What are Renin-Angiotensin-Aldosterone System (RAAS) inhibitors?

Renin-Angiotensin-Aldosterone System (RAAS) Inhibitors

RAAS inhibitors are medications that block different components of the renin-angiotensin-aldosterone system and include ACE inhibitors, ARBs, mineralocorticoid receptor antagonists, and direct renin inhibitors, which are used to treat hypertension, heart failure, and chronic kidney disease by reducing blood pressure, preventing target organ damage, and improving clinical outcomes. 1

Understanding the RAAS System

The renin-angiotensin-aldosterone system is a major endocrine/paracrine system that regulates:

• Blood pressure via angiotensin release
• Fluid and electrolyte homeostasis via aldosterone release 2

The RAAS cascade involves several key steps:

1. Renin release: Secreted by the kidney in response to decreased blood volume and renal perfusion
2. Angiotensinogen conversion: Renin cleaves angiotensinogen to form angiotensin I
3. Angiotensin I conversion: Angiotensin-converting enzyme (ACE) converts angiotensin I to angiotensin II
4. Angiotensin II effects: Causes vasoconstriction, catecholamine release, and promotes aldosterone secretion
5. Aldosterone effects: Increases sodium reabsorption and fluid retention 3

Dysregulation of the RAAS plays a critical role in the pathogenesis of cardiovascular and renal disorders 4.

Classes of RAAS Inhibitors

1. ACE Inhibitors

• Mechanism: Block the conversion of angiotensin I to angiotensin II and enhance the action of kinins and augment kinin-mediated prostaglandin production 5
• Examples: Lisinopril, enalapril, ramipril
• Benefits: Reduce mortality and morbidity in heart failure with reduced ejection fraction (HFrEF), lower blood pressure, provide renoprotective effects 1
• Side effects: Cough, angioedema, hyperkalemia, acute kidney injury

2. Angiotensin Receptor Blockers (ARBs)

• Mechanism: Block the angiotensin II type 1 (AT1) receptor, preventing the effects of angiotensin II 5
• Examples: Losartan, valsartan, candesartan
• Benefits: Similar cardiovascular benefits to ACE inhibitors but better tolerated 1
• Side effects: Hyperkalemia, acute kidney injury

3. Mineralocorticoid Receptor Antagonists (MRAs)

• Mechanism: Block aldosterone receptors, which are under control of both the RAAS and other systemic influences 5
• Examples: Spironolactone, eplerenone
• Benefits: Reduce mortality in HFrEF, effective for resistant hypertension, reduce myocardial fibrosis 1
• Side effects: Hyperkalemia, gynecomastia, menstrual irregularities

4. Direct Renin Inhibitors (DRIs)

• Mechanism: Directly inhibit renin, decreasing plasma renin activity and inhibiting the conversion of angiotensinogen to angiotensin I 3
• Examples: Aliskiren
• Benefits: Blood pressure reduction, potential organ protection 1
• Side effects: Hyperkalemia, increased adverse events with combination therapy

Clinical Applications of RAAS Inhibitors

Hypertension

• ACE inhibitors or ARBs are recommended as first-line options for patients with diabetes, chronic kidney disease, or high cardiovascular risk 1
• MRAs can be effective for resistant hypertension 1

Heart Failure

• For heart failure with reduced ejection fraction (HFrEF, EF <50%), an ACE inhibitor (or ARB if ACE inhibitor not tolerated) plus beta-blocker is recommended as initial therapy 1
• Adding an MRA is recommended for patients with persistent symptoms despite ACE inhibitor/ARB and beta-blocker therapy 1

Chronic Kidney Disease

• RAAS inhibitors are particularly beneficial in patients with diabetic or non-diabetic CKD 1
• ACE inhibitors and ARBs have shown renoprotective effects beyond blood pressure lowering 5

Polycystic Kidney Disease

• In children with autosomal dominant polycystic kidney disease (ADPKD) who have proteinuria, ACE inhibitors or ARBs should be used as primary treatment 5

Monitoring and Management of Side Effects

Hyperkalemia

• Regular monitoring of potassium levels is essential, especially when using MRAs or in patients with renal impairment or diabetes 1
• Discontinuation of RAAS inhibitors is recommended if potassium levels exceed 6.0 mEq/L 1

Renal Function

• Renal function impairment requires careful management, including reduced initial doses in patients with creatinine clearance ≤30 mL/min 1
• Temporary worsening of renal function may often stabilize, so premature discontinuation should be avoided unless severe deterioration occurs 1

Hypotension

• May occur especially when initiating therapy
• Consider lower starting doses in volume-depleted patients 1

Combination Therapy Considerations

• The combination of ACE inhibitors and calcium channel blockers is recommended for cardiovascular event reduction 1
• The combination of ARB and diuretic is effective for blood pressure control 1
• Dual RAAS blockade (combining ACE inhibitors and ARBs) is not generally recommended due to increased risk of renal events and hyperkalemia 1

Emerging Perspectives

Recent research suggests that while RAAS inhibitors are standard care in patients with hypertension, heart failure, or chronic kidney disease, there may be benefits to tailoring drug combinations to individual patient needs rather than generally prescribing ACE inhibitors or ARBs for everyone 6.

However, closer scrutiny of outcome data shows little evidence that the efficacy of RAAS blockers in hypertension extends beyond blood pressure reduction itself 7, highlighting the importance of achieving target blood pressure goals regardless of the specific agent used.