Drugs used in Heart Failure Ass.Prof. Dr.Naza M. Ali Lec. 5-6 G2 May 5 2019 G1 May 8 2019

Heart Failure Occurs when cardiac output is inadequate to provide the oxygen needed by the body. It is frequently associated with Chronic hypertension, Valvular disease, Coronary artery disease

The primary defect Is a reduction of cardiac contractile force & reduced ejection fraction that is detected during systole ( Systolic Failure) 2. Is stiffening or other changes of the ventricles that prevent adequate filling during diastole (Diastolic Failure) 3. A combination of systole and diastolic dysfunction

Sings and Symptoms

Compensatory Physiological Responses in HF The failing heart evokes 3 major compensatory mechanisms to enhance cardiac output: Increased sympathetic activity 2. Activation of the renin-angiotensin system 3. Myocardial hypertrophy

Cardiovascular consequences of heart failure.

Preload volume of blood before contraction, end diastolic volume. Afterload volume of blood in the ventricle, end systolic volume

Cardiac Output Stroke volume (SV): the volume of blood pumped from one ventricle of the heart with each beat

Some compensatory responses that Sympathetic discharge facilitates: Renin release, Angiotensin II increases NE release by sympathetic nerve endings ( dashed arrows ). Some compensatory responses that occur during congestive heart failure.

Frank-Starling curves 1. Normally as preload increases, cardiac performance increases. at a certain point, performance plateaus, then declines. 2. In HF due to systolic dysfunction the overall curve shifts downward, reflecting reduced cardiac performance at a given preload, and, as preload increases, there is less of an increase in cardiac performance. 3. With treatment performance is improved, although not normalized.

Therapeutic strategies in HF Chronic HF is typically managed by: Reduction in physical activity low dietary intake of sodium Use of diuretics, Inhibitors of the renin angiotensin system, Inotropic agents.

exacerbate HF should be avoided : Drugs that may precipitate or exacerbate HF should be avoided : NSAIDs Alcohol Calcium-channel blockers High dose β-blockers Some antiarrhythmic drugs

Drugs used in heart failure: Positive Inotropic Drugs 2. Direct Vasodilators 3. Miscellaneous drugs for chronic failure

1. Positive Inotropic Drugs Cardiac Glycosides Beta Agonist PDE Inhibitors 2. Direct Vasodilators Isosorbide dinitrate Hydralazine Nitroprusside 3.Miscellaneous drugs ACE inhibitors ARBs Diuretics & Aldosterone antagonists Beta blockers Drugs used in Heart Failure

Drugs used in heart failure Positive Inotropic Drugs Cardiac Glycosides ( Digoxin, Digitoxin ) Beta Agonists ( Dobutamine, Dopamine ) PDE Inhibitors( Inamrinone, Milrinone)

2. Direct Vasodilators Isosorbide dinitrate ( Venous dilator ) Hydralazine ( Arteriolar dilator ) Nitroprusside ( Both arteriolar & venous dilator)

3. Miscellaneous drugs for chronic failure Angiotensin Antagonists Diuretics & Aldosterone antagonists Beta blockers While Nesiritide is used in acute heart failure

1. Positive Inotropic Drugs: Cardiac Glycosides Digoxin is the prototype, Digitoxin Mechanism of action Inhibition of Na + /K + ATPase which results in small increase in intracellular sodium. And the concentration gradient across the membrane decreased This alter the driving force for sodium –calcium exchange by the exchanger, so less calcium is removed from the cell. The increase intracellular calcium is stored in sarcoplasmic reticulum and upon release increase contractile force.

Mechanism of action of digoxin. ATPase = adenosine triphosphatase

Cardiac Effects Mechanical effects The increase contractility lead to: ↑ ventricular ejection, ↓ end systolic & end diastolic size, ↑ cardiac output & ↑ renal perfusion. These effects permit a decrease in the compensatory sympathetic and renal responses. The decrease in sympathetic tone mean : reduced heart rate, preload & afterload permit the heart to function more efficiently.

2. Electrical effects Early responses Increased PR interval ,flattening of the T wave in ECG The effects on the atria and AV node are largely parasympathetic (mediated by vagus nerve) and can partially blocked by atropine.

b. Toxic responses Increased automaticity, due to intracellular calcium overload (is the most important manifestation of digitalis toxicity). Intracellular calicum overload result in delayed after depolarazations , may evoke extrasystoles, tachycardia, or fibrillation in any part of the heart.

Tissue Effects at therapeutic Dosage Effects at toxic Dosage Sinus node  Rate Atrial muscle  Refractory period Refractory period, arrhythmias Atrioventricular node Conduction velocity,  Refractory period Refractory period, Arrhythmias Electrocardiogram  PR interval Tachycardia , Fibrillation , arrest at extremely high dosage

Because cholinergic innervation is much richer in the atria, these actions affect atrial and AV nodal function more At toxic levels, sympathetic outflow is increased by digitalis.

Clinical Uses Congestive heart failure Atrial fibrillation

Pharmacokinetics Oral bioavailability of 60%-75% Widely distributed to tissues, & CNS Half-life is 36–40 hrs in normal renal function. Elimination by renal excretion 60% and hepatic metabolism 40%

Adverse effects: Digoxin levels must be closely monitored in the presence of renal insufficiency, and dosage adjustment may be necessary. Severe toxicity resulting in ventricular tachycardia may require administration of antiarrhythmic drugs Use of antibodies to digoxin (digoxin immune Fab), which bind and inactivate the drug.

Cardiac effects: GIT effects: CNS effects: Arrhythmia characterized by slowing of AV conduction A decrease in intracellular potassium is the primary predisposing factor in these effects. GIT effects: Anorexia, nausea, and vomiting CNS effects: headache, fatigue, confusion, blurred vision, alteration of color perception

Factors predisposing to digoxin toxicity: a. Electrolytic disturbances: Hypokalemia can precipitate serious arrhythmia. in patients receiving thiazide or loop diuretics, prevented by use a potassium- sparing diuretic Hypomagnesemia Hypercalcemia

b. Drugs: Quinidine, Verapamil, Amiodarone, displacing digoxin from tissue protein-binding sites & by competing with digoxin for renal excretion. Corticosteroids, Hypothyroidism, Hypoxia, Renal failure increase digoxin toxicity

β-Adrenergic agonists Dobutamine Dopamine ( IV infusion in acute failure) β-Adrenergic stimulation causing positive inotropic effects and vasodilation. Dobutamine leads to an increase intracellular cAMP

Phosphodiesterase inhibitors Inamrinone Milrinone increase the intracellular concentration of cAMP by inhibiting its breakdown by phosphodiesterase This results in an increase of intracellular calcium PDE inhibitors cause vasodilation

2. Direct Vasodilators Nitrates are commonly used venous dilators for patients with congestive HF and reduces preload Hydralazine decreases afterload, [Note: Calcium-channel blockers should be avoided in patients with HF.]

3. Miscellaneous drugs for chronic failure ACE inhibitors ACE inhibitors are the agents of choice in HF. Decrease vascular resistance, venous tone, and BP Reduce preload and afterload, increased cardiac output ACE inhibitors decreased both morbidity and mortality. Enalapril reduces arrhythmic death, MI & strokes.

Effects of ACE inhibitors

The presence of food may decrease absorption, they should be taken on an empty stomach. Except for captopril , ACE inhibitors are pro-drugs that require activation by hydrolysis via hepatic enzymes.

ARBs ( Inhibit AT1R) Competitive antagonists of angiotensin type 1 receptor. Losartan is the prototype drug Candesartan Telmisartan Valsartan All are orally active & require once-a-day Except Valsartan used twice daily Losartan differs from the others in that it undergoes extensive first-pass hepatic metabolism.

Diuretics Diuretics relieve pulmonary congestion & peripheral edema. Diuretics decrease plasma volume and decrease venous return to the heart (preload). This decreases the cardiac workload and the oxygen demand. Loop diuretics are commonly used diuretics in HF.

Aldosterone Antagonists Spironolactone is a direct antagonist of aldosterone preventing salt retention, myocardial hypertrophy, hypokalemia.

Adverse effects GIT ( gastritis & peptic ulcer) CNS effects ( lethargy & confusion). Endocrine abnormalities ( gynecomastia, decreased libido, menstrual irregularities).

Eplerenone Is a competitive antagonist of aldosterone at mineralocorticoid receptors. Eplerenone has a lower incidence of endocrine related side effects due to its reduced affinity for glucocorticoid, androgen, and progesterone receptors.

Beta Blockers The benefit of β-blockers is attributed, 1. to their ability to prevent the changes that occur because of chronic activation of the SNS, decrease heart rate and inhibit release of renin. β-blockers prevent the deleterious effects of NE on the cardiac muscle fibers, decreasing remodeling, hypertrophy & cell death.

Three β-blockers have shown benefit in HF: Bisoprolol ,Carvedilol , Metoprolol succinate reduce morbidity and mortality associated with HF Treatment should be started at low doses and gradually titrated to target doses based on patient tolerance and vital signs. Both carvedilol and metoprolol are metabolized by the CYP P450 ( 2D6 isoenzyme), and inhibitors of this metabolic pathway may increase levels of these drugs and increase the risk of adverse effects.