Drugs Used in Heart Failure Dr Haitham M

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Drugs Used in Heart Failure Dr. Haitham M. Al-Wali Ph. D Pharmacology FACULTY OF

Drugs Used in Heart Failure Dr. Haitham M. Al-Wali Ph. D Pharmacology FACULTY OF Pharmacy UNIVERSITY OF AL-NAHRAIN 20 February 2021 1

OBJECTIVES • Describe the different classes of drugs used for treatment of acute &

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 20 February 2021 2

Drugs Used in Heart Failure • Heart failure (HF) is a complex, progressive disorder

Drugs Used in Heart Failure • 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. • It’s cardinal symptoms are dyspnea, fatigue, and fluid retention. 20 February 2021 3

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PATHOPHYSIOLOGY • The physiologic defect in heart failure is a decrease in cardiac output

PATHOPHYSIOLOGY • The physiologic defect in heart failure is a decrease in cardiac output relative to the needs of the body. q. The causes of heart failure 1. loss of functional myocardium, as in myocardial infarction. 2. chronic hypertension, 3. valvular disease, 4. coronary artery disease, 5. variety of cardiomyopathies. 20 February 2021 6

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PATHOPHYSIOLOGY Ventricular function (Frank-Starling) curves. 20 February 2021 8

PATHOPHYSIOLOGY Ventricular function (Frank-Starling) curves. 20 February 2021 8

Compensatory responses that occur in heart failure. 20 February 2021 9

Compensatory responses that occur in heart failure. 20 February 2021 9

 • Increased blood volume results in edema and pulmonary congestion and contributes to

• Increased blood volume results in edema and pulmonary congestion and contributes to the increased end-diastolic fiber length. • Cardiomegaly (enlargement and remodeling of the heart), mediated by sympathetic discharge and angiotensin II. • Although these compensatory responses can temporarily improve cardiac output, they also increase the load on the heart, and the increased load contributes to further decline in cardiac function. Apoptosis is a later response. 20 February 2021 10

THERAPEUTIC STRATEGIES Ø The removal of retained salt and water with diuretics. Ø Reduction

THERAPEUTIC STRATEGIES Ø The removal of retained salt and water with diuretics. Ø Reduction of afterload and salt and water retention by means of angiotensin-converting enzyme (ACE) inhibitors. Ø Reduction of excessive sympathetic stimulation by means of β blockers. Ø Reduction of preload or afterload with vasodilators. Ø In systolic failure, direct augmentation of depressed cardiac contractility with positive inotropic drugs such as digitalis glycosides. 20 February 2021 11

CARDIAC GLYCOSIDES A. Prototypes and Pharmacokinetics • The cardiac glycosides called “digitalis” several come

CARDIAC GLYCOSIDES A. Prototypes and Pharmacokinetics • The cardiac glycosides called “digitalis” several come from the digitalis (foxglove) plant. • Digoxin is the prototype agent. • Digitoxin is 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%). 20 February 2021 12

CARDIAC GLYCOSIDES • B. Mechanism of Action • Inhibition of Na+/K+ ATPase (the “sodium

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. 20 February 2021 13

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CARDIAC GLYCOSIDES C. Cardiac Effects 1. Mechanical effects The increase in contractility evoked by

CARDIAC GLYCOSIDES C. Cardiac Effects 1. Mechanical effects 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. 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. 20 February 2021 15

CARDIAC GLYCOSIDES 2. Electrical effects include early cardiac parasympathomimetic responses and later arrhythmogenic actions.

CARDIAC GLYCOSIDES 2. Electrical effects include early cardiac parasympathomimetic responses and later arrhythmogenic actions. a. 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. 20 February 2021 16

CARDIAC GLYCOSIDES b. Toxic responses Increased automaticity, caused by intracellular calcium overload, is the

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. 20 February 2021 17

Electrocardiographic record showing digitalis induced bigeminy. 20 February 2021 18

Electrocardiographic record showing digitalis induced bigeminy. 20 February 2021 18

CARDIAC GLYCOSIDES D. Clinical Uses • 1. Congestive heart failure—Digitalis is used in the

CARDIAC GLYCOSIDES D. Clinical Uses • 1. Congestive heart failure—Digitalis is used in the treatment of chronic heart failure. digitalis may improve functional status (reducing symptoms), it does not prolong life. • Other agents (diuretics, ACE inhibitors, vasodilators) may be equally effective and less toxic, and some of these alternative therapies do prolong life. 20 February 2021 19

CARDIAC GLYCOSIDES • D. Clinical Uses • 2. Atrial fibrillation—In atrial flutter and fibrillation,

CARDIAC GLYCOSIDES • D. Clinical Uses • 2. Atrial fibrillation—In atrial flutter and fibrillation, it is desirable to reduce the conduction velocity or increase the refractory period of the AV node so that ventricular rate is controlled within a range compatible with efficient filling and ejection. • The parasympathomimetic action of digitalis does this therapeutic objective, although high doses may be required. 20 February 2021 20

CARDIAC GLYCOSIDES • E. Interactions • Quinidine causes reduction in digoxin clearance(↑ digoxin level

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. 20 February 2021 21

CARDIAC GLYCOSIDES • F. Digitalis Toxicity • The major signs of digitalis toxicity are

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. 20 February 2021 22

CARDIAC GLYCOSIDES • Treatment of digitalis toxicity includes: 1. Correction of potassium or magnesium

CARDIAC GLYCOSIDES • Treatment of digitalis toxicity includes: 1. Correction of potassium or magnesium deficiency 2. Antiarrhythmic drugs (eg, lidocaine or phenytoin) are favored, but drugs such as propranolol have also been used successfully. 3. Digoxin antibodies—Digoxin antibodies (Fab fragments; Digibind) 20 February 2021 23

OTHER DRUGS USED IN CONGESTIVE HEART FAILURE • A. Diuretics • Diuretics are the

OTHER DRUGS USED IN CONGESTIVE HEART FAILURE • A. Diuretics • Diuretics are the first-line therapy for both systolic and diastolic failure • Furosemide is useful agent for immediate reduction of the pulmonary congestion and severe edema • Thiazides such as hydrochlorothiazide are sometimes sufficient for mild chronic failure. • Spironolactone and eplerenone (aldosterone antagonist diuretics) have significant long-term benefits and can reduce mortality in chronic failure. 20 February 2021 24

B. Angiotensin Antagonists • Angiotensin antagonists reduce aldosterone secretion, salt and water retention, and

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 drugs for chronic heart failure. • The angiotensin receptor blockers (ARBs, eg, losartan) appear to have the same benefits as ACE inhibitors (eg, captopril) 20 February 2021 25

B. Angiotensin Antagonists • Angiotensin-converting enzyme (ACE) inhibitors block the enzyme that cleaves angiotensin

B. Angiotensin Antagonists • Angiotensin-converting enzyme (ACE) inhibitors block the enzyme that cleaves angiotensin I to form the potent vasoconstrictor angiotensin II. 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. 20 February 2021 26

C. Beta 1 -Adrenoceptor Agonists • Dobutamine and dopamine are often useful in acute

C. Beta 1 -Adrenoceptor Agonists • Dobutamine and dopamine are often useful in acute failure in which systolic function is markedly depressed. • However, they are NOT appropriate for chronic failure because of tolerance, lack of oral efficacy, and significant arrhythmogenic effects. 20 February 2021 27

C. Beta 1 -Adrenoceptor Agonists • β-Adrenergic Agonists increase in intracellular cyclic adenosine monophosphate

C. Beta 1 -Adrenoceptor Agonists • β-Adrenergic Agonists increase in intracellular cyclic adenosine monophosphate (c. AMP), 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. 20 February 2021 28

D. Beta-Adrenoceptor Antagonists • Several β blockers (carvedilol, labetalol, metoprolol, slow progression of chronic

D. Beta-Adrenoceptor Antagonists • Several β blockers (carvedilol, labetalol, metoprolol, slow progression of chronic heart failure. • The benefit of β-blockers is to prevent the changes that occur because of chronic activation of the sympathetic nervous system. • Beta blockers are of no value in acute failure and may be detrimental if systolic dysfunction is marked. 20 February 2021 29

E. Phosphodiesterase Inhibitors • Milrinone • Increase cyclic adenosine monophosphate (c. AMP) by inhibiting

E. Phosphodiesterase Inhibitors • Milrinone • Increase cyclic adenosine monophosphate (c. AMP) by inhibiting its breakdown by phosphodiesterase and cause an increase in cardiac intracellular calcium • Cause vasodilation, which may be responsible for a major part of their beneficial effect. 20 February 2021 30

F. Vasodilators • Vasodilator therapy with nitroprusside or nitroglycerin is often used for acute

F. Vasodilators • Vasodilator therapy with nitroprusside or nitroglycerin is often used for acute severe failure with congestion. • Nitrates are commonly used venous dilators to reduce preload for patients with chronic HF. • Arterial dilators, such as hydralazine reduce systemic arteriolar resistance and decrease afterload. 20 February 2021 31

F. Vasodilators • Nesiritide natriuretic peptide acts chiefly by causing vasodilation. It is given

F. Vasodilators • Nesiritide natriuretic peptide acts chiefly by causing vasodilation. It is given by IV infusion for acute failure only. • Chronic heart failure responds favorably to oral vasodilators such as hydralazine or isosorbide dinitrate (or both). • Calcium channel blockers (eg, verapamil) are of no value in heart failure. 20 February 2021 32