What are the side effects of Angiotensin-Converting Enzyme (ACE) inhibitors?

From the Guidelines

ACE inhibitors are associated with several side effects, including dry cough, dizziness, headache, and fatigue, with more serious side effects such as angioedema, hyperkalemia, and acute kidney injury, as reported in the most recent study 1. The most common adverse events associated with ACE inhibitors are dizziness or syncope, cough, and angina, with patients randomized to an ACE inhibitor being 3.9% more likely to experience dizziness/syncope and 8.9% more likely to experience cough 1. Some of the key side effects of ACE inhibitors include:

• Dry cough, occurring in up to 20% of patients 1
• Angioedema, occurring in less than 1% of patients, but more frequently in blacks and women 1
• Hyperkalemia, particularly in patients with diabetes or chronic renal failure 1
• Acute kidney injury, particularly in patients with renal artery stenosis or dehydration 1
• First-dose hypotension, especially in volume-depleted patients 1
• Taste disturbances, rash, or gastrointestinal symptoms like nausea or diarrhea 1 These side effects occur because ACE inhibitors block the conversion of angiotensin I to angiotensin II, affecting blood pressure regulation, electrolyte balance, and increasing bradykinin levels (which causes the characteristic cough) 1. Regular monitoring of blood pressure, kidney function, and potassium levels is important when taking these medications, and if a persistent cough develops, switching to an angiotensin receptor blocker (ARB) may be recommended as these medications work through a different mechanism and rarely cause cough 1.

From the FDA Drug Label

DRUG INTERACTIONS 7. 1 Diuretics Initiation of lisinopril in patients on diuretics may result in excessive reduction of blood pressure. 7. 3 Non-Steroidal Anti-Inflammatory Agents Including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, coadministration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including lisinopril, may result in deterioration of renal function, including possible acute renal failure. 7. 4 Dual Blockade of the Renin-Angiotensin System (RAS) Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. 7. 5 Lithium Lithium toxicity has been reported in patients receiving lithium concomitantly with drugs, which cause elimination of sodium, including ACE inhibitors. 7. 6 Gold Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including lisinopril.

The side effects of Angiotensin-Converting Enzyme (ACE) inhibitors include:

• Hypotension: excessive reduction of blood pressure, especially when used with diuretics or in patients who are elderly, volume-depleted, or with compromised renal function 2
• Hyperkalemia: increased risk when used with potassium-sparing diuretics or in patients with dual blockade of the RAS 2
• Renal failure: possible acute renal failure when used with NSAIDs, including selective COX-2 inhibitors, or in patients with dual blockade of the RAS 2
• Lithium toxicity: reported in patients receiving lithium concomitantly with ACE inhibitors 2
• Nitritoid reactions: facial flushing, nausea, vomiting, and hypotension when used with injectable gold (sodium aurothiomalate) 2

From the Research

Side Effects of Angiotensin-Converting Enzyme (ACE) Inhibitors

• The most common adverse effect of ACE inhibitors is a dry, tickly, and often bothersome cough, which may develop in around 10% of patients treated with ACE inhibitors 3.
• This cough can be severe enough to require discontinuation of the ACE inhibitor in half of the affected patients 3.
• ACE inhibitors can also cause angioedema, although this is a rare but serious side effect 4.
• Other potential side effects of ACE inhibitors include exacerbation of asthma or asthmatic symptoms, and an increase in bronchial reactivity 3.
• The mechanisms underlying ACE inhibitor-induced cough are likely linked to the suppression of kininase II activity, leading to an accumulation of kinins, substance P, and prostaglandins 3.

Incidence of Cough with Different ACE Inhibitors

• The incidence of cough varies among different ACE inhibitors, with moexipril and ramipril having a higher incidence of cough, while spirapril has a lower incidence 5.
• A study found that the incidence of cough with enalapril, captopril, perindopril, and lisinopril was 7%, 5.1%, 2.2%, and 1.6%, respectively 6.
• Women are more likely to experience cough with ACE inhibitors than men, with a statistically significant difference in the incidence of cough between men and women 6.

Comparison with Other Antihypertensive Agents

• ACE inhibitors have a higher incidence of cough compared to angiotensin receptor blockers (ARBs) and calcium channel blockers (CCBs) 5.
• A study found that candesartan cilexetil, an ARB, was not associated with cough in patients with enalapril-induced cough, and had a similar incidence of cough to placebo 7.
• ARBs may offer an alternative to ACE inhibitors in patients who experience cough or other side effects with ACE inhibitors 4.