MPP2 2024 Lecture 09 Heart Failure Drugs PDF

Heart Failure Drugs Lecture 09 Richard Klabunde, PhD Professor of Physiology MUCOM 1 Learning objectives Describe major cardiovascular, pulmonary and renal complications of heart failure Describe the therapeutic targets and goals for tre...

Heart Failure Drugs Lecture 09 Richard Klabunde, PhD Professor of Physiology MUCOM 1 Learning objectives Describe major cardiovascular, pulmonary and renal complications of heart failure Describe the therapeutic targets and goals for treating heart failure Describe how each of the following classes of drugs is used to treat heart failure, and provide examples of specific drugs: ○ Vasodilator drugs RAAS inhibitors (ACE inhibitors, ARBs, aldosterone antagonists) Direct acting vasodilator drugs ○ Beta–blockers ○ Cardiostimulatory (inotropic) drugs ○ Diuretics ○ SGLT2 inhibitors Drug treatment in acute versus chronic heart failure Treating HFrEF vs. HFpEF 2 Learning resources Guided Learning: Heart Failure at cvpharmacology.com Links found on slides 3 Cardiovascular, pulmonary and renal signs and symptoms of heart failure Reduced cardiac output and organ perfusion Reduced exercise tolerance Dyspnea ○ Pulmonary edema ○ Impaired lung gas exchange Fluid retention (increased blood volume) ○ Renal sodium retention ○ RAAS activation and increased vasopressin Elevated systemic vascular resistance ○ Sympathetic activation Cardiac remodeling Arrhythmias 4  Therapeutic goals The goal of drug therapy in heart failure is to improve cardiac function and reduce the clinical symptoms associated with heart failure, thereby decreasing morbidity and mortality If possible, correct underlying problem (e.g., valve disease, CAD, arrhythmias) Reduce clinical symptoms and morbidity ○ Pulmonary congestion & edema ○ Systemic edema ○ Dyspnea ○ Arrhythmias Improve cardiovascular function ○ Improve organ perfusion ○ Increase cardiovascular functional reserve Reduce mortality 5 Drug treatment – physiological targets Renin-angiotensin-aldosterone system ○ ACEIs, ARBs & ARNIs given to reduce afterload, preload; blood volume; remodeling Cardiac sympathetic activation ○ Beta-blockers given to reduce remodeling & arrhythmias Volume overload and edema ○ Diuretics given to reduce blood volume, venous pressures, preload, and edema Improving cardiac metabolic function ○ SGLT2 inhibitors 6  Vasodilators RAAS inhibitors, neprilysin inhibitors, and direct acting arterial and venous dilators 7 Vasodilator effects on Frank-Starling curves Mixed (reduces afterload & preload) ○ ACE inhibitors ○ AII receptor blockers (ARBs) ○ Sodium nitroprusside (acute failure; iv) ○ NEP (neutral endopeptidase) inhibitors Arterial (reduces afterload) ○ Hydralazine (more effective when combined with venodilator) Venous (reduces preload) ○ Isosorbide dinitrate (acute failure) 8 Reducing afterload in patients with systolic dysfunction Reducing afterload with an arterial vasodilator drug leads to: ○ ↓↓ ESV ○ ↓ EDV ○ ↑ SV ○ ↑ EF (from 25 to 33% in figure) Failing hearts are more responsive to afterload changes than normal hearts 9 Specific drugs: ACE inhibitors MOA: Block formation of angiotensin II Actions ○ Dilate arteries & veins ○ Diuresis ○ Down regulate sympathetic nerves (central & peripheral actions) ○ Decrease vasopressin release ○ Attenuate cardiac remodeling Examples: ○ lisinopril ○ enalapril 10 Specific drugs: ARBs Block angiotensin II (AT1) receptors (vascular, cardiac, renal, ANS) Actions are similar to ACEIs Examples ○ valsartan ○ losartan 11 Specific drugs: neprilysin inhibitors Neprilysin is an enzyme that breaks down ANP; therefore, inhibition increases circulating ANP, which attenuates the RAAS system and dilates vessels Sacubitril, which inhibits neprilysin, is combined with an ARB (valsartan) when used to treat acute heart failure ○ The combination is called an ARNI (angiotensin receptor neprilysin inhibitor) https://cvphysiology.com/blood-pressure/bp017 12 Specific drugs: hydralazine and isosorbide dinitrate Hydralazine ○ Direct acting, arterial vasodilator Reduces afterload ○ MOA: K+ channel opening; may inhibit vascular SR Ca++ release Isosorbide dinitrate ○ Nitrodilator that primarily dilates veins Reduces preload ○ MOA: increases vascular NO and cGMP 13 Beta-blockers 14 Beta-blockers in CHF Traditionally (20th century), β-blockers were contraindicated in CHF Efficacy demonstrated in clinical trials with newer β-blockers (significant reductions in risk of hospitalization and death) Produce reverse remodeling associated with heart failure; decrease chamber size and increase EF ○ Benefit observed after several months Usually used with a diuretic, ACE inhibitor 15 Beta-blockers in CHF cont. Specific drugs ○ Carvedilol Combined α1 & β-blocker ○ Metoprolol β1 blocker Rationale ○ Excessive beta-adrenergic stimulation in CHF down regulates β1 receptors, thereby reducing inotropic reserve ○ Excessive sympathetic activation contributes to hypertrophy and dysfunctional changes in signal transduction mechanisms ○ Antiarrhythmic benefit 16 Diuretics 17 Diuretics Increase Na+ and H2O excretion by the kidneys Actions ○ ↓ blood volume & CVP ○ ↓ ventricular preload ○ ↓ pulmonary & systemic edema ○ ↓ SVR (chronic therapy) Little effect on ventricular stroke volume and cardiac output unless overdosed 18 https://cvpharmacology.com/diuretic/diuretics 19 Diuretics Furosemide (loop diuretic) is the primary diuretic used in CHF Less potent thiazide diuretics are sometimes used in mild CHF Potential problems ○ K+ loss (loop and thiazide diuretics) ○ Excessive volume reduction Spironolactone & eplerenone* ○ Aldosterone antagonists acting on renal distal tubular segments ○ K+-sparing diuretic (prevents K+ loss) ○ Reduce mortality when used with ACE inhibitor and loop diuretic ○ *post-MI CHF 20 Cardiostimulatory (inotropic) drugs Beta-agonists, PDE inhibitors, and digoxin 21 Cardiostimulatory (inotropic) drugs Drug Classes Sympathomimetics Phosphodiesterase inhibitors (inodilators) Cardiac glycosides (digoxin) NOTE: Except for digoxin, these drug classes are used only for refractory, late-stage heart failure and acute cardiogenic shock 22 Sympathomimetics Sympathomimetics mimic the effects of sympathetic activation by stimulating beta-adrenoceptors Only used in acute failure – not chronic failure, except at end-stage Beta-agonists increase ○ cAMP ○ Ca++ influx ○ SR release of Ca++ ○ TN-C binding of Ca++ ○ SR reuptake of Ca++ 23 Sympathomimetics Dopamine Immediate precursor for norepinephrine synthesis in sympathetic nerve terminals dopamine β-hydroxylase dopamine norepinephrine Receptor affinity: β1 = β2 > α1 Acute heart failure, cardiogenic shock and acute renal failure (via DA1 activation) I.V. only; very short half-life (few minutes) 24 Dopamine cont Low doses: ○ Systemic vasodilation (β2-adrenoceptor); may cause renal vasodilation (DA1) ○ Positive inotropy and chronotropy caused by β1 activation High doses: ○ α1-mediated vasoconstriction, which increases systemic resistance and produces hypertension. Arrhythmogenic potential 25 Dobutamine (dopamine analog) Receptors: primarily β1-adrenoceptors Acute heart failure; cardiogenic shock; refractory heart failure I.V. only; very short half-life (~2 min) Loss of efficacy with β1-receptor down regulation Arrhythmogenic potential Data from Class IV, decompensated patients show increased 6-month mortality compared to placebo 26 Note: Sympathomimetic inotropic drugs increase cardiac output and reduce preload; however, they are proarrhythmic Sympathomimetic inotropic drugs are used only in acute decompensated heart failure, not chronic heart failure 27 Inodilators – phosphodiesterase (PDE3) inhibitors Milrinone (and inamrinone) MOA: Increases cAMP in the heart and vasculature Actions: ○ Systemic vasodilation ○ Mild-to moderate positive inotropy ○ Tachycardia Acute heart failure only Increases mortality in chronic failure Milrinone x Arrhythmogenic potential 28 Cardiac glycosides (digoxin) Inhibits Na+/K+-ATPase, which increases intracellular Ca++ through the Na+/Ca++ exchanger Stimulates inotropy; increases ejection fraction Decreases heart rate (parasympathomimetic effect) Inhibits sympathetic activity Low therapeutic index (