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DRUGS ACTING ON RAAS - ACE Inhibitors, ARBs, Enalapril, Losartan

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Q1. ACE Inhibitors - MOA, Therapeutic Uses, Adverse Effects, Drug Interactions, Contraindications & Precautions

Classification of ACE Inhibitors

• Captopril

• Enalapril (active: enalaprilat)
• Lisinopril (active per se - not a prodrug)
• Ramipril, Quinapril, Benazepril, Fosinopril, Perindopril, Trandolapril, Moexipril

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Mechanism of Action (MOA)

1. Converts Angiotensin I (inactive decapeptide) → Angiotensin II (active octapeptide, potent vasoconstrictor)
2. Degrades bradykinin (a vasodilator) into inactive peptides

• Angiotensin II formation is blocked → reduced vasoconstriction, reduced aldosterone secretion → less Na+ and water retention → BP falls
• Bradykinin accumulates → vasodilation, natriuresis (beneficial) but also causes cough and angioedema (adverse)

• Reduction of Total Peripheral Resistance (TPR) - no reflex tachycardia
• Reduced cardiac preload and afterload
• Reduced aldosterone → decreased sodium retention, mild diuresis
• Plasma Renin Activity (PRA) rises (loss of AngII negative feedback)
• Heart rate and cardiac output: unchanged at rest
• Regression of cardiac and vascular hypertrophy (cardioprotective)
• Preservation of renal function by dilating efferent arteriole more than afferent

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Pharmacokinetics

• Most are prodrugs (except captopril and lisinopril) - activated by hepatic esterases
• Captopril: absorbed on empty stomach; short t½ (2h), given 2-3 times/day
• Enalapril: t½ ~11h; given once or twice daily; renal excretion
• Lisinopril: not a prodrug; once daily; renally excreted
• All excreted renally - dose reduction needed in renal impairment

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Therapeutic Uses

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Adverse Effects

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Drug Interactions

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Contraindications

1. Pregnancy (all trimesters - fetotoxic, causes oligohydramnios, renal agenesis, neonatal death)
2. Bilateral renal artery stenosis (or unilateral RAS in single functioning kidney) - causes acute renal failure
3. History of angioedema with any ACE inhibitor
4. Severe hyperkalemia
5. Severe aortic stenosis (fixed output state - hypotension risk)

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Precautions

• Start with low dose in CHF, elderly, or those on diuretics (first-dose hypotension risk)
• Monitor serum creatinine and K+ within 1-2 weeks of starting
• Avoid NSAIDs
• Use with caution in renal impairment - reduce dose
• If cough develops, switch to ARB
• Do NOT use in bilateral RAS
• Stop before surgery in hemodynamically unstable patients

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Q2. Drugs Acting on RAAS - Enumerate, Note on Any Two

Drugs Acting on the Renin-Angiotensin-Aldosterone System (RAAS)

RAAS: Renin → Angiotensinogen → Angiotensin I → (ACE) → Angiotensin II → AT1/AT2 Receptors
                                                                        ↓
                                                               Aldosterone (adrenals)

A. Renin Inhibitors

• Aliskiren (direct renin inhibitor; oral; once daily)

B. ACE Inhibitors

• Captopril, Enalapril, Lisinopril, Ramipril, Quinapril, Fosinopril, Benazepril, Perindopril, Trandolapril, Moexipril

C. AT1-Receptor Blockers (ARBs / Sartans)

• Losartan, Candesartan, Valsartan, Irbesartan, Olmesartan, Telmisartan, Azilsartan, Eprosartan

D. Aldosterone Antagonists (Mineralocorticoid Receptor Antagonists)

• Spironolactone, Eplerenone

E. Angiotensin Receptor-Neprilysin Inhibitors (ARNIs)

• Sacubitril/Valsartan (Entresto) - blocks neprilysin (degrades natriuretic peptides) + AT1 receptor

F. Angiotensin II (Synthetic)

• Used in refractory vasodilatory shock (pharmacological AngII)

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Note on Two Drugs:

1. Aliskiren (Renin Inhibitor)

• MOA: Directly inhibits renin - the rate-limiting enzyme in RAAS. Prevents conversion of angiotensinogen to Angiotensin I. Reduces plasma renin activity (PRA), unlike ACE inhibitors/ARBs which increase renin.
• Uses: Hypertension; investigated in diabetic nephropathy
• Adverse effects: Diarrhea, hyperkalemia, renal impairment, angioedema (rare)
• Key distinction: Does NOT cause cough (no effect on bradykinin). Reduces PRA (unique among RAAS drugs)
• Contraindicated with ACE inhibitors or ARBs in diabetics (ALTITUDE trial - increased renal events)

2. Eplerenone (Aldosterone Antagonist)

• MOA: Selective mineralocorticoid receptor antagonist - blocks aldosterone-mediated Na+ retention and K+ excretion in renal collecting duct
• Uses: Hypertension, CHF post-MI (EPHESUS trial - reduced mortality), heart failure with reduced EF
• Advantage over spironolactone: More selective - no anti-androgenic or progestogenic side effects; no gynecomastia
• Adverse effects: Hyperkalemia (main concern), mild diuresis
• Precaution: Avoid with potassium-sparing diuretics; monitor renal function and K+

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Q3. Use of ACE Inhibitors in CHF - Rationale, Uses, Adverse Effects, Precautions

Pathophysiology of CHF Relevant to ACE Inhibitor Use

1. Sympathetic nervous system activation → tachycardia, vasoconstriction
2. RAAS activation → AngII causes vasoconstriction + aldosterone release → fluid/Na+ retention → increased preload and afterload (worsens cardiac function)
3. Ventricular remodeling - dilatation, hypertrophy, fibrosis (progressive)

Rationale for ACE Inhibitors in CHF

Uses in CHF

• All grades of CHF with reduced ejection fraction (HFrEF) - cornerstone of treatment
• Asymptomatic LV dysfunction (prevent progression to symptomatic CHF)
• Combined with beta-blockers, diuretics, and mineralocorticoid antagonists for maximum benefit
• Drugs used: Enalapril, Lisinopril, Captopril, Ramipril

Adverse Effects in CHF Context

• First-dose hypotension - most important and common in CHF (patients have activated RAAS; sudden AngII blockade causes sharp fall in BP). Start with very low dose (e.g., enalapril 2.5 mg), preferably at bedtime, in hospital if severe CHF
• Hyperkalemia - worsened in CHF as these patients may also be on K+-sparing diuretics or have renal impairment
• Worsening renal function - AngII was maintaining GFR in low-output state; up to 30% rise in creatinine is acceptable; >30% suggests bilateral RAS
• Cough - may worsen dyspnea in CHF patients; switch to ARB if intolerable

Precautions in CHF

1. Begin at low doses, especially if on high-dose diuretics (volume-depleted)
2. Monitor BP, creatinine, and K+ at 1-2 weeks, then 1 month, then every 3-6 months
3. Withhold if creatinine rises >30% above baseline
4. Withhold if K+ >5.5 mEq/L
5. Avoid NSAIDs - blunt hemodynamic benefits
6. Avoid in bilateral RAS, pregnancy
7. Not appropriate as sole therapy - combine with diuretic and beta-blocker

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Q4. ARBs vs ACE Inhibitors - Compare Adverse Effects and Precautions

Comparison Table

Common Precautions for Both

• Avoid in pregnancy (both cause identical fetal renal toxicity)
• Avoid in bilateral renal artery stenosis
• Monitor K+ and creatinine
• Start low in CHF or volume-depleted patients
• Avoid NSAIDs
• Do NOT combine ARB + ACE inhibitor - no added benefit; increased risk of hypotension, hyperkalemia, renal failure (ON-TARGET trial)

Key Exam Points

• ACE inhibitors are preferred initially; switch to ARB if cough is intolerable
• ARBs do NOT cause cough - this is the major clinical advantage
• If angioedema occurs with ACE inhibitor - do NOT automatically give ARB (angioedema can recur in ~10% of cases)
• Both are equally contraindicated in pregnancy

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Q5. Enalapril vs Losartan - Compare MOA, Therapeutic Indications, Adverse Effects, Precautions

Comparison Table: Enalapril vs Losartan

Therapeutic Indications

Adverse Effects

Precautions

Key Differences Summary

1. Cough - Enalapril causes it; Losartan does not (bradykinin difference)
2. Angioedema - More with enalapril; switch to losartan only with caution
3. Uric acid - Losartan lowers uric acid (useful in gout); enalapril does not
4. Diabetic nephropathy - Enalapril preferred in T1DM; Losartan has RCT evidence in T2DM (RENAAL trial)
5. LVH/Stroke prevention - Losartan had superior outcomes vs atenolol in LIFE trial
6. Prodrug activation - Enalapril: hepatic esterases; Losartan: CYP2C9/3A4 to EXP-3174
7. Renal clearance - Enalapril: predominantly renal; Losartan: predominantly hepatic/fecal

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Q6. Enalapril - Pharmacological Basis for Use in CHF; Precautions

Pharmacological Basis (Rationale) for Enalapril in CHF

• AngII: vasoconstriction → increased afterload → more cardiac work
• Aldosterone: Na+ + water retention → increased preload → pulmonary congestion, edema
• Cardiac fibrosis and hypertrophy (ventricular remodeling) - AngII is directly profibrotic
• Sympathetic activation (AngII facilitates norepinephrine release)

• Decreased TPR (afterload reduction)
• Decreased venous return (preload reduction)
• Increased cardiac output WITHOUT reflex tachycardia
• No direct positive inotropic effect - improvement is via unloading

Precautions for Enalapril in CHF

1. First-dose hypotension
   • CHF patients have activated RAAS; sudden AngII blockade → sharp BP drop
   • Start with 2.5 mg; give at bedtime; consider observation after first dose
   • Withhold if SBP <90 mmHg
2. Volume depletion
   • If patient is on high-dose diuretics → reduce diuretic dose before starting enalapril
3. Renal function monitoring
   • Check creatinine + electrolytes at baseline, 1-2 weeks, then periodically
   • Up to 30% rise in creatinine is acceptable (from efferent arteriole dilation - actually protective)

   • 30% rise or creatinine >3 mg/dL → withhold or reduce dose; rule out bilateral RAS

4. Hyperkalemia
   • CHF patients often on spironolactone/eplerenone + renal impairment → K+ rises
   • Monitor K+; avoid K+ supplements and K+-sparing diuretics unless monitored
   • Hold if K+ >5.5 mEq/L
5. Avoid NSAIDs
   • Block prostaglandin synthesis → reduce vasodilatory benefit of bradykinin + blunt diuretic effect
6. Contraindicated in:
   • Pregnancy
   • Bilateral renal artery stenosis
   • History of angioedema with ACE inhibitor
   • Severe aortic/mitral stenosis (fixed output)
   • Severe hypotension (SBP <90 mmHg)
7. Cough
   • In CHF, cough may be confused with pulmonary congestion
   • If cough is confirmed as drug-related, switch to an ARB (e.g., candesartan, valsartan - proven in CHF)

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Quick Reference Summary Table

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