Pharmacology of Drugs for Congestive Heart Failure

Congestive Heart failure is caused by low cardiac output and high sympathetic discharge. Diuretics reduce preload, ACE inhibitors lower afterload, beta blockers reduce sympathetic activity, and digitalis has inotropic effects. Newer medications target vasodilation and myosin activation to improve heart efficiency while lowering energy requirements. Combination therapy, following an assessment of cardiac function and volume status, is the most effective strategy to heart failure care.

1. Dr. Nikhilkumar S Sakle Assistant Professor Department of Pharmacology Y. B. Chavan College of Pharmacy, Aurangabad. Drugs for Heart Failure (Cardiac Glycosides) 1

2. It means that the heart's pumping power is weaker than normal. B lood moves through the heart and body at a slower rate and pressure in the heart increases. As a result, the heart cannot pump enough oxygen and nutrients to meet the body's needs. 2

3. The chambers of the heart may respond by stretching to hold more blood to pump through the body or by becoming stiff and thickened. This helps to keep the blood moving, but the heart muscle walls may eventually weaken and become unable to pump as efficiently 3

4. As a result, the kidneys may respond by causing the body to retain fluid (water) and salt . If fluid builds up in the arms, legs, ankles, feet, lungs, or other organs, the body becomes congested , and congestive heart failure is the term used to describe the condition. 4

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6. Cardiac Glycosides They increase myocardial contractility and output in a hypodynamic heart without a proportionate increase in O 2 consumption . These are glycosidic drugs having cardiac inotropic property . Thus, efficiency of failing heart is increased. 6

7. In contrast, ‘ Cardiac Stimulants ’ ( Adr , theophylline ) increase O 2 consumption rather disproportionately and tend to decrease myocardial efficiency. 7

8. Cardiac glycosides are found in several plants and in toad skin ( Bufotoxin ). Digitalis lanata is the source of Digoxin , the only glycoside that is currently in use. Others like Digitoxin (from Digitalis purpurea ) and Ouabain (from Strophan thus gratus ), etc. are no longer clinically used or marketed. 8

9. PHARMACOLOGICAL ACTIONS Heart: Digitalis has direct effects on myocardial contractility and electrophysiological properties. Force of contraction Digitalis causes a dose dependent increase in force of contraction of heart—a positive inotropic action . There is more complete emptying of failing and dilated ventricles—cardiac output is increased and end-diastolic volume is reduced. 9

10. Rate: Heart rate is decreased by digitalis. In addition, digitalis slows the heart by vagal and extravagal actions. 10

11. Mechanism of action 11

12. Blood vessels: Digitalis has mild direct vasoconstrictor action. Kidney: Diuresis occurs promptly in CHF patients, secondary to improvement in circulation and renal perfusion. The retained salt and water is gradually excreted. No diuresis occurs in normal individuals or in patients with edema due to other causes. 12

13. CNS: Digitalis has little apparent CNS effect in therapeutic dose. Higher doses cause CTZ activation → nausea and vomiting. Still higher doses produce hyperapnoea , central sympathetic stimulation, mental confusion, disorientation and visual disturbances. 13

14. ADVERSE EFFECTS Toxicity of digitalis is high, margin of safety is low ( Therapeutic index 1.5–3 ng /ml ). Extracardiac Anorexia, nausea, vomiting and abdominal pain are usually reported first: are due to gastric irritation, mesenteric vasoconstriction and CTZ stimulation. Fatigue, malaise, headache , mental confusion, restlessness, hyperapnoea , disorientation, psychosis and visual disturbances are the other complaints. Skin rashes and gynaecomastia are rare. 14

15. Cardiac Almost every type of arrhythmia can be produced by digitalis: pulsus bigeminus , nodal and ventricular extrasystoles , ventricular tachycardia and terminally ventricular fibrillation. Partial to complete A-V block may be the sole cardiac toxicity, or it may accompany other arrhythmias. Severe bradycardia , atrial extrasystoles , AF or AFl have also been noted. 15

16. PRECAUTIONS AND CONTRAINDICATIONS Hypokalemia : Elderly, renal or severe hepatic disease Myocardial ischaemia : Thyrotoxicosis : Myxoedema : Ventricular tachycardia Partial A-V block: Acute myocarditis : Wolff-Parkinson-White syndrome: 16

17. INTERACTIONS Diuretics: Calcium: Quinidine : Adrenergic drugs: Digoxin absorption may be reduced by metoclopramide , sucralfate , antacids, neomycin, sulfasalazine . Absorption of digoxin is increased by atropinic drugs, including tricyclic antidepressants. Propranolol , Verapamil , diltiazem and disopyramide : 17

18. TREATMENT OF CHF 18 Heart failure occurs when cardiac output is insufficient to meet the demands of tissue perfusion, or is able to do so only by elevating filling pressure. It is a progressive disease with gradually deteriorating cardiac performance. Heart failure may primarily be due to systolic dysfunction or diastolic dysfunction .

19. 19 Systolic dysfunction This refers to deficient pumping action of ventricles, i.e. ventricles are unable to develop sufficient wall tension to eject adequate quantity of blood and get progressively dilated. The most important cause of systolic dysfunction is coronary artery disease (CAD), myocardial infarction (MI) and loss of functioning myocardium. Other causes are valvular incompetence, dilated cardiomyopathy , viral (including HIV) myocarditis , tachyarrhythmias (mostly AF), etc

20. 20 Diastolic dysfunction The ventricular wall is thickened and unable to relax normally during diastole; ventricular filling is impaired and stroke volume is reduced, but the EF may be normal. Long standing hypertension is the most common cause of left ventricular hypertrophy (LVH) and subsequent diastolic dysfunction. It is mostly associated with ageing and myocardial stiffening. Aortic stenosis , hypertrophic cardiomyopathy , A-V shunts and congenital heart disease are the other important causes.

21. 21 However, most patients, especially long standing cases, have both systolic and diastolic dysfunction. Symptomatically also both are similar. Several compensatory mechanisms are brought into action to overcome the reduced cardiac output (CO). These include: Elevation of filling pressure Increase in sympathetic tone Activation of RAS Over production of aldosterone Endothelin production Release of natriuretic peptides (ANP and BNP)

22. TREATMENT OF CHF There are two distinct goals of drug therapy in CHF: (a) Relief of congestive/low output symptoms and restoration of cardiac performance. This can be achieved by: Inotropic drugs — Digoxin , dobutamine / dopamine, amrinone / milrinone . Diuretics — Furosemide , thiazides RAS inhibitors —ACE inhibitors/ARBs Vasodilators — Nitrate ( Veno ), Hydralazine , nitroprusside β - blocker — Metoprolol , bisoprolol , carvedilol , Nebivolol 22

23. (b) Arrest/reversal of disease progression and prolongation of survival, possible with: ACE inhibitors/ ARBs, β blockers Aldosterone antagonist — Spironolactone , eplerenone . Important nonpharmacological measures are rest and salt restriction. 23

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25. Uses 25 1. Congestive Heart failure 2. Cardiac arrhythmias Atrial fibrillation (AF) Atrial flutter (AFI) Paroxysmal supraventricular tachycardia (PSVT)