What are Angiotensin-Converting Enzyme (ACE) inhibitors and Angiotensin Receptor Blockers (ARBs)?

ACE Inhibitors and ARBs: Drug Classes for Cardiovascular and Renal Protection

ACE inhibitors and ARBs are two distinct drug classes that block the renin-angiotensin system through different mechanisms—ACE inhibitors prevent the formation of angiotensin II while ARBs block its receptor—both serving as first-line antihypertensive agents with proven cardiovascular and renal protective effects. 1

Mechanism of Action

ACE Inhibitors

• ACE inhibitors block angiotensin-converting enzyme (ACE), which catalyzes the conversion of angiotensin I to angiotensin II, the principal vasoconstrictor of the renin-angiotensin system. 2
• By inhibiting ACE, these drugs decrease plasma angiotensin II levels, leading to decreased vasopressor activity and decreased aldosterone secretion. 2
• ACE is identical to kininase II, an enzyme that degrades bradykinin, so ACE inhibitors increase bradykinin levels, which contributes to their therapeutic effects but also causes side effects like cough and angioedema. 2, 3
• Common ACE inhibitors include lisinopril, captopril, and enalapril. 2, 4

Angiotensin Receptor Blockers (ARBs)

• ARBs selectively block the binding of angiotensin II to the AT1 receptor in vascular smooth muscle and the adrenal gland, preventing vasoconstriction and aldosterone secretion. 5
• Unlike ACE inhibitors, ARBs do not inhibit ACE and therefore do not affect bradykinin degradation, which explains their lower incidence of cough and angioedema. 5
• ARBs have much greater affinity (>10,000-fold) for the AT1 receptor than for the AT2 receptor. 5
• Common ARBs include candesartan, valsartan, losartan, and irbesartan. 5, 6

Clinical Applications

Hypertension Management

• Both ACE inhibitors and ARBs are recommended as first-line therapy for hypertension by the American Heart Association and American Diabetes Association. 1
• In patients with diabetes and albuminuria/proteinuria, both drug classes reduce progression to more advanced kidney disease. 3
• ARBs are the preferred alternative for patients who cannot tolerate ACE inhibitors due to cough or angioedema. 1, 6

Chronic Kidney Disease and Diabetic Nephropathy

• ACE inhibitors or ARBs are the preferred first-line agents for blood pressure treatment in patients with diabetes, hypertension, eGFR <60 mL/min/1.73 m², and UACR ≥300 mg/g Cr because of their proven benefits for prevention of CKD progression. 3
• In hypertensive type 1 diabetic patients with any degree of albuminuria, ACE inhibitors delay the progression of nephropathy. 3
• In hypertensive type 2 diabetic patients with microalbuminuria, both ACE inhibitors and ARBs delay progression to macroalbuminuria. 3
• In patients with type 2 diabetes, hypertension, macroalbuminuria, and renal insufficiency (serum creatinine >1.5 mg/dl), ARBs delay the progression of nephropathy. 3
• ACE inhibitors and ARBs are generally considered to have similar benefits and risks for renal protection. 3

Heart Failure

• ACE inhibitors are recommended as first-line therapy for heart failure with reduced ejection fraction (HFrEF) by the American College of Cardiology. 1
• ARBs such as valsartan, candesartan, and losartan are recommended for patients who are intolerant to ACE inhibitors, as they provide similar benefits. 1, 6
• In patients with structural heart disease or LV dysfunction without HF symptoms (Stage B), ACE inhibitors or ARBs help prevent symptomatic HF and reduce mortality. 1

Post-Myocardial Infarction

• ACE inhibitors are recommended for patients with a history of MI and reduced ejection fraction to prevent symptomatic heart failure and reduce mortality. 1

Important Safety Considerations and Contraindications

Functional Renal Insufficiency

• ACE inhibitor therapy can be associated with "functional renal insufficiency" and/or hyperkalemia, most commonly developing shortly after initiation but can occur after months or years of therapy. 3
• Acute renal failure is most likely when renal perfusion pressure cannot be sustained due to substantial decreases in mean arterial pressure or when GFR is highly angiotensin II dependent. 3
• The GFR is especially dependent on angiotensin II during extracellular fluid volume depletion, high-grade bilateral renal artery stenosis, or stenosis of a dominant or single kidney (as in a renal transplant recipient). 3
• Use of ACE inhibitors and ARBs in patients with bilateral renal artery stenosis should be cautious, as they can cause renal dysfunction. 1

Hyperkalemia Risk

• Both ACE inhibitors and ARBs may exacerbate hyperkalemia in patients with diabetes. 3
• Regular monitoring of kidney function (including serum creatinine and potassium) is essential when initiating or adjusting therapy. 7

Combination Therapy NOT Recommended

• The combined use of ACE inhibitors and ARBs should be avoided, as two clinical trials found no benefits on CVD or CKD, and the drug combination had higher adverse event rates (hyperkalemia and/or acute kidney injury). 3

Tolerability Differences

• ACE inhibitors are associated with cough and a very low risk of angioedema and fatalities due to bradykinin accumulation. 8, 9
• Overall withdrawal rates due to adverse events are lower with ARBs than with ACE inhibitors. 8

Key Clinical Pitfalls to Avoid

• Do not prescribe ACE inhibitors or ARBs to patients without hypertension to prevent the development of CKD, as clinical trials have not demonstrated benefit in this setting. 3
• Monitor for acute kidney injury when initiating therapy, especially in volume-depleted patients or those with suspected renal artery stenosis. 3
• Avoid combining ACE inhibitors with ARBs due to increased adverse events without additional clinical benefit. 3
• If one class is not tolerated, substitute with the other class rather than combining them. 3