Safety Challenges of Combining ACEi/ARB and Diuretics with NSAIDs: A Review of "Triple Whammy" Nephrotoxicity, Risk Factors in Outpatient Populations, and Pharmacist Intervention Management

Abstract

The combination of Angiotensin-Converting Enzyme Inhibitors (ACEi) or Angiotensin Receptor Blockers (ARB) and diuretics with Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) can result in a drug interaction known as the "Triple Whammy". Concomitant use of these three drug classes is a leading cause of preventable iatrogenic Acute Kidney Injury (AKI) in outpatient populations. This narrative review aims to comprehensively outline the hemodynamic pathophysiology of "Triple Whammy" nephrotoxicity, analyze risk factors associated with AKI, and formulate pharmacist intervention management that applicable in primary healthcare settings. Literature review indicates that diuretics induce intravascular volume depletion, ACEi/ARBs abolish the compensatory vasoconstrictive response in efferent arterioles, and NSAIDs inhibit the synthesis of vasodilatory prostaglandins in afferent arterioles. This interaction leads to a failure of renal autoregulation and a drastic reduction in glomerular hydrostatic pressure. Drug combinations, duration of exposure, route of administration, cardiovascular comorbidities, and age are key risk factors for AKI. Preventing AKI requires pharmacist intervention through screening processes, the use of alternative medications, and reinforcement with Continuing Medical Education (CME)