Can Lisinopril Cause a Cough?
Yes, lisinopril definitively causes cough as a well-established class effect of all ACE inhibitors, occurring in approximately 5-35% of patients, and is the most common reason for discontinuing long-term ACE inhibitor therapy. 1, 2
Mechanism of Cough Development
The cough develops through accumulation of bradykinin and substance P in the upper airway, which ACE normally breaks down. 3 When lisinopril inhibits ACE, these substances accumulate along with prostaglandins, leading to sensitization of airway sensory nerves and increased cough reflex sensitivity. 1, 3, 4
Clinical Characteristics to Recognize
Type: The cough is characteristically dry, non-productive, and accompanied by a persistent tickling or scratching sensation in the back of the throat. 1, 3
Timing: Onset is highly variable—it may appear within hours of the first dose or be delayed for weeks to months after starting therapy. 1, 3, 5 In one study, 59% of patients developed cough after the first month of treatment (30-180 days). 6
Dose relationship: The cough is not dose-dependent, so reducing the lisinopril dose will not eliminate it. 1, 3, 5
Nocturnal pattern: 79.4% of patients report increased intensity at night. 5
Incidence and Risk Factors
The FDA drug label reports cough occurring 2.5% more frequently than placebo in hypertension trials. 2 However, real-world incidence is substantially higher:
Overall incidence: 5-35% across studies, with most reporting 10-29%. 1, 3, 5, 7
Women: 37.9% incidence versus 15.5% in men—a statistically significant difference. 5, 6
Chinese patients: Nearly 50% incidence compared to 5-10% in white patients of European descent. 1
Diagnostic Approach
To confirm lisinopril as the cause, discontinue the medication regardless of when the cough started relative to drug initiation. 1 This is critical because:
Other causes of cough (pulmonary congestion, respiratory infections, post-nasal drip) must be excluded first. 1, 8
The temporal relationship between starting lisinopril and cough onset does not rule out ACE inhibitor causation. 1
Diagnosis is confirmed when cough resolves after stopping the drug—typically within 1-4 weeks, though it may take up to 3 months in some patients. 1, 8, 3
Rechallenge with another ACE inhibitor will reproduce the cough, confirming the diagnosis. 1
Management Algorithm
Step 1: Discontinue lisinopril immediately—this is the only uniformly effective treatment. 1, 8
Step 2: Switch to an angiotensin receptor blocker (ARB) as the first-line alternative. 8, 9 ARBs do not affect bradykinin metabolism and typically do not cause cough. 8 The ACC/AHA gives this a Class I, Level A recommendation for heart failure patients. 9
Step 3: If ARBs are contraindicated, consider calcium channel blockers or thiazide-like diuretics. 8
Alternative: Attempting to Continue Lisinopril
If there is a compelling indication for ACE inhibitor therapy and the cough is not severe, several agents may attenuate the cough in randomized controlled trials: 8
- Inhaled sodium cromoglycate 8
- Theophylline 8
- Calcium channel antagonists (amlodipine, nifedipine) 8
- NSAIDs (sulindac, indomethacin)—use cautiously in elderly 8, 4
- Ferrous sulfate 8
However, physicians should only consider these options if the cough is mild, as discontinuation remains the definitive treatment. 1
Important Clinical Pitfall
In approximately 30% of patients with confirmed ACE inhibitor-induced cough, the cough may not recur after a third trial of therapy. 8, 3 If the cough resolves after initial discontinuation and there is a compelling indication for ACE inhibitor therapy, a repeat trial may be attempted. 8 This surprising finding suggests the phenomenon is not always permanent.
Cross-Reactivity Considerations
All ACE inhibitors cause cough: Switching from lisinopril to captopril, enalapril, or ramipril will reproduce the cough. 1, 6, 7
ARBs rarely cause cough: While one case report describes losartan-induced cough that resolved with enalapril substitution 10, this is exceptionally rare and contradicts the established mechanism, as ARBs do not affect bradykinin metabolism. 8