Lisinopril mechanism of action
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Mechanism of Action of Lisinopril
Introduction to Lisinopril and ACE Inhibition
Lisinopril is a widely used angiotensin-converting enzyme (ACE) inhibitor that plays a crucial role in managing hypertension and heart failure. It functions by inhibiting the ACE enzyme, which is responsible for converting angiotensin I to angiotensin II, a potent vasoconstrictor. By blocking this conversion, lisinopril reduces the levels of angiotensin II, leading to vasodilation and decreased blood pressure .
Impact on Angiotensin II and Aldosterone
The inhibition of ACE by lisinopril not only reduces angiotensin II levels but also decreases the secretion of aldosterone from the adrenal cortex. Aldosterone is a hormone that promotes sodium and water retention. By reducing aldosterone levels, lisinopril increases sodium excretion and water outflow, contributing to its antihypertensive effects .
Cardioprotective Effects
Lisinopril has demonstrated significant cardioprotective properties. It enhances the recovery of cardiomyocytes during reoxygenation and mitigates oxidative damage. This is achieved through mechanisms involving the endogenous renin-angiotensin system and possibly direct cellular actions. Additionally, lisinopril has been shown to reduce oxidative stress and fibrosis in human cardiomyocytes by upregulating protective proteins such as catalase, SOD2, and thioredoxin, and reducing fibrotic mediators like osteopontin and Galectin-3.
Renal Protection and Antiproteinuric Effects
In the context of chronic glomerulonephritis, lisinopril exerts a potent antiproteinuric effect by protecting glomerular epithelial cells and reducing the expression of transforming growth factor-β (TGF-β) and plasminogen activator inhibitor-1 (PAI-1). This helps in preventing glomerulosclerosis and tubulointerstitial fibrosis, thereby improving extracellular matrix metabolism and renal function.
Interaction with ACE2 and Implications for COVID-19
Recent studies have shown that lisinopril increases the expression of ACE2, the cellular receptor for SARS-CoV-2, in various tissues. This upregulation could have implications for the transmission and pathogenesis of COVID-19. Interestingly, the combination of lisinopril with losartan, an angiotensin receptor blocker, prevents this increase in ACE2 levels, suggesting a complex interaction between these medications.
Pharmacokinetics and Bioavailability
Lisinopril is an orally active, nonsulfhydryl ACE inhibitor that is not metabolized or bound to proteins. It is excreted unchanged in the urine, with a bioavailability of approximately 25%. The drug achieves peak serum concentrations 6-8 hours after oral dosing and reaches a steady state in 2-3 days. Its absorption is mediated by a peptide carrier system, which explains its prolonged ACE inhibition and low oral bioavailability .
Conclusion
Lisinopril's mechanism of action primarily involves the inhibition of ACE, leading to reduced levels of angiotensin II and aldosterone, resulting in vasodilation and decreased blood pressure. Its cardioprotective and renal protective effects, along with its impact on oxidative stress and fibrosis, make it a valuable therapeutic agent. However, its interaction with ACE2 and potential implications for COVID-19 warrant further investigation.
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