OUTCOMES:

I
At the end of the session
the students will b e able
to:
• Identify the
different drugs used for
congestive heart failure.
• Understand the
drug's mechanism of
action used for
CHF.
 • ••• • •
OUTLINE:
• Definition
• Classes of CHF
• F o r m s of CHF
• Pathophysiology
• Tr e a t m e n t
 • ••• • •
READINGS:
• Katzung, B.G. et al.
I Basic and Clinical
Pharmacology, 14 t h
edition
• Wecker, L. ( 20 18) .
Brody's Human
Pharmacology,
6th Edition.
Mechanism­ Based
Therapeutics
 •• • •• •
Watch these Videos:
(FORMS of CHF)
https://www.physio-
pedia.com/Pharmacological Management of Congestive Heart Failure
(Mechanism of action of Digoxin)
https:ljwww.youtube.com/watch?v=T4NujeyPTAo

INOTROPES - Modes of action

https://www.youtube.com/watch?v=7fYiEtz6zXk

Congestive Heart Failure: Left-sided vs Right-sided, Systolic vs

Diastolic, Animation.
https://www.youtube.com/watch?v=b30HSA7Tz7U
 •
HEART
,
FAILURE
- - - - - - - - -

, •!• cardiac disorder that

impairs the ability of the
ventricle to deliver
adequate quantities of
blood to the
metabolizing tissues
during normal activity or
at rest
Healthy Heart Congested Heart
 CLASSES OF HEART
FAILURE
CLASS degree of effort necessary to elicit HF
I symptoms equals to those that would
limit normal individuals.
CLASS symptoms occurs with ordinary exertion
II
CLASS symptoms occurs with less- than-ordinary
Ill exertion.

CLASS IV symptoms occurs while at rest

 Forms of Heart
Failure
LOW OUTPUT VS HIGH OUTPUT

LOW HIGH OUTPUT

Metabolic demands
OUTPUT are INCREASED
Metabolic demands are (hyperthyroidism
NORMAL but heart is
anemia)a nd the heart is
unable to meet them
unable to meet them
 Forms of Heart
Failure
DIASTOLIC VS SYSTOLIC
DYSFUNCTION

DIASTOLIC
• DYSFUNCTIO
Res ult of hypert rophy an
d
Nst iffen ing of myocardium,
• reduced
Re d u cedfilling
CO,
normal fraction
ejection
Does not respond to
• inot ropic dru
gs t.,cft vc n t:rk le
d o e s n ot
e je c t R 1fftd en t b lood .

'

H e .:,,rt m u ,..i;l:e 1,
_

k .,nd no t
DUfYIPl"l:I, pro pe tt v
IGHT-SIDED FAILURE VS. LEFT-SIDED FAILUR

.------
Congestion of peripheral tissues Decreased card.ac o ut
pu t

Oedema
Activity intolerance I Pulmonary

1nd asc,tes
I Uver congestion I igns of decre_ased
issue petfusion
congest.ion

lm •red Cyanos&S and sqins of

liver function hypoxa

GI tract congestion Cough w,th

frothy
I
Anor.-xla GI dltt n s s WPurht l o s s I sputum

PERIPHERAL PULMONARY
EDEMA EDEMA
 Signs and symptoms of all
types of
HF
Tachycardia Normal EKG

Decreased exercise
tolerance
Shortness of breath
Cardiomegaly E n l a rg od h o
1;1r1 t
 PATHOPHYSIOLOGY
HF and decreased cardiac output trigger a
complex scheme of compensatory
mechanisms designed to normalize
cardiac output.
A.
COMPENSATION
1. SYMPATHETIC RESPONSES
2. HORMONAL STIMULATION
 CHF Vicious
Cycle low OUTPUT
Inc. Preload Inc. Afterload ! Renal Blood

l
Flow

Vasoconst iction
Inc. salt Inc. Norepinephrine
RENIN
3.CONCENTRIC CARDIAC
HYPERTROPHY

4. FRANK-STARLING MECHANISM
-
increased fiber dilation heightens the
contractile force, which then
increases the energy released.
,
·,
''
"'
"""
"
""
' ,,,""
'
,,"" ",
-----=- :.::.,.;..",'
 B.
DECOMPENSATION
AFTERLOAD
- tension in ventricular muscles during
contraction.

In the left ventricle, this tension is

determined by the amount of force needed to
overcome pressure in the pulmonary artery.
PRELOAD - force exerted on the ventricular
muscle at the end of diastole that determines
the degree of muscle fiber stretch.

Also known as ventricular end diastolic

pressure; also a key factor in contractility.
 TREATMENT
GOALS
A. To remove or mitigate the
underlying causes or risk factors
- by eliminating ingestion of certain
drugs or other substances
PHARMACOLOGI
C TREATMENT
1.
Digoxin
Used in conjunction with diuretics, ACE
inhibitors, -adrenergic blockers to
improve the symptoms and clinical
status of patients with HF
 Aglycon
e
(genin) H 20 22 l
O actone

11 1 1
19
3 6
H3C , .H 14
H
15
1 8 O
0 B
3 5 H
Sugar - 0

Steroi
d
 Ouabain Digoxin Digitoxin
Lipid Low Medium High
solubility
(oiVwater
coefficient
)
Oral 0 75 >90
availability
(percentag
e
absorbed)
Half-life in 21 40 168
body
(hours)
 Ouabain Digoxin Digitoxin

Plasma 0 20-40 > 90

protein
binding
(percentage
bound)
Percentage 0 <40 > 80
metabolized
Volume of 18 6.3 0.6
distribution
(L/kg)
 Digoxin Digitoxin
Antibiotics can affect
the concentration of
digoxin
metabolized in the liver
Excretion: kidneys Excretion: into the gut via
Its renal clearance is the bile.
proportional to creatinine
clearance

Renal impairment does

adjust digoxin dosage in not significantly
patients with renal prolong
 Cardiac glycosides

MECHANISM OF ACTION

inhibit Na+/K+ ATPase, the

membrane-bound transporter
often called the sodium
pump.C a ++
N a+ N a ·, c a -
l is N a · /K' - K
+

AT P a s e

I
r:i--- D i gi
ta
jca•• ! Na •
i
'i' T N- C - - i 1n o tr op
Ca .. b i n d i n g
y

htt ps:lj www.yout ube .co m/watch?v=T4NujeyPTAo

Mechanical
Effects
• Increase contractility of the
heart muscle
• by increasing the free
calcium
concentration
• (+) inotropic effect / I
Mechanical Effects
•The increase in calcium
concentration is the result of
a two-step process:

1. Na+/K+ ATPase inhibition

2.reduction of calcium I
expulsion
I
 Electrical
Effects
• mixture of direct and autonomic actions.

decrease in action potential

•as a result of increased potassium conductance
that is caused by increased intracellular
calcium.

**Shortening of the action potential

contributes to the shortening of atrial and
ventricular refractoriness
 Tissue

Variable Atrial AV Node Purkinje

Muscle System,
Ventricles

Effective !(PANS} j(PANS} !(Direct}

refractory
period

Conduction i (PANS) t (PANS) Negligible

velocity
 Tissue
Variable Atrial AV Node Purkinje
Muscle System,
Ventricles
Automaticity j(Direct) j(Direct) j(Direct)

Electrocardio
gram
Before Negligible j PR t QT interval; T
arrhythmias interval wave 1• nvers1• on;
ST
segment
depression
Effects on Other Organs

•gastrointestinal tract
•Anorexia
•Nausea
•Vomiting
•Diarrhea
Central nervous system effects

•vagal and chemoreceptor zone

stimulation.
•disorientation and
hallucinations
-especially in the elderly
•visual disturbances
•Agitation and convulsions
•Gynecomastia
• is a rare effect
• it is not certain whether this effect
represents a peripheral estrogenic action
of these steroid drugs or a
manifestation of hypothalamic
stimulation.
 THERAPEUTIC EFFECTS of
DIGOXIN
POSITIVE INOTROPIC EFFECTS
DEACTIVATION OF rennin-angiotensin-
aldosterone compensation
 Digoxin

•available in tablet, injection, elixir

and capsule forms.

•With narrow therapeutic index

DOSAGE AND ADMINISTRATION of Digoxin

Therapeutic plasma 0.5-1.5 n g / m l

concentration
Toxic plasma > 2 ng/ml
concentration
Daily dose (slow loading 0.25 (0.125-0.5) mg
or maintenance)
Rapid digitalizing dose 0.5-0.75 m g every 8
(rarely used) hours for three doses
PRECAUTIONS AND MONITORING
EFFECTS
A.
POTASSIUM

•t
• -- potassium levels
• favor
cardiacdigoxincells binding to
and increase its effect

digitalis toxicity
•t potassium levels
•decrease digoxin binding and effect.
--
•!•Thisis likely in patientstaking potassium,or a
captopril-like agent.
 B. CALCIUM
ions

•act synergistically with digoxin

•tc a lcium jt orce of myocardial contraction.
 C. MAGNESIUM levels

• inversely related to digoxin activity.

• ..J n agne s ium -t" tox icity

A. RISK OF
TOXICITY
• increases with coadminstration
of:
•Quinidine, propafenone,
•verapamil, spironolactone
•flecainide, and amiodarone

*****Quinidine decreases the

renal clearance of Digoxin
B. SIGNS OF
TOXICITY

1. Anorexia, a common and early sign

2. Fatigue, headache, and malaise
3. Nausea and vomiting
4. Mental confusion and disorientation
 B. SIGNS OF
TOXICITY
•!•Alterationin visuaI perceptions (blurring,
yellowing, a halo effect)
•!•Cardiac effects
•!•premature ventricular contractions and
ventricular tachycardia and fibrillation
•!•SA and AV block
•!•Atrial tachycardia and AV block
 . TREATMENT OF
TOXICITY Management/ Antidote
If the patient is Administer potassium
hypokalemic: supplements

Arrhythmias lidocaine or phenytoin

Cholestyramine binds to digitalis glycosides to

prevent absorption of digitalis
in the bile.
Patients with very purified digoxin Fab fragment
high serum digoxin antibodies.
levels
Other drugs used in CHF
 Fluid
retention
in lungs

Sall
Fluld
retention
In body
 Diuretics

MOA: to reduce venous pressure and ventricular

preload GOAL: to reduce and eventually eliminate signs
and symptoms of fluid retention and peripheral
edema.
THIAZIDE diuretics lose their effectiveness in HF
patients with moderately impaired
renal function
LOOP diuretics increase sodium excretion to 20-25% of
the filtered load
reverse pulmonary edema
POTASSIUM­ Given to patients already on Digoxin or
SPARING ACE inhibitors
 Vasodilators

reduce pulmonary congestion

effective in acute heart failure because they provide a
reduction in preload (through venodilation), or reduction in
afterload (through arteriolar dilation), or both

NITROPRUSSIDE provide potent dilation of both arteries

and veins

HYDRALAZINE decreases afterload and increases

cardiac output.

PRAZOSIN arteriovenous dilator

NITRATES decreases preload

reduce damaging remodeling of the heart

HYDRALAZI NE + Reduce b o t h preload and

n afterload
itrosovasod iIators
with ISOSORBIDE
DINITRATE reduce afterload

with NITROGLYCERIN
reduce preload
 ACE
INHIBITORS
first line agents in the treatment of HF
beneficial effect on cardiac remodeling.
PVR afterload
s a l t and water retention preload

added to a diuretic
Also indicated for patients with left
ventricular dysfunction without symptoms of
HF.
for long-term management of chronic HF
Combine with a -blocker, diuretic & digoxin
Dose must be carefully titrated to the
 ACE
side effects: INHIBITORS
hypotension, dizziness, reduced renal function,
cough, and potassium retention

*****discontinue the drug for several days and try

to restart at lower dose
Contraindications:
•history of intolerance
•serum potassium >5.5 meq/L
• symptomatic hypotension
• severe renal stenosis
• pregnancy
 Other drugs

Omapatrilat inhibits both ACE and

neutral endopeptidase
increase exercise tolerance

-adrenergic Used in stable severe heart failure

blockers used in conjunction with diuretics,
(bisoprolol, ACE inhibitors and usually digoxin
carvedilol, and
metoprolol) should not be taken without diuretics in
patients with a current or recent history of
fluid retention

MONITOR bradycardiaand the potential for

heart block
 INOTROPIC AGENTS

used in the emergency treatment of patients with HF and in

patients refractory to or unable to take digitalis
A. DOPAMINE {IV) used in acute heart failure , 1'
B. DOBUTAMINE (IV) 1'
TPRCO, in ventricular filling
pressure
BIPVRIDINES
MOA: Inhibits phosphodiesterases , 1'
cAMP
C. INAMRINONE (IV)
Unstable in dextrose

sol'n
D. MILRINONE {IV) has both a positive inotropic effect
and a vasodilating effect
ADR: hvootension.
•A synthetic brain natriuretic peptide
(BNP)
•approved for the IV treatment of patients with
acutely decompensated HF associated with shortness
of breath at rest or with minimal activity.

MOA: it binds to natriuretic peptide receptors in

blood vessels, resulting in increased production
in guanosine 3'5' cGMP in target tissues, which
mediates vasodilation.

ADR: Excessive hypotension

ENDOTHELIN INHIBITORS
Bosentan competitive use1• n teratogenic
inhibition pulmonary and
of HPN. hepatotoxic
endothelin
tezosentan

NATRIURETIC PEPTIDES
atrial natriuretic peptide Carperitide
{ANP)
urodilatin ularitide
Levosimendan sensitizes the troponin
system to calcium
inhibit PDE
Aliskiren renin inhibition
Steps in the Treatment of Chronic HF
1. Reduce workload of the heart
a. Limit activity level
b. Reduce weight
c. Control hypertension
2. Restrict sodium
3. Restrict water (rarely required)
4. Give diuretics
5. Give ACE inhibitor or angiotensin receptor blocker
6.Give digitalis if systolic dysfunction with 3rd heart
sound or atrial fibrillation is present
7.Give -blockers to patients with stable class II-IV
heart failure
8. Give vasodilators
 Performane Heart
e deGrease Congestion failure Cardiac
(l output
D spnea

Diuretics -, y ema
Es
d

-J
Na+, H20
retention preload Ta hycardia
lnotropism
Spironolactone . .,. _

"
c:::::::::::=1== Fibrosis
Aldost HyQertrop y
erone =

•
AT,-blockers
P-Blocker
Angiotensin Digitalis
II Posit ive
ACE
inhibitors inotropic
Renin-Angiotensin System t Sympathetic System
t
Compensatory mechanisms