ACE Inhibitors

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Summary

ACE inhibitors (ACEIs) are a class of drugs that work by inhibiting angiotensin-converting enzyme (ACE).  ACE inhibitors as a drug class have names ending in the suffix -pril, including lisinopril, enalapril, ramipril, captopril, and benazepril. The clinical effects of ACE inhibitors can be primarily broken into two main effects: first, they prevent conversion of angiotensin I into angiotensin II by ACE. Second, ACE is also used for bradykinin breakdown, so ACE inhibitors can increase bradykinin levels. 

Reducing levels of angiotensin II decreases blood pressure by way of reducing vasoconstriction and reducing aldosterone release. This can be helpful in the treatment of hypertension, although high doses of ACE inhibitors can go too far the other way and induce hypotension. By reducing systemic blood pressure, ACE inhibitors reduce the work of the heart and are therefore useful in the treatment of heart failure. In heart failure patients, ACE inhibitors are first-line because they confer a mortality benefit. ACE inhibitors also have a renoprotective effect, which means that they can protect the kidneys in patients with hypertension or diabetes. 

Besides the hypotension that we already talked about, other side effects of ACE inhibitors include angioedema and the development of a dry cough, both which are related to increased bradykinin levels in the body. ACE inhibitors can also cause hyperkalemia by reducing aldosterone release. Lastly, ACE inhibitors are teratogenic and should be particularly avoided in pregnant women to reduce the risk of kidney malformations in the fetus.

Key Points

  • ACE Inhibitors (ACEIs)
    • Drug names (-pril endings)
      • Captopril
      • Lisinopril
      • Enalapril
      • Ramipril
      • Benazepril
    • Mechanism
      • Inhibition of angiotensin-converting enzyme (ACE)
        • Decreased production of angiotensin II
          • ACE normally converts angiotensin I to angiotensin II
          • Causes a decrease in blood pressure
            • Inhibition of vasoconstriction by angiotensin II
            • Decreased downstream aldosterone release causes reduced blood volume
            • Note: a compensatory increase in renin (plasma renin activity = PRA) may be observed
          • Decreased GFR may also be seen
            • Prevents angiotensin II from constricting the efferent arteriole, which decreases GFR by reducing hydrostatic pressure in the glomerulus
        • Increased bradykinin levels
          • ACE normally inactivates bradykinin
          • Causes an accumulation of bradykinin, causing cough and angioedema
    • Clinical Use
      •  Systolic heart failure
        • Provides a mortality benefit, by slowing pathologic cardiac tissue growth and remodeling
        • Preferred especially in patients with hypertension
      • Hypertension
        • First-line drugs of choice for patients with diabetes and hypertension
      • Diabetic nephropathy
        • Decreases rate of glomerular basement membrane thickening and progression of proteinuria, which can reduce the risk of chronic kidney disease
    • Adverse Effects
      • Cough
        • Cough is described as non-productive or dry
        • Thought to result from accumulation of bradykinin
      • Angioedema
        • Rapid-onset swelling of the eyes, tongue, lips, and larynx that may compromise the airway
        • Thought to result from accumulation of bradykinin
        • ACEIs are contraindicated in patients at risk of angioedema (e.g. C1 esterase inhibitor deficiency)
      • Hyperkalemia
        • Decreased aldosterone production causes increased potassium reabsorption in the kidney, which can lead to hyperkalemia
      • Teratogen
        • All RAAS system inhibitors are teratogens that cause fetal kidney malformations
        • These drugs should be avoided in pregnant women
      • Hypotension
        • Obvious side effect of all antihypertensives
      • Increase creatinine
        • Via a reduction in GFR due to dilation of the efferent arterioles
        • This creatinine bump is not clinically significant, as the renoprotective effects of ACE inhibitors predominate
      • Avoid in bilateral renal artery stenosis (BRAS)
        • In BRAS, angiotensin II is necessary to maintain GFR. Inhibiting angiotensin II’s effects can lead to rapid renal failure
        • Look for a large rise in creatinine shortly after starting an ACE inhibitor