Heart Failure 2024 Zarqa University PDF

Zarqa University Pharmacy school Clinical Pharmacy Department Pharmacology I Drugs Used in Heart Failure Dr. Haneen Basheer Dr. Shorouk Ibraheem 1ST semester 2023/2024 The normal blood cycle  Definitions Heart failure...

Zarqa University Pharmacy school Clinical Pharmacy Department Pharmacology I Drugs Used in Heart Failure Dr. Haneen Basheer Dr. Shorouk Ibraheem 1ST semester 2023/2024 The normal blood cycle  Definitions Heart failure (HF) is a progressive clinical syndrome that can result from any changes in cardiac structure or function that impair the ability of the ventricle to fill with or eject blood. Heart failure (HF) is a complex, progressive disorder in which the heart is unable to pump sufficient blood to meet the needs of the body.(Unable to provide the oxygen level needed to the body) HF may be caused by an abnormality in systolic function, diastolic function, or both. The leading causes of HF are coronary artery disease and hypertension. The primary manifestations of the syndrome are dyspnea, fatigue, and fluid retention.  Heart Failure can be classified into: High-output heart (physiological): is an increase in the body’s metabolic demands that rises an increase in cardiac output (CO) of a generally normally functioning heart. low-output heart (pathological): low CO secondary to impaired cardiac function. The term heart failure refers to low-output HF. 4  Types of HF 1. Heart failure with reduced ejection fraction. (HFrEF) 2. Heart Failure with preserved ejection fraction. (HFpEF) Cases are due to a reduction of cardiac contractile force and ejection fraction (systolic failure) (ie, reduced left ventricular ejection fraction [LVEF]), now referred to as heart failure with reduced ejection fraction (HFrEF), was previously thought to be the sole disturbance in cardiac function responsible for HF. Other cases: changes of the ventricles that prevent adequate filling during diastole; ejection fraction may be normal (diastolic failure) - Many patients with HF syndrome have relatively normal systolic function (ie, normal LVEF). This is now referred to as HF with preserved LVEF (HFpEF). The remainder of cases can be attributed to a combination of systolic and diastolic dysfunction.  Cont Historically, this disorder was commonly referred to as congestive HF; the preferred nomenclature is now HF since a patient may have the clinical syndrome of HF without having symptoms of congestion.  Acute heart failure The term acute heart failure (AHF) is used to signify either an acute decompensation of a patient with a history of chronic HF or to refer to a patient presenting with new-onset HF symptoms. Complications of heart failure, particularly acute heart failure, include respiratory and/or renal failure.  Pathophysiology of HF The primary signs & symptoms of all types of HF include: - Tachycardia. Why? - Decreased exercise tolerance. - Shortness of breath. - Cardiomegaly. - Peripheral & pulmonary edema (the congestion of congestive heart failure) are often but not always present.  Decreased exercise tolerance with rapid muscular fatigue is the major direct consequence of diminished cardiac output.  The other manifestations result from the attempts by the body to compensate for the intrinsic cardiac defect. The homeostatic responses to depressed cardiac output are extremely important and are mediated mainly by the sympathetic nervous system and the renin-angiotensin-aldosterone system.  The result is a vicious cycle that is characteristic of heart failure. Apoptosis is a later response,and results in a reduction in the number of functioning myocytes  Goals of Treatment: 1) Reducing symptoms & slowing progression as much as possible during relatively stable periods 2) Managing acute episodes of decompensated failure.  HF drugs ARB, ARNI hydralazine and isosorbide dinitrate Chronic NA glucose cotransporter inhibitors / What are the approved drugs/  Treatment Considerable evidence indicates that renin- angiotensin system (RAS), certain β- adrenoceptor blockers, and the aldosterone antagonists spironolactone and eplerenone, a sodium-glucose cotransporter 2 (SGLT2) inhibitor have long-term beneficial effects.  Chronic failure Pharmacologic therapies for heart failure include: 1. the removal of retained salt and water with diuretics (loop is most required) 2. reduction of afterload and salt and water retention by means Renin-angiotensin System Inhibitors (ACEI,ARB, ARNI angiotensin receptor-neprilysin inhibitor) 3. reduction of excessive sympathetic stimulation by means of β blockers 4. reduction of preload or afterload with vasodilators (hydralazine and isosorbide dinitrate ) 5. a sodium-glucose cotransporter 2 (SGLT2) inhibitor: give SGLT2 inhibitors to patients with symptomatic chronic HFrEF to decrease cardiovascular mortality and hospitalization for heart failure irrespective of the presence of type 2 diabetes 6. Mineralocorticoid receptor antagonist (MRA) if estimated glomerular filtration rate (eGFR) is > 30 mL/min/1.73 m2 and serum potassium is < 5 mEq/L 7. In systolic failure, direct augmentation of depressed cardiac contractility with positive inotropic drugs such as digitalis glycosides.  Acute Failure Current clinical evidence suggests that acute heart failure should be treated with a loop diuretic; if severe, a prompt-acting positive inotropic agent such as a β agonist or phosphodiesterase inhibitor, and vasodilators should be used as required to optimize filling pressures and blood pressure. Nesiritide, a recombinant form of brain natriuretic peptide (BNP), has vasodilating and diuretic properties and has been heavily promoted for use in acute failure.  Drugs without positive inotropic effect First-line therapies for chronic heart failure Are directed at non-cardiac targets is more valuable in the long-term treatment of HF than traditional positive inotropic agents  Inhibitor of the renin-angiotensin system (RAS) These agents have been shown to reduce morbidity and mortality in chronic heart failure. Although they have no direct positive inotropic action, angiotensin antagonists reduce aldosterone secretion, salt and water retention, and vascular resistance 1ST line IF show NO signs or symptoms of volume overload (edema) ACE inhibitors may be used in combination with diuretics, β- blockers, digoxin, and aldosterone antagonists. Patients with recent myocardial infarction also benefit from ACEI. It is recommended that ACE inhibitors be initiated immediately after myocardial infarction  ARNI modulation of the natriuretic peptide system is inhibition of the neutral endopeptidase enzyme, neprilysin, which is responsible for the degradation of BNP and atrial natriuretic peptide (ANP), as well as angiotensin II, bradykinin, and other peptides. Sacubitril is a prodrug that is metabolized to an active neprilysin inhibitor plus an ARB. A combination of valsartan plus sacubitril has recently been approved for use in HFrEF.  Diuretics Are the first-line therapy for both systolic and diastolic failure and are used in heart failure before digitalis and other drugs are considered*. (if symptoms of fluid retention present) Reduce the symptoms of volume overload, including orthopnea and paroxysmal nocturnal dyspnea. Decrease preload and afterload**. Furosemide is a very useful agent for immediate reduction of the pulmonary congestion and severe edema associated with acute heart failure and for moderate or severe chronic failure. Thiazides such as hydrochlorothiazide are sometimes sufficient for mild chronic failure. Clinical studies suggest that, unlike other diuretics, spironolactone and eplerenone (aldosterone antagonist diuretics) have significant long-term benefits and can reduce mortality in chronic failure.  Beta-Adrenoceptor Antagonists Beta blockers (carvedilol, bisoprolol, ER metoprolol succinate, (Chapter 10) have been shown in long-term studies to slow progression of chronic heart failure. The benefit is recognized in patients with hypertrophic cardiomyopathy but has also been shown to occur in patients without cardiomyopathy. Beta blockers are of no value in acute failure and may be detrimental if systolic dysfunction is marked β-Blockade is recommended for all patients with heart disease except those who are at high risk but have no symptoms and those who are in acute HF.  Vasodilator Chronic heart failure sometimes responds favorably to oral vasodilators such as hydralazine or isosorbide dinitrate (or both) this combination has been shown to reduce mortality due to heart failure in African Americans. If the patient is intolerant of ACE inhibitors or β- blockers, or if additional vasodilator response is required Calcium channel blockers (eg, verapamil) are of no value in heart failure.  Digitalis Is the genus name for the family of plants that provide most of the medically useful cardiac glycosides , e.g, digoxin (prototype). All of the cardiac glycosides combine a steroid nucleus linked to a lactone ring at the 17 position and a series of sugars at carbon 3 of the nucleus. Because they lack an easily ionisable group, their solubility is not pH- dependent. Common Foxglove  Pharmacokinetics - Digoxin, the only cardiac glycoside used in the USA. - is 65–80% absorbed after oral administration. - Absorption of other glycosides varies from zero to nearly 100%. - Once present in the blood, all cardiac glycosides are widely distributed to tissues, including the CNS. - Digoxin is not extensively metabolized in humans. - Almost 2/3 is excreted unchanged by the kidneys. - Its renal clearance is proportional to creatinine clearance. - Half-life is 36–40 h in patients with normal renal function. - Need to adjust digoxin dosage in patients with renal impairment.  Pharmacodynamics – MECHANISM OF ACTION At the molecular level, all therapeutically useful cardiac glycosides inhibit Na+/K+ - ATPase, the membrane-bound transporter often called the sodium pump. This inhibitory action is largely responsible for the therapeutic effect (Positive Inotropy) as well as a major portion of the toxicity of digitalis. harmacodynamics – SYSTEM ORGAN EFFECT A. Cardiac Effects 1. Mechanical effects: Cardiac glycosides increase contraction of the cardiac sarcomere by increasing the free [Ca+2] in the vicinity of the contractile proteins during systole. The increase in [Ca+2] is the result of a two-step process: 1) an increase of intracellular [Na+] because of Na+/K+-ATPase inhibition 2) a relative reduction of calcium expulsion from the cell by the Na+/ Ca+2Exchanger caused by the increase in intracellular Na+. The increased cytoplasmic Ca+2 is sequestered by SERCA in the SR for later release. The net result of the action of therapeutic concentrations of a cardiac glycoside is a distinctive increase in cardiac contractility. +ve inotropic effect.  The increase in contractility evoked by digitalis results in increased ventricular ejection, decreased end-systolic and end-diastolic size, increased cardiac output, and increased renal perfusion Decrease in the compensatory sympathetic and renal responses previously described. Reduced heart rate, preload, and afterload permit the heart to function more efficiently 2. Electrical effects: The effects of digitalis on the electrical properties of the heart are a mixture of direct & autonomic actions: Direct actions on the membranes of cardiac cells follow a well- defined progression: an early, brief prolongation of the action potential, followed by shortening (especially the plateau phase).  The decrease in action potential duration is probably the result of increased K+ conductance that is caused by increased intracellular Ca+2. All these effects can be observed at therapeutic concentrations in the absence of overt toxicity. - At higher concentrations, resting membrane potential is reduced (made less negative) as a result of inhibition of the sodium pump and reduced intracellular potassium. As toxicity progresses, oscillatory depolarizing afterpotentials appear following normally evoked action potentials. -The afterpotentials (also known as delayed after-depolarizations, DADs) are associated with overloading of the intracellular Ca+2 stores and oscillations in the free intracellular [Ca+2]. -When afterpotentials reach threshold, they elicit action potentials (premature depolarizations, ectopic “beats”) that are coupled to the preceding normal action potentials. - If afterpotentials in the Purkinje conducting system regularly reach threshold in this way, bigeminy will be recorded on the ECG. With further intoxication, each after potential-evoked action potential will itself elicit a suprathreshold after-potential, and a self-sustaining tachycardia will be established. If allowed to progress, such a tachycardia may deteriorate into fibrillation; in the case of ventricular fibrillation, the arrhythmia will be rapidly fatal unless corrected. Autonomic actions of cardiac glycosides on the heart involve both the parasympathetic & the sympathetic systems: In the lower portion of the dose range, cardioselective parasympathomimetic effects predominate. In fact, these atropine-blockable effects account for a significant portion of the early electrical effects of digitalis  This action involves sensitization of the baroreceptors, central vagal stimulation, and facilitation of muscarinic transmission at the cardiac muscle cell. Because cholinergic innervation is much richer in the atria, these actions affect atrial and atrioventricular nodal function more than Purkinje or ventricular function. Some of the cholinomimetic effects are useful in the treatment of certain arrhythmias.  At toxic levels, sympathetic outflow is increased by digitalis. This effect is not essential for typical digitalis toxicity but sensitizes the myocardium & exaggerates all the toxic effects of the drug. The most common cardiac manifestations of digitalis toxicity include AV junctional rhythm, premature ventricular depolarizations, bigeminal rhythm, & second-degree AV blockade. However, it is claimed that digitalis can cause virtually any arrhythmia. B. Effects on Other Organs Cardiac glycosides affect all excitable tissues, including smooth muscle & the CNS. The GIT is the most common site of digitalis toxicity outside the heart. effects include anorexia, nausea, vomiting, & diarrhea.  This toxicity is caused in part by direct effects on the GIT & in part by CNS actions. CNS effects include vagal & chemoreceptor trigger zone stimulation. Less often, disorientation and hallucinations— especially in the elderly—and visual disturbances are noted. - Gynecomastia is a rare effect reported in men taking digitalis. C. Interactions with K+, Ca+2, and Mg+2 K+ & digitalis interact in two ways: 1. They inhibit each other’s binding to Na+/K+ -ATPase; therefore, hyperkalemia reduces the actions of cardiac glycosides, whereas hypokalemia facilitates these actions. 2. Abnormal cardiac automaticity is inhibited by hyperkalemia  Moderately increased extracellular K+ therefore reduces the effects of digitalis, especially the toxic effects. Ca+2 facilitates the toxic actions of cardiac glycosides by accelerating the overloading of intracellular Ca+2 stores that appears to be responsible for digitalis-induced abnormal automaticity. Hypercalcemia therefore increases the risk of a digitalis-induced arrhythmia. The effects of Mg+2 ion are opposite to those of Ca+2. These interactions mandate careful evaluation of serum electrolytes in patients with digitalis- induced arrhythmias. Digitalis toxicity, especially arrhythmogenesis, is increased by hypokalemia,  Clinical indication of digoxin Digoxin is indicated in patients with heart failure and atrial fibrillation. It is usually given only when diuretics and ACE inhibitors have failed to control symptoms. Only about 50% of patients with when symptoms are mild, slow loading (digitalization) with 0.125–0.25 mg/d is safer and just as effective as the rapid method (0.5–0.75 mg every 8 hours for three doses, followed by 0.125–0.25 mg/d). Contraindication: Ventricular fibrillation  Case Digoxin has a narrow therapeutic window, and its dosing must be carefully managed. The drug’s minimum effective concentration is about 1 ng/mL. About 60% is excreted in the urine; the rest is metabolized in the liver. The normal clearance of digoxin is 7 L/h/70 kg; volume of distribution is 500 L/70 kg; and bioavailability is 70%. If your 70-kg patient’s renal function is only 30% of normal, what daily oral maintenance dosage should be used to achieve a safe plasma concentration of 1 ng/mL?  Ivabradine MOA: selective If sodium channel blockers (eg, ivabradine), reduce cardiac rate by inhibiting the hyperpolarization-activated sodium channel in the sinoatrial node. Consider using ivabradine in symptomatic patients with : HFrEF, in sinus rhythm, ejection fraction ≤ 35% and heart rate ≥ 70 beats/minute who are either intolerant of, or on maximally tolerated beta blockers (presistant tachycardia) Contraindications: Clinically significant hypotension Clinically significant bradycardia Statin