## Mechanism-Based Distinction **Key Point:** The fundamental pharmacological difference between ACE inhibitors and ARBs lies in their site of action in the renin-angiotensin-aldosterone system (RAAS). ### Mechanism Comparison | Feature | ACE Inhibitors | ARBs | |---------|---|---| | **Site of action** | Blocks ACE enzyme; prevents conversion of angiotensin I → angiotensin II | Blocks AT1 receptor directly | | **Angiotensin II levels** | Decreased (enzyme inhibition) | Increased (negative feedback) | | **Bradykinin metabolism** | Impaired (ACE also breaks down bradykinin) | Normal (ARBs don't affect bradykinin) | | **Dry cough incidence** | 10–20% (bradykinin-mediated) | <2% | | **Mortality benefit in HF** | Proven (CONSENSUS, SOLVD trials) | Primarily as alternative to ACE-I | **High-Yield:** ACE inhibitors are the first-line RAAS inhibitor in systolic heart failure and post-MI; ARBs are reserved for ACE inhibitor intolerance (cough, angioedema). **Clinical Pearl:** The dry cough from ACE inhibitors is a class effect caused by accumulation of bradykinin (a potent vasodilator and inflammatory mediator), which ACE normally degrades. ARBs do not cause this because they do not affect bradykinin metabolism. ## Why This Distinction Matters The direct AT1 receptor blockade by ARBs is mechanistically distinct from enzyme inhibition by ACE inhibitors. This difference explains both the side-effect profile (no cough with ARBs) and the clinical outcomes (ACE inhibitors have stronger mortality data in HF). [cite:Harrison 21e Ch 297]
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