Why Lisinopril Causes Cough
Lisinopril causes cough through the accumulation of bradykinin and substance P in the upper airway, which occurs because ACE (the enzyme that normally degrades these substances) is inhibited by the medication. 1
Mechanism of ACE Inhibitor-Induced Cough
The pathophysiology involves several interconnected processes:
Bradykinin accumulation is the primary mechanism—ACE normally breaks down bradykinin, but when inhibited by lisinopril, bradykinin levels rise in the airways 1
Substance P accumulation also occurs, as ACE is responsible for degrading this neurochemical mediator of the cough reflex 1
Prostaglandin production is stimulated by the elevated bradykinin levels, further contributing to cough 1
Sensitization of airway sensory nerves (specifically C-fibers) results from bradykinin-induced stimulation, making patients more sensitive to cough triggers 1, 2
Increased cough reflex sensitivity has been demonstrated experimentally—patients with ACE inhibitor-induced cough show heightened responses to capsaicin stimulation, which resolves after stopping the medication 1
Clinical Characteristics
The cough has distinctive features that help identify it:
Dry, nonproductive, and tickling quality is typical, often described as a scratching sensation in the throat 1, 3
Timing is variable—onset may occur within hours of the first dose or be delayed for weeks to months after starting therapy 1, 4
Not dose-dependent—changing the dose of lisinopril will not eliminate the cough 1
Worse at night with frequent sleep interference reported 3
Class effect—all ACE inhibitors cause this problem at similar rates, so switching to another ACE inhibitor (like enalapril or ramipril) will not help 5
Prevalence and Risk Factors
Occurs in 5-35% of patients treated with ACE inhibitors, though prospective studies of chronic cough find ACE inhibitors responsible in only 0-3% of cases presenting specifically for cough evaluation 1
More common in nonsmokers 1
More common in persons of Chinese origin 1
Confirmed by FDA labeling—cough occurred 2.5% more frequently than placebo in hypertension trials 6
Important Clinical Pitfall
The cough is NOT related to bronchospasm or enhanced bronchial responsiveness—this is a common misconception. The mechanism is purely related to sensory nerve sensitization, not airway constriction. 1
Resolution Timeline
Typically resolves within 1-4 weeks after discontinuing lisinopril 1
May take up to 3 months in a subgroup of patients—this delayed resolution can lead to misdiagnosis if clinicians expect immediate improvement 1, 4
Rechallenge consideration—approximately 30% of patients with confirmed ACE inhibitor-induced cough who were challenged and dechallenged twice did not develop cough after a third trial, suggesting the phenomenon may not always recur 1