Drugs Used in Congestive

Heart Failure

Virgette Gay P. Mollaneda, M.D,

FPCP, FPCC
MHAM-SWU

 HALLMARK OF HEART FAILURE:

REDUCTION IN STROKE VOLUME
REDUCTION IN CARDIAC OUTPUT

Pathophysiology and Treatment of Heart Failure

HEART
FAILURE

DECREASED
CARDIAC OUTPUT

INCREASED VENOUS
PRESSURE
CONGESTION
AND EDEMA
DYSPNEA
AND
ORTHOPNEA

DECREASED
TISSUE PERFUSION

WEAKNESS AND
FATIGUE

NEUROENDOCRINE
SYSTEM ACTIVATION
SYMPATHETIC
NERVOUS SYSTEM

CARDIAC
REMODELING
VASOCONSTRICTION

INCREASED
AFTERLOAD

RAAS

Na AND H20
RETENTION

Treatment
of
Congestive
Heart
Failure: Cardiac Glycosides, Inotropic
and Vasodilator Therapy
Overview of congestive heart failure:
Is a condition in which the heart is unable to
pump sufficient blood to meet the needs of the
body.

Two Components of failure

a. Impaired cardiac contractility
b. Circulatory congestion (increase work load
imposed on the heart)

CONGESTIVE HEART FAILURE

Occurs in 10% of the population over 75

Can result in death through progressive
heart damage or sudden death
Overworking of the heart leads to
cardiomegaly and myocardial
hypertrophy

CLASSIFICATION:
SYSTOLIC DYSFUNCTION:
Inadequate force is generated to eject
blood normally
Reduce cardiac output, ejection fraction (<
45%)
Typical of acute heart failure
Secondary to Acute myocardial infarction
Responsive to inotropics

CLASSIFICATION:
DIASTOLIC DYSFUNCTION
Inadequate relaxation to permit normal
filling
Hypertrophy and stiffening of myocardium
Cardiac output may be reduced
Ejection fraction is normal
Do not respond optimally to inotropic
agents

PRECIPITATING CAUSES OF
HEART FAILURE:

Infection
Anemia
Thyrotoxicosis & pregnancy
Arrythmias
Rheumatic, viral & other forms of myocarditis
Infective endocarditis
Systemic hypertension
Myocardial infarction
Physical, dietary, fluid, environmental & emotional
excesses
Pulmonary embolism

Cardiovascular Consequences of heart failure

CARDIAC FAILURE
Venous
Pressure

Cardiac output
Sympathetic
activity

Blood pressure
Renal Blood flow
Renin- Angiotensin
Aldosterone

Capillary filtration

Sodium retention
Edema

SYMPTOMS:
Due to inadequate perfusion of peripheral
tissues (fatigue, dyspnea)
Elevated intracardiac filling pressures
(orthopnea, PND, peripheral edema)

PHYSICAL EXAM:
Jugular venous
distention
S3
Rales
Pleural effusion
Edema
Hepatomegaly
Ascites

Therapeutic goal for CHF is to increase Cardiac

output, this is achieve by:
1. Increasing the strength of the cardiac muscle
(positive inotropic effect)
2. Reducing the load on the myocardium
by fluid volume; and reducing preload (left
ventricular filling pressure LVFP), and of aortic
impedance (systemic vascular resistance SVR) by
vasodilatation.

DRUGS USED TO TREAT CONGESTIVE

HEART FAILURE
INOTROPIC AGENTS
VASODILATORS
-CAPTOPRIL
-ENALAPRIL
-FOSINOPRIL
-LISINOPRIL
-QUINAPRIL
-HYDRALAZINE
-ISOSORBIDE

-DIGOXIN
-DIGITOXIN

-DOBUTAMINE

-AMRINONE
-MILRINONE

-MINOXIDIL
-SODIUM
NIITROPRUSSIDE

DIURETICS

-BUMETANIDE
-FUROSEMIDE
-HYDROCHLOROTHIAZIDE
-METALAZONE

INCREASE CARDIAC OUTPUT

REDUCE PULMONARY AND
SYSTEMIC CONGESTION
SLOW OR REVERSE CARDIAC
REMODELING

Drugs that increases the strenght of

cardiac contractility:The Inotropic agents
A. Cardiac Glycosides
are cardenolides (lactone ring + a steriod
attached to a sugar molecule glycoside)
collectively known as digitalis glycosides

Sources
1. Foxglove (Digitalis) plant.
a. Digitalis purpurea (Digitoxin)
b. Digitalis lanata (Digoxin)
2. Seeds of strophantus gratus (Quabain)

Digitalis purpurea

Foxglove

Strophantus gratus

Lily of the valley

Lychnis

Mechanism of action
Inotropic Effect
- Inhibit Na+ - K + activated adenosine
triphosphate (Na+, K+ - ATPase)
- this results to increase intracellular Na+ and

intracellular

K.

Na+

exchange of intracellular Ca

reduces
++

normal

for extracellular

Na+ and yields elevated intracellular Ca++ , with

each action potential, there is greater release
of Ca++ to activate the contractile process. Net
result is positive inotropic effect.

Na+ - K

- ATPase
Inhibited by Digitalis

Concentration of Na+ intracellularly

Leads to a greater influx of Ca++
Elevated intracellular Ca++
Ca++ attaches to troponin

Actin filaments expose

Actin - myosin interaction
Cardiac cell contraction
(positive inotropy)

Pharmacodynamics
Cardiac action
Extracardiac action

Pharmacologic effects of Digitalis

1. Cardiac effects
a. effect on cardiac contractility increases
the force of myocardial contraction. (most
beneficial effect) C.O.
b. effect on the electro physiologic properties
of the heart.
the vagal tone of the heart
indirectly
- prolong the refractory period of the
AV node
conduction velocity though the A-V
node

Heart rate - in
CHF pnts slows heart rate
(chronotropic effect)
normal indiv. - no effect no H.R.
Excessive dose - (+
Tachycardia effect)

Chronotropic

2. Extra cardiac Effects

a. Gastrointestinal stimulation of CTZ Zone
nausea and vomiting
b. peripheral vascular resistance - due to in
cardiac output
C. systolic B. P. due to increase in stroke volume
D.diastolic B.P. Due to improve circulation
E. diuretic effect due to improve renal bld flow
F. yellow vision (in toxicity)

Pharmacologic properties and selected drugs :

Oral absorption

Digoxin
Digitoxin

Digoxin
Digitoxin

65 80 %

Protein binding

Serum + 1/2 half life

25 %

1.5 day (Lanoxin)

96 %

4 6 days
(crystodigin)

90 100 %

Maintenance dose

Elimination

35 % of loading dose

Renal route
Metabolize And via Liver

10 % of loading dose
excreted via biliary route

PROPERTIES OF CARDIAC
GLYCOSIDES:
OUABAIN

DIGOXIN

DIGITOXIN

Lipid solubility
(oil/water
coefficient)

Low

Medium

High

Oral availability
(% absorbed)

75

> 90

Half-life in the
body (hrs)

21

40

168

Plasma protein
binding (%
bound)

<20

>80

Volume of
distribution

18

6.3

0.6

PHARMACOKINETICS:
-T1/2 is long (40 hrs)
-Therapeutic plasma concentration: 0.5-2 ng/ml
-Toxic plasma concentration: >2 ng/ml
* by giving a large initial dose in a process called
"digitalization"
- after intial dosages, digitalis is given in "maintenance"
amounts sufficient to replace that which is excreted
to avoid exceeding therapeutic range during digitalization:
- the loading dose should be adjusted according to the health
of the patient
- slow digitalization (over 1 week) is the safest technique
- plasma digoxin levels should be monitored

Commonly used digitalis Preparations

Digitalis
preparation

Digitalizing
dose range oral

IV

Daily maintenance
oral

Digitalis

1.2 2.0g

Digitoxin

1.0 1.6mg

1.0 1.6mg

0.05 03mg

Digoxin

0.75 1.5mg

0.5 1.5mg

0-125- 0.5mg

Deslanoside

0.1 0.2g

1.0 1.6mg

Digitalization and maintenance dosage

A. Digoxin
- if no urgency use first oral digitalizing dose
- maintenance dose is adjusted on the basis of
clinical an laboratory assessment. Steady- state
level is achieved in 5 half-lives (8 days)
- for rapid digitalization administer I.V for
several minutes. Onset of action is within 5-30
minutes. Maximal effect is within 1-5 hrs.

B. Digitoxin
- total oral loading dose- given every 6 hrs in
divided dose, over a course of 36-48 hrs.
- maximal effect of an oral dose is reached
approximately 9 hrs.
- once optimal benefit has been achieved adjust
maintenance dose to 10 % of digitalizing dose.

Factors Prediposing Digitalis Toxicity

1. Electrolyte disturbance Hypokalemia,
Hypercalcemia, Hypernatremia, Hypomagnesemia
and alkalosis - toxicity
2. Disease state Hypothyroidism, hypoxia, renal
failure and myocarditis
3. Drugs Quinidine, amiodarone ,verapamil,
Potassium depleting diuretics, steroids

Therapeutic Uses of Digitalis

1. Congestive Heart Failure
2. Arrhythmias Atrial Fibrillation and Atrial
Flutter
3. Myocardial Infarction with failure

Adverse Reactions
1. Most common GIT symptom
2. Most dangerous arrhythmias which may
terminate to ventricular fibrillation.
3. CNS effects headache, blurred vision,
alteration of color perception (yellow vision),
haloes on dark objects.

Drug Interaction
Drug
Kaolin pectin

Effect/ Drug interaction

pharmacologic effect of
digoxin by interfering
absorption from GIT

Drug Interaction
Drug

Effect/ Drug interaction

Diuretics-thiazide ;loop

- produce hypokalemia may

augment digitalis toxicity

Quinidine toxicity

serum conc. of digitalis

(displaces digoxin from
binding sites).

Barbiturate

effect of digitalis by
inducing liver microsomal
enzyme

Rifampicin

effect of digitalis by
inducing liver microsomal
enzyme

Drug Interaction
Drug

Effect/ Drug interaction

Cholestyramine

binds with digoxin or

digotoxin in intestine,
their effectiveness

Sympathomimetic

predisposition to Cardiac
arrhythmias agents

Calcium- channel blocking

agent (verapamil).

cause toxicity by adding to

drug effects.

Mng't of digitalis Toxicity

1. Potassium Cl help in alleviating arrhythmias
2. Antiarrhythmic drugs Phenytoin and
Lidocaine can correct disturbances in cardiac
rhythm. (if ineffective may use propanolol or
procainamide).
3. Severe toxicity - Antidigoxin antibodies
(digoxin
immune
FAB)
(Digibund)
or
hemoperfusion high affinity of binding to
glycoside which is then excreted in the urine
useful in extreme toxicity.

Other inotropic agents

II- Non- glycoside,
nonsympathomimeticPhosphodiesterase inhibitor
a. amrinone lactate(Inocor)
b. milrinone (corotrope)
III- beta 1 agonist
a. Dobutamine Hcl
b. Dopamine

OTHER POSITIVE INOTROPIC

DRUGS USED IN HEART FAILURE:
BIPYRIDINES
Amrinone & Milrinone
Parenteral forms only
Half-life: 2-3 hrs
10-40% excreted in the urine
MOA: increase inward calcium influx in the
heart during action potential & inhibits
phosphodiesterase
ADVERSE EFFECTS: nausea, vomiting,
thrombocytopenia, liver enzyme changes

BETA ADRENOCEPTOR
STIMULANTS:
DOBUTAMINE
Increases cardiac output
Decrease in ventricular filling pressure
Given parenterally
CONTRAINDICATIONS:
pheochromocytoma, tachyarrythmias
ADVERSE EFFECTS: precipitation or
exacerbation of arrhythmia

OTHER AGENTS USE IN CONGESTIVE HEART

FALURE

Vasodilators
- Reduces aortic impedance or increases venous
capacitance
- Useful in treating severe decompensated CHF
refractory to diuretics and digitalis

Vasodilators

Venous
Dilatation
(reduction
of preload )

Arteriolar
(reduction
of afterload)

Nitroglycerine

+++

++

Isosorbide
dinitrate/
Isosorbide
mononitrate

+++

+++

Hydralazine
Minoxidil

----

+++

Sodium
Nitroprusside

---+++

+++
+++

Vasodilators Venous

Dilatation

(reduction
of preload )

Arteriolar
(reduction
of afterload)

Prazocin

+++

++

Enalapril
(ACE inhibitor)

+++

++

Captopril
(ACE inhibitor)

+++

++

++

Nifedipine

Choice of Vasodilators
A. For emergency short term therapy ( during
hospitalization
Nitroprusside has a direct balanced effect on
arterial and venous beds.
B. Long term therapy: ( outpatient )
1.Nitroglycerine fast acting
2.Isosorbide dinitrate /isosorbide mononitrate - longer
duration of action
3.ANGIOTENSIN CONVERTING ENZYME INHIBITOR
( ACE INHIBITORS )

ANGIOTENSIN-CONVERTING ENZYME
INHIBITORS: e.g Captopril, Enalapril
Reduce peripheral resistance reduce
afterload
Reduce salt & water retention ( by
reducing aldosterone secretion) reduce
preload
Reduce the long term remodelling of the
heart vessels ( maybe responsible for the
observed reduction in the mortality &
morbidity)
CONTRAINDICATED IN PREGNANCY

ANGIOTENSIN RECEPTOR
BLOCKER
Protype drug : Losartan, Valsartan
Competitive inhibitor of angiotensin II at
the angiotensin II receptor , thereby
inhibiting the release of aldosterone
Reduces Na+ reabsortion in nephron
therefore reducing fluid volume
Useful in patient who cannot tolerate ACEI
Adverse effect : hyperkalemia

 ACEI and ARB causes venodilatation and induce

natriuresis thereby reducing preload
- combined with digitalis to decrease mortality and
increase survival

Reduces sodium reabsorption in nephron thereby

reducing fluid volume
REDUCES LEFT VENTRICULAR FILING PRESSURE THUS
REDUCING VENTRICULAR VOLUME AND MYOCARDIAL
TENSION

- Furosemide is
edema.

employed for acute pulmonary

Agents:
1. Thiazide

- can cause Hypokalemia which

can precipitate serious
arrhythmias, gout

2. Furosemide
(Loop diuretics)

- can cause Hy ponatremia ,

Hypokalemia which
can precipitate serious arrhythmias,
gout,ototoxicity ( very rare)

3. Spironolactone
(aldosterone
antagonist)

is a potassium sparing diuretic.

can cause serious hyperkalemia

( MUST MONITOR serum K+ level)

Beta-Adrenoceptor Antagonists:
- Several beta blockers (carvedilol, labetalol, metoprolol)
have been shown in long-term studies to reduce
progression of chronic heart failure. This benefit of blockers had long been recognized in patients with
hypertrophic cardiomyopathy but has now been shown to
also occur in patients without cardiomyopathy.
Beta- blockers are not of value in acute failure and may be
detrimental if systolic dysfunction is marked.

Major steps in the management of CHF

Aims

Therapy

A. Reduce heart work

- limit physical activity

- control hypertension
- weight reduction
- sedation (if needed)

B. Reduce blood volume

- diuretics

C. Improve efficiency of
heart

- Digitalis

D. Fine tune control of

circulation

- vasodilators (captopril)

EMERGENCY
MANAGEMENT

INPATIENT
MANAGEMENT

OUTPATIENT
MANAGEMENT

IV ACEI

ACEI

ACEI and ARB

IV LOOP DIURETIC
(FUROSEMIDE)

LOOP DIURETIC

LOOP DIURETIC

BETA BLOCKER

BETA BLOCKER

NITRATES :
NITROGLYGERINE
IV NITROPRUSSIDE

DOBUTAMINE

DIGOXIN

OXYGEN

NITRATES

NITRATES
( NITROGLYCERINE
of ISOSORBIDE
DINITRATE OR
MONONITRATE)

MORPHINE

Case

A 56 YR OLD MAN WAS ADMITTED TO THE E. R

WITH WORSENING DYSPNEA , AND
ORTHOPNEA. HE HAD A HISTORY OF LONG
STANDING HYPERTENSION AND HAS BEEN
TAKING CALCIBLOC. HE HAS JUGULAR
VENOUS DISTENTION TO 15cm, BASAL LUNG
CRACKLES AND A +3 PITTING EDEMA IN
BOTH EXTREMITIES .
A) WHAT IS YOUR DIAGNOSIS
B) GIVE YOUR INITIAL DRUGS
C) GIVE THE MECHANISM OF ACTION OF THE
DRUGS

Thank you very much!