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

Renin-Angiotensin-Aldosterone System (RAAS) Inhibitors

RAAS inhibitors are a group of medications that block different components of the renin-angiotensin-aldosterone system and include ACE inhibitors, angiotensin receptor blockers (ARBs), mineralocorticoid receptor antagonists (MRAs), and direct renin inhibitors (DRIs), which are cornerstone treatments for cardiovascular diseases due to their proven mortality and morbidity benefits. 1

Types of RAAS Inhibitors

• Angiotensin Converting Enzyme Inhibitors (ACEIs): Block the enzyme that converts angiotensin I to angiotensin II, while also enhancing the action of kinins and augmenting kinin-mediated prostaglandin production 1
• Angiotensin Receptor Blockers (ARBs): Selectively block the binding of angiotensin II to the AT1 receptor in tissues like vascular smooth muscle and the adrenal gland 2
• Mineralocorticoid Receptor Antagonists (MRAs): Block aldosterone receptors which are under control of both the RAAS and other systemic/local influences 1
• Direct Renin Inhibitors (DRIs): Block the generation of angiotensin I from angiotensinogen by inhibiting the active enzymatic site of renin (e.g., aliskiren) 3, 4

Mechanism of Action

• RAAS inhibitors target a hormonal cascade that regulates blood pressure, tissue perfusion, and extracellular volume 4
• Angiotensin II is the principal pressor agent of the renin-angiotensin system with effects including:
  • Vasoconstriction
  • Stimulation of aldosterone synthesis and release
  • Cardiac stimulation
  • Renal reabsorption of sodium 2
• Different RAAS inhibitors work at various points in this cascade:
  • ACEIs prevent the formation of angiotensin II from angiotensin I 1
  • ARBs block the effects of angiotensin II at receptor sites 2
  • MRAs block aldosterone's effects at the receptor level 1
  • DRIs inhibit the rate-limiting step in the RAAS cascade by blocking renin activity 3

Clinical Importance and Applications

• RAAS inhibitors are the cornerstone of treatment for multiple cardiovascular conditions:

  • Heart failure with reduced ejection fraction (HFrEF) - Class IA recommendation 1
  • Arterial hypertension 1
  • Coronary artery disease 1
  • Post-myocardial infarction 1
  • Left ventricular hypertrophy 1
  • Diabetic nephropathy and chronic kidney disease 1

• RAAS inhibitors provide mortality and morbidity benefits through:

  • Blood pressure reduction 5
  • Limiting cardiac and vascular remodeling 1
  • Reducing oxidative stress in the vasculature 1
  • Improving endothelial function 1
  • Decreasing fibrosis and inflammation 1

Side Effects and Monitoring

• Hyperkalaemia: A common side effect, especially in patients with:

  • Advanced chronic kidney disease (up to 73% of patients) 1
  • Heart failure (up to 40% of patients) 1
  • When using dual RAAS inhibition (5-10% incidence) 1
  • When combined with other potassium-sparing medications 6

• Hypotension: Can occur especially when initiating therapy or when combined with diuretics 6

• Renal function impairment: Monitor creatinine and eGFR, particularly in patients with pre-existing kidney disease 6

• Angioedema: Rare but serious side effect, more common with ACEIs than ARBs 1

Clinical Considerations

• Monitor potassium levels regularly, especially in patients with risk factors for hyperkalemia 1
• Start with lower doses in patients who are volume-depleted or on diuretics 6
• ACEIs may have additional benefits beyond ARBs due to their effects on the kinin system 1
• Avoid dual RAAS blockade in most patients due to increased risks of hypotension, hyperkalemia, and renal dysfunction 6
• In patients with diabetes and chronic kidney disease, RAAS inhibitors have specific indications due to overwhelming evidence of benefit 1

Therapeutic Considerations

• For heart failure patients, guidelines recommend initiating an ACEI (or ARB if ACEI intolerant) before adding an MRA 1
• For resistant hypertension, an MRA should be implemented before diagnosing true resistant hypertension 1
• Loop diuretics can be used to manage hyperkalemia in patients on RAAS inhibitors 1
• RAAS inhibitors attenuate potassium loss caused by thiazide diuretics, often eliminating the need for potassium supplements 1

Recent Developments

• Newer approaches include:
  • Direct renin inhibitors like aliskiren 3
  • Novel dual-acting RAAS-blocking agents 7
  • Potassium binders to manage hyperkalemia while maintaining RAAS inhibition 1