Lisinopril induced cough mechanism
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Lisinopril-Induced Cough: Mechanism and Key Mediators
ACE Inhibition, Bradykinin, and Substance P Accumulation
Lisinopril, an angiotensin-converting enzyme (ACE) inhibitor, is well known to cause a persistent, dry cough in a significant number of patients. The primary mechanism involves the inhibition of ACE, which normally breaks down bradykinin and substance P—two peptides that can trigger the cough reflex. When ACE is inhibited by lisinopril, levels of bradykinin and substance P increase, leading to heightened stimulation of cough pathways Just1989Nazir2016Nazir2016.
Central and Peripheral Sensitization of the Cough Reflex
Research in animal models shows that lisinopril can directly upregulate the cough reflex by acting on the central nervous system, specifically the caudal nucleus tractus solitarii, a key site for cough-related nerve signals. This effect is mediated by the accumulation of bradykinin and substance P, which sensitize the cough reflex both centrally and peripherally . Blocking bradykinin B2 or NK1 (substance P) receptors can reverse this cough potentiation, further supporting their role in the mechanism .
Role of Prostaglandins and C-Fiber Stimulation
Another contributing factor is the stimulation of lung afferent C fibers, possibly through increased prostaglandin E2 production. Prostaglandins are known to sensitize nerve endings and promote cough. The involvement of prostaglandins is supported by findings that nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit prostaglandin synthesis, can reduce ACE inhibitor-induced cough Just1989Ito1995. Animal studies also show that pretreatment with indomethacin, a prostaglandin synthesis inhibitor, reduces the cough response caused by lisinopril .
Clinical Features and Incidence
Lisinopril-induced cough is typically described as dry, nonproductive, and persistent, often accompanied by a tickling or irritating sensation in the throat. The cough can begin within days to months after starting therapy and usually resolves within 1 to 4 weeks after stopping the drug Nazir2016Nazir2016. The incidence of cough with lisinopril is higher compared to other ACE inhibitors and is significantly more frequent than with angiotensin II receptor blockers (ARBs) like losartan, which do not cause the same accumulation of bradykinin and substance P Lacourcière1995Mutolo2013Lacourciére1994+1 MORE.
Conclusion
Lisinopril-induced cough is primarily caused by the accumulation of bradykinin and substance P due to ACE inhibition, leading to increased sensitivity of the cough reflex both centrally and peripherally. Prostaglandins and stimulation of lung C fibers also play a role. This side effect is common, persistent, and resolves after discontinuation of the drug. ARBs like losartan are effective alternatives for patients who develop this cough, as they do not share the same mechanism.
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