Chapter 13

HEART FAILURE
The

progressive inability of heart to

supply adequate blood flow to vital
organs.
The heart cannot meet the metabolic
requirements of the peripheral systems.
Although it performs its tasks, it cannot
meet the demands of the body.
One of the complications of
hypertension.
CHF accumulation of certain body fluids. HEART FAILURE
is always accompanied by EDEMA.

CAUSES OF HEART
FAILURE
Mechanical Abnormalities

Pericardium
sac that
encloses
the heart.

Accumulation of body fluids in pericardium thus compressing

Pericardial Tamponadethe heart. Results to decrease in contraction.

Worsening of
Ischemia results
to Myocardial
infarction/failure
(death of
myocardial cells)
resulting to fewer
myocardial cells
available in
performing tasks
thus lesser force.

Coronary

Artery Disease-

Myocardial Failure (Ischemia)

Cardiomyopathy
Inflammation (Hypertrophy)

One of the major causes of HF.

Arteries in heart supply blood to
myocardial tissues. Arteries in the
heart are narrowing due to plaque
formation of cholesterol in arteries.
So there would be Ischemia (limited
blood supply in myocardial cells).

Arrhythmias
Diabetes
Toxic

CERTAIN AGENTS TARGETING THE HEART THAT

PROMOTES FAILURE:

Injury

1. DOXORUBICIN anthracycline (Antitumor agent/anticancer)

2. EMETIN in ipecac syrup (emetic agent)
3. COCAINE reuptake inhibitor, psychomotor stimulant
4. CHRONIC USE OF ETHYL ALCOHOL
*CHRONIC Hindi agad-agad

Cardinal

always present immediately

CARDINAL SYMPTOMS OF HF
Dyspnea
Difficulty in breathing.
HF is accompanied by edema so there is
possible congestion in the pulmonary
system.

Edema
HF is accompanied always by
edema/swelling.

Fatigue
Easily getting tired.

Ejection Fraction

Ratio of the blood pumped out from the

ventricle out of the blood filled in the
ventricle.

Stroke
Volume
-volume
of blood
pumped
out per
beat.

Stroke
volume

EDV
Volume of blood received by ventricle after
relaxation (diastole)

EDV END DIASTOLIC VOLUME

Important
determinant

in the
diagnosis
of the type
of HF.

Stroke volume represents

the amount of blood ejected
by the heart with each beat.

Ejection Fraction
Measurement

What it Means

55-70%

Normal

40-55%

Below Normal

Cannot meet
demand due
to less
amount of
blood ejected

<40%

May confirm diagnosis

of heart failure

<35%

Patient may be at risk

of life-threatening
irregular heartbeats
(arrhythmia)

2 types of HF

LEFT & RIGHT SIDED FAILURE Only

under the SYSTOLIC FAILURE

DIASTOLIC
Normal contraction, but the ventricles
do not relax properly / stiff.
Less blood enters during normal filling.
(NORMAL Ejection Fraction)

SYSTOLIC
Left ventricle doesn't contract with
enough force. Less blood exit.
More prevalent.
(70% of cases of HF can be accounted)

Major Types of Heart

Failure

Diastolic Failure
Hypertrophy

enlargement of

myocardial cells

Stiffening

results to impaired

dilation

Loss

of adequate
relaxation necessary in
reducing filling and CO
Normal ejection fraction
- but cannot meet demand

Significantly

reduced
stroke volume less volume
ejected per beat

Systolic Failure

Reduced

mechanical

pumping
(contractility)
Reduced EF (<45%)

HIGH OUTPUT FAILURE

The

demands of the body are so

great that even CO is insufficient.

Cardiac and Vascular Changes

Accompanying HF
CARDIAC

Stroke Volume &

CO
ED Pressure
Ventricular dilation or
hypertrophy
Impaired filling
process (diastolic
dysfunction)
Ejection Fraction
(systolic dysfunction)

VASCULAR

systemic vascular
resistance

arterial pressure
Impaired arterial
pressure
Impaired organ
perfusion
Venous compliance
Venous pressure
blood volume

MEACHANISM OF MYOCARDIAL CONTRACTION

1. Trigger Ca+ from the extracellular matrix will enter
through the L-type (Long) Ca+ channel.
2. When trigger Ca+ is present in the cytosol,
it will bind to ryanodine receptor.
3. When trigger Ca+ is bound to ryanodine receptor,
it will stimulate the release of Ca+ in the SR (Sarcoplasmic Reticulum).
4. Cytosolic Ca+ will stimulate the contraction in the Actin-Myosin Complex.
5. Free or excess cytosolic Ca+ will be recycled back in the SR
through SERCA Transporter (Sarcoplasmic Endoplasmic Reticulum
Calcium ATPase).
6. Free or excess cytosolic Ca+ will exit in the extracellular matrix
through NCX (Sodium Calcium Exchanger).
Efflux of Ca+ and influx of Na+.

Compensatory Mechanisms
TAKSIL ANG
During Heart FailureNANGYAYARI

Ginagawa mo
dahil akala mo
makakatulong
sa puso mo
pero siya ang
Neurohumoral Compensation
wawarak sa puso
mo.

Body will release different substances

to somehow cope up with the situation.
But only worsens in the end.

Renin-angiotensin-aldosterone system (Angiotensin II end product)

Pag may HF, (producing fluid retention (EDEMA) & sympathetic activity resulting to vasoconstriction)
Endothelin release (Endothelin intrinsic vasoconstrictor)
ALL
NE, EPI affinity to
Compensatory Sympathetic stimulation (Release of NE, EPI)
1
Mechanisms
(vasoconstriction)

Through BARORECEPTOR activation

1 (Ino,
are fully
Chrono,
Dromo)
Release of Natriuretic peptides (Brain Natriuretic
Peptide)
activated
When there is
reduction in the
force of contraction
exerted by the
heart, Natriuretic
Peptides are
released.

BNP has cardioprotective

effect to protect the heart. But
the stimulus is chronic so it is
still ineffective.

ET, endothelin; NE and

AII = vasoconstriction and
increased afterload

Vasoconstriction
Due

to ANG2, Endothelin & Catecholamines

Resistance in arteries that causes heart to
exert more effort so the blood may be ejected.
Afterload pressure required for the blood to
eject

Since in SYSTOLIC HF, the problem is contraction, the heart cannot

cope up with the arterys activity. The arteries keep on
constricting due to compensatory mechanism while the heart
cannot follow due to its poor contraction. Thus, resulting to
EJECTION FRACTION and CO

In HF, the stimulus is chronic or paulit-ulit (cycle) so it gets tired

and results to poor cardiac performance.

When catecholamines are released, initially okay ang effect sa

1. But in HF, the stimulus is chronic so there is down
regulation of 1 receptors. Kahit magbind ang catecholamines
sa 1, no positive Ino Chrono Dromo effect. Kaya wala pa ding
kwenta.

HYPERTROPHY
Enlargement

Due to death
of myocardial
cells,
naiistress
yung natirang
cells kaya
nagwoworkout sila kaya
sila lumalaki
(parang
nagpapalaki
ng muscle sa
gym)

Konti sila
pero
bawat
piraso ng
myocyte
malaki.

of
myocardial cells
due to:
Death of some
cardiac muscles
caused by
ischemia (MI) and
release of
caspases
Caspases enzymes that induce
APOPTOSIS (programmed cell death).
Thereby exacerbating hypertrophy.

REMODELING:

Uncontrolled production of cardiac myocytes.

But they prematurely die. Up to the point when
other hypertrophic cardiac muscles also die.
(EXTREME THINNING) There will be
dilated cardiac myopathy.

Dilation and other

structural changes
that occur in the
stressed myocardium.
*Dilated Cardiac
Myopathy

tendency of not
meeting the demands
of the body.

Remodeling
The

term applied to dilation (other than

that due to passive stretch) and other
slow structural changes that occur in
the stressed myocardium
1. Proliferation of connective tissue cells as
well as abnormal myocardial cells with
some biochemical characteristics of fetal
myocytes
2. Myocytes in the failing heart die at an
accelerated rate through apoptosis,
leaving the remaining myocytes subject to
even greater stress

Pathophysiology of Cardiac
Performance
PRELOAD

Venous Tone
- Leads to preload

Pressure required to achieve a particular EDV.

Represented by sarcomere stretching prior
to contraction.
VEINS and relaxation process are considered.
Venous
blood volume and venous tone increases
Tone
fiber length or filling pressure, and
vasoconstric increases oxygen demand in the
*when least
tion
pressure is
myocardium.
observed in
Reduced by diuretics and venodilators
the veins,
Sarcomere
basic
functional
unit of
muscles.

majority of
blood is found
in the veins.

(ADJUST THE VEINS kasi diba may HF siya so heart

cannot accommodate blood coming in)

Pathophysiology of Cardiac
Performance
AFTERLOAD

Pressure required for the blood to be ejected

Resistance against which the heart must pump

blood

ARTERIES and contraction are considered

CO in chronic failure results to reflex SVR
mediated by:
sympathetic outflow and circulating
catecholamines (baroreceptor reflex)
Activation of Renin-Angiotensin system
Endothelin a potent vasoconstrictor peptide

Reduced by arteriolar

Lower PVR in the

vasodilators
arteries

*arteriolar vasodilators have no effect on preload! YAY

Pathophysiology of Cardiac
Performance
CONTRACTILITY

(in SYSTOLIC FAILURE)

Heart

performance is adjusted!!! OMG

contractility result in reduction of:
velocity of muscle shortening
rate of intraventricular pressure
development
stroke output is reduced

Inotropic drugs contractility

***Combination therapy is also used in HF. Using of

inotropic agents and vasodilators promote
distribution of blood to meet requirements.

Pathophysiology of Cardiac
Performance
HEART

RATE

(chronotropy)

Major determinant of CO
HR through sympathetic
activation of adrenoceptors
is the first compensatory
mechanism that comes into
play to maintain CO
Accdg. to latest statistics of American
Heart Association, the lifespan of
patients with HF is 5 years if not
managed well.

Goals in the Treatment of

HF
Reducing

symptoms
Slowing progression as much as possible
during relatively stable periods
Prevent hospitalization through managing
acute episodes of decompensated
(functional deterioration) failure
ACUTE DECOMPENSATED HEART FAILURE
-common to people with chronic HF. There is volume overload due to edema.
Worsens congestion. Requires hospitalization.

Patient

education
Prevent mortality

(Proper exercise, diet, lifestyle)

***One of the causes of HF is Hypertension

HEART FAILURE Vicious

Circle

2 Vasopressor Agents

(initial benefit only bec. It

promotes vasoconstriction

3 Beta-blockers,
ACE inhibitors
and ARBs

***HF is multifactorial

Inotropes
(contracti
on)

5 Diuretics

4 Vasodilators

CLASSIFICATION
(NYHA)
STAGE

Subjective to doctors
observation

DISABILITY

CLASS I

Has cardiac disease but without limitations of physical

activity. Ordinary activity does not cause undue fatigue,
dyspnea, or palpitations.

CLASS II

Has cardiac disease that results in slight limitations of

physical activity. Ordinary activity results in fatigue,
palpitations, dyspnea, or angina.

CLASS III

Has cardiac disease that results in marked limitations of

physical activity. Although they are comfortable at rest, less
than ordinary activity will lead to symptoms.

CLASS IV

Has cardiac disease that results in an inability to carry on

physical activity without discomfort. Symptoms of heart
failure are present even at rest.
25

CLASSIFICATION
(ACC/AHA)

HF

HF

HF

Majority of cases

HF

Terminal case

Objective

Inotropes Increase contraction

Drugs for CHF

WITHOUT INOTROPIC
EFFECTS (Also for HTN)

POSITIVE INOTROPES
Cardiac

Glycosides

Digoxin (Prototype)
Phosphodiesterase
Bipyridines
Inhibitors

Inamrinone

(formerly

AMRINONE)

Milrinone

Diuretics
ACE

Inhibitors, ARBs
and related agents
Vasodilators
Beta blockers

first-line agents
for CHF

Beta-receptor
stimulants

Dobutamine

(unang binibigay kasi hindi

pa ganun kalala ang
sitwasyon)

agonist)

(1 selective

Other Positive Inotropic

Drugs (Under clinical trial)
ISTAROXIME (same MOA of Cardiac Glycoside)

investigational steroid derivative.

inhibit Na+/K+/ATPase and facilitates
Sequestration
sequestration of Ca2+ by
the SR. hides or isolates.
LEVOSIMENDAN

Ca2+ sensitizer

increases sensitivity of Ca2+ to ActinMyosin complex thereby promoting contaction.

sensitizes the troponin system to calcium

and inhibit phosphodiesterase

Explanation of sequestration of Ca2+ in

ISTAROXIME

During cardiac contraction, there are excess/free cytosolic

Ca2+ ions.

2 Transporters responsible for restoring or extruding

excess/free cytosolic Ca2+ ions:
SERCA (return to SR)
NCX (Efflux of Ca2+ going to extracellular matrix)

Its better that Ca2+ goes to SERCA para nakay SR lang siya
para magamit ulit.

With the use of ISTAROXIME, naitatago (sequester) ulit sa SR

ang excess/free cytosolic Ca2+ para magamit ulit for
contraction.

Cardiac
Glycosides

Their inotropic effects

were discovered 200
years ago.

Commonly
used in USA
Commonly
used in Europe

DIGOXIN first line agent for atrial fibrillation

Prelo
ad

RENAL

BILE

Excreted through
FECES
High
risk of
toxicity

When
bound to
proteins,
they are not
available
for action.

@LIVER

Less time
to reach
STEADY
STATE

Longer
time to
reach
STEADY
STATE

Cardiac Excitation-Contraction
Coupling
Na+ Channels
K+ Channels
L-type Ca2+ Channels
Na+-K+ ATPase Pump (Sodium Pump)
Na+-Ca2+ Exhanger (NCX)
(For

next slide) SERCA

Sarcoplasmic endoplasmic
reticulum Ca+2 ATPase, a calcium
uptake transporter

Cardiac Excitation-Contraction
Coupling
1. Several ions play important roles in playing this process.
2.

Ions action in the body is measured in millivolts (charge)

3.

In resting membrane potential, cells are negatively

charges (-85 millivolts)

4.

At rest, there is continuous efflux of K+ ions from the cell.

So the inside of cell becomes less positive. (repolarization)

5.

When cells are stimulated, K+ channels are closed. Many

fast-gated Na+ channels open up. There will be influx of
Na+ ions inside the cell. Millivolt value will increase.

6.

When Na+ ions enter the cell, when it reaches

depolarization, the Na+ channels will close. The K+
channels will open thereby theres
efflux of K+
(Early repolarization) -> less positive

7.

L-type Ca2+ channels open. From extracellular matrix,

there is influx of Ca2+. Simultaneous or sabay nagbukas
ang K+ at Ca2+ but Na+ is closed. Balance of Ca2+ influx
and K+ efflux. Plateau phase is reached.

Cardiac Excitation-Contraction
Coupling
8.

As trigger Ca2+ enters, contraction occurs.

9.

Then Ca2+ channels will close. There will be stimulation of

opening of more K+ channels thus many K+ ions will efflux
(declining stage)
---less positive inside the cell. efflux of K+, influx of
Ca2+.

10.
11.

Until such time when many K+ ions efflux so nagiging resting

ulit siya. (Repolarization)

12.

Under resting stage, relaxation is reached.

13.

Aside from K+ efflux, paano nagkakaroon ng relaxation sa

cardiac muscle? (not all Ca2+ ions will be used. Others go
inside SERCA. Other will be ejected out of the cell through
NCX. Ca2+ go out of the cell but Na goes inside the cell. NCX
will not be activated unless NaKATPase pump is stimulated.)
NaKATPase pump needs ATP bec it is against conc. gradient.
At normal condition, K+ always go out and Na always go in.
When action is stimulated (depolarized = less negative), K+
goes out and Na+ goes in. With the use of ATPase pump,
PISO. Through activation of NaKATPase, NCX will be activated.

Cardiac Excitation-Contraction
Coupling
14.

Upon relaxation, Ca2+ efflux or will go in SR.

15.

Paano nagkakaroon ng positive inotropic effect ang cardiac

glycoside? Cardiac glycoside inhibit NaKATPase. NCX will not
be activated so Ca2+ that are supposedly being extruded
from the cardiac cell is inhibited also. Ca2+ is left inside the
cardiac muscle so mas nafafacilitate ang pagbalik ni Ca2+
sa SERCA. Ca2+ ions that are restored inside the SR, they
can be used again, unlike through NCX they cannot. The
net effect with the use of Digoxin is increase
intracellular Ca2+ inside the cardiac muscle.

16.

ATPase pump is important so that there would be K+ supply

inside the cell against concentration gradient.

17.

Again, Digoxin inhibits NaKATPase pump therefore, K+

outside the cell cannot enter anymore and Na+ cannot exit.
If Na+ does not go out, NCX will not be activated.
Therefore, Ca2+ conc. inside the cell will increase.

18.

When there is increased conc. of Ca2+ inside the cell,

POSITIVE INOTROPIC EFFECT, tataas ang force of
contraction.

Cardiac Excitation-Contraction
Coupling
19.

When NaKATPase is inhibited, tataas ang intracellular

Na+ ions kasi hindi activated ang NaKATPase pump, so
hindi siya makalabas. Block ang NCX (pinapasok ang
Na+ ilabas ang Ca2+) since blocked yun, di
nakakalabas si Ca2+

20.

Decrease K+ intracellularly, kasi hindi nakakapasok

ang K+. Ang gumagalaw lang lagi ay ang normal K+
channels na along conc. gradient which means laging
palabas ang K+.

21.

Lowers resting membrane potential means your

cardiac muscle is now less negative. Ca2+ and
Na+ ay naiiwan sa loob ng cell kaya less negative.
That is the effect of Digoxin.

INCREASED INTRACELLULAR
CALCIUM

Digoxin in CHF

Blocks Na+-K+ ATPase Pump

[Na]i
[Ca]i (positive inotropic result)
[K]i
Resting membrane potential (less negative)

Mechanical Effects of
Digoxin
contraction

of cardiac sarcomere by
free Ca2+ conc. (Positive Inotropic
effect)
intracellular Na+ (Na+K+ATPase
inhibition)---direct action of Digoxin
Ca2+ expulsion from cell (NCX blockade)
so nasa loob na ng myocardial cell ang
Ca2+

Effect of Positive Inotropic

Action on Cardiac
Performance
CHRNOTROPIC
(Heart rate)
EFFECT OF
DIGOXIN:
Negative

DIGOXIN
Malakas ang tibok
pero mabagal.

Volume of blood
left in the ventricle
after contraction.

Autonomic Actions of
Digoxin

DIGOXIN
has narrow
Therapeauti
c Index.

Dose dependent.
The higher the dose,
more sympathetic
effect.

Involve

both parasympathetic and

sympathetic systems
Lower dose range, cardioselective
parasympathetic effects predominate.
Cholinergic innervation isNotmuch
richer
in
direct sympathetic
action
will occur. Its not the major
the ATRIA (atrial and AV nodal
function)
determinant of its toxic

effect.
At toxic levels, sympathetic outflow.

Cholinomimetic (vagus stimulation) effects are useful

in treatment of certain arrhythmias.
DIGOXIN can be used for Atrial Fibrillation
& Sinus Tachycardia

Negative Chronotropic
Effect
of Digoxin
Net effect:
HR
Vagus nerve
has parasympathetic effect
Refractory
Period
-Period of time
where
stimulated
cardiac cells
cannot facilitate
another action
potential.
While cardiac
cells are
contracting, it
cannot
stimulate
another
cardiac
stimulation.

I.

Digoxin has parasympathetic

effect at therapeutic range
bec. it stimulates vagus action
centrally.

Stimulates vagus centrally

longer
Refractoriness (matagal ang tibok) of AV nodeThe
the refractory

Ventricular response to Atrial rate

Controls HR in Atrial Fibrillation

period, the
(Chain event na sila)
longer the
heart rate.

Slows depolarization rate of SA

node
sinus rate
HR in Sinus Tachycardia

But the force

is prolonged
bec. Ca2+ is
prolonged.
Atrial
fibrillation
fast pumping
of the atrium
(4oo bpm)

II.

Under therapeutic
Decreases Sympathetic
Tone

Baroreceptor Stimulation

effect.

Cardiac glycosides: Digoxin

of AV node thus
ventricular response to atrial rate
Digoxin is used as first-line drug in
patients with CHF who are in Atrial
Fibrillation
refractoriness

DIGOXIN

Vagus stimulation: Parasympathetic effect of digoxin decreases action of Sinoatrial node

(pace-maker) thus longer refractory period = NEGATIVE CHRONOTROPIC EFFECT
(HR)
Force of contraction
increase

3 Major Effects of
DIGOXIN
Mechanical

primarily force of myocardial contraction. (Positive

inotropic effect) intracellular Ca2+ (due to blockade of NaKATPase pump and NCX)
Positive
systole.

inotropic effect = Ejection Fraction and CO.

Preload = diastole.

Autonomic
promotes

End Systolic Volume.

HR

& Electrical

(and electrical affects)

or chronotropy and dromotropy or conduction velocity.

Purkinje Fibers
SA node & AV node Atria
Purkinje
Fibers ventricles
AV node
AV bundle between atria and ventricle
Flow of electricity to heart: EVERY FLOW OF ELECTRICITY, THERE IS CONTRACTION & RELAXATION
SA node (pace-maker or starter at normal condition) AV node AV bundle Purkinje Fibers
AV bundle

SA node

Electrical = Conduction Velocity

Cardiac Glycosides are

arrhythmogenic can cause
arrhythmia by little changes
of its dosage.

Cardiac Effects: Electrical

Tissues

Sinus (SA

Effects at
Therapeutic
Dosage

HR

Due to muscarinic in
Atria

Effects at Toxic
dosage

HR

Due to narrow Ther. Index

node)

AV node
Ectopic
beats
(outside
pace-maker)

Refractory
period
Conduction
velocity
Faster HR in ventricle but will not
propagate in the whole heart.

if toxic dose

Purkinje
system
(ventricular
muscle)

Slight Refractory
period

Refractory period time it takes for the cardiac

muscle to complete its contraction-relaxation
process before it undergoes another contraction.

ECG

Refractory period
TOXIC (Atria) slow HR
Arrhythmias
propagate whole heart
TOXIC (Ventricle) fast HR

Extrasystoles,
Tachycardia,
Fibrillation

Ectopic beats of the purkinje fibers can

be overcome by SA node at therapeutic
dose kaya ang effect ay slight
decrease lang sa Refractory period.

PR interval
QT interval

Tachycardia,
fibrillation, arrest at
extremely high doses

Adverse effects of Cardiac

Glycosides

When ptx has hypokalemia, taking

Digoxin is life-threatening. When
there is hypokalemia, it intensifies
the ability of Digoxin to block
NaKATPase.

Narrow

therapeutic dose ratios.

May promote cardiac K+ loss and
hypokalemia which precipitate lifeBlockingwhen
of NaKATPaseused
will reinforceMECHANICAL,
threatening arrhythmias
AUTONOMIC & ELECTRICAL effects = more toxic
with diuretics
Hypokalemia facilitates enzyme-inhibiting
actions of cardiac glycosides
Abdominal

discomfort

(emesis, anorexia,

nausea, diarrhea)

DIGOXIN
is highly
lipophilic = tendency
to
Visual
disturbance
(green-yellow
halos around
penetrate BBB in CNS (Optic nerve)
bright objects)

Emesis- CTZ stimulation

Plasma Concentration of
Digoxin and Required Doses
Therapeutic plasma
concentration

0.5 1.5 ng/mL

Toxic plasma
concentration

> 2 ng/mL

Daily dose (slow

loading or
maintenance)

0.25 (0.125 0.5)mg

Rapid digitalizing
dose (rarely used)

0.5 0.75 mg
q.8h x 3 doses

Interactions with K+, Ca2+,

and Mg2+

Potassium

Hyperkalemia reduces enzyme-inhibiting actions of

cardiac glycosides and inhibit abnormal cardiac
Antagonize effect of Digoxin
automaticity

Hypokalemia
facilitates enzyme-inhibiting actions of
Reinforce MECHANICAL, AUTONOMIC & ELECTRICAL effect = more toxic (Intensify effect of Digoxin)
cardiac glycosides

Hypercalcemia

facilitates toxic actions of

cardiac glycosides by accelerating the overloading
Intensify effect of Digoxin
of intracellular Ca2+ - digitalis induced abnormal
automaticity

Magnesium effects appear to be opposite those of

calcium

Digoxin increases
intracellular Ca2+. The
more Ca2+ found in the
system, more contraction.

or K+ conc., Mg2+ always follow. (SAME EFFECT to POTASSIUM INTERACTION)

Hypomagnesemia
risk of a digitalis-induced
arrhythmia

DIGOXIN capable of being reabsorbed (biliary recycling).

Thereby preventing increase in dosing frequency. Imbis na
2x a day, 1x day nalang kasi narerecycle. NEEDS
MICROBIAL FLORA FOR METABOLISM OF DIGOXIN

AMIO. QUINI, VERA + DIGOXIN =

Alteration of renal clearance
(instead of Digoxin being excreted,
the 3 epals will intervene.

Erythro & Tetra

are broad
spectrum
antibiotics.

When
microbial flora
is killed, they
are not
capable of
metabolizing
Digoxin

PHARMACOKINETI
C

ADME is
altered

PHARMACODYNA
MIC
ADDITIVE EFFECT =>
1+1=2

K+ conc. = Intensify effect of

Digoxin

Treatment of Digitalis
Toxicity
Withdrawal

of drugs

Discontinued the use of cardiac

glycosides and K+-depleting diuretics.
Correction
Pag maraming
K+, resting
membrane
potential until
hindi na titibok
ang puso.

of electrolyte imbalances

Not IV
BOLU
S

Oral or by slow IV infusion of KCl

If hypokalemia is present
Do not give K+, if there is severe A-V block or if
serum K+ levels are high

Magnesium replacement
Hypomagnesemia may accompany
hypokalemia
The lower the amount of Mg2+, lower
K+ also = risky for Digoxin use,
Additive effect. So we need to add
more Mg2+

Treatment of Digitalis
Toxicity
Administration

of antiarrhythmias

Phenytoin For Ventricular & Atrial

arrhythmias.
Lidocaine and procainamide For
Ventricular
Tachyarrhythmias.
Propranolol For Ventricular &
Supraventricular Tachycardia
(but not in the presence of A-V block)
Atropine For Sinus bradycardia &
various degrees of A-V block.

Treatment of Digitalis
Toxicity
Administration

of Digoxin-specific antibody
fragment DIGIBIND or DIGIFAB (monoclonal
antiboidy)

For Life-threatening digoxin or digitoxin

overdosage.
For Acute treatment of Digitalis toxicity.
For Patients exhibiting shock or cardiac arrest
due to Digoxin use.
For ventricular arrhythmias.
For progressive bradyarrhythmias in Atrium.
For severe hyperkalemia during Acute toxicity.
***Chronic = hypokalemia

PHOSPHODIESTERASE III INHIBITORS

(BIPIRIDINES)
Composed of:
INAMRINONE
MILRINONE

1 selective agonist (DOBUTAMINE)

has Gs protein. So, its secondary
messenger is cAMP.

PDE 3 = degrades cAMP. So if

you block it, mareretain yung
conc. ng cAMP in the heart.

Many classes of
PDE. When
Bipiridines inhibit
PDE 3, effect is on
the heart.
Viagra inhibits PDE
5

INAMRINONE
MILRINONE
Inhibition of PDE enzymes
= conc. of cAMP & force of
contraction

cAMP
increase
force of
contraction
(+inotropic)

3 Groups of POSITIVE INOTROPES

1. Digitalis
2. Blockers of NaKATPase thereby blocking
also NCX
3. Bipiridines
4. PDE 3 Inhibitors
5. Dobutamine

Bypiridines
Inamrinone

and Milrinone
contractility and promote
vasodilation
Intravenous only
For Acute Decompensated Heart
Failure (Has volume overload
requiring hospitalization)
For Severe Exacerbation of
Chronic Heart Failure (requires
hospitalization)

Adverse effects of PDE

inhibitors
Arrhythmias
Hypotension
Abdominal

pain

Fever
Dizziness
Nausea

& vomiting
Hepatotoxicity
Thrombocytopenia
conc. of thrombocytes / platelets

DOBUTAMINE
Selective

beta1 agonist
Parenterally administered
CO

with a ventricular filling pressure, Preload

Positive

Chronotropic (Force Rate of

Contraction)

Arrhythmogenic (All positive inotropic agents)

Has

vasodilative effects (ventricular filling pressure,

Preload)

Widely

used in

ACUTE HF

(Thats why dobutamine is only used in ACUTE HF and parenterally used bec. if prolonged, wala ng use due to down
regulation pag chronic na ang HF)

DRUGS
WITHOUT
POSITIVE
INOTROPIC
EFFECTS USED
IN CHF
Diuretics
ACE inhibitors
Angiotensin receptor
antagonists (ARBs)
Aldosterone antagonists
Beta blockers

Diuretics in CHF

(may be used as first-

line agents in HF)

Major

MOA in HF is to:

Reduce venous pressure and ventricular

preload
Reduce

symptoms of volume overload

by:
extracellular volume
venous return (amount of blood coming
into the ventricle)
Diuretics (Loop/thiazide) + Digoxin for chronic tx = K+
(Additive effect)

Diuretics in CHF

Spironolactone

(to minimize

K+ loss)
Aldosterone antagonist
Prevents Na+ & water retention
block aldosterone which intensifies reabsorption process in collecting duct)

Prevent

endothelial dysfunction
Prevent myocardial fibrosis

(due to its ability to

Diuretics in CHF
Adverse effects :
Hypokalemia - Loop diuretics and
thiazides
K+ sparing diuretics overcome
these disadvantage

ACE Inhibitors for

CHF

MITOGENIC EFFECTS
-Effect in heart:
Remodelling & Fibrosis

ACE Inhibitors in CHF

Reduce
PVR & BV

Reduce Arterial Resistance (afterload)

Reduce Venous Tension (preload)
Reduces the aldosterone secretion

(due to blockade of ANG2)

Inhibit cardiac and vascular remodeling

Adverse

(due to blockade of ANG2)

effects :

Dry irritating persistent cough

Hyperkalemia
Angioedema
Fetal toxicity (Renal dysgenesis)

ARBs in CHF
Considered

in patients intolerant
of ACE inhibitors due to incessant
cough.
Losartan
Irbesartan
Candesartan

Diuretics + ACE inhibitors

Vasodilators in CHF

Reduce
PVR

Isosorbide

Preload
Afterloa
d

dinitrate + hydralazine

Can reduce damaging remodeling of

the heart.
Used specially for ptx who cannot tolerate ACE
inhibitors.
Can reduce PRELOAD & AFTERLOAD.
Amlodipine

Calcium
channel
blocker

Afterloa
d

1
and prazosin are
blocker
other vasodilators can be used in
CHF

Nesiritide-synthetic BNP (Brain Natriuretic

Peptide) released by Compensatory Mechanism. BNP is for

Cardioprotective & Vasodilating. NESIRITIDE increases cGMP thus causes
vasodilation. Also has diuretic effect bec. it is a Natriuretic.

Bosentan

& Tezosentan Endothelin

antagonist. Endothelin causes vasoconstriction
thus when blocked, causes vasodilation.

Nitrates in CHF

Limited for HF
Beta blockers in CHF

Beta-blockers
in CHF
increases
receptor
sensitivity
(Up
Regulation)
because in
HF there is
Down
Regulation.

Through
caspases

Acts

primarily by inhibiting the

sympathetic nervous system
Increases beta receptor sensitivity
(up regulation)
Anti-arrhythmic properties (can
inhibit positive chronotropic effect)
---So it has negative chronotropic effect
Anti-oxidant properties
BMC = Bisoprolol, Metoprolol,
Carvedilol

Beta blockers for CHF

Start

at low dose and monitor for

bradycardia
Not all beta blockers are useful in
CHF
Carvedilol and Metoprolol are the
most commonly used for CHF
amongst beta blockers
Bisoprolol have also shown to
reduce mortality