Published: June 2002

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A Dangerous Trio

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Prescriber Update 23(2): 20
June 2002

Dr Ruth Savage, Medical Assessor,
Centre for Adverse Reactions Monitoring, Dunedin

ACE inhibitors, non-steroidal anti-inflammatory agents and diuretics may act synergistically to cause acute renal failure and exacerbation of renal impairment in pre-disposed individuals.  COX-2 inhibitors and angiotensin II receptor antagonists are alternative members of this dangerous trio.

Evidence from Australian adverse reaction reports

Evidence for the combination of angiotensin converting enzyme (ACE) inhibitors, non-steroidal anti-inflammatory agents (NSAIAs) and diuretics precipitating renal failure comes from the Australian Adverse Drug Reactions Advisory Committee (ADRAC).  In 1999¹  ADRAC noted that in 46 of the 78 reports of acute renal failure, patients were taking one or more of a NSAIA, diuretic or ACE inhibitor; seven patients were taking all three.  There are now 56 reports in the ADRAC database of renal failure, or worsening renal failure, associated with celecoxib.  Twenty-four of these patients were also taking a diuretic and either an ACE inhibitor or angiotensin II receptor antagonist.²

Combination inhibits renal compensatory mechanisms

Hypovolaemic states including dehydration, congestive cardiac failure, impaired renal function and anaesthesia may predispose patients to renal insufficiency by lowering the afferent glomerular arteriolar pressure.  In order to maintain glomerular perfusion pressure in these circumstances, renal prostaglandin activity dilates the afferent arterioles, and the renin-angiotensin system is activated leading to constriction of the efferent arterioles.  Renal failure may be precipitated by NSAIAs and COX-2 inhibitors impairing renal prostaglandin biosynthesis, and by ACE inhibitors and angiotensin receptor blockers reducing angiotensin II activity.

Avoid the trio in at-risk patients

Some patients with predisposing conditions are likely to require ACE-inhibitors and/or diuretics, and should not be co-prescribed NSAIAs or COX-2 inhibitors.  In patients taking all three medicines who become predisposed (e.g. due to dehydration from diarrhoea), NSAIAs and COX-2 inhibitors should be withdrawn, and renal function and plasma potassium concentrations monitored closely.  The doses of the other medicines should be adjusted accordingly.

The elderly are particularly susceptible to acute renal failure due to the dangerous trio.  Most will have some degree of renal impairment (even with a normal serum creatinine concentration), possibly with renal function as low as 50% of normal.  Older patients are also prone to diuretic-induced dehydration and hypotension, and their fluid intake is often inadequate.

Competing interests (author): none declared.

Correspondence to Dr Ruth Savage, CARM, PO Box 913, Dunedin.

References

1. Boyd IW, Mathew TH, Thomas MC. COX-2 inhibitors and renal failure: the triple whammy revisited [letter]. Med J Aust 2000:173; 274.
2. Personal communication, 29 October 2001. Executive Officer, Adverse Drug Reactions Unit, Therapeutic Goods Administration, Australia.