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💊 HEART FAILURE - PHARMACOLOGY & THERAPEUTICS

Dr. Priyanka Sachdev Style - Made Easy | Mnemonics | Clinical Pearls

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🫀 QUICK ORIENTATION - What You MUST Know First

Clinical Pearl: Only in HFrEF do drugs like ACE inhibitors, beta-blockers, ARBs, MRAs, ARNI, SGLT2i, and ivabradine improve SURVIVAL. In HFpEF - only symptom relief.

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🔄 PATHOPHYSIOLOGY - THE VICIOUS CYCLE

Mnemonic: "SHAMAN" - 6 Compensatory Mechanisms

Clinical Pearl: All compensatory responses become harmful long-term - they increase cardiac workload → drugs target ALL these pathways.

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🧭 OVERVIEW - DRUG MAP FOR HFrEF

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SECTION I: RAAS INHIBITORS

🅰️ A. ACE Inhibitors

Perindopril, Amlodin (enalapril), Lisinopril, Enalapril | Fosinopril, ACC (captopril), Cilazapril, Enalaprilat (IV)

Angiotensin I ---[ACE]--→ Angiotensin II (BLOCKED by ACEi)
Bradykinin ----[ACE]--→ Inactive peptide (ACEi prevents this degradation)

• Block ACE → ↓Angiotensin II → ↓Vasoconstriction (↓afterload) + ↓Aldosterone → ↓Na/water retention (↓preload)
• Bradykinin builds up → causes DRY COUGH (most common side effect)

Clinical Pearls:

• Captopril: only ACE inhibitor to take on EMPTY STOMACH (food ↓ absorption)
• Fosinopril: unique - dual elimination (renal + fecal) - safe in renal failure
• Enalaprilat: only IV formulation of ACE inhibitor
• All ACE inhibitors are prodrugs EXCEPT captopril and enalaprilat (injectable)
• TERATOGENIC - avoid in pregnancy (Category D/X)
• Monitor: serum K+, serum creatinine, and blood pressure

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🅱️ B. Angiotensin Receptor Blockers (ARBs)

Losartan, Olmesartan, Valsartan | Candesartan, Azilsartan, Telmisartan

Clinical Pearl: Losartan is unique among ARBs - undergoes extensive first-pass metabolism to an active metabolite. All other ARBs have inactive metabolites. Key Rule: NEVER combine ACE inhibitor + ARB + MRA simultaneously (triple RAAS blockade → dangerous hyperkalemia + AKI).

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🅲 C. Mineralocorticoid Receptor Antagonists (MRAs)

Clinical Pearls:

• Spironolactone causes gynecomastia in men and menstrual irregularities in women - switch to eplerenone if this occurs
• MRAs are potassium-SPARING - risk of hyperkalemia when combined with ACE-i or ARB - monitor potassium!
• Indicated in symptomatic HFrEF AND in HFrEF post-MI

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SECTION II: ARNI (Sacubitril/Valsartan)

Trade Name: ENTRESTO

Sacubitril ---[plasma esterases]--→ LBQ657 (active)
    ↓
Inhibits Neprilysin
    ↓
↑ Natriuretic peptides (ANP, BNP) → vasodilation + natriuresis + ↓fibrosis
    ↓
Combined with Valsartan (AT1 blocker)
    = ↓Afterload + ↓Preload + ↓Remodeling

The PARADIGM-HF Trial: Sacubitril/Valsartan vs enalapril - ARNI won → reduces mortality and HF hospitalization significantly

ACE inhibitor MUST be stopped at least 36 hours BEFORE starting ARNI to prevent dangerous angioedema (both ACEi and sacubitril increase bradykinin by different mechanisms)

• Hypotension (most common)
• Angioedema (contraindicated if prior ACEi-related angioedema)
• Hyperkalemia
• Renal insufficiency

Contraindicated: Concurrent ACE inhibitor use, history of angioedema, pregnancy

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SECTION III: BETA-BLOCKERS IN HF

🔑 The "Magical Three" Beta-Blockers for HFrEF

"Only BCM reduce mortality in HFrEF" - no other beta-blockers (atenolol, propranolol) are proven!

• Chronic SNS activation → receptor downregulation + cardiac remodeling + fibrosis
• Beta-blockers prevent these chronic harms → improve EF over weeks-months (reverse remodeling)
• Start low, go slow - always titrate up gradually

• Carvedilol + metoprolol → metabolized by CYP2D6 (inhibitors like fluoxetine ↑ levels)
• Carvedilol → also substrate of P-gp (P-gp inhibitors ↑ levels)
• Use with caution with amiodarone, verapamil, diltiazem (additive AV block)

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SECTION IV: DIURETICS

Loop Diuretics (Cornerstone of Symptom Relief)

Bumetanide, Furosemide, Torsemide

• Act on thick ascending limb - block Na/K/2Cl cotransporter
• Reduce preload → ↓pulmonary/peripheral congestion
• Do NOT improve survival in HF - purely symptomatic treatment

Clinical Pearl: Loop diuretics do NOT improve mortality in HF - they only relieve congestion symptoms (dyspnea, edema, orthopnea). Never stop them in a fluid-overloaded patient!

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SECTION V: IVABRADINE (HCN Channel Blocker)

• Blocks HCN (If current) channel in SA node
• ↓ Rate of spontaneous depolarization → ↓ Heart rate
• NO effect on contractility, BP, AV conduction, or ventricular repolarization

• HFrEF + sinus rhythm + HR > 70 bpm + optimized beta-blocker therapy (or beta-blocker contraindicated)
• Slower HR → ↑ diastolic filling time → ↑ stroke volume

Bradycardia, Luminous phenomena (halos/brightness in vision - unique!), Atrial fibrillation (↑ risk), Birth defects (teratogenic)

Clinical Pearl: Ivabradine works ONLY in sinus rhythm - it does NOT work for rate control in atrial fibrillation (because AF has no SA node driving it). Administered with meals (↑ absorption). Metabolized by CYP3A4 - avoid potent 3A4 inhibitors.

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SECTION VI: VASODILATORS

A. Hydralazine (Arterial Vasodilator)

1. Patients intolerant of ACE inhibitor/ARB
2. Self-identified African-American patients with HFrEF on GDMT (Fixed combination = BiDil)

• Headache, dizziness, hypotension
• Reflex tachycardia (always combine with beta-blocker!)
• Drug-induced lupus (rare - especially in slow acetylators)
• Peripheral edema (combine with diuretic)

Pharmacokinetics: Short half-life (2-4 hrs) → dose 2-4x/day. Metabolized by hepatic acetylation. Slow acetylators → more drug-induced lupus.

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B. Nitrates (Venous + Arterial Dilators)

Clinical Pearl - Nitroprusside Cyanide Toxicity: Nitroprusside → breaks down on contact with cell walls → releases CN⁻ and NO. CN⁻ + thiosulfate → thiocyanate (renal excretion). When thiosulfate is depleted (high dose/prolonged use/renal failure) → cyanide toxicity. Treat with sodium thiosulfate or hydroxocobalamin.

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SECTION VII: SGLT2 INHIBITORS (The New Superstars!)

Dapagliflozin & Empagliflozin

• Inhibit SGLT2 in proximal tubule → ↓glucose reabsorption → glucosuria
• ↓ Na+ reabsorption → natriuresis → ↓ plasma volume → ↓ preload + afterload
• May selectively reduce interstitial fluid (vs intravascular) - less reflexive neurohormonal activation than loop diuretics!
• Possibly inhibit NHE (Na-H exchanger) in myocardium → prevent Ca2+ overload → cardioprotection

• Symptomatic HFrEF + on optimal therapy (ACEi/ARNI + BB + MRA)
• Also benefit HFpEF (dapagliflozin, empagliflozin)
• Also: reduce new HF development in T2DM patients

Genitourinary infections (candida, UTI), Urinary frequency (glucosuria), Thyocetoacidosis (DKA - rare), Fournier gangrene (rare, severe), Urosepsis, Kidney injury (volume depletion)

Clinical Pearl: When starting SGLT2i in a patient already on loop diuretics - may need to reduce diuretic dose due to additive natriuresis. Risk of hypoglycemia when combined with insulin or sulfonylureas.

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SECTION VIII: DIGOXIN (Cardiac Glycoside)

💡 The Original Heart Failure Drug

Digoxin inhibits Na+/K+-ATPase pump
↓
Na+ builds up inside cell
↓
Na+/Ca2+ exchanger works less (needs Na+ gradient to export Ca2+)
↓
Ca2+ builds up inside cell
↓
↑ Contractility (positive inotropic effect)

• Contractility ↑ (positive inotrope)
• Vagal tone ↑ → ↓ HR, ↓ AV conduction (useful in AF)
• Neurohormonal inhibition at low doses → ↓ sympathetic activation

• HFrEF symptomatic on optimal therapy
• Atrial fibrillation with rapid ventricular rate in HF
• Target serum level: 0.5-0.9 ng/mL (low - to minimize toxicity)

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⚠️ DIGOXIN TOXICITY - HIGH YIELD EXAM TOPIC

• Vomiting/nausea/anorexia
• Vision changes (blurred, yellowish-green - "yellow vision", halos)
• Vertigo/confusion

• Arrhythmias (most dangerous!) - any arrhythmia can occur
• Most characteristic: Atrial tachycardia with AV block ("Paroxysmal AT with block")
• Also: PVCs, bigeminy, complete heart block

CLASSIC EXAM QUESTION: A patient on digoxin develops toxicity after starting furosemide. Why? Furosemide causes hypokalemia → ↑ digoxin binding → toxicity!

• Mild: Stop digoxin, correct hypokalemia, correct hypomagnesemia
• Severe (life-threatening arrhythmias): Digoxin-specific Fab antibody fragments (Digibind/DigiFab)

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SECTION IX: VERICIGUAT (sGC Stimulator) - NEW DRUG

• In HF: oxidative stress inactivates endogenous NO
• Vericiguat directly stimulates sGC (at a different site than NO) AND sensitizes sGC to residual NO
• → ↑ cGMP → ↓ fibrosis, vasodilation, ↓ hypertrophy, ↑ LV compliance

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SECTION X: ACUTE DECOMPENSATED HF (ADHF)

Drugs Used in Hospital (IV Setting)

Mnemonic: "Dobutamine = DOn't raise BP (dilates)" | "Dopamine = DOse matters"

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DRUGS TO AVOID IN HF

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QUICK SUMMARY TABLE - EXAM-READY

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🏆 TOP 10 CLINICAL PEARLS FOR EXAMS

1. "Captopril on an empty stomach" - only ACE inhibitor where food decreases absorption
2. "The 36-hour rule" - ACE inhibitor must be stopped ≥36h before starting sacubitril/valsartan
3. "BCM for mortality" - only Bisoprolol, Carvedilol, Metoprolol succinate proven in HFrEF
4. "Digoxin + Hypokalemia = Toxicity" - furosemide → ↓K+ → digoxin toxicity (classic trap!)
5. "Ivabradine only works in sinus rhythm" - ineffective in AF for rate control
6. "Spironolactone gynecomastia → switch to eplerenone"
7. "Fosinopril dual elimination" - safe in renal failure (renal + fecal elimination)
8. "Nitroprusside + prolonged use/renal failure = cyanide toxicity" - treat with thiosulfate
9. "Hydralazine-induced lupus" - especially in slow acetylators
10. "SGLT2i reduce interstitial (not intravascular) fluid" - less neurohormonal activation than loop diuretics

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⭐ THE 4 PILLARS OF HFrEF - MORTALITY REDUCERS

A = ARNI (Sacubitril/Valsartan) [or ACEi/ARB if ARNI not tolerated]
B = Beta-blocker (BCM)
M = MRA (Mineralocorticoid Receptor Antagonist)
S = SGLT2 inhibitor

These four together represent the current guideline-directed medical therapy (GDMT) for HFrEF.

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