Drugs Used in Heart Failure

1. Drugs Used inHeart Failure Dr. Haitham M. Al-Wali Ph.D Pharmacology FACULTY OF Pharmacy UNIVERSITY OF AL-NAHRAIN

2. OBJECTIVES • Describe the different classes of drugs used for treatment of acute & chronic heart failure • Describe the mechanism of action , therapeutic uses , side effects & drug interactions of individual drugs used for the treatment of heart failure

3. Drugs Used inHeart Failure • Heart failure (HF) is a complex, progressive disorder in which the heart isunable to pump sufficient blood to meet the needs of the body. • It’s cardinalsymptoms are dyspnea, fatigue, and fluid retention.

6. PATHOPHYSIOLOGY • The physiologic defect in heartfailure is a decrease in cardiac output relative to the needs ofthe body. • The causes of heart failure • loss of functional myocardium,as in myocardial infarction. • chronic hypertension, • valvulardisease, • coronary artery disease, • variety of cardiomyopathies.

8. PATHOPHYSIOLOGYVentricular function (Frank-Starling) curves.

9. Compensatory responses that occur in heart failure.

10. Increased blood volume results inedema and pulmonary congestion and contributes to the increasedend-diastolic fiber length. • Cardiomegaly (enlargement and remodelingof the heart), mediated by sympathetic discharge and angiotensin II. • Although these compensatory responses can temporarilyimprove cardiac output, they also increasethe load on the heart, and the increased load contributes to furtherdecline in cardiac function. Apoptosis is a later response.

11. THERAPEUTIC STRATEGIES • The removal ofretained salt and water with diuretics. • Reduction of afterload and saltand water retention by means of angiotensin-converting enzyme(ACE) inhibitors. • Reduction of excessive sympathetic stimulation by means of β blockers. • Reduction of preload or afterload with vasodilators. • In systolic failure, direct augmentation of depressed cardiac contractility with positive inotropic drugs such as digitalis glycosides.

12. CARDIAC GLYCOSIDES A. Prototypes and Pharmacokinetics • The cardiac glycosides called “digitalis” several come from the digitalis (foxglove) plant. • Digoxin is the prototype agent. • Digitoxinis a very similar but longer-acting molecule; it also comes from the foxglove plant but is no longer available. • Digoxin has an oral bioavailability of 60–75%, and a half-life of 36–40 h. • Elimination is by renal excretion (about 60%) and hepatic metabolism (40%).

13. CARDIAC GLYCOSIDES • B. Mechanism of Action • Inhibition of Na+/K+ ATPase (the “sodium pump”) of the cell membrane by digitalis. Which results in a small increase in intracellular sodium. • The increased sodium alters the driving force for sodium calcium exchange by the exchanger, NCX, so that less calcium is removed from the cell. The increased intracellular calcium is stored in the sarcoplasmic reticulum and upon release increases contractile force.

15. CARDIAC GLYCOSIDES C. Cardiac Effects • Mechanical effects Theincrease in contractility evoked by digitalis results in increased ventricular ejection, decreased end-systolic and end-diastolic size, increased cardiac output, and increased renal perfusion. These beneficial effects permit a decrease in the compensatory sympathetic and renal responses previously described. The decrease in sympathetic tone is especially reduced heart rate, preload, and afterload permit the heart to function more efficiently.

16. CARDIAC GLYCOSIDES 2. Electrical effects include early cardiac parasympathomimeticresponses and later arrhythmogenic actions. • Early responses : Increased PR interval, caused by the decrease in atrioventricular (AV) conduction velocity, and flattening of the T wave (ECG) effects. (mediated by the vagus nerve) and can be partially blocked by atropine. The effect of digitalis is to slow ventricular rate. Shortened QT interval, inversion of the T wave, and ST segment depression may occur later.

17. CARDIAC GLYCOSIDES b. Toxic responses Increased automaticity, caused by intracellular calcium overload, is the most important manifestation of digitalis toxicity. which may evoke extrasystoles, tachycardia, or fibrillation in any part of the heart. In the ventricles, the extrasystoles are recognized as premature ventricular beats (PVBs). The rhythm is called bigeminy.

18. Electrocardiographic record showing digitalis induced bigeminy.

19. CARDIAC GLYCOSIDES D. Clinical Uses • 1. Congestive heart failure—Digitalis is used in the treatment of chronic heartfailure. digitalis may improve functional status (reducing symptoms), itdoes not prolong life. • Other agents (diuretics, ACE inhibitors,vasodilators) may be equally effective and less toxic, and some ofthese alternative therapies do prolong life.

20. CARDIAC GLYCOSIDES • D. Clinical Uses • 2. Atrial fibrillation—In atrial flutter and fibrillation, it isdesirable to reduce the conduction velocity or increase the refractoryperiod of the AV node so that ventricular rate is controlledwithin a range compatible with efficient filling and ejection. • The parasympathomimetic action of digitalis doesthis therapeutic objective, although high doses may be required.

21. CARDIAC GLYCOSIDES • E. Interactions • Quinidine causes reduction in digoxin clearance(↑ digoxin level ). • Several other drugs have the same effect (amiodarone, verapamil, others), but the interactions with these drugs are not clinically significant. • Digitalis toxicity, especially arrhythmogenesis, is increased by hypokalemia, hypomagnesemia, and hypercalcemia. Loop diuretics and thiazides. • Digitalis induced vomiting may deplete serum magnesium and similarly facilitate toxicity.

22. CARDIAC GLYCOSIDES • F. Digitalis Toxicity • The major signs of digitalis toxicity are arrhythmias, nausea, vomiting, and diarrhea. Rarely, confusion or hallucinations and visual or endocrine abnormalities • Severe, acute intoxication caused by suicidal or accidental overdose results in cardiac depression leading to cardiac arrest rather than tachycardia or fibrillation.

23. CARDIAC GLYCOSIDES • Treatment of digitalis toxicity includes: • Correction of potassium or magnesium deficiency • Antiarrhythmic drugs (eg, lidocaine or phenytoin) are favored, but drugs such as propranolol have also been used successfully. • Digoxin antibodies—Digoxin antibodies (Fab fragments; Digibind)

24. OTHER DRUGS USED IN CONGESTIVE HEART FAILURE • A. Diuretics • Diuretics are the first-line therapy for both systolic and diastolic failure • Furosemideis useful agent for immediate reduction of the pulmonary congestion and severe edema • Thiazidessuch as hydrochlorothiazide are sometimes sufficient for mild chronic failure. • Spironolactoneand eplerenone (aldosterone antagonist diuretics) have significant long-term benefits and can reduce mortality in chronic failure.

25. B. Angiotensin Antagonists • Angiotensin antagonists reduce aldosterone secretion,salt and water retention, and vascular resistance • They are now considered, along with diuretics, to be first-line drugsfor chronic heart failure. • The angiotensin receptor blockers (ARBs,eg, losartan) appear to have the same benefits as ACE inhibitors(eg, captopril)

26. B. Angiotensin Antagonists • Angiotensin-converting enzyme (ACE) inhibitorsblock the enzyme thatcleaves angiotensin I to form the potent vasoconstrictor angiotensinII. They also diminish the inactivation of bradykinin. • ARBs have the advantage of more complete blockade of angiotensin II action, because ACE inhibitors inhibit only one enzyme responsible for the production of angiotensin-II.

27. C. Beta1-Adrenoceptor Agonists • Dobutamineand dopamine are often useful in acute failure inwhich systolic function is markedly depressed. • However, they are NOTappropriate for chronic failure because of tolerance,lack of oral efficacy, and significant arrhythmogenic effects.

28. C. Beta1-Adrenoceptor Agonists • β-Adrenergic Agonists increase in intracellular cyclic adenosine monophosphate (cAMP), which results in the activation of protein kinase. Protein kinase then phosphorylates slow calcium channels, thereby increasing entry of calcium ions into the myocardial cells and enhancing contraction.

29. D. Beta-Adrenoceptor Antagonists • Several β blockers (carvedilol, labetalol, metoprolol, slow progressionof chronic heart failure. • The benefit of β-blockers is to prevent the changes that occur because of chronic activation of the sympathetic nervous system. • Betablockers are of no value in acute failure and may be detrimental ifsystolic dysfunction is marked.

30. E. Phosphodiesterase Inhibitors • Milrinone • Increase cyclic adenosine monophosphate (cAMP) by inhibitingits breakdown by phosphodiesterase and cause an increasein cardiac intracellular calcium • Causevasodilation, which may be responsible for a major part of theirbeneficial effect.

31. F. Vasodilators • Vasodilator therapy with nitroprusside or nitroglycerin is oftenused for acute severe failure with congestion. • Nitrates are commonly used venous dilators to reduce preload for patients with chronic HF. • Arterial dilators, such as hydralazinereduce systemic arteriolar resistance and decrease afterload.

32. F. Vasodilators • Nesiritidenatriuretic peptide actschiefly by causing vasodilation. It is given by IV infusion for acute failure only. • Chronic heart failure responds favorably tooral vasodilators such as hydralazine or isosorbidedinitrate(orboth). • Calcium channel blockers(eg, verapamil) are of no value in heart failure.