1. Drugs Used in Heart Failure
M Shafiei, PhD
Department of Pharmacology

2. Case Study
A 50-year-old man has developed dyspnea with exertion several weeks after a viral illness. This is accompanied by swelling feet and ankles and some increasing fatigue. On physical examination he is found to be mildly short of breath lying down, but feels better sitting upright. Pulse is 105 and regular, and blood pressure is 90/60 mm Hg. An echocardiogram shows a LVEF of about 25%. The diagnosis is dilated cardiomyopathy secondary to viral infection. What treatments are available for the patient?
Short of breath: dyspnea
Normal LVEF: 50-70%

3. Congestive Heart Failure (CHF)
Heart failure occurs when cardiac output is inadequate to provide the oxygen needed by the body.
A 5-year mortality rate is about 50%.
The most common cause is coronary artery disease, with hypertension also an important factor.

4. Types of Heart Failure Low output failure
Systolic failure (EF < 40-45%)
Diastolic failure
High output failure
Normal EF: 60%

5. Heart Failure
A progressive disease that is characterized by a gradual reduction in cardiac performance.
It is also punctuated in many cases by episodes of acute decompensation, often requiring hospitalization.

6. Heart Failure
Treatment is therefore directed at two somewhat different goals:
Reducing symptoms and slowing progression during stable periods
Managing acute episodes of decompensated failure

7. Pathogenesis of Heart Failure
Primary defect in early systolic HF resides in excitation-contraction coupling machinery
Clinical condition also involves many other organs, including:
Baroreceptor reflex
Sympathetic nervous system
Kidneys
Angiotensin II and other peptides (eg, ANP, ET)
Aldosterone
Apoptosis of cardiac cells
Although the primary defect in early systolic heart failure resides in excitation-contraction coupling machinery, clinical condition also involves many other organs. Recognition of those factors has resulted in evolution of a variety of drug treatment strategies.

8. Drug Groups Commonly Used in Heart Failure
Diuretics
Aldosterone receptor antagonists
Angiotensin-converting enzyme (ACE) inhibitors
Angiotensin receptor blockers (ARBs)
b blockers
Cardiac glycosides
Vasodilators
b agonists
Bipyridines
Natriuretic peptide
Therapy directed at non-cardiac targets is more valuable in the long-term treatment.

9. Treatment of Heart Failure
Extensive trails have shown that just the following drug groups actually prolong life in patients with chronic heart failure:
ACE inhibitors
ARBs
b blockers
Aldosterone receptor antagonists
Combined hydralazine-nitrate therapy

10. Treatment of Heart Failure
Positive inotropic drugs can be helpful in acute failure.
Cardiac glycosides also reduce symptoms in chronic systolic heart failure.
Other positive inotropic drugs have consistently reduced survival in chronic failure.

11. Control of Normal Cardiac Contractility

12. Pathophysiology of Heart Failure

13. Extrinsic Compensatory Responses
Cardiac output
Carotid sinus firing Renal blood flow
Sympathetic discharge Renin release
Angiotensin II
Preload Afterload
Remodeling
Force
Beta-1 adrenoceptors down-regulate.
Rate
Cardiac Output
(via compensation)

14. Intrinsic Compensatory Mechanism
Myocardial hypertrophy
Remodeling is the term applied to dilation & other slow structural changes in the stressed myocardium.
Ultimately, myocytes die through apoptosis.

15. Cardiac Performance in Heart Failure①
Cardiac performance
↓CO ②
↓CO
↑NE, AgII, ET
↓EF
↓CO ③
↑ NE, AgII, ET
↓EF
↑Afterload
↑Afterload
Time

16. Pathophysiology of Cardiac Performance
Cardiac performance is a function of:
Preload
Afterload
Contractility
Heart rate
Preload represents all the factors that contribute to passive ventricular wall stress (or tension) at the end of diastole," and "Afterload represents all the factors that contribute to total myocardial wall stress (or tension) during systolic ejection."
Frank-Starling Relation

17. Basic Pharmacology of Drugs Used in Heart Failure
Drugs with Positive Inotropic Effect

18. Digitalis Digoxin William Withering (18th century)
Chemistry of cardiac glycosides
Lactone ring
Activity
Digoxin
A lactone ring at the 17 position and a series of sugars at carbon 3 of the nucleus.
Steroid

19. Pharmacokinetics of Digoxin
Is 65-80% absorbed after oral administration.
Is excreted mostly unchanged by the kidneys.
Its renal clearance is proportionate to creatinine clearance.

20. Digital Mechanical Effects
Na-K ATPase
Na-Ca Exchanger
2 K+
3 Na+
Ca2+
Treatment of heart failure.
Digoxin: Mechanism of action
Digoxin attaches to specific receptors which form a part of the enzyme, Na+/K+-dependent ATP-ase (sodium pump), inhibiting it. This blockade produces a progressive increase in the intracellular concentration of Na, which in turn activates the exchange of Na+-Ca++ and increases the influx of Ca++ and its intracellular concentration, [Ca++]i. This increase in the [Ca++]i at the level of the contractile proteins explains the resultant increase in cardiac contractility.
Myofilaments
Ca2+
3 Na+
CONTRACTILITY

21. Digital Electrical Effects
Direct electrical actions:
An early, brief prolongation followed by shortening of action potential occurs (contributes to the shortening of refractoriness).
At higher concentration, resting membrane potential is reduced.
Slows conduction in such depolarized cardiac tissues.
Normal
Digital

22. Digital Electrical Effects
Direct electrical actions:
As toxicity progress oscillatory delayed afterdepolarizations appear (digitalis-induced bigeminy).
Ventricular tachycardia
Ventricular fibrillation

23. Digital Indirect Electrical Effects (Autonomic Actions)
Parasympathetic effects (in lower doses):
Sensitization of baroreceptors
Facilitation of muscarinic transmission at the cardiac muscle (SA & AV nodes are more affected)
…..

24. Digital Indirect Electrical Effects (Autonomic Actions)
Sympathetic effects (at toxic levels):
Sensitizes the myocardium, leading to:
ventricular tachycardia & fibrillation

25. Effects on Other Organs
Inhibition of Na+/K+ ATPase results in depolarization.
Thus, increases spontaneous activity in excitable tissues, i.e., neurons and smooth muscle cells.

26. Effects on Other Organs
GI tract (direct & indirect):
Anorexia, nausea, vomiting & diarrhea
CNS:
Vagal & CTZ
Disorientation & hallucinations
Visual disturbances
Gynecomastia in men (rare)
An often described but rarely seen adverse effect of digoxin is a disturbance of color vision (mostly yellow and green color).

27. Chemoreceptor Trigger Zone (CTZ)
The chemoreceptor trigger zone (CTZ) is an area of the medulla that receives inputs from blood-borne drugs or hormones, and communicates with the vomiting center, to initiate vomiting. The CTZ is close to the area postrema on the floor of the fourth ventricle and is outside of the blood-brain barrier.
Neurokinin 1 (NK1)

28. Interaction with K+ Potassium and digitalis:
They inhibit each other’s binding to Na+/K+ ATPase.
Abnormal cardiac automaticity is inhibited by hyperkalemia.

29. Interaction with Ca2+ & Mg2+
Calcium and digitalis:
Hypercalcemia accelerates the overloading of intracellular calcium.
Magnesium and digitalis
May inhibit Ca2+ inward current.

30. Indications of Digoxin
In patients with :
heart failure and atrial fibrillation
a dilated heart and third heart sound
It is usually given only when diuretics & ACE inhibitors have failed to control symptoms.
The third sound occurs at the beginning of diastole approximately 0.12 to 0.18 seconds after S2. S3 may be normal in people under 40 years of age and some trained athletes but should disappear before middle age. Re-emergence of this sound late in life is abnormal and may indicate serious problems like heart failure. This heart sound when present in a child or young adult implies the presence of a supple ventricle that can undergo rapid filling. Conversely, when heard in a middle-aged or older adult, an S3 is often a sign of disease, indicating increased ventricular filling due to congestive heart failure or severe mitral or tricuspid regurgitation.

31. Digitalis has no net effect on mortality
Digitalis in CHF
It reduces the death rate from progressive CHF (Cp < 0.9 ng/ml).
Also increases the sudden death (Cp > 1.5 ng/ml).
A serum level of 1 ng/ml or less is appropriate.
Digitalis has no net effect on mortality

32. Management of Toxicity of Digitalis
During therapy of significant toxicity the followings should be monitored :
TDM
Electrolyte status
ECG
Therapy for toxicity manifested as visual changes or GI disturbances generally requires no more than reducing the dose.

33. Management of Toxicity of Digitalis
In very severe intoxication:
a) No use of antiarrhythmic drug
b) Insertion of a temporary cardiac
pacemaker
c) Administration of digoxin antibody
(digoxin immune fab)

34. Other Positive Inotropic Drugs
Phosphodiesterase inhibitors (parenteral)
Bipyridines: Inamrinone & Milrinone
cAMP AMP
cGMP GMP
Increase myocardial contractility.
Have an important vasodilating effect.
Used in acute heart failure.
PDE
PDE

35. Other Positive Inotropic Drugs
Beta-adrenoceptor stimulants
Dobutamine
Dopamine

36. 2) Drugs without Positive Inotropic Effect

37. Diuretics Mainstay of heart failure management
Reduction of preload results in reduction of:
Edema
Cardiac size

38. Aldosterone antagonist diuretics reduce
Aldosterone antagonist diuretics reduce myocardial & vascular fibrosis caused by aldosterone:
Spironolactone
Eplerenone (less androgenic side effects)
Aldosterone antagonist diuretics reduce
morbidity & mortality

39. Renin-Angiotensin System Inhibitors

40. ACE inhibitors reduce morbidity & mortality
Reduce peripheral resistance  reduce afterload
Reduce salt & water retention  reduce preload
Reduce sympathetic activity
Reduce long-term remodeling of the heart & vessels
ACE inhibitors reduce morbidity & mortality

41. Angiotensin II Receptor Blockers (ARBs)
Produce similar but more limited beneficial effects.

42. Renin Inhibitors Aliskiren Approved for primary hypertension
In clinical trails for heart failure
Preliminary results suggests an efficacy similar to that of ACE inhibitors.
Aliskiren. Pronunciation: (a-lis-KYE-ren) or a-LIS-ke-ren

43. Hydralazine-isosorbide dinitrate reduce
Vasodilators
Are effective in acute heart failure.
Reduce afterload or preload or both
Long-term use of hydralazine and isosorbide dinitrate can reduce remodeling.
Hydralazine-isosorbide dinitrate reduce
morbidity & mortality

44. Vasodilators
Nesiritide (a synthetic form of endogenous “brain natriuretic peptide” (BNP) causes:
a) venous & arteriolar dilation
b) diuresis
Approved for use in acute heart failure.
Plasma concentrations of endogenous BNP rise in most patients with heart failure and are correlated with severity.
Bosentan (a competitive inhibitor of endothelin) is approved for pulmonary hypertension. It has significant teratogenic and hepatotoxic effects.

45. Beta-Adrenoceptor Blockers
Studies with bisoprolol, carvedilol & metoprolol have shown a reduction in mortality in patient with stable severe CHF (class II-IV).
b -Blockers reduce morbidity & mortality

46. Metoprolol & CHF

47. Beta-Adrenoceptor Blockers
The suggested mechanisms include:
Attenuation of the adverse effects of high level of catecholamines (including apoptosis and remodeling)
Up-regulation of beta-receptors
Decreased heart rate

48. Case Study
A 50-year-old man has developed dyspnea with exertion several weeks after a viral illness. This is accompanied by swelling feet and ankles and some increasing fatigue. On physical examination he is found to be mildly short of breath lying down, but feels better sitting upright. Pulse is 105 and regular, and blood pressure is 90/60 mm Hg. An echocardiogram shows a LVEF of about 25%. The diagnosis is dilated cardiomyopathy secondary to viral infection. What treatments are available for the patient?
Short of breath: dyspnea

49. Case Study The patient is placed on a low-sodium diet.
He was treated with:
furosemide 40 mg twice daily
digoxin 0.25 mg daily
enalapril 20 mg twice daily