Why can lisinopril (Angiotensin-Converting Enzyme (ACE) inhibitor) cause a chronic cough?

Mechanism of Lisinopril-Induced Chronic Cough

Lisinopril causes chronic cough primarily through the accumulation of bradykinin and substance P in the upper airway and lungs, as these substances are normally degraded by angiotensin-converting enzyme (ACE) which is inhibited by the medication. 1

Pathophysiological Mechanism

The mechanism of ACE inhibitor-induced cough involves several key processes:

1. Bradykinin Accumulation:

   • ACE normally degrades bradykinin in the respiratory tract
   • When ACE is inhibited by lisinopril, bradykinin accumulates 1
   • Bradykinin-induced sensitization of airway sensory nerves is a primary mechanism 1

2. Substance P Accumulation:

   • Substance P is another protussive mediator normally degraded by ACE
   • Accumulation in the upper airway and lungs when ACE is inhibited 1

3. Prostaglandin Production:

   • Bradykinin stimulates the production of prostaglandins
   • These prostaglandins further contribute to cough reflex sensitization 1

4. Increased Cough Reflex Sensitivity:

   • Patients with ACE inhibitor-induced cough demonstrate increased sensitivity to experimental stimulation with capsaicin 1
   • This heightened sensitivity resolves after discontinuation of the ACE inhibitor 1

Clinical Characteristics of ACE Inhibitor-Induced Cough

• Typically dry and nonproductive 2
• Often worse at night and may interfere with sleep 2
• Not dose-dependent 1, 3
• More common in:
  • Women 1, 2, 3
  • Nonsmokers 1
  • Persons of Chinese origin 1
  • Patients with congestive heart failure (compared to those with hypertension) 1

Genetic Factors

• Bradykinin receptor gene polymorphism has been associated with ACE inhibitor-induced cough 1
• This genetic variation may explain why some patients are more susceptible than others

Management of ACE Inhibitor-Induced Cough

The most effective intervention for ACE inhibitor-induced cough is discontinuation of the medication:

• Cough typically resolves within 1-4 weeks after stopping the ACE inhibitor 1
• In some patients, cough may persist for up to 3 months 1
• For patients requiring continued renin-angiotensin system blockade, switching to an angiotensin receptor blocker (ARB) is recommended, as ARBs generally do not cause cough 1, 4

Important Clinical Considerations

• Incidence of ACE inhibitor-induced cough ranges from 5-35% of patients 1
• Onset can occur within hours of the first dose or be delayed for weeks to months 1
• ACE inhibitors may sensitize the cough reflex, potentially potentiating other causes of chronic cough 1
• In approximately 30% of patients with previous ACE inhibitor-induced cough, the cough may not recur with rechallenge 1

Caveat

While rare cases of cough with angiotensin receptor blockers have been reported 5, the incidence is significantly lower than with ACE inhibitors and similar to that of control drugs like hydrochlorothiazide 1, 4.