Last Updated 2-2015

1. CV Pharmacology
Pharmacological Management of
Congestive Heart Failure
Prepared and Presented by:
Marc Imhotep Cray, M.D.
BMS & CK Teacher
Companion Reading (Notes):
Pharmacological Treatment of
Heart Failure (Klabunde)
Drugs Acting on the
Cardiovascular System (Cray)
Formative Assessment
Cardiovascular Pharmacology
Review Test
Clinical:
e-Medicine article
Congestive Heart Failure and
Pulmonary Edema
http://www.emedicine.com/emerg/TOPIC108.HTM

2. 2
Learning Objectives:
1. Understand the underlying hemodynamic
abnormalities in heart failure and the therapeutic
approaches to its treatment
2. Understand the properties of angiotensin
converting enzyme inhibitors, angiotensin II
receptor blockers and vasodilators used to treat
heart failure and the rationale behind their use
3. Understand the properties of intravenous agents
(dobutamine, dopamine and PDE inhibitors) used in
the treatment of heart failure
4. Understand the actions of beta blockers and the
rationale for their use in the treatment of heart
failure
5. Know the pharmacologic action, toxicities and uses
of cardiac glycosides
By the end of this presentation the
learner should:

3. 3
Definition of HF
 Chronic heart failure (HF) is an imbalance in
pump function in which heart fails to
adequately maintain circulation of blood.
 The most severe manifestation of HF,
pulmonary edema, develops when this
imbalance causes an increase in lung fluid
secondary to leakage from pulmonary capillaries
into the interstitium and alveoli of the lung…
See cloud e-Medicine Article
Congestive Heart Failure and Pulmonary Edema

4. 4
Classification of HF
1. The side of the heart involved, (left heart
failure versus right heart failure)
2. Whether the abnormality is due to
contraction or relaxation of the heart
(Systolic Dysfunction vs. Diastolic
Dysfunction )
3. Whether the problem is primarily increased
venous back pressure (behind) the heart,
or failure to supply adequate arterial
perfusion (in front of) the heart
(backward vs. forward failure)
4. Whether the abnormality is due to low
cardiac output with high systemic vascular
resistance or high cardiac output with low
vascular resistance (low-output heart
failure vs. high-output heart failure)
5. The degree of functional impairment
conferred by the abnormality (as in the
NYHA functional classification)
There are many different ways to
categorize heart failure, including:

5. 5
Congestive Heart Failure: Causes
•Myocardial infarction
•Coronary artery disease
•Valve disease
•Idiopathic cardiomyopathy
•Viral or bacterial cardiomyopathy
•Myocarditis
•Pericarditis
•Arrhythmias
•Chronic hypertension
•Thyroid disease
•Pregnancy
•Septic shock

6. 6
Congestive Heart Failure:
Causes (cont.)
1. Arrhythmias: In patients with heart disease and with a
history of congestive failure, an acute arrhythmia is a
common precipitating cause of HF
 Tachyarrhythmias decrease filling time and as a result
decrease cardiac output
 A-V dissociation results in loss of the atrial contribution to
ventricular filling.
 end-diastolic volume is reduced with an attendant reduction in
cardiac output
 Abnormal intraventricular conduction may cause a reduced
synchronicity of contraction with a reduction in myocardial
performance
 Severe bradycardia in the absence of increased stroke
volume can seriously reduce cardiac output and thus precipitate
HF
 Increased stroke volume may not be possible if the patient has
significant heart disease

7. 7
Congestive Heart Failure:
Causes (cont.)
2. Myocardial Infarction: A myocardial infarction, reducing left
ventricular function, may precipitate HF in a previously
hemodynamically compensated patient
3. Pulmonary Embolism: Physically inactive patients with low
cardiac output may develop deep venous thrombi which may produce
pulmonary emboli and elevation of pulmonary arterial pressure
• Increased pulmonary artery pressure may worsen or cause left
ventricular failure
4. Systemic Hypertension: Rapid increases in arterial blood
pressure with associated increases in peripheral resistance can increase
afterload to an extent sufficient to produce heart failure.

8. Congestive Heart Failure:
Causes (cont.)
8
5. Other causes:
• Thyrotoxicosis
• Pregnancy
• Infection
• Anemia
• Rheumatic and other
forms of Myocarditis
• Physical, dietary, fluid
• Environmental and
emotional excesses
• Infective Endocarditis

9. 9
Pathophysiology in HF
 HF is summarized best
as an imbalance in
Starling forces or an
imbalance in the
degree of end-diastolic
fiber stretch
proportional to the
systolic mechanical
work expended in an
ensuing contraction.
http://www.cvpharmacology.com/clinical topics/heart failure-2.htm
Cardiac and Vascular
Changes Accompanying
Heart Failure
Cardiac
Decreased SV and CO
Increased end-diastolic
pressure
Vascular
Increased SVR
Decreased arterial pressure
Decreased venous compliance
Increased venous pressure
Increased blood volume

10. Pathophysiology in HF(2)
10
Compensatory Mechanisms During Heart Failure
Cardiac
Frank-Starling mechanism
Ventricular dilation or hypertrophy
Tachycardia
Autonomic Nerves
Increased sympathetic adrenergic activity
Reduced vagal activity to heart
Hormones
Renin-angiotensin-aldosterone system (RAAS)
Vasopressin (antidiuretic hormone/ADH)
Circulating catecholamines
Natriuretic peptides

11. 11
Pathophysiology in HF (2)
 The fundamental abnormality in
heart failure is embodied in:
 depression of the myocardial
force-velocity relationship and
length-active tension curves that
result in impairment of
myocardial contractility (see
Figure, right)
 When a normal heart transitions
from the resting state (1) to exercise
(2) a significant increase in
ventricular performance occurs.
 By contrast in the failing heart, the
exercise-induced increases in
ventricular performance are minimal
(3' to 3).
From: http://www.pharmacology2000.com/Cardio/HF/HFobj1.htm

12. The renin-angiotensin-
aldosterone system (RAAS)
12
Source: http://cvphysiology.com/BloodPressure/BP015.htm

13. Physiologic Effects of AII
13
N.B.The RAAS is modulated by natriuretic peptides (ANP and
BNP) released by the heart. These natriuretic peptides acts as
an important counter-regulatory system
Constricts resistance vessels (via AII [AT1] receptors) thereby
increasing systemic vascular resistance and arterial pressure
Stimulates sodium transport (reabsorption) at several renal tubular
sites, thereby increasing sodium and water retention
Acts on adrenal cortex to release aldosterone, which in turn acts on
kidneys to increase sodium and fluid retention
Stimulates release of vasopressin (antidiuretic hormone, ADH) from
the posterior pituitary, which increases fluid retention by kidneys
Stimulates thirst centers within the brain
Facilitates norepinephrine release from sympathetic nerve endings
and inhibits norepinephrine re-uptake by nerve endings, thereby
enhancing sympathetic adrenergic function
Stimulates cardiac hypertrophy and vascular hypertrophy

14. 14
Source: http://www.mc.uky.edu/pharmacology/instruction/pha824hf/PHA824hf.html
Pathophys. & Pharm. in HF Illustrated

15. Clinical Perspective and
Considerations
15
Heart failure, inability of circulatory system to meet
metabolic demands of body, is a multifaceted “disease
state” (syndrome) involving several organ systems
and neurohumoral factors including heart, kidney,
vascular system and brain
There are several forms of heart failure with multiple
etiologies
The treatment of heart failure is a particularly
difficult therapeutic problem with no single drug or
drug class adequate to provide complete relief from
the signs and symptoms of the syndrome

16. Clinical Perspective and
Considerations (2)
16
The drugs used and their specific therapeutic
approaches depend on underlying pathophysiology and
severity of the disease
While drug therapy is capable of symptomatic relief, it
does not correct the underlying pathology
Regardless of treatment, 50 % of individuals die within
5 years of developing HF.
In an era where morbidity and mortality from other
cardiovascular diseases are decreasing, deaths from HF
are increasing

17. Framingham Criteria for
Congestive Heart Failure
17
Diagnosis of HF requires the simultaneous presence of at
least 2 major criteria or 1 major criterion in conjunction with
2 minor criteria.
Major criteria:
•Paroxysmal nocturnal dyspnea
•Neck vein distention
•Rales
•Radiographic cardiomegaly (increasing heart size on chest
radiography)
•Acute pulmonary edema
•S3 gallop
•Increased central venous pressure (>16 cm H2O at right
atrium)
•Hepatojugular reflux
•Weight loss >4.5 kg in 5 days in response to treatment

18. Framingham Criteria for
Congestive Heart Failure (2)
18
Minor criteria:
•Bilateral ankle edema
•Nocturnal cough
•Dyspnea on ordinary exertion
•Hepatomegaly
•Pleural effusion
•Decrease in vital capacity by one third from maximum
recorded
•Tachycardia (heart rate>120 beats/min.)
N.B. Minor criteria are acceptable only if they can not be
attributed to another medical condition (such as
pulmonary hypertension, chronic lung disease, cirrhosis,
ascites, or nephrotic syndrome)
http://www.fpnotebook.com/CV/Exam/FrmnghmHrtFlrDgnstcCrtr.htm

19. 19
New York Heart Association (NYHA)
Functional Classification
 The New York Heart Association (NYHA)
Functional Classification provides a simple
way of classifying the extent of heart failure
 It places patients in one of four categories
based on how much they are limited during
physical activity
 limitations/symptoms are in regards to
normal breathing and varying degrees in
shortness of breath and or angina pain
http://www.fpnotebook.com/CV/Exam/FrmnghmHrtFlrDgnstcCrtr.htm

20. 20
New York Heart Association (NYHA)
Functional Classification (2)
NYHA Class Symptoms
I
No symptoms and no limitation in ordinary physical
activity, e.g. shortness of breath when walking,
climbing stairs etc.
II
mild symptoms (mild shortness of breath and/or
angina) and slight limitation during ordinary activity.
III
Marked limitation in activity due to symptoms,
even during less-than-ordinary activity, e.g. walking
short distances (20-100 m). Comfortable only at rest.
IV
Severe limitations. Experiences symptoms even
while at rest. Mostly bedbound patients.
Source: http://www.medicalcriteria.com/criteria/nyha.htm

21. 21
Rationale for Drug Therapy (Clickable)
 The primary goal of drug
therapy in heart failure is
to improve cardiac function
and reduce the clinical
symptoms associated with
heart failure (e.g., edema,
shortness of breath,
exercise intolerance). B D= Vasodilator Effect
B E= Inotropic Effect

22. DRUGS AND DRUG CLASSES USED
TO TREAT HEART FAILURE
(See last slide for complete list)
22
1. Vasodilators - Drugs that decrease either preload or
afterload
 ACE inhibitors, AT1 blockers, and other vasodilators and
diuretics
a) Arterial selective vasodilators decrease PVR and afterload
on the failing myocardium
 reduction in afterload leads to an increased CO and improved tissue
perfusion
b) Venous selective vasodilators increase venous capacitance,
thus decreasing preload
 A small reduction in venous tone can result in a pooling of large amounts
of blood
 This would decrease left ventricular filling pressure and pulmonary
congestion

23. DRUGS AND DRUG CLASSES USED
TO TREAT HEART FAILURE (2)
23
c) The major vasodilators used are ACE inhibitors and
angiotensin II receptor antagonists (ARBs)
d) Other agents include organic nitrates, hydralazine and
nitroprusside ( all 3 reduce both preload & afterload)
e) In addition, diuretics promote the elimination of
edematous fluid, improving tissue perfusion and
pulmonary function
N.B. Chronic thiazide diuretic Tx also results in relaxation
of resistance vessels)

24. DRUGS AND DRUG CLASSES USED
TO TREAT HEART FAILURE (3)
24
2. Positive Inotropic Agents Drugs that increase
contractile force; beta1 receptor agonists, cAMP PDE
inhibitors, cardiac glycosides
3. Beta blockers (not acute HF, but decrease mortality in
chronic HF)
4. Diuretics Cornerstone drugs in the treatment of heart
failure. Noteworthy are loop diuretics and aldosterone
receptor antagonists.
N.B. In addition to effects on circulatory system, some of
these agents also block the cellular responses that lead to
cardiac remodeling and hypertrophy

25. 25
Overview of HF Pharmacological
Management
Treatment of HF aims
 to relieve symptoms,
 to maintain a euvolemic state (normal fluid
level in the circulatory system), and
 to improve prognosis by delaying
progression of heart failure and reducing
cardiovascular risk

26. 26
Overview of HF Pharmacological
Management(2)
Drugs used include:
1. diuretic agents,
2. vasodilator agents,
3. positive inotropes,
4. ACE inhibitors,
5. beta blockers,
6. aldosterone antagonists
Related Terms:
1. contractility (inotropy),
2. heart rate (chronotropy)
3. conduction velocity
(dromotropy)

27. 27
Overview of HF Pharmacological
Management (3)
Angiotensin-modulating agents
 ACE inhibitor (ACE) therapy is recommended
for all patients with systolic heart failure,
irrespective of symptomatic severity or blood
pressure
 ACE inhibitors improve symptoms, decrease mortality
and reduce ventricular hypertrophy
 Angiotensin II receptor antagonist therapy
(also referred to as AT1-antagonists or
angiotensin receptor blockers/ARBs), particularly
using candesartan, is an acceptable alternative
if the patient is unable to tolerate ACEI therapy

28. 28
Overview of HF Pharmacological
Management(4)
Angiotensin-modulating agents cont.
 ACEIs and ARBs decrease afterload by
antagonizing the vasopressor effect of
angiotensin, thereby decreasing the amount of
work the heart must perform
 It is also believed that angiotensin directly
affects cardiac remodeling, and blocking its
activity can thereby slow deterioration of
cardiac function

29. Cardiorenal Effects of ACEIs
29
Vasodilation (arterial &
venous)
- reduce arterial & venous
pressure
- reduce ventricular afterload &
preload
Decrease blood volume
- natriuretic
- diuretic
Depress sympathetic activity
Inhibit cardiac and vascular
hypertrophy
http://cvpharmacology.com/vasodilator/ACE.htm

30. Overview of HF Pharmacological
Management (5)
30
Many ACE inhibitors have been developed
 Captopril was the first agent developed and hence is the
prototype
Enalapril is a prodrug that is de-esterified by plasma esterases
to enalaprilat
Most of the ACEIs are activated in this fashion
Benazepril - Metabolized to benazeprilat
Captopril
Enalapril - Metabolized to enalaprilat
Fosinopril - Metabolized to fosinoprilat
Lisinopril
Moexipril- Metabolized to moexiprilat
Quinapril - Metabolized to quinaprilat
Ramipril - Metabolized to ramiprilat
Trandolapril-Metabolized to tandolaprilat
Perindopril - metabolized to perindoprilat

31. 31
Overview of HF Pharmacological
Management (6)
Commonly used Angiotensin Converting Enzyme (ACE) Inhibitors

32. 32
Overview of HF Pharmacological
Management(7)
MOA of Angiotensin Converting Enzyme (ACE) Inhibitors

33. 33
Overview of HF Pharmacological
Management (8)
Diuretics
 Diuretic therapy is indicated for relief of congestive
symptoms. Several classes are used, with
combinations reserved for severe heart failure
 Loop diuretics (e.g. furosemide, bumetanide) –
most commonly used class in HF, usually for
moderate HF
 Thiazide diuretics (e.g. hydrochlorothiazide,
chlorthalidone, chlorthiazide) – may be useful for
mild HF, but typically used in severe HF in
combination with loop diuretics, resulting in a
synergistic effect

34. 34
Overview of HF Pharmacological
Management (9)
Diuretics cont.
 Potassium-sparing diuretics (e.g.
amiloride) – used first-line use to correct
hypokalaemia.
 Spironolactone is used as add-on therapy
to ACEI plus loop diuretic in severe HF
 Eplerenone (Inspra®) is specifically
indicated for post-MI reduction of
cardiovascular risk

35. 35
Overview of HF Pharmacological
Management (10)
Beta blockers
 Until recently (within the last 20 years), β-
blockers were contraindicated in HF, owing to
their negative inotropic effect and ability to
produce bradycardia – effects which worsen
heart failure
 However, current guidelines recommend β-
blocker therapy for patients with systolic heart
failure due to left ventricular systolic dysfunction
after stabilization with diuretic and ACEI therapy,
irrespective of symptomatic severity or blood
pressure

36. 36
Overview of HF Pharmacological
Management (11)
Beta blockers cont.
As with ACEI therapy, the addition of a β-blocker can
decrease mortality and improve left ventricular function
 Several β-blockers are specifically indicated for HF
including:
1. bisoprolol,
2. carvedilol, and
3. extended-release metoprolol
antagonism of β1 inotropic and chronotropic effects decreases
the amount of work the heart must perform

37. 37
Overview of HF Pharmacological
Management (12)
Beta blockers cont.
It is also thought that catecholamines and
other sympathomimetics have an effect
on cardiac remodeling, and blocking their
activity can slow the deterioration of
cardiac function
See: The Importance of Beta Blockers in the Treatment of Heart Failure
American Academy of Family Physicians

38. Overview of HF Pharmacological
Management (13)
38
CARDIAC GLYCOSIDES (Digitalis )
(Some history)
Cardiac glycosides are one of the oldest
groups of drugs used in cardiovascular
therapeutics
There is evidence of use in Egyptian and
Roman times
William Withering published medical accounts
of use of the "foxglove" for the treatment of
"dropsy."
Originally, extracts of d. purpurea were used
 Two active principals, digoxin and digitoxin,
are now used in cardiovascular therapeutics
The uses of these drugs are in heart failure
and supraventricular tachyarrhythmias.
These agents have a low therapeutic index
Digitalis purpurea
(Common Foxglove)

39. 39
Overview of HF Pharmacological
Management (14)
Positive inotropes
 Digoxin / Cardiac glycosides (a mildly positive inotrope
and negative chronotrope), once used as first-line therapy,
is now reserved for control of ventricular rhythm in
patients with atrial fibrillation; or where adequate control is
not achieved with an ACEI, a beta blocker and a loop
diuretic
 There is no evidence that digoxin reduces mortality in HF,
although some studies suggest a decreased rate in hospital
admissions
 It is contraindicated in cardiac tamponade and restrictive
cardiomyopathy
N.B. Cardiac glycosides not first line Tx for HF due to risk of toxicities

40. 40
Overview of HF Pharmacological
Management(15) Cardiac glycosides
Mechanism of Positive
Inotropic Action
 Cardiac glycosides inhibit the
myocardial cell Na+, K+, ATPase
 This enzyme is responsible for
maintaining ionic gradient of
myocardial cell.
 Inhibition of the Na+, K+,
ATPase results in an increase in
intracellular Na+. Decrease in
Na+ gradient diminishes
exchange of Na+ for Ca2+
 Increase in intracellular Ca2+ is
responsible for the positive
inotropic action
http://cvpharmacology.com/cardiostimulatory/digitalis.htm

41. 41
Antiarrhythmic Actions
 Cardiac glycosides also work in the carotid arch and
baroreceptors to increase the sensitivity of these sites
results enhanced neural traffic to CNS
cardiovascular centers resulting in enhanced vagal outflow
to the myocardium
 At the SA node this increase in vagal tone:
1. Increases SA nodal refractory period
2. Slows SA nodal conduction velocity
 At the AV node (major site of antiarrhythmic action)
the increase in vagal tone:
1. Increases AV nodal refractory period
2. Slows AV nodal conduction velocity
Overview of HF Pharmacological
Management(15) Cardiac glycosides

42. 42
Pharmacokinetics of Cardiac Glycosides
AGENT
GASTRO
INTESTINAL
ABSORPTION
ONSET
OF
ACTION
(MIN)
PEAK
EFFECT
(HR)
AVERAG
E HALF
LIFE
PRINCIPAL
METABOLIC
ROUTE
(EXCRETORY
PATHWAY)
AVERAGE
DIGITALIZING
DOSES
USUAL
DAILY ORAL
MAINTENAN
CE DOSESoral IV
Digoxin 30 to 100% 15 to 30 1 1/2 to 5
36 to 48
hours
Renal; some
gastrointestinal
excretion
1.25 to
1.5 mg
0.75 to
1.00 mg
0.25 to 0.5 mg
Digitoxin 90 to 100% 25 to 120 4 to 12
4 to 6
days
Hepatic; renal
excretion of
metabolites
0.7 to
1.2 mg
1.00 mg 0.1 mg
Special Considerations / Next Slide
Overview of HF Pharmacological
Management(16) Cardiac glycosides

43. Special Considerations
43
Factors that can alter the therapeutic response
to cardiac glycosides:
 Renal disease decreased renal clearance of digoxin
 Drug Interactions that:
a) Decrease bioavailability Cholestyramine
b) Decrease renal clearance Amiodarone ,Verapamil ,
Quinidine

 Hypokalemia and Electrolytes
Hypokalemia increases the likelihood of toxicity
Alterations in potassium levels could be exacerbated
by co-administration of diuretics
 Age elderly are more sensitive to cardiac glycosides
 Hypoxia increases the likelihood of toxicity

44. 44
Positive inotropes cont.
 The inotropic agent dobutamine is advised only in the
short-term use of acutely decompensated heart failure,
and has no other uses (Bata1 receptor agonist)
 Phosphodiesterase inhibitors such as milrinone are
sometimes utilized in severe cardiomyopathy (increase
cAMP/See phosphodiesterase inhibitors )
 The mechanism of action is through antagonism of
adenosine receptors, resulting in inotropic effects and
modest diuretic effects
Overview of HF Pharmacological
Management(17)

45. 45
Alternative vasodilators
 The combination of isosorbide dinitrate/hydralazine is the
only vasodilator regimen, other than ACE inhibitors or
angiotensin II receptor antagonists, with proven survival
benefits
 This combination appears to be particularly beneficial in
HF patients with an African American background, who
respond less effectively to ACEI therapy
See next slide
Overview of HF Pharmacological
Management (18)

46. Overview of HF Pharmacological
Management (19)
46
Exner DV, Dries DL, Domanski MJ, Cohn JN (2001). "Lesser
response to angiotensin-converting-enzyme inhibitor therapy
in black as compared with white patients with left ventricular
dysfunction". N Engl J Med. 344 (18): 1351–7.
doi:10.1056/NEJM200105033441802.
Taylor AL, etal; (2004). African-American Heart Failure Trial
Investigators. "Combination of isosorbide dinitrate and
hydralazine in blacks with heart failure". N Engl J Med 351
(20): 2049–57. doi:10.1056/NEJMoa042934.

47. 47From: Medical Pharmacology at a Glance, 7th Ed. Michael J. Neal. 2012 John Wiley & Sons, Ltd: Pg. 49
Drugs Used in Heart Failure:
Schematic Summary

48. END OF PRESENTATION
THANK YOU FOR YOUR
ATTENTION
48

49. Recommended links and resource
for further study:
Cardiovascular Physiology
Concepts, 2nd edition,
LLW (2011)
Diuretics
- thiazide diuretics
- loop diuretics
- natriuretic peptides
Vasodilators (dilate arteries and veins)
- angiotensin converting enzyme (ACE) inhibitors
- angiotensin receptor blockers (ARBs)
- direct acting arterial dilators
- nitrodilators
- natriuretic peptides
- phosphodiesterase inhibitors
Cardiostimulatory or inotropic drugs (stimulate contractility)
- digitalis
- beta-agonists (sympathomimetic drugs)
- phosphodiesterase inhibitors
Cardioinhibitory
- beta-blockers
- calcium-channel blockers (for diastolic dysfunction)
Classes of drugs used in the treatment of heart failure by Richard E.
Klabunde, PhD are given below. Clicking on the drug class will link
you to the page describing the pharmacology of that drug class.