Drugs Used in Heart Failure M Shafiei, PhD Department of Pharmacology

Case Study A 50-year-old man has developed dyspnea with exertion several weeks after a viral illness. This is accompanied by swelling feet and ankles and some increasing fatigue. On physical examination he is found to be mildly short of breath lying down, but feels better sitting upright. Pulse is 105 and regular, and blood pressure is 90/60 mm Hg. An echocardiogram shows a LVEF of about 25%. The diagnosis is dilated cardiomyopathy secondary to viral infection. What treatments are available for the patient? Short of breath: dyspnea Normal LVEF: 50-70%

Congestive Heart Failure (CHF) Heart failure occurs when cardiac output is inadequate to provide the oxygen needed by the body. A 5-year mortality rate is about 50%. The most common cause is coronary artery disease, with hypertension also an important factor.

Types of Heart Failure Low output failure Systolic failure (EF < 40-45%) Diastolic failure High output failure Normal EF: 60%

Heart Failure A progressive disease that is characterized by a gradual reduction in cardiac performance. It is also punctuated in many cases by episodes of acute decompensation, often requiring hospitalization.

Heart Failure Treatment is therefore directed at two somewhat different goals: Reducing symptoms and slowing progression during stable periods Managing acute episodes of decompensated failure

Pathogenesis of Heart Failure Primary defect in early systolic HF resides in excitation-contraction coupling machinery Clinical condition also involves many other organs, including: Baroreceptor reflex Sympathetic nervous system Kidneys Angiotensin II and other peptides (eg, ANP, ET) Aldosterone Apoptosis of cardiac cells Although the primary defect in early systolic heart failure resides in excitation-contraction coupling machinery, clinical condition also involves many other organs. Recognition of those factors has resulted in evolution of a variety of drug treatment strategies.

Drug Groups Commonly Used in Heart Failure Diuretics Aldosterone receptor antagonists Angiotensin-converting enzyme (ACE) inhibitors Angiotensin receptor blockers (ARBs) b blockers Cardiac glycosides Vasodilators b agonists Bipyridines Natriuretic peptide Therapy directed at non-cardiac targets is more valuable in the long-term treatment.

Treatment of Heart Failure Extensive trails have shown that just the following drug groups actually prolong life in patients with chronic heart failure: ACE inhibitors ARBs b blockers Aldosterone receptor antagonists Combined hydralazine-nitrate therapy

Treatment of Heart Failure Positive inotropic drugs can be helpful in acute failure. Cardiac glycosides also reduce symptoms in chronic systolic heart failure. Other positive inotropic drugs have consistently reduced survival in chronic failure.

Control of Normal Cardiac Contractility

Pathophysiology of Heart Failure

Extrinsic Compensatory Responses Cardiac output Carotid sinus firing Renal blood flow Sympathetic discharge Renin release Angiotensin II Preload Afterload Remodeling Force Beta-1 adrenoceptors down-regulate. Rate Cardiac Output (via compensation)

Intrinsic Compensatory Mechanism Myocardial hypertrophy Remodeling is the term applied to dilation & other slow structural changes in the stressed myocardium. Ultimately, myocytes die through apoptosis.

Cardiac Performance in Heart Failure ① Cardiac performance ↓CO ② ↓CO ↑NE, AgII, ET ↓EF ↓CO ③ ↑ NE, AgII, ET ↓EF ↑Afterload ↑Afterload Time

Pathophysiology of Cardiac Performance Cardiac performance is a function of: Preload Afterload Contractility Heart rate Preload represents all the factors that contribute to passive ventricular wall stress (or tension) at the end of diastole," and "Afterload represents all the factors that contribute to total myocardial wall stress (or tension) during systolic ejection." Frank-Starling Relation

Basic Pharmacology of Drugs Used in Heart Failure Drugs with Positive Inotropic Effect

Digitalis Digoxin William Withering (18th century) Chemistry of cardiac glycosides Lactone ring Activity Digoxin A lactone ring at the 17 position and a series of sugars at carbon 3 of the nucleus. Steroid

Pharmacokinetics of Digoxin Is 65-80% absorbed after oral administration. Is excreted mostly unchanged by the kidneys. Its renal clearance is proportionate to creatinine clearance.

Digital Mechanical Effects Na-K ATPase Na-Ca Exchanger 2 K+ 3 Na+ Ca2+ Treatment of heart failure. Digoxin: Mechanism of action Digoxin attaches to specific receptors which form a part of the enzyme, Na+/K+-dependent ATP-ase (sodium pump), inhibiting it. This blockade produces a progressive increase in the intracellular concentration of Na, which in turn activates the exchange of Na+-Ca++ and increases the influx of Ca++ and its intracellular concentration, [Ca++]i. This increase in the [Ca++]i at the level of the contractile proteins explains the resultant increase in cardiac contractility. Myofilaments Ca2+ 3 Na+ CONTRACTILITY

Digital Electrical Effects Direct electrical actions: An early, brief prolongation followed by shortening of action potential occurs (contributes to the shortening of refractoriness). At higher concentration, resting membrane potential is reduced. Slows conduction in such depolarized cardiac tissues. Normal Digital

Digital Electrical Effects Direct electrical actions: As toxicity progress oscillatory delayed afterdepolarizations appear (digitalis-induced bigeminy). Ventricular tachycardia Ventricular fibrillation

Digital Indirect Electrical Effects (Autonomic Actions) Parasympathetic effects (in lower doses): Sensitization of baroreceptors Facilitation of muscarinic transmission at the cardiac muscle (SA & AV nodes are more affected) …..

Digital Indirect Electrical Effects (Autonomic Actions) Sympathetic effects (at toxic levels): Sensitizes the myocardium, leading to: ventricular tachycardia & fibrillation

Effects on Other Organs Inhibition of Na+/K+ ATPase results in depolarization. Thus, increases spontaneous activity in excitable tissues, i.e., neurons and smooth muscle cells.

Effects on Other Organs GI tract (direct & indirect): Anorexia, nausea, vomiting & diarrhea CNS: Vagal & CTZ Disorientation & hallucinations Visual disturbances Gynecomastia in men (rare) An often described but rarely seen adverse effect of digoxin is a disturbance of color vision (mostly yellow and green color).

Chemoreceptor Trigger Zone (CTZ) The chemoreceptor trigger zone (CTZ) is an area of the medulla that receives inputs from blood-borne drugs or hormones, and communicates with the vomiting center, to initiate vomiting. The CTZ is close to the area postrema on the floor of the fourth ventricle and is outside of the blood-brain barrier. Neurokinin 1 (NK1)

Interaction with K+ Potassium and digitalis: They inhibit each other’s binding to Na+/K+ ATPase. Abnormal cardiac automaticity is inhibited by hyperkalemia.

Interaction with Ca2+ & Mg2+ Calcium and digitalis: Hypercalcemia accelerates the overloading of intracellular calcium. Magnesium and digitalis May inhibit Ca2+ inward current.

Indications of Digoxin In patients with : heart failure and atrial fibrillation a dilated heart and third heart sound It is usually given only when diuretics & ACE inhibitors have failed to control symptoms. The third sound occurs at the beginning of diastole approximately 0.12 to 0.18 seconds after S2. S3 may be normal in people under 40 years of age and some trained athletes but should disappear before middle age. Re-emergence of this sound late in life is abnormal and may indicate serious problems like heart failure. This heart sound when present in a child or young adult implies the presence of a supple ventricle that can undergo rapid filling. Conversely, when heard in a middle-aged or older adult, an S3 is often a sign of disease, indicating increased ventricular filling due to congestive heart failure or severe mitral or tricuspid regurgitation.

Digitalis has no net effect on mortality Digitalis in CHF It reduces the death rate from progressive CHF (Cp < 0.9 ng/ml). Also increases the sudden death (Cp > 1.5 ng/ml). A serum level of 1 ng/ml or less is appropriate. Digitalis has no net effect on mortality

Management of Toxicity of Digitalis During therapy of significant toxicity the followings should be monitored : TDM Electrolyte status ECG Therapy for toxicity manifested as visual changes or GI disturbances generally requires no more than reducing the dose.

Management of Toxicity of Digitalis In very severe intoxication: a) No use of antiarrhythmic drug b) Insertion of a temporary cardiac pacemaker c) Administration of digoxin antibody (digoxin immune fab)

Other Positive Inotropic Drugs Phosphodiesterase inhibitors (parenteral) Bipyridines: Inamrinone & Milrinone cAMP AMP cGMP GMP Increase myocardial contractility. Have an important vasodilating effect. Used in acute heart failure. PDE PDE

Other Positive Inotropic Drugs Beta-adrenoceptor stimulants Dobutamine Dopamine

2) Drugs without Positive Inotropic Effect

Diuretics Mainstay of heart failure management Reduction of preload results in reduction of: Edema Cardiac size

Aldosterone antagonist diuretics reduce Aldosterone antagonist diuretics reduce myocardial & vascular fibrosis caused by aldosterone: Spironolactone Eplerenone (less androgenic side effects) Aldosterone antagonist diuretics reduce morbidity & mortality

Renin-Angiotensin System Inhibitors

ACE inhibitors reduce morbidity & mortality Reduce peripheral resistance  reduce afterload Reduce salt & water retention  reduce preload Reduce sympathetic activity Reduce long-term remodeling of the heart & vessels ACE inhibitors reduce morbidity & mortality

Angiotensin II Receptor Blockers (ARBs) Produce similar but more limited beneficial effects.

Renin Inhibitors Aliskiren Approved for primary hypertension In clinical trails for heart failure Preliminary results suggests an efficacy similar to that of ACE inhibitors. Aliskiren. Pronunciation: (a-lis-KYE-ren) or a-LIS-ke-ren

Hydralazine-isosorbide dinitrate reduce Vasodilators Are effective in acute heart failure. Reduce afterload or preload or both Long-term use of hydralazine and isosorbide dinitrate can reduce remodeling. Hydralazine-isosorbide dinitrate reduce morbidity & mortality

Vasodilators Nesiritide (a synthetic form of endogenous “brain natriuretic peptide” (BNP) causes: a) venous & arteriolar dilation b) diuresis Approved for use in acute heart failure. Plasma concentrations of endogenous BNP rise in most patients with heart failure and are correlated with severity. Bosentan (a competitive inhibitor of endothelin) is approved for pulmonary hypertension. It has significant teratogenic and hepatotoxic effects.

Beta-Adrenoceptor Blockers Studies with bisoprolol, carvedilol & metoprolol have shown a reduction in mortality in patient with stable severe CHF (class II-IV). b -Blockers reduce morbidity & mortality

Metoprolol & CHF

Beta-Adrenoceptor Blockers The suggested mechanisms include: Attenuation of the adverse effects of high level of catecholamines (including apoptosis and remodeling) Up-regulation of beta-receptors Decreased heart rate

Case Study A 50-year-old man has developed dyspnea with exertion several weeks after a viral illness. This is accompanied by swelling feet and ankles and some increasing fatigue. On physical examination he is found to be mildly short of breath lying down, but feels better sitting upright. Pulse is 105 and regular, and blood pressure is 90/60 mm Hg. An echocardiogram shows a LVEF of about 25%. The diagnosis is dilated cardiomyopathy secondary to viral infection. What treatments are available for the patient? Short of breath: dyspnea

Case Study The patient is placed on a low-sodium diet. He was treated with: furosemide 40 mg twice daily digoxin 0.25 mg daily enalapril 20 mg twice daily