Triple whammy

The triple whammy is a term used to describe the negative consequences of combining angiotensin-converting enzyme (ACE) inhibitors, diuretics, and nonsteroidal anti-inflammatory drugs (NSAIDs). The triple whammy may also refer to the health risk posed by combining angiotensin II receptor blockers (ARBs)—instead of ACE inhibitors—with diuretics and NSAIDs. These combinations can result in acute renal failure (replaced by the term acute kidney injury in the mid-2000s), especially in older people. Acute renal failure is a serious kidney condition that develops rapidly and can lead to death.

Medications That Create the Triple Whammy

ACE inhibitors or ARBs, both of which are used to lower blood pressure, can be part of the combination that results in the triple whammy. ACE inhibitors are medications that cause the blood vessels to relax, thereby lowering blood pressure. They inhibit the activity of the enzyme that produces angiotensin II, which is a substance that narrows blood vessels and increases blood pressure. Because ACE inhibitors slow the activity of this enzyme, the production of angiotensin II is decreased. ACE inhibitors are used to treat numerous conditions, including high blood pressure and certain cardiovascular diseases. Common ACE inhibitors include benazepril (brand name, Lotensin), enalapril (Vasotec), lisinopril (Zestril), perindopril (Aceon), and ramipril (Altace). ARBs are similar to ACE inhibitors in that they also relax the blood vessels and help lower blood pressure. The main difference is that while ACE inhibitors slow the activity of the enzyme that produces angiotensin II, ARBs block the action of angiotensin II. Doctors often prescribe ARBs to treat conditions such as high blood pressure and heart failure. Common ARBs include candesartan (brand name, Atacand), eprosartan (Teveten), irbesartan (Avapro), losartan (Cozaar), valsartan (Diovan and Prexxartan), and olmesartan (Benicar).

Diuretics, which are commonly referred to as water pills, are medications that promote the removal of salt and water from the body. These medications cause the kidneys to add salt to the urine, which, in turn, helps remove water from the body. Diuretics are typically used to treat conditions such as high blood pressure and glaucoma. Three main kinds of diuretics exist—thiazide diuretics, loop diuretics, and potassium-sparing diuretics. Each type of diuretic affects a different part of the kidney. Common diuretics include chlorothiazide (brand name, Diuril) and hydrochlorothiazide (Microzide), which are thiazide diuretics; ethacrynic acid (Edecrin) and furosemide (Lasix), which are loop diuretics; and spironolactone (Aldactone) and triamterene (Dyrenium), which are potassium-sparing diuretics.

NSAIDs are medications that reduce pain, fever, and inflammation. They are distinguished from medications that contain steroids. There are different types of NSAIDs, including propionic acid derivatives, acetic acid derivatives, enolic acid (oxicam) derivatives, fenamic acid derivatives, and selective COX-2 inhibitors (coxibs). Some NSAIDs are available over the counter (OTC), meaning a prescription is not required. Common NSAIDs include aspirin, ibuprofen, and naproxen.

The Triple Whammy Effect

The combination of ACE inhibitors or ARBs with diuretics and NSAIDs results in a triple whammy effect, which can lead to acute renal failure. Also called acute kidney failure or acute kidney injury, acute renal failure is the sudden loss of kidney function. With this condition, the kidneys lose their ability to filter waste from the blood, resulting in a dangerous buildup of toxins. Acute renal failure develops very quickly—usually within a few hours or days—and requires intense treatment. Normal kidney function can be restored if the individual is otherwise healthy; however, acute renal failure can be fatal. According to most research, acute renal failure that results from the triple whammy effect has a fatality rate of about 10 percent in the general population, but in critically ill patients, this rate can be as high as 80 percent.

The triple whammy effect causes acute renal failure because of the combined impact the three medications have on the body. Angiotensin II plays a role in normal renal blood flow. However, because ACE inhibitors and ARBs reduce angiotensin II levels, renal blood flow is negatively affected. Diuretics and NSAIDs also negatively affect renal blood flow; therefore, a combination of these medications compounds this negative effect and can lead to acute renal failure. Furthermore, diuretics increase the chance of dehydration, which, in turn, increases the chance of kidney failure. Research suggests that the increased risk may be driven mainly by the combination of diuretics and NSAIDs and that ACE inhibitors or ARBs may not always add significantly to this risk. Research also shows that COX-2–targeting painkillers (NSAIDs) are not safer for the kidneys than regular NSAIDs and can still cause acute renal failure.

Older people who take a combination of ACE inhibitors (or ARBs), diuretics, and NSAIDs are especially at risk of acute renal failure. Older adults often have preexisting renal impairment, so the triple whammy effect created by this combination of medications makes them more susceptible to the condition. In addition, older people who take diuretics and NSAIDs are more likely to be sensitive to their adverse side effects, which include possible dehydration from the diuretics and potential kidney problems from the NSAIDs. This makes older people even more susceptible to acute renal failure. For all of these reasons, older adults should be very cautious about taking medications that can result in the triple whammy effect. Practice guidelines emphasize preventing this risk by avoiding unnecessary NSAID use in high-risk patients and using monitoring or alerts when these medicines are prescribed together.

Besides older people, other individuals may also be vulnerable to acute renal failure when taking ACE inhibitors (or ARBs), diuretics, and NSAIDs. For example, people who have renal impairment are at risk, as are people with conditions such as severe liver disease or heart failure. Additionally, anyone who becomes dehydrated due to vomiting, diarrhea, or sepsis is prone to the triple whammy effect.

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