Important Drug Interactions for Angiotensin-Converting Enzyme Inhibitors

Patients taking any of the widely prescribed angiotensin-converting enzyme (ACE) inhibitors (see Table 1, below) should be aware that they have clinically important interactions with many other commonly used prescription and over-the-counter medications.

ACE inhibitors are a large class of drugs that are all approved by the Food and Drug Administration (FDA) to treat hypertension (high blood pressure). Certain ACE inhibitors also are approved to treat one or more of the following: heart failure, heart attacks, other types of cardiovascular disease and diabetic kidney disease. The first such drug, captopril (generic only), was approved by the FDA in 1981.

Table 1: List of FDA-Approved Oral ACE Inhibitors*

*All are designated as Limited Use.
†Brand-name combination products were excluded.

The list of drugs that can interact with ACE inhibitors and result in potential harm includes, among others, angiotensin receptor blockers (ARBs), diuretics and nonsteroidal anti-inflammatory drugs (NSAIDs) (see Table 2, below, for examples).[1],[2]

Table 2: Examples of Oral Drugs That Have Clinically Important Interactions With ACE Inhibitors

†Brand-name combination products were excluded, except for the combination product sacubitril and valsartan (ENTRESTO).
*Designated as Limited Use
**Designated as Do Not Use
***Designated as Do Not Use for Seven Years (until July 2022)

ARBs and aliskiren (TEKTURNA)

ARBs, such as irbesartan (AVAPRO) and losartan (COZAAR), are another class of drugs used to treat hypertension. Some ARBs are also used to treat heart failure and slow the progression of chronic kidney disease.

Aliskiren is another drug for treating hypertension. It inhibits the blood-pressure–raising substance renin.

ACE inhibitors, ARBs and aliskiren all act on a biological pathway central to the regulation of blood pressure and the body’s saltwater balance, known as the renin-angiotensin-aldosterone system. When used individually, these drugs are of great benefit in treating hypertension, heart failure and other conditions.

However, using an ACE inhibitor concomitantly with an ARB or aliskiren increases the risk of adverse effects — particularly low blood pressure, dangerously high blood potassium levels (which can lead to abnormal heart rhythms) and kidney failure — while offering no added benefit over using just one of these drugs. We therefore advise against such drug combinations.

Diuretics

Diuretics (often called water pills) are used to treat hypertension, heart failure and other conditions that cause fluid overload. Concomitant use of ACE inhibitors with diuretics, particularly very potent diuretics like bumetanide (BUMEX) and furosemide (LASIX), may result in an excessive decrease in blood pressure, which can cause light-headedness and fainting.

In addition, concomitant use of ACE inhibitors with so-called potassium-sparing diuretics, such as spironolactone (ALDACTONE, CAROSPIR), may cause dangerously high blood potassium levels. Therefore, patients using such drug combinations need periodic blood tests to monitor potassium levels.

NSAIDs

NSAIDs — such as ibuprofen (ADVIL, IBU-TAB, MIDOL LIQUID GELS, MOTRIN, TAB-PROFEN) and naproxen (ALEVE, ANAPROX DS, NAPRELAN, NAPROSYN), which are available in both prescription and over-the-counter versions — are widely used to treat pain and inflammation due to arthritis and a wide array of other disorders.

In patients who are elderly, dehydrated (from diuretic use, inadequate fluid intake or other circumstances) or have impaired kidney function, concomitant use of ACE inhibitors with NSAIDs may result in acute kidney failure. Therefore, patients using these drugs in combination need periodic blood tests to monitor kidney function.

Lithium (LITHOBID)

Lithium is a mood-stabilizing drug that is used to treat bipolar disorder, also known as manic depression, a chronic mental illness that causes unusual shifts in mood, energy and activity levels.

Use of ACE inhibitors in combination with lithium may cause blood lithium to increase to toxic levels. Nausea, diarrhea, vomiting, loss of appetite, drowsiness, muscle weakness and decreased coordination are early signs of lithium toxicity. With increasing blood lithium levels, patients can experience giddiness, ataxia (severe lack of muscle control or coordination of voluntary movements), slurred speech, blurred vision, tinnitus (perception of noise or ringing in the ears) and markedly increased urine output. Severe lithium toxicity can lead to seizures, coma, abnormal heart rhythms and even death.

For patients taking ACE inhibitors, lithium therapy generally should be initiated at a lower dose, and the dose should be increased slowly. Patients also should undergo frequent blood tests to check lithium levels until they achieve a stable blood level of the drug. Patients who have been on a stable dose of lithium and subsequently begin taking an ACE inhibitor should undergo more frequent blood tests for lithium levels and be monitored closely for symptoms of lithium toxicity until the blood lithium level is shown to be stable in the desired range.

Other notable interactions

Angioedema — a sudden swelling of the face, lips, tongue and throat — is a rare but potentially life-threatening adverse reaction to ACE inhibitors. Although this reaction usually occurs with the first dose, it may occur years later.

Concomitant use of ACE inhibitors with certain drugs — including the heart-failure combination drug sacubitril and valsartan (ENTRESTO) and the immunosuppressant/organ transplant drug sirolimus (RAPAMUNE) — may increase the risk of angioedema. ACE inhibitors should not be used with Entresto because the risk of angioedema with this combination is so great.

What You Can Do

If you need treatment with an ACE inhibitor, review all of your other medications with your doctor to assess for potentially significant drug interactions. If you are taking certain medications that interact with ACE inhibitors, you may need to adjust the dosage of the interacting drug or undergo more frequent monitoring of the blood levels of the interacting drug or of your kidney function and blood potassium levels, or your doctor may advise you to take a different drug. Be aware that other drugs not listed in this article also may have dangerous interactions with ACE inhibitors.
 

References

[1] IBM Micromedex. Drug interactions. http://www.micromedexsolutions.com/home/dispatch. Search term: “lisinopril.” Accessed October 22, 2020.

[2] Merck Sharp & Dohme. Label: lisinopril (PRINIVIL). November 2019. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=f6f3c339-2c9d-4d07-14a1-6d6c7daf26c6&type=display. Accessed October 22, 2020.