Heart Failure Pharmacology PDF

Pharmacolo gy Dr.Ola Mohammed M.B.Ch.B/ MSc. Clinical pharmacology Pathophysiology of Heart Failure Heart failure (HF) involves the inability of the heart to pump sufficient blood due to impaired filling and/or ejection capabilities. Major causes include ischemi...

Pharmacolo gy Dr.Ola Mohammed M.B.Ch.B/ MSc. Clinical pharmacology Pathophysiology of Heart Failure Heart failure (HF) involves the inability of the heart to pump sufficient blood due to impaired filling and/or ejection capabilities. Major causes include ischemic heart disease, hypertension, valvular disorders, arrhythmias, cardiomyopathies, and less commonly, conditions like severe anemia or the use of certain anticancer drugs like doxorubicin. Chronic activation of the sympathetic nervous system (SNS) and renin–angiotensin–aldosterone system (RAAS) results in cardiac remodeling characterized by myocyte loss, hypertrophy, and fibrosis, leading to a decline in heart function. Compensatory Mechanisms in HF  Increased Sympathetic Activity: Low blood pressure activates baroreceptors, which trigger the SNS. This increases heart rate and contraction strength by stimulating β-adrenergic receptors, which raises preload but also the workload on the heart, leading to deterioration over time.  RAAS Activation: Reduced renal blood flow leads to renin release, activating angiotensin II and aldosterone, resulting in vasoconstriction, sodium and water retention, and elevated blood volume. Excessive fluid can cause pulmonary and peripheral edema, alongside harmful remodeling of cardiac tissues.  Natriuretic Peptides: These peptides counteract fluid overload by promoting vasodilation and natriuresis (excretion of sodium in urine), ultimately alleviating symptoms by inhibiting renin and aldosterone release.  Myocardial Dysfunction: Heart muscle stretching increases contraction strength initially, but excessive elongation weakens contractions, leading to systolic failure (HFrEF). In diastolic dysfunction, hypertrophy reduces the heart’s ability to fill, leading to HFpEF. Heart failure symptoms  Pharmacologic treatment of HF Each drug class acts on different aspects of HF physiology to improve outcomes: ↓ Preload and afterload. ↑ Myocardial contractility.  Angiotensin-converting enzyme (ACE) inhibitors ACE inhibitors decrease vascular resistance and venous tone, thus lowering afterload and preload, which improves cardiac output and counteracts angiotensin II-mediated effects. Recommended for all patients with HFrEF, they reduce mortality and morbidity, but should be started at low doses. Most ACE inhibitors are prodrugs activated in the liver. They vary in half-life (2-12 hours), with longer ACE inhibition beyond plasma half-life. Adverse Effects: Include postural hypotension, renal insufficiency, hyperkalemia, cough (due to bradykinin), and angioedema. Regular monitoring of potassium and creatinine is necessary.  Angiotensin receptor blockers (ARBs)  Block angiotensin II receptors, producing similar effects to ACE inhibitors but without raising bradykinin, which reduces cough and angioedema.  ARBs are alternatives for patients who cannot tolerate ACE inhibitors.  Typically given once daily, highly plasma-bound. Losartan is unique with first- pass metabolism producing an active metabolite.  Adverse Effects: Similar to ACE inhibitors, but with lower risks of cough and angioedema.  Mineralocorticoid Receptor Antagonists (MRAs)  MRAs, like spironolactone, inhibit aldosterone, reducing sodium retention and cardiac remodeling. Decrease mortality.  Indicated for symptomatic HFrEF patients, especially post-myocardial infarction.  Adverse Effects: Hyperkalemia is a major risk, along with endocrine side effects like gynecomastia from spironolactone.  Angiotensin Receptor–Neprilysin Inhibitor (ARNIs) (Sacubitril/valsartan)  Neprilysin is the enzyme responsible for breaking down vasoactive peptides, such as angiotensin I and II, bradykinin, and natriuretic peptides.  Combining ARBs with neprilysin inhibitors, leading to increased natriuretic peptides and reducing angiotensin II’s harmful effects without further potentiating bradykinin. Together, the combination decreases afterload, preload, and myocardial fibrosis.  Recommended as a replacement for ACE inhibitors in symptomatic HFrEF patients on optimal therapy.  Adverse Effects: Similar to ACE inhibitors, with a higher risk of hypotension. Not recommended for patients with a history of angioedema.  Beta-Blockers (Bisoprolol, Carvedilol, and Metoprolol succinate)  These drugs mitigate harmful SNS activation, preventing norepinephrine-induced cardiac remodeling. Carvedilol, a non-selective blocker, also has α-blocking and antioxidant properties, adding to its benefits.  Recommended for chronic HFrEF and some HFpEF patients requiring heart rate control.  Gradual dose increase is crucial to avoid adverse effects.  Adverse Effects: Possible worsening of HF symptoms at the start; gradual dosing is important.  Diuretics  Diuretics, especially loop diuretics like furosemide, reduce plasma volume and preload, relieving symptoms of fluid overload.  Primarily for symptom management in fluid-overloaded HF patients.  Adverse Effects: Risks include dehydration, hyponatremia, and hypokalemia, so regular electrolyte monitoring is essential.  Hyperpolarization-activated cyclic nucleotide-gated channel blocker : HCN blocker  Ivabradine selectively slowing the If current in the SA node, reducing heart rate without affecting contractility , AV conduction, ventricular repolarization, or blood pressure.  Used in HFrEF for patients with a heart rate above 70 BPM who are on optimized therapy, especially if beta-blockers are not tolerated.  Adverse Effects: Bradycardia and Because ivabradine is mostly selective for the SA node, it is not effective for rate control in atrial fibrillation and has been shown to increase the risk of atrial fibrillation. Ivabradine inhibits similar channels in the eye, and luminous phenomena (for example, brightness or halos) may occur.  Vaso- and Venodilators  Venous dilators (e.g., nitrates , nitroprusside ) reduce preload, while arterial dilators (e.g., hydralazine) decrease afterload.  For patients who cannot tolerate ACE inhibitors/ARBs or need additional vasodilation.  Adverse Effects: Include headache, dizziness, and, for hydralazine, a risk of drug-induced lupus erythematosus.  SODIUM-GLUCOSE COTRANSPORTER 2 INHIBITORS SGLT2 Inhibitors  SGLT2 inhibitors (Dapagliflozin and empagliflozin) reduce plasma volume through glucosuria and natriuresis, thereby lowering preload and afterload. SGLT2 inhibitors may also preventing cardiac fibrosis. SGLT2 inhibitors like dapagliflozin reduce HF hospitalizations and mortality in patients with HFrEF.  Adverse Effects: Include volume depletion, renal issues, and urogenital infections.  Additional monitoring is needed for hypoglycemia when used with insulin or sulfonylureas.  Inotropic Drugs  Increase cardiac contractility via enhanced intracellular calcium. They are typically reserved for acute, severe HF due to their association with increased mortality in long-term use. 1.Cardiac glycosides are often called digitalis or digitalis glycosides, because most of the drugs come from the digitalis (foxglove) plant. The only available agent is digoxin. Inhibits Na+/K+ ATPase, increasing calcium and contractility. It’s mainly used in symptomatic HFrEF and atrial fibrillation. Vagal tone is also enhanced, so both heart rate and myocardial oxygen demand decrease. Digoxin slows conduction velocity through the AV node, making it useful for atrial fibrillation. A low serum drug concentration of digoxin (0.5-0.9 ng/mL) is beneficial in HFrEF. It is mainly eliminated intact by the kidney, requiring dose adjustment in renal dysfunction. Digoxin has a narrow therapeutic range, requiring careful dosing and monitoring due to risks of toxicity and arrhythmias. Anorexia, nausea, vomiting, blurred vision, or yellowish vision may be initial indicators of toxicity. Decreased levels of serum potassium (hypokalemia) predispose a patient to digoxin toxicity, because digoxin normally competes with potassium for the same binding site on the Na +/K+- ATPase pump. Digoxin should also be used with caution with other drugs that slow AV conduction , such as B- blockers, verapamil, and diltiazem. Digitalis toxicity Causes 1. High dose of digoxin. 2. Hypokalemia (digitalis compete with K+ for na+ /K+ ATPase). 3. By using enzyme inhibitor drugs. Rx K+, atropine for bradycardia, phenytoin for arrhythmia, metoclopramide for vomiting ,rehydration , digibind: fractionated antibody that bind digoxin and remove it by urine. 2. Phosphodiesterase inhibitors Milrinone is a phosphodiesterase inhibitor that increases the intracellular concentration of cAMP. Like B-adrenergic agonists, this results in an increase of intracellular calcium and, therefore, cardiac contractility. Milrinone is usually given for short-term treatment of acute decompensated HF with low cardiac output. [Note: Milrinone can also reduce pulmonary vasculature resistance, making it useful for acute treatment of pulmonary hypertension and right heart failure.] 3. B-Adrenergic agonists, such as dobutamine and dopamine , improve cardiac performance by causing positive inotropic effects and vasodilation (in the case of dobutamine). B-Adrenergic agonists ultimately lead to increased entry of calcium ions into myocardial cells and enhanced contraction. Both drugs must be given by intravenous infusion and are primarily used in the short-term treatment of acute decompensated HF Soluble guanylate cyclase stimulators Vericiguat directly stimulates sGC and sensitizes sGC to endogenous NO. NO diffuses through cells to stimulate sGC to synthesize cGMP. An increase in cGMP improve left ventricular compliance, vasodilate, reduce inflammation, and prevent hypertrophy and fibrosis. Vericiguat is contraindicated in pregnancy due to an increased risk of cardiac malformations and should not be used in breast-feeding. Use of vericiguat should be avoided with nitrates or phosphodiesterase inhibitors due to the risk of excessive hypotension. Acute vs. Chronic HF Management  Chronic HF: Managed through lifestyle modifications (fluid and sodium restriction) and optimized drug combinations. HFpEF treatment emphasizes RAAS and SNS inhibitors, while HFrEF often requires multiple drug classes.  Acute Decompensated HF: Short-term treatment may involve inotropes and intravenous vasodilators in a hospital setting for rapid stabilization. Drugs known to worsen HF, like NSAIDs, should be avoided.