Pharmacology Drugs used in heart failure

Pharmacology Drugs used in heart failure

1. Drugs used in heart failure
1

2. Heart Failure (HF)
Heart Failure Definition:
Heart failure (HF) is a complex clinical syndrome that can
result from any structural or functional cardiac disorder that
impairs the ability of the ventricle to fill with or eject blood.
Simply: the heart is unable to pump enough blood with each
beat.
Congestive heart failure (CHF), is a type of heart failure,
although sometimes the two terms are interchangeably.
2

3. Terminology:
Heart Failure (HF); is a physiological state in which cardiac output is
insufficient to meet the needs of the body and lungs.
Congestive Heart Failure (CHF); is often used as one of the common
symptoms is swelling or water retention.
Chronic Heart Failure; is a long-term condition, usually kept stable by the
treatment of symptoms.
Acute decompensated Heart Failure (ADHF); is a worsening of chronic
heart failure symptoms which can result in acute respiratory distress.
3

4. Ejection fraction (EF): is the fraction of outbound blood pumped from the
heart with each heartbeat. It is commonly measured by echocardiogram;
Normal EF; 55-70% (means;55-70% of the total amount of blood in the left
ventricle is pushed out with each heartbeat).
A measurement under 40% may be evidence of heart failure .
Symptoms of EF under 40%
Less blood goes to the brain …………..confused
Lungs may fill up with fluid ………….short of breath.
Kidneys may not be able to get rid of the fluid………salt and water
retention
Ankles and feet may swell up.
4

5. Types of Heart Failure
According to structure;
-Left sided (left ventricle) Heart Failure;
-Right sided (Right Ventricle) Heart Failure;
-Mixed presentations (left and right) are commonly
According to function;
•Systolic failure: the ventricles (usually left or both left and right) loses its ability to
contract normally. (thin, weak heart muscle).
•Diastolic Failure: (also called diastolic dysfunction): the ventricles loses its ability to relax
normally (because the muscle has become thick stiff). The heart can’t properly fill with
blood during the resting period between each beat.
Ejection fraction (EF);
Reduced ejection fraction (HFrEF); also referred to as systolic heart failure. The heart
muscle does not contract effectively and less oxygen-rich blood is pumped out to the body
(heart failure with ejection fraction Under 40%).
Preserved ejection fraction (HFpEF); also referred to as diastolic heart failure. The heart
muscle contracts normally but the ventricles do not relax as they should during ventricular
filling (heart failure with normal ejection fraction).
•
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6. Heart Failure Risk Factors:
High Blood Pressure (Hypertension)
Coronary Artery Disease
Past Heart Attack (Myocardial Infarction)
Abnormal Heart Valves
Heart muscle disease
Congenital Heart Defects;
Lung disease
Obesity
Other conditions (less commonly):
-Severe anemia (low red blood cell count)
-Hyperthyroidism (overactive thyroid gland)
-Arrhythmia (abnormal heart rhythm)
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7. Heart Failure Symptoms:
Shortness of Breath (Dyspnea); breathlessness during activity (most commonly), at
rest, or while sleeping, which may come on suddenly. Due to; the blood backs up in the
pulmonary veins, return blood from the lungs to the heart, because the heart can’t keep up
with the supply. This causes fluid to leak into the lungs.
Persistent Coughing or wheezing; Due to, the blood flow out of the heart slows, blood
returning to the heart through the veins backs up, causing fluid to build up in the tissues.
The kidneys are less able to dispose of sodium and water, also causing fluid retention in
the tissues
Lack of appetite and nausea. Due to ; the digestive system receives less blood,
causing problems with digestion.
Confusion or impaired thinking. Due to; changing levels of certain substances in the
blood. Such as sodium. Can cause confusing.
Increase heart rate (palpitation). Due to; loss in pumping capacity, the heart beats
faster.
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8. Pathophysiology of heart failure
Pump fails → decreased stroke volume /CO.
Compensatory mechanisms kick in to increase CO
The failing heart evokes three major compensatory
mechanisms to enhance cardiac output:
1.Increased sympathetic activity
2.Activation of the renin-angiotensin-aldosterone system
3.Myocardial hypertrophy & remodeling
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9. Pathophysiology of heart failure
1.Increased sympathetic activity:
Sympathetic nervous system stimulation → release of epinephrine/nor-
epinephrine
Increase HR
This results in an increased heart rate and a greater force of contraction
of the heart muscle (β1 receptors)
In addition, vasoconstriction (α
1
-mediated) enhances venous return and
increases cardiac afterload, which further reduces ejection fraction
and cardiac output
9

10. Packer. Progr Cardiovasc Dis. 1998;39(suppl I):39-52.Packer. Progr Cardiovasc Dis. 1998;39(suppl I):39-52.
 CNS sympathetic outflowCNS sympathetic outflow
Disease progressionDisease progression
 Cardiac sympatheticCardiac sympathetic
activityactivity

11--
receptorsreceptors

22--
receptorsreceptors

11--
receptorsreceptors
VasoconstrictionVasoconstriction
Sodium retentionSodium retention
Myocardial toxicityMyocardial toxicity
Increased arrhythmiasIncreased arrhythmias
 SympatheticSympathetic
activity to kidneysactivity to kidneys
+ peripheral vasculature+ peripheral vasculature
ActivationActivation
of RASof RAS

11--
11--
Sympathetic Activation in Heart FailureSympathetic Activation in Heart Failure

11. Pathophysiology of heart failure
2.Activation of the Renin-Angiotensin-Aldosterone system:
•A fall in cardiac output decreases blood flow to the kidney,
prompting the release of renin, with a resulting increase in the
formation of angiotensin II
•Increased angiotensin II production leads to increased aldosterone
secretion (with sodium and water retention) which augments
preload, to increased afterload, and to remodelling of both heart and
vessels
•Blood volume increases, and more blood is returned to the heart. If
the heart is unable to pump this extra volume, venous pressure
increases and peripheral edema and pulmonary edema occur
•Vascular resistance is further increased by angiotensin II
11

12. VasoconstrictionVasoconstriction
Oxidative StressOxidative Stress
Cell GrowthCell Growth ProteinuriaProteinuria
LV remodelingLV remodeling
Vascular remodelingVascular remodeling
AngiotensinogenAngiotensinogen
Angiotensin IAngiotensin I
Angiotensin IIAngiotensin II
AT I receptorAT I receptor
ReninRenin
AngiotensinAngiotensin
ConvertingConverting
EnzymeEnzyme
Compensatory Mechanisms: Compensatory Mechanisms:
Renin-Angiotensin-Aldosterone (RAAS)Renin-Angiotensin-Aldosterone (RAAS)

13. Pathophysiology of heart failure
3.Myocardial hypertrophy & remodelling:
•The heart increases in size, and the chambers dilate and become
more globular
•Initially, stretching of the heart muscle leads to a stronger
contraction of the heart
•However, excessive elongation of the fibers results in weaker
contractions, and the geometry diminishes the ability to eject
blood
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14. Classes of Heart Failure
A) The most commonly used classification system, the New York Heart Association
(NYHA) Functional Classification. It places patients in one of four categories based on how
much they are limited during physical activity.
Class I - No limitation of physical activity (i.e., ordinary physical activity does not
causes undue fatigue, palpitation or dyspnea.
Class II- Slight limitation of physical activity (i.e; comfortable at rest but during
ordinary physical activity results in fatigue, palpitation or dyspnea).
Class III- Marked limitation of physical activity (i.e.; comfortable at rest, less than
ordinary activity causes fatigue, palpitation or dyspnea).
Class IV- Unable to carry on any physical activity without discomfort (i.e.;
symptoms of heart failure at rest, if any physical activity is undertaken,
discomfort increases).
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15. B) The American College of Cardiology / American Heart Association (ACC/AHA)
Staging system (Objective Assessment); is defined by the following 4 stages.
Stage A -No objective evidence of cardiovascular disease.
-No symptoms and no limitation in ordinary physical activity.
Stage B -Objective evidence of minimal cardiovascular disease
-Mild symptoms and slight limitation during ordinary activity
Stage C -Objective evidence of moderately severe cardiovascular disease
-Marked limitation in activity due to symptoms, even during less- than- ordinary
activity
-Comfortable only at rest.
Stage D -Objective evidence of severe cardiovascular disease.
-Severe limitations.
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16. 16

17. Chronic Management of Congestive Heart Failure:
Goals of therapy
1- modify or control factors (e.g., Hypertension, obesity, diabetes)
2- manage structural heart disease
3- reduce morbidity and mortality
4- prevent or minimize Na and water retention
5- eliminate or minimize HF symptoms
6- Block compensatory neurohormonal activation caused by reduced cardiac
output (CO).
7- Slow progression of worsening cardiac function.
Treatment plan may include;
1- lifestyle Changes
2- Medications
3- Device Therapy
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18. Lifestyle Modifications
Quitting smoking
Monitoring Weight Changes
Dietary Changes
Sodium (Salt) Restriction; all patients with heart failure should limit
their sodium intake to less than 1.500 mg a day.
Avoid processed meats (hot dogs, sausage and bologna).
Aim to eat a diet that includes fruits and vegetables, whole grains, fat-
free or low-fat dairy products and lean proteins.
Limit the amount of saturated fat and cholesterol in the diet
Consume only a moderate amount of caffeine per day, no more than
a cup or two of coffee .
Avoid alcohol intake.
Exercise
Managing Stress
Fluid regulation
Developing support.
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19. Medications
Recently, there are 8 classes of drugs have been shown to be effective in
treatment of heart failure.
Depending on the :
1) severity of HF or 2) type of HF and 3) individual patient factors, one or
more of these classes of drugs are administered.
Treatment options of acute decompensated heart failure (ADHF) is
different from treatment options of chronic heart failure (CHF).
In acute decompensated heart failure (ADHF), the patient need hospitalization to
re-establish adequate perfusion and oxygen delivery to end organs.
The major drug classes used in ADHF include diuretics (reducing the fluid level)
inotropes (improve heart contraction, and vasodilators (decrease heart load).
First line therapy for people with CHF due to reduced systolic function (HF,rEF)
should include angiotensin- converting enzyme (ACE) inhibitors or angiotensin
receptor blocks (ARBs) with B-blockers.
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20. 1) Angiotensin converting enzyme (ACE) inhibitors
ADHFCHF

2) Angiotensin II Receptor blockers (ARBs) 
3) Angiotensin receptor Neprilysin inhibitors (ARNIs) 

4) -Adrenergic blocking agents (- Blockers)  

5. Diuretics A. Loop diuretics
 
  B. Thiazide diuretics
 
6. Aldosterone antagonists   
7. Vasodilators A. Hydralazine + Isosorbide dinitrate
 
 
  B. Na
+
Nitroprusside
or IV nitroglycerine
 
  C. Nesiritide
 
8. Inotropic agents A. Cardiac glycerides  
 
  B. -Adrenergic agonists
 
  C. Phosphodiesterase III inhibitors
 
- ADHF: Acute decompensated heart failure.
- CHF: Chronic heart failure
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21. 21

22.  
 
 
 
 
 
 
Drug
Captopril
Enalapril
Fosinopril
Lisinopril
Perindopril
Quinapril
Ramipril
Trandolapril
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23. 2. Angiotensin II receptor Blockers (ARBs)
- ARBs are recommended in patients with HFrEF with current or prior symptoms
who are unable to take an ACE inhibitor.
- ARBS are similar to ACE inhibitor which are discussed previously.
- ARBS have the advantage of more complete blockade of angiotensin II action.
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24. 24

25. Sacubitril is a pro-drug that is activated to LBQ657, which inhibits neprilysin
enzyme.
- Neprilysin, is an enzyme that breaks down natural vasoactive peptides
including natriuretic peptides and bradykinin, Thus, sacubitril increases the
levels of these peptides, causing vasodilation and reduction of expands
extracellular fluid (ECF) volume via  sodium excretion.
- The recommended starting dose of entresto is 49/51 mg (Sacubitril/Valsartan) twice
daily. Double the dose of Entresto® after 2 to 4 weeks t o the target maintenance dose
of 97/103 mg (Sacubitril/Valsartan) twice daily.
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26. 26

27. Benefits of -blockers (when added to an ACE inhibitor), decrease mortality
(35%). Decrease hospitalizations (25%) and improve symptoms.
- Should be initiated at a very low dose only, and do not discontinues
suddenly.
- Dose, start low and increase (double) the dose every 2 weeks (or slower, if
needed) to target dose, aim to achieve target dose in 8-12 weeks.
Drug
Bisoprolol
Carvedilol CR
Metoprolol Succinate (CR/XL)
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28. 28

29. - Dose start with a low initial dose, titrate according to the patient's weights and
diuresis.
- Monitoring serum K and Mg as needed especially with loop diuretics.
- Diuretics and Recommended dosing.
Loop
diuretics
Initial daily doseThiazide diureticsInitial daily
dose
Furosemid
e
20-20mg once or
twice
Hydrochlorothiazi
de
25mg once or
twice
Bumetani
de
0.5-1mg once or
twice
Chlorthalidone 12.5-25.0mg
once
Torsemi
de
10-20 mg once    
Furosemide is the most commonly used diuretics in HF.
For ADHF:
Diuretics considered first line therapy for management of ADHF associated with fluid
overload.
Most commonly used, furosemide 40mg orally = furosemide 20mg IV = bumetanide 1mg
IV or orally = torsemide 20mg IV or orally.
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30. 6. Aldosterone antagonists
- In addition to sodium and water retention, aldosterone has been
shown to cause coronary inflammation, cardiac hypertrophy, myocardial
fibrosis and ventricular arrhythmias.
- Spironolactone is a nonselective aldosterone antagonist,
Eplerenone is selective antagonist.
- Eplerenone has a lower incidence of endocrine related side
effects than spironolactone, due to its reduced affinity for glucocorticoid,
androgen and progesterone receptors.
Aldosterone antagonists are recommended in patients with:
Patients with NYHA class II-IV HF who have LVEF of 35% or less.
Patients with HFrEF after myocardial infarction.
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31. 31

32. 7. Vasodilators
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33. 33

34. 34

35. May, 2016; The American College of Cardiology (ACC), American Heart
Association (AHA), and Heart Failure Society of America (HFSA) recently
updated and added two new drugs to heart failure guidelines:
sacubitril/valsartan (Entresto®) and ivabradine (Procoralan®).
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36. 8. Inotropic agents
A. Cardiac Glycosides
Digoxin (Lanoxin®) Digitoxin (Unidigin®)Ouabain (Uabanin®)
Cardiac glycosides are a family of compounds that are derived from the foxglove
plant (Digitalis purpurea).
- Cardiac glycosides are organic compounds containing a glycoside often
called digitalis or digitalis glycosides.
-The therapeutic benefits of digitalis were first described in 1785.
Cardiac glycosides act on the contractile force of the cardiac muscle.
The most widely used agent is digoxin.
Digitoxin is seldom used due to its to its considerable duration of action.
Ouabain is a cardiac glycoside but is very rarely clinically used and obtained
from strophanthus gratus. It is commonly used in cell biological studies.
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37.     Digoxin Digitoxin Ouabain
  Routes of administration Oral & IV Oral Only IV only
Pharma-
cokinetics
 
Oral bioavailability 75% 90-100% 0%
  Half Life (t12) 36 hours (1.5 days) 7 days 21 hours
  Lipid solubility Moderate High Less
  Plasma protein binding 25% 95% 0%
  Potency Moderate High Less
  Elimination Kidneys Liver Kidneys
  Excreting Urine only Urine and feces Unine only
  Kidney dysfunction Not safe Safe Not safe
  Liver dysfunction Safe Not safe Safe
Plasma Normal 0.5-2 ng/ml 10-40ng/ml  
Levels Recommended
Toxic
0.5-0.9 ng/ml
>2ng/ml
----------
>45ng/ml
 
  Therapeutic index Extremely low Extremely low Extremely low
Pharmacokinetic
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38. Effects on the hearts:
+ve inotropic effect (increase force of contraction) by direct
effect on the heart.
-ve chronotropic effect (decrease heart rate) by direct effect and
vagal effect (unclear mechanism).
-ve dromotropic effect (reduces conduction velocity of electrical
impulses through the AV node).
Increase cardiac output and increase cardiac efficiency.
Decrease blood volume (diuresis due to  CO) in CHF only.
Kidney, diuretic effects only in CHF patients (due to it  CO   renal blood flow and  rennin release 
aldosterone release  Na
+
and water excretion.
Finally it cause, short strong systole with long diastole.
38

39. ATP
3 Na
+
3 Na
+
3 Na
+
3 Na
+
2 K
+
2 K
+
2 Ca
++
Ca
++
2 Ca
++
Ca
++
Ca
++
Ca
++
Sarcoplasmic
Reticulum
Myofibrils
L-Type Calcium
Channel
↑Na
+
39

40. 40

41. 41

42.  
Monitoring serum digoxin concentration (SDC)
42

43. Side effect of digitalis compounds
43

44. Digitalis toxicity
Factors that increase digitalis toxicity:
Drugs increase toxicity e. g. thiazide and loop diuretic (hypokalemia).
Organ dysfunction e. g. kidneys (Digoxin) and liver (digitoxin).
Dosing errors
Old age (> 70 years of age).
Serum electrolytes disturbances; hypokalemia, hypomagnesaemia or
hypercalcemia.
44

45. * Treatments of digitalis toxicity:
Digoxin immune Fab (Ovine) (Digibind®)
- Digoxin Immune Fab (Ovine), is a sterile lyophilized powder of antigen binding
fragments (Fab) derived from specific anti-digoxin antibodies raised in sheep.
- Digibind binds molecules of digoxin, making them unavailable for binding at
their site of action on cells in the body.
- Digoxin immune fab (Ovine), is indicated for treatment of potentially life-
threatening digoxin intoxication.
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46. B.  - Adrenergic Agonists (only for ADHDF)
Dopamine (intropin®) Dobutamine (Dbutrex®)
46

47. B. Phosphodiesterase III inhibitors (Only for ADHF)
Amrinone (Incor®) Milrinone (Primacor®).
Mechanism of action:
PDE III is present in cardiac muscle and vascular smooth.
PDE III responsible for degrades cAMP.
Inhibition of PDE III, cAMP cannot be inactivated  accumulation
of cAMP.
 cAMP in cardiac muscle  increase Ca
+2
influx  contraction of
the heart  + ve inotropic effect.
47

48. 48

49. 49

50. * Algorithm for pharmacologic management of HFrEF
50

51. General treatment goals of diastolic dysfunction:
- Control hypertension.
- Control tachycardia.
- Reduce preload.
- Aggressively investigate, repair and treat myocardial ischemia.
Pharmacologic therapy for diastolic dysfunction:
- ACE inhibitors or ARBs: reduce hospitalizations and treat
hypertension.
- - blockers verapamil and diltiazem: benefits are targeted symptoms
relief.
- Digoxin; no effect on all cause mortality or on all cause CV
hospitalizations.
Diastolic HF
51
* Management of HF
PEF or Diastolic dysfunction:

52. 52

53. Device therapy
Implantable cardioverter defibrillator (ICD) and cardiac resynchronization (CR)
is a small device that’s placed in the chest or abdomen. Act by generation of electrical
pulses or shocks to help control life threatening arrhythmias, especially those that can
cause sudden cardiac arrest (SCA).
- ICD have one or two wires, called leads, CRT system adds a third, attaching a lead
to the left ventricle.
- ICD: recommended for primary prevention of sudden cardiac death.
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