Clinical Article: The Triple Whammy

HPS Pharmacies Knowledge Centre

The Triple Whammy

Nurdan Ozkan, Clinical Pharmacist

HPS – Norwest, New South Wales


Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) antagonise the control of hypertension and heart failure achieved by ACE (angiotensin converting enzyme) inhibitors and diuretics. Using an NSAID as well as a diuretic doubles the risk of hospitalisation for heart failure over that of taking diuretics alone. Loboz and Shenfield advise that ‘care is necessary to balance the demonstrated advantages of these medications against the risk of inducing renal failure’.

The ‘triple whammy’ is the term used to describe the adverse effect of combinations of diuretics, NSAIDs (including cyclooxygenase-2 inhibitors), and ACE inhibitors (or angiotensin receptor antagonists). This triple whammy effect may lead to acute renal failure especially in the elderly, those with pre-existing renal impairment, and dehydration. Over half the iatrogenic renal failure cases reported to the Adverse Drug Reactions Committee (ADRAC)* are due to one or more (in combination) of these medicines, and carry a 10% fatality rate.

Diuretic induced decrease in plasma volume, inhibition of prostaglandin-mediated control of glomerular afferent arteriolar tone, and inhibition of angiotensin control of efferent arteriolar tone are some of the proposed mechanisms involved.


1. During normal renal blood flow, angiotensin II acts as a vasoconstrictor, promotes sodium reabsorption and induces thirst. By decreasing angiotensin II levels, ACE inhibitors and angiotensin receptor antagonists dilate the efferent arteriole, which leads to a reduction of glomerular perfusion pressure and glomerular filtration rate (GFR). This effect can occur at initiation, or as a delayed response.

2. Diuretics can lead to volume depletion. Concurrent use of diuretics and ACE inhibitors can precipitate acute renal failure, as GFR can no longer be maintained, due to insufficient renal haemodynamics. Dehydration, reduced cardiac output (heart failure), and sepsis can also cause volume depletion, thus care must be taken in these patients on a combination of NSAID and ACE inhibitor/angiotensin receptor antagonists.

3. Prostaglandins maintain dilation of the pre-glomerular arteriole, which promotes blood flow through the glomerulus. NSAIDs (both selective and non-selective agents) constrict the blood flow into the glomerulus via the afferent arteriole by inhibiting these prostaglandins.

Figure 1. The ‘triple whammy’ effect to reduce glomerular filtration rate.

When used in combination, these medications can lead to acute renal failure.


Whilst ACE inhibitors and diuretics have a significant role to play in the prevention of stroke and myocardial infarction, and in hypertension, it is important to ensure that this is not at the risk of inducing renal failure, especially in the elderly. NSAIDs should be avoided in heart failure, hypertension, and chronic renal failure, and the triple whammy should be avoided where possible. However, if the combination is necessary, prescribers should monitor creatinine and electrolyte levels, and be alert for situations such as illness, dehydration or initiation of an NSAID, which may predispose these patients to renal failure.

*N.B. ADRAC has now been replaced by ACSOM (Advisory Committee on the Safety of Medicines).


  1. Adverse Drug Reactions Advisory Committee. ACE inhibitor, diuretic and NSAID: a dangerous combination. Aust Adv Drug Reactions Bull 2003; 22: 14-15.
  2. Loboz KK, Shenfield GM. Drug combinations and impaired renal function – the ‘triple whammy’. Br J Clin Pharmacol 2005; 59(2): 239–243.
  3. Schoolwerth AC, Sica DA, Ballermann BJ, Wilcox CS. Renal Considerations in Angiotensin Converting Enzyme Inhibitor Therapy. A statement for healthcare professionals from the Council on the Kidney in Cardiovascular Disease and the Council for High Blood Pressure Research of the American Heart Association. Circulation 2001; 104; 1985-91.
  4. Adverse Drug Reactions Advisory Committee. Beware the triple whammy. Aust Adv Drug Reactions Bull 2006; 25(5): 18.
  5. Rossi S (Editor), Australian Medicines Handbook 2013 (online). Adelaide: Australian Medicines Handbook Pty Ltd; 2013.