Direct Renin Inhibitors block the RAAS pathway at its most proximal step by inhibiting renin.

This prevents conversion of angiotensinogen → angiotensin I.

Currently, the only clinically available agent is:

• Aliskiren

Renin normally: Angiotensinogen → Angiotensin I → Angiotensin II → AT1 receptor effects

Direct renin inhibitors:

• Inhibit renin activity • Decrease formation of angiotensin I • Decrease angiotensin II levels • Decrease aldosterone secretion

Net Effects:

• ↓ Systemic vascular resistance • ↓ Sodium retention • ↓ Blood pressure

This acts upstream of: • ACE Inhibitors • Angiotensin Receptor Blockers

• Approved for treatment of primary hypertension • Comparable BP reduction to ACE inhibitors and ARBs

→ Hypertension Module

Not commonly used as first-line therapy.

Large trials showed:

• No clear superiority over ACE inhibitors or ARBs • Increased adverse events when combined with ACEi or ARB • Increased risk of hyperkalemia and renal impairment in diabetics

Result: Direct renin inhibitors are rarely used in routine practice.

• Hyperkalemia • Hypotension • Renal impairment • Rare angioedema • Diarrhea (dose-related)

• Pregnancy • Concomitant ACE inhibitor or ARB in diabetics • Bilateral renal artery stenosis • Severe renal impairment

Avoid combining with: • ACE Inhibitors • ARBs

Monitor:

• Serum creatinine • Potassium

Similar monitoring requirements as ACE inhibitors and ARBs.

Renin Inhibitor: • Blocks RAAS at its origin • ↓ Angiotensin I and II

ACE Inhibitor: • Blocks Angiotensin I → II conversion

ARB: • Blocks AT1 receptor

Despite theoretical appeal, clinical benefit is similar — not superior — to ACEi/ARB.

✔ Only available agent: Aliskiren ✔ Lowers BP effectively ✔ No proven superiority over ACEi/ARB ✔ Do NOT combine with ACEi or ARB ✔ Rarely used in modern practice

Related:

→ ACE Inhibitors → Angiotensin Receptor Blockers → Hypertension Module → Return to CV Modules