Ace inhibitors and cough
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ACE Inhibitors and Cough: Incidence and Risk Factors
A dry, persistent cough is a well-known side effect of angiotensin-converting enzyme (ACE) inhibitors, with reported incidence rates ranging from about 5% to as high as 35% in different studies, though most estimates fall between 10% and 20% Yeşil1994Overlack1996Minh1990+4 MORE. The risk of developing cough is higher in women than in men, and the onset can occur anywhere from hours after the first dose to several months into therapy Yeşil1994Semple1995Sato2015. Some studies also note that the cough is not dose-related and can occur with all ACE inhibitors, though certain agents like enalapril and captopril may be associated with a higher incidence compared to others such as lisinopril and perindopril Yeşil1994Hu2023.
Mechanisms of ACE Inhibitor-Induced Cough
The exact mechanism behind ACE inhibitor-induced cough is not fully understood, but the most widely accepted theory involves the accumulation of bradykinin and substance P in the respiratory tract due to inhibition of their breakdown by ACE. This accumulation stimulates cough reflex pathways, particularly through vagal nerve fibers, and may also involve increased prostaglandin production Overlack1996Dicpinigaitis2006Leonova2025+1 MORE. Genetic factors, including polymorphisms in the ACE gene and bradykinin receptor genes, have been linked to increased susceptibility to this side effect, and ongoing research is identifying additional genetic markers that may predict risk .
Comparison with Other Antihypertensive Agents
ACE inhibitors are more likely to cause cough than angiotensin receptor blockers (ARBs) or calcium channel blockers (CCBs). The relative risk of cough is significantly higher with ACE inhibitors compared to placebo, ARBs, and CCBs Hu2023Dicpinigaitis2006. For patients at higher risk of developing cough, ARBs or CCBs are recommended alternatives Hu2023Dicpinigaitis2006.
Clinical Course and Management of ACE Inhibitor-Induced Cough
The cough associated with ACE inhibitors is typically dry and non-productive. It often resolves within days to weeks after discontinuing the medication, though in some cases it may persist for up to three months Yeşil1994Overlack1996Minh1990+1 MORE. Rechallenging with the same or a different ACE inhibitor usually results in recurrence of the cough, so switching to another ACE inhibitor is generally not effective Overlack1996Minh1990Dicpinigaitis2006. The only consistently effective treatment is stopping the ACE inhibitor Overlack1996Dicpinigaitis2006. In rare cases where discontinuation is not possible, some pharmacologic agents such as cromolyn, baclofen, theophylline, sulindac, and local anesthetics have been tried to manage the cough, but these are not standard practice Luque1999Semple1995.
Strategies to Minimize Cough Risk
Some studies suggest that taking ACE inhibitors at bedtime or combining them with calcium antagonists or diuretics may reduce the frequency of cough, though these strategies are not universally adopted . In a minority of patients, the cough may resolve spontaneously even if the ACE inhibitor is continued .
Conclusion
ACE inhibitor-induced cough is a common, sometimes bothersome side effect that can lead to discontinuation of therapy. The risk is higher in women and varies among different ACE inhibitors, but all agents in this class can cause cough. The underlying mechanism is likely related to bradykinin and substance P accumulation, with genetic factors playing a role in susceptibility. The most effective management is discontinuation of the ACE inhibitor, with ARBs or CCBs serving as suitable alternatives for affected patients.
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