1. Drugs used in Heart Failure
Dr. Naza M. Ali
Lec. 1-2

2. 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

3. The primary defect
1. Is a reduction of cardiac contractile force & 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

4. Sings and symptoms

5. 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

6. Cardiovascular consequences of heart failure.

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

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

9. Some compensatory responses that occur during congestive heart failure.
Sympathetic discharge facilitates renin release, and angiotensin II increases
norepinephrine release by sympathetic nerve endings ( dashed
arrows ).

10. 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.

11. Therapeutic strategies in HF
Chronic HF is typically managed by:
a reduction in physical activity
low dietary intake of sodium
use of diuretics, inhibitors of the renin angiotensin system, and inotropic agents.

12. exacerbate HF should be avoided :
Drugs that may precipitate or
exacerbate HF should be avoided :
NSAIDs (nonsteroidal anti-inflammatory drugs)
Alcohol
Calcium-channel blockers
High dose β-blockers
Some antiarrhythmic drugs

13. Drugs used in heart failure
Positive Inotropic Drugs
Cardiac glycosides ( Digoxin, Digitoxin)
Beta agonists ( Dobutamine, Dopamine )
PDE Inhibitors( Inamrinone, Milrinone)

14. 2. Vasodilators
Isosorbide dinitrate (venous dilator)
Hydralazine (arteriolar dilator)
Nitroprusside (both arteriolar & venous dilator)

15. 3. Miscellaneous drugs for chronic failure Angiotensin Antagonists
Diuretics
Beta blockers (Carvedilol, Bisoprolol, Metoprolol)
Aldosterone antagonists
Nesiritide in acute failure

16. 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.
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.

18. Cardiac effects Mechanical effects The increase contractility lead to:
increase ventricular ejection,
decrease end systolic & end diastolic size,
increase cardiac output & increase 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.

19. 2. Electrical effects
include early cardiac parasympathomimetic responses and arrhythmogenic actions
a. 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.

20. 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.

21. 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

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

23. Clinical Uses
Congestive heart failure
Atrial fibrillation (The parasympathommemtic action of digitalis often accomplishes this therapeutic objective)

24. 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%

25. 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
The use of antibodies to digoxin (digoxin immune Fab), which bind and inactivate the drug.

26. 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

27. 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 or
supplementation with potassium chloride.
Hypercalcemia
Hypomagnesemia

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

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

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

31. 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.]

32. 3. Miscellaneous drugs for chronic failure
Angiotensin-converting enzyme inhibitors /ACE
ACE inhibitors are the agents of choice in HF.
Decrease vascular resistance, venous tone, and BP
They reduce preload and afterload, resulting in an increased cardiac output
ACE inhibitors has significantly decreased both morbidity and mortality.
Enalapril reduces arrhythmic death, MI & strokes.

34. 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.

35. Angiotensin-receptor blockers / ARB
Competitive antagonists of angiotensin type 1 receptor.
Losartan is the prototype drug
Candesartan
Telmisartan
Valsartan
All are orally active & require once-a-day
Losartan differs from the others in that it undergoes extensive first-pass hepatic metabolism.

36. 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.
Diuretics may also decrease afterload by reducing
plasma volume, thereby decreasing BP.
Loop diuretics are commonly used diuretics in HF.

37. Aldosterone Antagonists
Spironolactone is a direct antagonist of aldosterone,
preventing salt retention, myocardial hypertrophy, hypokalemia.
Because spironolactone promotes potassium retention, patients should not be taking potassium supplements.

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

39. 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.