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CardiovascularRenal Drugs

Heart Failure

DETERMINANTS OF VENTRICULAR FUNCTION

CONTRACTILITY
PRELOAD

AFTERLOAD
STROKE
VOLUME

- Synergistic LV contraction
- LV wall integrity
- Valvular competence

CARDIAC OUTPUT

HEART
RATE

Heart failure
is the pathophysiological state in which the heart is
unable to pump sufficient blood to satisfy the metabolic
demands of the body with enough preload.
Heart failure is a complex, progressive disorder, in which the
cardiac output is insufficient for the needs of the body. It is often
accompanied by abnormal increases in blood volume and
interstitial fluid

HEART FAILURE
causes

Underlying causes of heart failure include:


chronic hypertension,
valvular disease,
arteriosclerotic heart disease,
volume overload,
dilated cardiomyopathy,
myocardial infarction.

The Progressive Development


of Cardiovascular Disease
Risk Factors
Endothelial Dysfunction
Atherosclerosis
CAD
Myocardial Ischemia
Coronary Thrombosis
Myocardial Infarction
Arrhythmia & Loss of Muscle
Remodeling
Ventricular Dilation
Congestive Heart Failure
Endstage Heart Disease

HEART FAILURE

pathogenesis

Thus, in chronic congestive heart failure,


cardiac pump performance falls below a level
required by the bodys organs for maintaining
function and metabolism.
The natural history of heart failure is
characterized by a slow deterioration of cardiac
function, punctuated by episodes of acute cardiac
decompensation that are often associated with
pulmonary or peripheral edema or both.

Heart Failure
Pathophysiology
Cardiac injury
Increased load
Reduced systemic perfusion
Activation of RAS, SNS, and cytokines

Altered gene
expression

Growth and
remodeling

Ischemia and
energy depletion

Apoptosis

Necrosis

Cell death

Direct
toxicity

Pathophysiology of heart failure


Impaired myocardium

Cardiac output , heart failure

Neurohumoral stimulation
RAS and sympathetic-adrenergic

Vasoconstriction
increased heart rate
Salt and water retention increased energy
(augments preload)
expenditure
Hypertrophy

Leads to deterioration and death of cardiac cell

HEART FAILURE
pathogenesis
Diminished
cardiac
performance leads to a
precardial congestion of
venous
blood.
Congestion in front of
the left ventricle causes
dyspnea and pulmonary
edema.
Ankle
edemas,
enlarged
liver,
and
ascites signal congestion
in front of the right
ventricle.

HEART FAILURE classification

The degree of severity of myocardial failure is categorized according


to the New York Heart Association (NYHA) Functional Classification
System. Stages IIV reflect an increasing level of disability.

Heart failure - classification


The 2005 American College of Cardiology/American
Heart Association guideline for management of chronic heart
failure specified four stages in the development of heart
failure.
Patients in stage A are at high risk because of other disease
but have no signs or symptoms of heart failure.
Stage B patients have evidence of structural heart disease
but no symptoms of heart failure.
Stage C patients have structural heart disease and
symptoms of failure, and symptoms are responsive to
ordinary therapy. Stage D patients have heart failure
refractory to ordinary therapy, and special interventions
(resynchronization therapy, transplant) are required.

Heart failure - classification


Once stage C is reached, the severity of heart failure is
usually described according to a scale devised by the New
York Heart Association.
Class I failure is associated with no limitations on
ordinary activities and symptoms that occur only with
greater than ordinary exercise.
Class II is characterized by slight limitation of ordinary
activities, which result in fatigue and palpitations with
ordinary physical activity.
Class III failure results in no symptoms at rest, but
fatigue, shortness of breath, and tachycardia occur with less
than ordinary physical activity.
Class IV is associated with symptoms even when the
patient is at rest.

Effects of Neurohormonal
Stimulation in Heart Failure
Heart

Heart rate
Contractility
Stroke volume
Cardiac output
Conduction velocity
Myocardial oxygen
consumption

Peripheral Circulation

Arterial vasoconstriction
Venoconstriction
Systemic vascular
resistance
Redistribution of blood
flow
Renal vasoconstriction

HEART FAILURE
compensatory mechanisms
The major responses include the following:
tachycardia an early manifestation of increased
sympathetic tone;
increased peripheral vascular resistance;
retention of salt and water by the kidney an early
compensatory response, mediated by the rennin
angiotensin aldosterone system;
cardiomegaly (enlargement of the heart);
apoptosis results in a reduction in the number of
functioning myocytes and their replacement by
connective tissue.

HEART FAILURE
compensatory mechanisms
Thus,
compensatory
include activation of the

mechanisms

1. sympathetic nerve system and of the


2. reninangiotensin system.

Increased
release
of
norepinephrine raises cardiac
rate and evokes peripheral
vasoconstriction.
Increased
production
of
angiotensin II promotes both
vasoconstriction and release of
aldosterone from the adrenals.
These compensations increase
cardiac afterload and plasma
volume is expanded because the

HEART FAILURE
compensatory mechanisms
Although
such
auxiliary
measures

afford

transient

counter
help

in

maintaining cardiac output, (nor)epinephrine,


aldosterone, and angiotensin II promote the
progression

of

myocardial

insufficiency:

hypertrophy and fibrosis are the outcome.

HEART FAILURE
compensatory mechanisms
Thus, these compensatory
responses increase the work
of the heart and, therefore,
can contribute to further
decline in cardiac function.
If the adaptive mechanisms
fail to maintain cardiac
output, heart failure is
decompensated.

Vicious Cycle of Heart Failure


Myocardial dysfunction

Increased
cardiac
workload

Increased
venous
return

Diminished Cardiac output

Increased force
and rate of
myocardial
contraction

Renal
retention of
sodium and water

Edema

Increased
Sympathetic
Activity

Diminished
renal
blood flow

Renin release

Vasoconstriction
Angiotensin II

Aldosterone

Pathophysiology and Therapeutic Approaches


to Heart Failure
LV Function
Vasodialtors
ACE Inhibitors

Digoxin

Cardiac Output
Peripheral vasoconstriction
Blood flow

Salt and Water


Retention

Diuretics

Neurohormonal
Activation

ACE Inhibitors
Blockers

Common Physical Findings


of Heart Failure
Elevated jugular venous pressure
Hepatojugular reflux
Displaced apical impulse
S3 gallop
Pulmonary rales
Hepatomegaly
Peripheral edema
Ascites

Clinical manifestation
Left heart failure: SOB (Shortness of breath or
Dyspnea), cough,rales,gallop
Right heart failure: gastrointestinal
congestion,anorexia,nausea,a sense of fullness after
meals,hepato-jugular reflux,swelling of feet or ankles
Low cardiac output: fatigue and weakness,oliguria
Biventricular heart failure:both clinical manifestation of left
and right heart failure,one of which maybe predominant.

For progressive
duration
Congestive heart
failure is classified
into acute and
chronic heart
failure

For anatomical
type
Congestive heart
failure is
classified into left
side, right side
and biventricular
heart failure

Progression of Heart
Failure
Coronary artery disease Cardiomyopathic factors

Atrial Fibrillation

Hypertension

Valvular disease

Left ventricular
injury

Diabetes

Pathologic
Remodeling

Death

Low ejection
fraction

Heart Failure Clinical Stages


NORMAL
No symptoms
Normal exercise
Normal LV fxn
No symptoms
Normal exercise
Abnormal LV fxn

Asymptomatic
LV Dysfunction
Compensated
No symptoms
Exercise
Abnormal LV fxn

Decompensated
Symptoms
Exercise
Abnormal LV fxn

Refractory
Symptoms not
controlled
with treatment

Prevalence of Heart Failure

SUCCESSFUL THERAPY OF CHRONIC CONGESTIVE FAILURE IS BASED


ON INHIBITION OF COMPENSATION MECHANISMS

Therapeutic strategies for chronic heart failure


include:
a. reduction in physical activity;
b. low dietary intake of sodium (< 1500 mg/day);
c. treatment of comorbid conditions;

HEART FAILURE
Therapeutic strategies
the removal retained salt and water with diuretics;
reduction of afterload and salt and water retention
by means of angiotensin-converting enzyme (ACE)
inhibitors;
reduction of excessive sympathetic stimulation by
means of blockers;
reduction of preload or afterload with vasodilators;
direct augmentation of depressed cardiac
contractility w i t h p o s i t i v e i n o t r o p i c d r u g s
such as digitalis glycosides.

HEART FAILURE
Therapeutic strategies

Drugs that may exacerbate heart failure,


such as
1.NSAIDs,
2.alcohol,
3.calcium channel blockers,
4.high dose of - blockers, and some
5.antiarrhythmic drugs
should be avoided if possible.

HEART FAILURE
Therapeutic strategies

Chronic failure is best treated with:


diuretics (often a loop agent plus
spironolactone)
plus an ACE inhibitor and,
if tolerated, a blocker.
digitalis may be helpful if systolic
dysfunction is prominent.

HEART FAILURE
Inotropic drugs - cardiac glycosides

Positive inotropic agents enhance cardiac muscle


contractility and, thus, increase cardiac output.
All cardiac glycosides (cardiosteroids) include

1. a steroid nucleus and


2. a lactone ring,
3. most also have one or more sugar residues.

CARDIAC GLYCOSIDES
pharmacokinetics

The cardiac glycosides are often called digitalis because most


of the drugs come from the digitalis (foxglove) plant.
Digoxin is the prototype agent. It has an oral bioavailability of 6075%, and a half-life of 36-40 h. Elimination is by renal excretion
(about 60%) and hepatic metabolism (40%).

CARDIAC GLYCOSIDES
Mechanism of action

Sodium pump (Na+/K+ ATP-ase) a transport


molecule in the membranes of all vertebrate cells;
responsible for the maintenance of normal low
intracellular sodium and high intracellular
potassium concentrations; it uses ATP to pump
these ions against their concentration gradients.

CARDIAC GLYCOSIDES
Mechanism of action
Digitalis inhibit Na+/K+ - ATP- ase of the cell membrane in the
cardiac muscle. Inhibition of Na+/K+ ATP - ase results in an
increase in intracellular sodium. This leads to a rapid rise in
cytosolic Ca2+ levels, which causes contraction.

CARDIAC EFFECTS OF GLICOSIDES:

1. positive inotropic effect (increased contractility);


2. positive batmotropic effect (increased automaticity);
3. negative dromotropic effect (decreased velocity in
atrioventricular conduction);
4. negative chronotropic effect (reduced heart rate).

CARDIAC GLYCOSIDES
pharmacologic effects
The increase in contractility evoked by digitalis results
in increased cardiac output. This beneficial effect permit a
decrease in the compensatory sympathetic response. It is
especially beneficial - reduced heart rate, preload, and
afterload permit the heart to function more efficiently.
Cardiac glycosides evoke the decrease in
atrioventricular conduction velocity and slowing
ventricular rate (mediated by the vagus nerve - central
vagal stimulation).

CLINICAL USES
Congestive heart failure

Digitalis is the traditional


positive inotropic (cardiotonic) agent used in the
treatment of chronic heart
failure. The most widely
used agent is digoxin.
Digoxin therapy is indicated
in patients with severe left
ventricular systolic dysfunction after initiation of
ACE inhibitor and diuretic
therapy.

CLINICAL USES
Congestive heart failure
Because the half-lives of cardiac
glycosides are long, the drugs
accumulate significantly in the body,
and dosing regimens must be carefully
designed and monitored.
At present, no effective oral
inotropic agent exist other than digoxin.
Patients with mild to moderate heart
failure will often respond to treatment
with ACE inhibitors and diuretics,
and they do not require digoxin.

CLINICAL USES
Congestive heart failure
However, careful clinical studies indicate that while digitalis
may improve functional status, it does not prolong life. Other
agents diuretics, ACE inhibitors, vasodilators may be equally
effective and less toxic, and some of these alternative therapies
do prolong life.

CLINICAL USES
Congestive heart failure

Atrial fibrillation or flutter, where


inhibition of AV conduction protects
the ventricles from excessive atrial
impulse
activity
and
thereby
improves cardiac performance.
The parasympathomimetic action
of digitalis reduce the conduction
velocity and increase the refractory
period of the AV node which account
for its use in atrial flutter and
fibrillation.

DIGOXIN`S MAJOR INDICATION IS HEART FAILURE WITH ATRIAL FIBRILLATION

HEART FAILURE
Digitalis toxicity
The major signs of digitalis toxicity are
Cardiac arrhythmias - sinus bradycardia, AV-block, ventricular
extrasystoles, ventricular fibrillation (ECG),
anorexia, nausea, vomiting, and diarrhea

CNS disturbances: characteristically, altered color


vision (xanthopsia), and also fatigue, disorientation,
hallucinations, confusion.
In general, decreased serum level of potassium
(hypokalemia) facilitates digoxin toxicity

Increased automaticity (caused by calcium accumulation in cardiac cells)


may evoke extrasystoles, tachycardia, or fibrillation in any part of the heart. In
the ventricles, the extrasystoles are recognized as premature ventricular beats
(PVBs):
Premature ventricular beats - An abnormal beat arising from a cell below
the AV node - often from a Purkinje fiber, sometimes from a ventricular fiber.
Rarely, confusion or hallucinations and visual aberrations may occur.
Central nervous system effects also include:
Headache
Fatigue
Blurred vision
Alteration of color perception
Halos on dark objects.
The treatment of arrhythmias is important because this manifestation of digitalis
toxicity is common and dangerous.
Severe, acute intoxication caused by suicidal or accidental extreme overdose
results in cardiac depression leading to cardiac arrest rather than tachycardia or
fibrillation.

renal: loss of electrolytes and


water; this must be differentiated
from mobilization of edema fluid
accumulated in front of the heart
during congestive failure, an effect
expected with therapeutic dosage.

TREATMENT
Treatment of digitalis toxicity includes several steps:
Discontinuing cardiac glycoside therapy;
Correction of potassium or magnesium deficiency mild
toxicity may often be managed by omitting 1 or 2 doses
of digitalis and giving oral or parenteral K+ supplements.
Antiarrhythmic drugs lidocaine or phenytoin, or
propranolol.
Digoxin antibodies to digoxin (digoxin immune Fab)
are extremely effective. They are effective for poisoning
with many cardiac glycosides. They bind and inactivate
the drug.

OTHER DRUGS USED IN CONGESTIVE


HEART FAILURE

The other major agents used in heart failure include


diuretics,
ACE inhibitors,
1 selective sympathomimetics,

blockers,
phosphodiesterase inhibitors (PDE - inhibitors), and
vasodilators.

PDE inhibitors - phosphodiesterase inhibitors that increase the


intracellular concentration of cAMP. This results in an increase of
intracellular calcium, and therefore, cardiac contractility. Short-term
use of intravenous milrinone has some symptomatic benefit when it is
used in patients with refractory heart failure. Examples: high
concentrations of theophylline, inamrinone.
Diuretics - are the first line therapy for both systolic and
diastolic failure and are used in heart failure before digitalis. Diuretics
decrease plasma volume and, subsequently, decrease venous return to
the heart (preload). Loop diuretics are the most commonly used
diuretics in heart failure.
Furosemide is very useful agent for immediate reduction of the
pulmonary congestion and severe edema associated with acute heart
failure and for moderate or severe chronic failure. Thiazides such as
hydrochlorothiazide are sometimes sufficient for mild chronic failure.
Spironolactone (aldosterone antagonist diuretics) have significant
long-term benefits and can reduce mortality in chronic failure.

Angiotensin II antagonists
Angiotensin II antagonists (ACE inhibitors
angiotensin converting enzyme) - By reducing
circulating angiotensin II levels (angiotensin II is the
potent vasoconstrictor) ACE inhibitors also decrease
the secretion of aldosterone resulting in decreased
sodium and water retention. They are now considered,
along with diuretics, to be first line drugs for chronic
heart failure.
The angiotensin receptor blockers losartan have the
same benefits as ACE-inhibitors (captopril, enalapril,
ramipril).

Beta adrenoceptor agonists - Dobutamine (1selective agonist) and dopamine are often useful in acute
failure. Dobutamine must be given by intravenous infusion
and is primarily used in the treatment of acute heart failure
in a hospital setting.
Beta adrenoceptor antagonists - Carvedilol,
labetalol, metoprolol are useful to reduce progression of
chronic heart failure.
blockers are not of value in acute failure and may
be detrimental if systolic dysfunction is marked.
Carvedilol and metoprolol reduce morbidity and mortality
associated with heart failure. Treatment should be started
at low doses and gradually titrated to effective doses based
on patient tolerance.

PDE-inhibitors - Inamrinone and milrinone are the major


representatives of this group. These drugs increase cyclic
adenosine monophosphate (cAMP) by inhibition its breakdown by
phosphodiesterase and cause an increase in cardiac intracellular
calcium. They also cause vasodilation.
Vasodilators - Vasodilators therapy with nitroprusside or
nitroglycerin is often used for acute severe failure with congestion.
Chronic heart failure sometimes responds favorably to oral
vasodilators such as hydralazine or isosorbide dinitrate or both.
Calcium channel blockers (eg, verapamil) should be avoided in
patients with heart failure.

TREATMENT
Correction of aggravating factors
Pregnancy

Endocarditis

Arrhythmias (AF)

Obesity

Infections

Hypertension

Hyperthyroidism

Physical activity

Thromboembolism

Dietary excess

MEDICATIONS

PHARMACOLOGIC THERAPY
Improved
symptoms

Decreased
mortality

Prevention
of CHF

Neurohumoral
Control

DIURETICS

yes

NO

DIGOXIN

yes

minimal

yes

INOTROPES

yes

mort.

no

Vasodil.(Nitrates)

yes

yes

no

yes

YES

yes

YES

yes

+/-

YES

ACEI
Other neurohormonal
control drugs

TREATMENT
Normal
Asymptomatic
LV dysfunction
EF <40%
Symptomatic CHF
ACEI
NYHA II
Diuretics mild
Neurohormonal
inhibitors
Digoxin?

Symptomatic CHF
NYHA - III

Loop
Diuretics

Secondary prevention
Modification of physical activity

Symptomatic CHF
NYHA - IV
Inotropes
Specialized therapy
Transplant

DIURETICS
Thiazides

Cortex

Inhibit active exchange of Cl-Na


in the cortical diluting segment of the
ascending loop of Henle

K-sparing
Inhibit reabsorption of Na in the
distal convoluted and collecting tubule

Loop diuretics

Medulla

Inhibit exchange of Cl-Na-K in


the thick segment of the ascending
loop of Henle

Loop of Henle

Collecting tubule

THIAZIDES
MECHANISM OF ACTION
Excrete 5 - 10% of filtered Na+
Elimination of K
Inhibit carbonic anhydrase:
increase elimination of HCO3
Excretion of uric acid, Ca and Mg
No dose - effect relationship

LOOP DIURETICS
MECHANISM OF ACTION
Excrete 15 - 20% of filtered Na+
Elimination of K+, Ca+ and Mg++
Resistance of afferent arterioles
- Cortical flow and GFR
-

Release renal PGs

NSAIDs may antagonize diuresis

K-SPARING DIURETICS
MECHANISM OF ACTION
Eliminate < 5% of filtered Na+
Inhibit exchange of Na+ for K+ or H+
Spironolactone = competitive
antagonist for the aldosterone receptor
Amiloride and triamterene block
Na+ channels controlled by aldosterone

DIURETIC EFFECTS
Volume and preload
Improve symptoms of congestion
No direct effect on CO, but excessive preload reduction may
Improves arterial distensibility
Neurohormonal activatio
Levels of NA, Ang II and ARP
Exception:

with spironolactone

DIURETICS
ADVERSE REACTIONS
Thiazide and Loop Diuretics
Changes in electrolytes:
Volume
Na+, K+, Ca++, Mg++
metabolic alkalosis
Metabolic changes:
glycemia, uremia, gout
LDL-C and TG
Cutaneous allergic reactions

DIURETICS
ADVERSE REACTIONS
K-SPARING DIURETICS
Changes in electrolytes
Na+,

K+, acidosis

Musculoskeletal:
Cramps, weakness
Cutaneous allergic reactions :

DIGOXIN
Na-K ATPase

Na

K+ Na+

Na-Ca Exchange

Na+

Myofilaments

CONTRACTILITY

Ca++

Ca++

DIGOXIN
PHARMACOKINETIC PROPERTIES
Oral absorption (%)
Protein binding (%)
Volume of distribution (l/Kg)
Half life
Elimination
Onset (min)
i.v.
oral
Maximal effect (h)
i.v.
oral
Duration
Therapeutic level (ng/ml)

60 - 75
25
6 (3-9)
36 (26-46) h
Renal
5 - 30
30 - 90
2-4
3-6
2 - 6 days
0.5 - 2

DIGOXIN
DIGITALIZATION STRATEGIES

Loading dose (mg)


i.v
0.5 + 0.25 / 4 h
ILD: 0.75-1

oral 12-24 h

oral 2-5 d

0.75 + 0.25 / 6 h 0.25 / 6-12 h


1.25-1.5

1.5-1.75

Maintenance
Dose
(mg)
0.125-0.5 / d
0.25 / d

ILD = average INITIAL dose required for digoxin loading

DIGOXIN
HEMODYNAMIC EFFECTS

Cardiac output
LVejection fraction
LVEDP
Exercisetolerance
Natriuresis
Neurohormonalactivation

DIGOXIN
NEUROHORMONAL EFFECTS
Plasma Noradrenaline
Peripheral nervous system activity
RAAS activity
Vagal tone

DIGOXIN
EFFECT ON CHF PROGRESSION

30
WORSENING OF CHF %

DIGOXIN: 0.125 - 0.5 mg /d


(0.7 - 2.0 ng/ml)
EF < 35%
Class I-III (digoxin+diuretic+ACEI)
Also significantly decreased exercise
time and LVEF.

Placebo n=93
DIGOXIN
Withdrawal

20
p = 0.001

10
DIGOXIN n=85

RADIANCE
N Engl J Med 1993;329:1

20

40

60

Days

80 100

OVERALL MORTALITY
50
40
30

Placebo
20

p = 0.8

n=3403

10

DIGOXIN
n=3397

DIG

0
0

N Engl J Med 1997;336:525

12

24

36

48 Months

DIGOXIN
LONG TERM EFFECTS
Survival similar to placebo
Fewer hospital admissions
More serious arrhythmias
More myocardial infarctions

DIGOXIN
CLINICAL USES
AF with rapid ventricular response
CHF refractory to other drugs
Other indications?
Can be combined with other drugs

DIGOXIN
CONTRAINDICATIONS

ABSOLUTE:
- Digoxin toxicity

RELATIVE
- Advanced A-V block without pacemaker
- Bradycardia or sick sinus without PM
- PVCs and TV
- Marked hypokalemia
- W-P-W with atrial fibrillation

DIGOXIN TOXICITY
CARDIAC MANIFESTATIONS

ARRHYTHMIAS :
- Ventricular (PVCs, TV, VF)
- Supraventricular (PACs, SVT)

BLOCKS:
- S-A and A-V blocks

CHF EXACERBATION

DIGOXIN TOXICITY
EXTRACARDIAC MANIFESTATIONS

GASTROINTESTINAL:
- Nausea, vomiting, diarrhea

NERVOUS:
- Depression, disorientation, paresthesias

VISUAL:
- Blurred vision, scotomas and yellow-green vision

POSITIVE INOTROPES
CARDIAC GLYCOSIDES
SYMPATHOMIMETICS
Catecholamines
-adrenergic agonists

PHOSPHODIESTERASE INHIBITORS
Amrinone

Milrinone

Enoximone

Piroximone

Others

-ADRENERGIC STIMULANTS
CLASSIFICATION

B1 Stimulants
Increase contractility
Dobutamine
Doxaminol Xamoterol
ButopaminePrenalterol Tazolol

B2 Stimulants
Pirbuterol
Carbuterol

Produce arterial vasodilatation and reduce SVR


Rimiterol
Fenoterol

Tretoquinol
Salbutamol

Mixed
Dopamine

Terbutaline
Salmefamol

Soterenol
Quinterenol

DOPAMINE AND DOBUTAMINE


EFFECTS
DA (g / Kg / min)

Dobutamine

<2
DA1 / DA2

2-5
1

>5
1 +

Contractility

++

++

++

Heart Rate

++

Arterial Press.

++

++

++

++

Receptors

Renal perfusion
Arrhythmia

POSITIVE INOTROPES
CONCLUSIONS
May increase mortality
Safer in lower doses
Use only in refractory CHF
NOT for use as chronic therapy

VASODILATORS
CLASSIFICATION

VENOUS
Nitrates
Molsidomine

MIXED

Arterial
Vasodilatation

Calcium antagonists
-adrenergic Blockers
ACEI
Angiotensin II inhibitors
K+ channel activators
Nitroprusside

ARTERIAL
Minoxidil
Hydralazine

Venous
Vasodilatation

NITRATES
HEMODYNAMIC EFFECTS

1- VENOUS VASODILATATION
Pulmonary congestion

Preload

Ventricular size
Vent. Wall stress
MVO2

2- Coronary vasodilatation
Myocardial perfusion

3- Arterial vasodilatation

Cardiac output

Afterload

Blood pressure

4- Others

NITRATES
TOLERANCE
Can be avoided or minimized

- Intermittent administration

- Use the lowest possible dose

NITRATES
CONTRAINDICATIONS
Previous hypersensitivity
Hypotension ( < 80 mmHg)
AMI with low ventricular filling pressure
1st trimester of pregnancy

WITH CAUTION:

Constrictive pericarditis
Intracranial hypertension
Hypertrophic cardiomyopathy

NITRATES
CLINICAL USES
Pulmonary congestion
Orthopnea and paroxysmal nocturnal dyspnea
CHF with myocardial ischemia
In acute CHF and pulmonary edema: NTG s.l. or i.v.

ACE-i. Mechanism of Action


VASOCONSTRICTION

VASODILATATION

ALDOSTERONE

PROSTAGLANDINS
Kininogen

VASOPRESSIN
SYMPATHETIC

Kallikrein

Angiotensinogen
RENIN

Angiotensin I

A.C.E.
ANGIOTENSIN II

tPA

Inhibitor

BRADYKININ

Kininase II
Inactive Fragments

ACEI
HEMODYNAMIC EFFECTS
Arteriovenous Vasodilatation
-

PAD, PCWP and LVEDP

SVR and BP

CO and exercise tolerance

No change in HR / contractility

Renal, coronary and cerebral flow

ACEI
FUNCTIONAL CAPACITY
100

No
Additional
Treatment
Necessary
(%)

95

Quinapril
continued
n=114

90

p<0.001

85

Quinapril
stopped
Placebo
n=110

80
Class II-III

75
Quinapril Heart Failure Trial
JACC 1993;22:1557

10

Weeks

12

14

16

18

20

ACEI
ADVANTAGES
Inhibit LV remodeling post-MI
Modify the progression of chronic CHF
-

Survival
Hospitalizations

- Improve the quality of life


In contrast to others vasodilators,
do not produce neurohormonal activation
or reflex tachycardia

ACEI
SURVIVAL POST MI
ACEI

Benefit

Pt Selection

ISIS-4

Captopril

0.5 / 5 wk

All with AMI

GISSI-3

Lisinopril

0.8 / 6 wk

All with AMI

SAVE

Captopril

4.2 / 3.5 yr

EF < 40
asymptomatic

SMILE

Zofenopril

4.1 / 1 yr

Ant. AMI, No TRL

TRACE

Trandolapril

7.6 / 3 yr

Vent Dysfx / Clinical CHF

EF < 35
AIRE

Ramipril

6 / 1 yr

Clinical CHF

ACEI
INDICATIONS
Clinical cardiac insufficiency
- All patients

Asymptomatic ventricular
dysfunction
- LVEF < 35 %

ACEI
UNDESIRABLE EFFECTS
Inherent in their mechanism of action

- Hypotension

- Dry cough

- Hyperkalemia

- Renal Insuff.

- Angioneurotic edema

ACEI
CONTRAINDICATIONS
Renal artery stenosis
Renal insufficiency
Hyperkalemia
Arterial hypotension
Intolerance (due to side effects)

ANGIOTENSIN II INHIBITORS ARB)


MECHANISM OF ACTION
RENIN

Angiotensinogen
Other paths
AT1
RECEPTOR
BLOCKERS

Vasoconstriction

AT1

Angiotensin I
ACE
ANGIOTENSIN II

RECEPTORS

Proliferative
Action

AT2

Vasodilatation

Antiproliferative
Action

AT1 RECEPTOR BLOCKERS


DRUGS

Losartan

Valsartan
Irbersartan
Candersartan
Competitive and selective
blocking of AT1 receptors

ALDOSTERONE INHIBITORS

Spironolactone

ALDOSTERONE

Competitive antagonist of the


aldosterone receptor
(myocardium, arterial walls, kidney)

Retention Na+
Retention H2O

Excretion K+
Excretion Mg2+

Edema

Collagen
deposition

Fibrosis
Arrhythmias

- myocardium
- vessels

ALDOSTERONE INHIBITORS
INDICATIONS
FOR DIURETIC EFFECT
Pulmonary congestion (dyspnea)
Systemic congestion (edema)
FOR ELECTROLYTE EFFECTS
Hypo K+, Hypo Mg+
Arrhythmias
Better than K+ supplements
FOR NEUROHORMONAL EFFECTS
Please see RALES results, N Engl J
Med 1999:341:709-717

ALDOSTERONE INHIBITORS
CONTRAINDICATIONS

Hyperkalemia
Severe renal insufficiency
Metabolic acidosis

-ADRENERGIC BLOCKERS
POSSIBLE BENEFICIAL EFFECTS

Density of 1 receptors
Inhibit cardiotoxicity of catecholamines
Neurohormonalactivation
HR
Antihypertensive and antianginal
Antiarrhythmic
Antioxidant
Antiproliferative

BLOCKERS
CARVEDILOL
4 studies in U.S.;
1 in Australia/New Zealand
U.S. studies with control group
Mortality with Placebo 8.2%
Mortality with Carvedilol2.9%
Initial low doses, progressive

p < 0.0001

-ADRENERGIC BLOCKERS
INDICATIONS

and UTILIZATION

Begin with very low doses


Slow augmentation of dose
Slow withdrawal ?

-ADRENERGIC BLOCKERS
IDEAL CANDIDATE?

Suspected adrenergic activation


Arrhythmias
Hypertension
Angina

-ADRENERGIC BLOCKERS
CONTRAINDICATIONS
Hypotension: BP < 100 mmHg
Bradycardia: HR < 50 bpm
Clinical instability
Chronic bronchitis, ASTHMA
Severe chronic renal insufficiency

CALCIUM ANTAGONISTS
POTENTIAL EFFECTS
Antiischemic
Peripheral Vasodilatation
Inotropy

CALCIUM ANTAGONISTS
POSSIBLE UTILITY
Diltiazem contraindicated
Verapamil and Nifedipine
not recommended
Vasoselective (amlodipine, nisoldipine),
may be useful in ischemia + CHF

ANTICOAGULANTS
PREVIOUS EMBOLIC EPISODE
ATRIAL FIBRILLATION
Identified thrombus
LV Aneurysm (3-6 mo post MI)
Class III-IV in the presence of:
- EF < 30
- Aneurysm or very dilated LV

ANTIARRHYTHMICS
Sustained VT, with/without symptoms
- Blockers
- Amiodarone
Sudden death from VF
- Consider
implantable
defibrillator

Drugs used in Heart Failure (contd)


Treatment of mild HF usually starts with an angiotensin
converting enzyme (ACE) inhibitor.
- decr load on the heart.
- decr symptoms.
- slow disease progression.
- prolong life.
- For more severe cases, add a diuretic (e.g.,
bendroflumethiazide, furosemide).
- For severe cases, in which a ACE inhibitor and diuretic fail,
then an inotropic drug (e.g., Digoxin), which incr the force
of cardiac muscle contraction by incr the rise of [Ca 2+]cyto
that accompanies each AP (inhibit the Na +/K+-ATPase).
[See below]
- -blockers may be added.
- Additional diuretics (next time) may be added.

ACE Inhibitors
The most appropriate vasodilators used in HF,
because they decr both arterial and venous
resistance.
Preventing the incr in (vasoconstrictor) angiotensin
II that is often present in HF.
Result: Incr cardiac output and because of the decr
in renovascular resistance, there is an incr in RBF
This, plus the decr in aldosterone, incr Na + and H2O
excretion decr blood vol and venous return to the
heart.
Also decr direct growth action that angiotensin has
on the heart.
[Angiotensin antagonists (e.g., losartan)may not
have the same benefits as ACE inhibitors].

-Receptor Antagonists ( Blockers)


Acutely, -blockers can decrease myocardial
contractility and worsen HF.
Long-term, however, administration has been
shown to improve the survival of stable patients
with HF (blocking the damaging effects of
overactive sympathetic activity).
Start with a low dose and gradually incr over wksto-mos.
Carvedilol, bisoprolol, and metaprolol, given with
an ACE inhibitor and diuretic for ~1 yr has been
shown to reduce mortality from 11-17% to 7-12%.

Inotropic Drugs
Digoxin a cardiac glycoside extracted from foxglove
leaves (Digitalis sp) is the most important inotrope.
Increase the contractile force.
Particularly indicated in patients with atrial fibrillation.
Inhibits the Na+/K+-ATPase, which is responsible for
Na+/K+ exchange across the muscle cell membrane
incr [Na+]in incr [Ca2+]in incr force of myocardial
contraction.
Digoxin and K+ ions compete for a receptor (Na+/K+ATPase) on the ext membrane.
So, the effects of digoxin may be dengerously incr by
hypokalemia, produced, for example, by diuretics.

Positive Inotropic Mechanism of Digoxin

Inotropic Drugs (contd)


Direct Effects:
- AP and refractory period are shortened because..
- The incr [Ca2+]in stimulates K+ channels.
- Toxic concentrations cause depol and oscillatory
depolarizing after pot appear after normal Aps
(caused by incr [Ca2+]in.
- If these delayed afterpot reach T0, Aps are
generated, causing ectopic beats.
-With incr toxicity, the ectobic beat itself elicits
further beats, causing a self-sustaining arrhythmia
(vent tach), which may vent fibrillation.

Inotropic Drugs (contd)


Indirect Effects:
Digoxin incr vagal activity and faciliates muscarinic
transmission to the heart. This
i.
Slow HR
ii. Slows atrioventricular conductance.
iii. Prolongs the refractory period of the atrioventrivular
node.
Effects on Other Organs:
Digoxin may cause anorexia, nausea, vomiting or diarrhea
by affecting the smooth muscle of the gut.

Inotropic Drugs (contd)


Toxicity:
-Digoxin toxicity is quite common because
arrhythmias can occur at concentrations that are
only 2-3 x that of the optimal therapeutic dose.
- Treatment may entail K supplements,
antiarrhythmic drugs (lidocaine or phenytoin) or
even digoxin-specific Ab fragments (Fab).

Sympathomimetic Agents
Activate cardiac -receptors AC cAMP
phosphorylation of L-type Ca2+ channels
(opens) incr [Ca2+]influx and the force of
myocardial contraction.
Dobutamine used in acute severe HF.
Dopamine incr renal perfusion by stimulates
dopamine receptors in the renal vasculature.