Why does lisinopril cause dry cough?

From the Guidelines

Lisinopril, an angiotensin-converting enzyme (ACE) inhibitor, can cause a dry cough in some patients due to the increased levels of bradykinin, a potent vasodilator, in the lungs, as suggested by 1. This leads to inflammation and irritation of the airways, resulting in a persistent, non-productive cough.

Key Points

• The cough is usually dry and hacking, and can occur at any time during treatment with lisinopril, but typically develops within the first few months of therapy, as noted in 1.
• The incidence of cough is estimated to be around 5-20% of patients taking lisinopril, and is more common in women and patients of Asian descent, as reported in 1.
• If the cough is severe or bothersome, alternative antihypertensive medications, such as angiotensin receptor blockers (ARBs), may be considered, as recommended in 1.

Mechanism and Management

• The mechanism of ACE inhibitor-induced cough remains unresolved, but likely involves the protussive mediators bradykinin and substance P, as well as prostaglandins, as discussed in 1.
• The diagnosis of ACE inhibitor-induced cough is confirmed by the resolution of cough after discontinuation of the offending agent, usually within 1 to 4 weeks, as stated in 1.

From the FDA Drug Label

The following adverse reactions (events 2% greater on lisinopril than on placebo) were observed with lisinopril alone: headache (by 3.8%), dizziness (by 3.5%), cough (by 2. 5%).

• Cough is listed as an adverse reaction to lisinopril. The FDA drug label does not provide a specific reason for why lisinopril causes dry cough, only that it is an observed adverse reaction 2.

From the Research

Mechanism of Lisinopril-Induced Cough

• The exact mechanism of lisinopril-induced cough is not fully understood, but it is thought to be related to the effects of angiotensin-converting enzyme inhibitors (ACEIs) on the kininogen-kinin system, specifically the accumulation of bradykinin 3.
• Bradykinin may lead to the activation of pro-inflammatory peptides and the release of histamine, causing cough reflex hypersensitivity 3.
• Another possible mechanism is the inhibition of the breakdown of substance P, a neurotransmitter involved in the transmission of pain and cough 4.

Incidence of Lisinopril-Induced Cough

• The incidence of cough in patients taking lisinopril varies, but it is generally reported to be around 1-6% 5, 3.
• A systematic review and network meta-analysis found that lisinopril had a moderate risk of inducing cough, with a surface under the cumulative ranking curve (SUCRA) of 64.7% 6.
• The incidence of cough is higher in women than in men, and it is more common in patients taking certain ACEIs, such as enalapril and captopril, than in those taking lisinopril or perindopril 5.

Management of Lisinopril-Induced Cough

• The cough usually disappears upon withdrawal of the ACEI, and treatment can be restarted after the cough has resolved 7, 5.
• In some cases, a dose reduction may lead to improvement, and adding a calcium channel blocker to the ACEI may also help to alleviate the cough 7, 3.
• Nonsteroidal anti-inflammatory drugs may also be effective in controlling the cough in some patients 4.