====== Direct Renin Inhibitors ======

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:

• [[cardio:raas:aliskiren|Aliskiren]]

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===== Mechanism of Action =====

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:
• [[cardio:raas:acei|ACE Inhibitors]]
• [[cardio:raas:arb|Angiotensin Receptor Blockers]]

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===== Indications =====

==== Hypertension ====

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

→ [[cardio:hypertension:start|Hypertension Module]]

Not commonly used as first-line therapy.

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===== Why It Is Rarely Used =====

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.

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===== Adverse Effects =====

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

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===== Contraindications =====

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

Avoid combining with:
• [[cardio:raas:acei|ACE Inhibitors]]
• [[cardio:raas:arb|ARBs]]

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===== Monitoring =====

Monitor:

• Serum creatinine
• Potassium

Similar monitoring requirements as ACE inhibitors and ARBs.

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===== RAAS Comparison =====

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.

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===== Clinical Pearls =====

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

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Related:

→ [[cardio:raas:acei|ACE Inhibitors]]
→ [[cardio:raas:arb|Angiotensin Receptor Blockers]]
→ [[cardio:hypertension:start|Hypertension Module]]
→ [[cardio:intro:start|Return to CV Modules]]