1. Drugs used in Heart Failure
Ass.Prof. Dr.Naza M. Ali
Lec. 5-6
G2 May
G1 May

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
Is a reduction of cardiac contractile force & reduced 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

6. Sings and Symptoms

7. 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

8. Cardiovascular consequences of heart failure.

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

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

11. Some compensatory responses that
Sympathetic discharge facilitates:
Renin release,
Angiotensin II
increases NE release by sympathetic nerve endings
( dashed arrows ).
Some compensatory responses that
occur during congestive heart failure.

12. 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.

13. Therapeutic strategies in HF
Chronic HF is typically managed by:
Reduction in physical activity
low dietary intake of sodium
Use of diuretics,
Inhibitors of the renin angiotensin system,
Inotropic agents.

14. exacerbate HF should be avoided :
Drugs that may precipitate or
exacerbate HF should be avoided :
NSAIDs
Alcohol
Calcium-channel blockers
High dose β-blockers
Some antiarrhythmic drugs

15. Drugs used in heart failure:
Positive Inotropic Drugs
2. Direct Vasodilators
3. Miscellaneous drugs for chronic failure

16. 1. Positive Inotropic Drugs
Cardiac Glycosides
Beta Agonist
PDE Inhibitors
2. Direct Vasodilators
Isosorbide dinitrate
Hydralazine
Nitroprusside
3.Miscellaneous drugs
ACE inhibitors
ARBs
Diuretics & Aldosterone antagonists
Beta blockers
Drugs used in
Heart Failure

17. Drugs used in heart failure Positive Inotropic Drugs
Cardiac Glycosides ( Digoxin, Digitoxin )
Beta Agonists ( Dobutamine, Dopamine )
PDE Inhibitors( Inamrinone, Milrinone)

18. 2. Direct Vasodilators Isosorbide dinitrate ( Venous dilator )
Hydralazine ( Arteriolar dilator )
Nitroprusside ( Both arteriolar & venous dilator)

19. 3. Miscellaneous drugs for chronic failure
Angiotensin Antagonists
Diuretics & Aldosterone antagonists
Beta blockers
While Nesiritide is used in acute heart failure

20. 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.
And the concentration gradient across the membrane decreased
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.

21. Mechanism of action of digoxin.
ATPase = adenosine triphosphatase

22. Cardiac Effects Mechanical effects The increase contractility lead to:
↑ ventricular ejection,
↓ end systolic & end diastolic size, ↑ cardiac output & ↑ 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.

23. 2. Electrical effects 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.

25. 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.

26. 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

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

28. Clinical Uses
Congestive heart failure
Atrial fibrillation

29. 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%

30. 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
Use of antibodies to digoxin (digoxin immune Fab), which bind and inactivate the drug.

31. 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

32. 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
Hypomagnesemia
Hypercalcemia

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

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

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

36. 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.]

37. 3. Miscellaneous drugs for chronic failure ACE inhibitors
ACE inhibitors are the agents of choice in HF.
Decrease vascular resistance, venous tone, and BP
Reduce preload and afterload, increased cardiac output
ACE inhibitors decreased both morbidity and mortality.
Enalapril reduces arrhythmic death, MI & strokes.

38. Effects of ACE inhibitors

39. 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.

40. ARBs ( Inhibit AT1R)
Competitive antagonists of angiotensin type 1 receptor.
Losartan is the prototype drug
Candesartan
Telmisartan
Valsartan
All are orally active & require once-a-day Except Valsartan used twice daily
Losartan differs from the others in that it undergoes extensive first-pass hepatic metabolism.

41. 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.
Loop diuretics are commonly used diuretics in HF.

42. Aldosterone Antagonists
Spironolactone is a direct antagonist of aldosterone
preventing salt retention, myocardial hypertrophy, hypokalemia.

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

44. 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.

45. Beta Blockers The benefit of β-blockers is attributed,
1. to their ability to prevent the changes that occur
because of chronic activation of the SNS,
decrease heart rate and inhibit release of renin.
β-blockers prevent the deleterious effects of NE on the cardiac muscle fibers, decreasing remodeling, hypertrophy & cell death.

46. Three β-blockers have shown benefit in HF:
Bisoprolol ,Carvedilol , Metoprolol succinate
reduce morbidity and mortality associated with HF
Treatment should be started at low doses and gradually titrated to target doses based on patient tolerance and vital signs.
Both carvedilol and metoprolol are metabolized by the CYP P450 ( 2D6 isoenzyme), and inhibitors of this metabolic pathway may increase levels of these drugs and increase the risk of adverse effects.