high blood pressure, too.
'Prudent' Care While much of the foregoing is still speculative, Robert Schrier and William Henrich, editorializing on the subject in JAMA (251, 1302, 1984) advise: A prudent approach is simply to measure the serum creatinine concentration before and during therapy in the group of patients known to be at selective risk for reversible acute renal failure-the elderly and patients with volume depletion, receiving diuretics, in heart failure, or with underlying renal disease. In this way, a decrease in renal function will be recognized early and drug therapy can be discontinued. But the same issue of JAMA also contained an article from David Fox and Hershel Jick of the Boston Collaborative Drug Surveillance Program, which at first glance appears to bring much of the hypothesizing on NSAID-induced renal damage back down to earth. Fox and Jick claim that their epidemiological data on thousands of patients show "no association between the use of NSAIDs and drug-attributed elevation of serum urea nitrogen levels." What confounds the Fox-Jick study, and perhaps might lull us into a false sense of security if we failed to keep in mind other considerations, is that their patient population was not limited to those known to be at risk from· use of NSAIDs. As another New England Journal article "(G. Ciabattoni et al., 310, 279, 1984) noted, it is only in certain abnormal states that "renal blood flow and glomerular filtration rate become critically dependent on intact cyclooxygenase activity.''
Sulindac' s Edge For those patients who do have preexisting conditions that may make (continued on page 30)
19
NSAIDs.: Kidney Damage Possible (continued from page 19)
them susceptible to renal damage, sulindac, because of its differential action on the various steps in prostaglandin synthesis, may be the drug of choice. This is because it permits the continued synthesis of the prostaglandin derivative prostacyclin, which appears to be the prostaglandin product that is vital for main-
Toxic Effects Of Vitamin Doses (continued from page 24)
in 2-12 hours after the initial toxic symptoms, and is characterized by shock, acidosis, cyanosis, and fever. The acidosis is a consequence of accumulation of lactic and citric acids, and from the restructuring of the iron through metabolism. In the fourth and final phase, which usually appears two to four days after ingestion, death of liver cells occurs. If children are caught "redhanded" in a vitamin binge, Lipscomb says, it's wise to induce vomiting with syrup of ipecac. Fleet phosphate enema may be employed for gastric lavage, too.
taining the patency of kidney blood vessels in patients with renal impairment. . Ciabattoni et al. investigated 20 women with chronic glomerular disease: 10 were assigned to one-week treatment with ibuprofen (1.2 g/day), and 10 to one week of sulindac (0.4 g/day). At base-line, all 20 showed significantly reduced urinary excretion of 6-keto-prostaglandin F1a, a stable breakdown product of prostacyclin. But the other measured product of arachidonic metabolism, prostaglandin E2 , was excreted at normal levels. Treatment with sulindac, it was discovered, "was not associated with any significant change in urinary excretion of either prostaglandin E2 or 6-keto-prostaglandin F 1a." Nor did serum creatinine level or creatinine clearance rate increase. On the other hand, ibuprofen did reduce urinary excretion of both these products of prostaglandin synthesis. These changes were associated with reversible functional changes, manifested as an average increase of 40% in serum creatinine levels, and a corresponding decrease in creatinine clearance (19% ).
These functional changes were directly related to the reduction in 6keto-prostaglandin F1a, rather than with prostaglandin E2 , which supports the authors' hypothesis that it is the prostacyclin product that's crucial to maintaining the flow of blood through the kidney.
Screening for Anticancer Drugs (continued from page 22)
led to the introduction of several important agents, Hoth stated that we really don't know whether many more of those 20,000 compounds might have shown activity, if only a different testing protocol had been used. The advent of more rational screening methods, however, must wait until more work has been finished on the other side of the bridge-until the intricacies of elements like retroviruses, protooncogenes, oncogenes, and all the rest of our often conflicting theorizing on the causation of cancer has been sufficiently unraveled.
People APhA President Maurice Q. Beetel was selected as 1984 Parke-Davis Visiting Lecturer at Ferris State College School of Pharmacy. The American Pharmaceutical Association Board of Trustees elected Pharmacists Priscilla C. Brown of Germantown, NC and Nicholas G. Popovich of West Lafayette, IN to two-year terms on the Board of Pharmaceutical Specialties. Elected to three-year terms on the BPS were Pharmacists John M. Owen Jr. of Wichita, KS and Donald R. Baugher of Beardstown, IL. Sarah H. Newman of Washington, DC was elected to serve as the BPS public member. Hospital phannacy graduate student Lynn Hornquist of the Uni-
30
versity of Minnesota College of Pharmacy was appointed to the board of governors of University Hospitals by .the University of Minnesota Board of Regents. Rodney D. Ice has joined Benedict Nuclear Pharmaceuticals, Inc. as vice president for professional affairs . Fristsch Dodge & Olcott has appointed Don Marmo group leader for flavor development. Susan Miller has joined SmithKline Beckman as associate senior investigator, drug delivery systems. At the Minnesota State Pharmaceutical Association, pharmacistattorney Jayne Peterson was named executive assistant.
Dale A. Spears became director of pharmacy at Fawcett Memorial Hospital, Port Charlotte, FL. The 1984 Ebert Prize for best original research work published in APhA' s Journal of Pharmaceutical Sciences during 1983 went to George Zografi, professor of pharmaceutics at the University of WisconsinMadison School of Pharmacy. Gordon L. Amidon of the University of Michigan School of Pharmacy and SmithKline Consumer Products and Lynn Van Campen of Boehringer Indelheim Ltd. were cited as "honored co-authors" of the awardwinning publication.
American Pharmacy Vol. NS24, No. 6, June 1984/350
Toxic Reactions How does this effect come about? In normal animals and humans, renal blood flow is not impaired after treatment with an NSAID like indomethacin. But when certain special physiologic conditions prevail, for instance, when patients are depleted of sodium and so have suffered a generalized decrease in fluid volume, the body's pressor mechanisms (both adrenergic and renin-angiote~sin systems) become
American Pharmacy Vol. NS24, No. 6, June 1984/339
activated. Both norepinephrine and angiotensin II then act so as to constrict the renal blood vessels. At the same time, though, prostaglandins will be secreted as well, and these serve to mitigate the effects of both norepinephrine and angiotensin, by inducing a countervailing vasodilation. When prostaglandin synthesis is blocked by NSAID action, therefore, both~ renal blood flow and glomerular filtration rate will be dim inished. And if vasoconstriction becomes severe enough, kidney tissue may fail to receive its vital supply of oxygen; temporary-and sometimes permanent-damage to functional kidney cells will result. On the basis of this explanation, patients with certain conditions would seem to be especially at risk for toxic reactions in the kidney due to NSAIDs, particularly after chronic administration: • Volume depletion; • · Shock; • Septicemia; • Congestive heart failure; • Cirrhosis. Patients with chronic renal disease and the elderly may also be at some risk.
Water Balance Prostaglandins also serve to regulate the maintenance of water balance in animals and humans. Therefore, when renal prostaglandin- synthesis is blocked by an NSAID, major disturbances in the concentration of body fluids may occur. Both water and sodium will be retained, and a highly concentrated urine will be formed. Edema and a decrease in the effectiveness of diuretic drugs like furosemide may result as well. This action may be independent of the effect of NSAIDS on renal blood flow. Or the decrease in renal blood flow may in turn decrease the filtered load of sodium chloride, resulting in salt retention. However, both actions-sodium retention and increased vasocon-
striction-make it possible that NSAIDs may act to aggravate hypertension, so these drugs should be used with caution in patients with high blood pressure, too.
'Prudent' Care While much of the foregoing is still speculative, Robert Schrier and William Henrich, editorializing on the subject in JAMA (251, 1302, 1984) advise: A prudent approach is simply to measure the serum creatinine concentration before and during therapy in the group of patients known to be at selective risk for reversible acute renal failure-the elderly and patients with volume depletion, receiving diuretics, in heart failure, or with underlying renal disease. In this way, a decrease in renal function will be recognized early and drug therapy can be discontinued. But the same issue of JAMA also contained an article from David Fox and Hershel Jick of the Boston Collaborative Drug Surveillance Program, which at first glance appears to bring much of the hypothesizing on NSAID-induced renal damage back down to earth. Fox and Jick claim that their epidemiological data on thousands of patients show "no association between the use of NSAIDs and drug-attributed elevation of serum urea nitrogen levels." What confounds the Fox-Jick study, and perhaps might lull us into a false sense of security if we failed to keep in mind other considerations, is that their patient population was not limited to those known to be at risk from· use of NSAIDs. As another New England Journal article "(G. Ciabattoni et al., 310, 279, 1984) noted, it is only in certain abnormal states that "renal blood flow and glomerular filtration rate become critically dependent on intact cyclooxygenase activity.''
Sulindac' s Edge For those patients who do have preexisting conditions that may make (continued on page 30)
19
NSAIDs.: Kidney Damage Possible (continued from page 19)
them susceptible to renal damage, sulindac, because of its differential action on the various steps in prostaglandin synthesis, may be the drug of choice. This is because it permits the continued synthesis of the prostaglandin derivative prostacyclin, which appears to be the prostaglandin product that is vital for main-
Toxic Effects Of Vitamin Doses (continued from page 24)
in 2-12 hours after the initial toxic symptoms, and is characterized by shock, acidosis, cyanosis, and fever. The acidosis is a consequence of accumulation of lactic and citric acids, and from the restructuring of the iron through metabolism. In the fourth and final phase, which usually appears two to four days after ingestion, death of liver cells occurs. If children are caught "redhanded" in a vitamin binge, Lipscomb says, it's wise to induce vomiting with syrup of ipecac. Fleet phosphate enema may be employed for gastric lavage, too.
taining the patency of kidney blood vessels in patients with renal impairment. . Ciabattoni et al. investigated 20 women with chronic glomerular disease: 10 were assigned to one-week treatment with ibuprofen (1.2 g/day), and 10 to one week of sulindac (0.4 g/day). At base-line, all 20 showed significantly reduced urinary excretion of 6-keto-prostaglandin F1a, a stable breakdown product of prostacyclin. But the other measured product of arachidonic metabolism, prostaglandin E2 , was excreted at normal levels. Treatment with sulindac, it was discovered, "was not associated with any significant change in urinary excretion of either prostaglandin E2 or 6-keto-prostaglandin F 1a." Nor did serum creatinine level or creatinine clearance rate increase. On the other hand, ibuprofen did reduce urinary excretion of both these products of prostaglandin synthesis. These changes were associated with reversible functional changes, manifested as an average increase of 40% in serum creatinine levels, and a corresponding decrease in creatinine clearance (19% ).
These functional changes were directly related to the reduction in 6keto-prostaglandin F1a, rather than with prostaglandin E2 , which supports the authors' hypothesis that it is the prostacyclin product that's crucial to maintaining the flow of blood through the kidney.
Screening for Anticancer Drugs (continued from page 22)
led to the introduction of several important agents, Hoth stated that we really don't know whether many more of those 20,000 compounds might have shown activity, if only a different testing protocol had been used. The advent of more rational screening methods, however, must wait until more work has been finished on the other side of the bridge-until the intricacies of elements like retroviruses, protooncogenes, oncogenes, and all the rest of our often conflicting theorizing on the causation of cancer has been sufficiently unraveled.
People APhA President Maurice Q. Beetel was selected as 1984 Parke-Davis Visiting Lecturer at Ferris State College School of Pharmacy. The American Pharmaceutical Association Board of Trustees elected Pharmacists Priscilla C. Brown of Germantown, NC and Nicholas G. Popovich of West Lafayette, IN to two-year terms on the Board of Pharmaceutical Specialties. Elected to three-year terms on the BPS were Pharmacists John M. Owen Jr. of Wichita, KS and Donald R. Baugher of Beardstown, IL. Sarah H. Newman of Washington, DC was elected to serve as the BPS public member. Hospital phannacy graduate student Lynn Hornquist of the Uni-
30
versity of Minnesota College of Pharmacy was appointed to the board of governors of University Hospitals by .the University of Minnesota Board of Regents. Rodney D. Ice has joined Benedict Nuclear Pharmaceuticals, Inc. as vice president for professional affairs . Fristsch Dodge & Olcott has appointed Don Marmo group leader for flavor development. Susan Miller has joined SmithKline Beckman as associate senior investigator, drug delivery systems. At the Minnesota State Pharmaceutical Association, pharmacistattorney Jayne Peterson was named executive assistant.
Dale A. Spears became director of pharmacy at Fawcett Memorial Hospital, Port Charlotte, FL. The 1984 Ebert Prize for best original research work published in APhA' s Journal of Pharmaceutical Sciences during 1983 went to George Zografi, professor of pharmaceutics at the University of WisconsinMadison School of Pharmacy. Gordon L. Amidon of the University of Michigan School of Pharmacy and SmithKline Consumer Products and Lynn Van Campen of Boehringer Indelheim Ltd. were cited as "honored co-authors" of the awardwinning publication.
American Pharmacy Vol. NS24, No. 6, June 1984/350