Why does perindopril (Angiotensin-Converting Enzyme (ACE) inhibitor) cause a cough?

From the Guidelines

Perindopril causes cough because it inhibits the breakdown of bradykinin in the lungs, leading to the accumulation of bradykinin and the stimulation of sensory nerve fibers, which triggers the release of inflammatory mediators and results in bronchial irritation and cough. As an ACE inhibitor, perindopril blocks the angiotensin-converting enzyme, which normally degrades bradykinin 1. The resulting accumulation of bradykinin in the respiratory tract stimulates sensory nerve fibers and triggers the release of inflammatory mediators like substance P and prostaglandins. This cascade leads to bronchial irritation and the characteristic dry, persistent, and often ticklish cough experienced by approximately 5-35% of patients taking ACE inhibitors like perindopril 1. The cough typically develops within weeks to months of starting therapy and resolves within 1-4 weeks after discontinuation.

Some key points to consider:

• The incidence of ACE inhibitor-induced cough has been reported to be in the range of 5 to 35% among patients treated with these agents 1.
• The only uniformly effective treatment for ACE inhibitor-induced cough is the cessation of treatment with the offending agent 1.
• If a patient develops this troublesome cough, switching to an angiotensin receptor blocker (ARB) like losartan or valsartan is usually recommended, as these medications provide similar cardiovascular benefits without affecting bradykinin metabolism 1.
• ACE inhibitors have been shown to reduce morbidity and mortality in patients with heart failure with reduced ejection fraction (HFrEF), but they can produce angioedema and should be given with caution to patients with low systemic blood pressures, renal insufficiency, or elevated serum potassium 1.

Overall, the use of ACE inhibitors like perindopril is beneficial for patients with prior or current symptoms of chronic HFrEF to reduce morbidity and mortality, but they can cause cough in some patients, and alternative treatments like ARBs may be necessary in these cases 1.

From the FDA Drug Label

Cough: Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, always resolving after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough. In controlled trials with perindopril, cough was present in 12% of perindopril patients and 4.5% of patients given placebo.

Perindopril causes a cough presumably due to the inhibition of the degradation of endogenous bradykinin. This is a common side effect of ACE inhibitors, and it always resolves after discontinuation of therapy. In clinical trials, cough was present in 12% of perindopril patients compared to 4.5% of patients given placebo 2.

• Key points:
  • Cough is a common side effect of perindopril
  • It is presumably caused by the inhibition of the degradation of endogenous bradykinin
  • Cough resolves after discontinuation of therapy
  • Cough was present in 12% of perindopril patients in clinical trials 2

From the Research

Mechanism of Cough in Perindopril

• Perindopril, an Angiotensin-Converting Enzyme (ACE) inhibitor, causes a cough in some patients due to its mechanism of action, which involves inhibiting the conversion of angiotensin I to angiotensin II and inhibiting the degradation of bradykinin 3.
• The incidence of cough associated with perindopril varies, but it is generally considered to be lower than other ACE inhibitors, likely due to its high tissue ACE affinity 3.

Incidence of Cough in Perindopril

• Studies have reported that the incidence of cough with perindopril is relatively low, with less than 2% of patients discontinuing therapy due to cough 4.
• Other studies have also reported a low incidence of cough with perindopril, ranging from 1.3% to 1.6% of patients 5, 6.

Comparison with Other ACE Inhibitors

• Perindopril has a similar adverse event profile to other ACE inhibitors, with cough being the most common event reported during treatment 5.
• However, the incidence of cough with perindopril is considered to be lower than other ACE inhibitors, making it a suitable option for patients who experience cough with other ACE inhibitors 3.

Management of Cough in Perindopril

• Patients who experience a dry cough while taking perindopril may be switched to an angiotensin-receptor blocker or other classes of antihypertensive drugs 3.
• Alternatively, a challenge/re-challenge approach may be used to determine if re-introduction of perindopril is associated with recurrence of symptoms 3.