CVS-_Congestive_Heart_Failure.pdf

Congestive Heart Failure
Sanjaya Mani Dixit
Assistant Prof of Pharmacology

Contents
• Introduction
• CO-Preload, Afterload, Contractility, Stroke Volume
• Pathogenesis
• Causes - Risk Factors - Symptoms
• Pharmacotherapy of CHF
– Cardioselective Glycosides
– Diuretics
– Beta Blockers
– Vasodilators

Congestive heart failure
• A condition in which the heart is unable
to pump sufficient blood to meet the
needs of body.
• Not a disease but a “syndrome”
• Associated with long-standing HTN and
CAD

• CHF is accompanied by abnormal increases in
blood volume and interstitial fluid; the heart,
veins, and capillaries are therefore generally
dilated with blood.
• Hence the term “congestive” heart failure,
since the symptoms include:
– pulmonary congestion with left heart failure, &
– peripheral edema with right heart failure.

Factors Affecting Cardiac Output
Cardiac Output
Preload
Afterload Contractility
Heart Rate Stroke Volume
= X

Preload– Cardiac Output
Preload
The volume of
blood/amount of
fiber stretch in the
ventricles at the end
of diastole (i.e.,
before the next
contraction)
Preload increases with:
• Fluid volume increases
• Vasoconstriction (“squeezes”
blood from vascular system into
heart)
Preload decreases with:
• Fluid volume losses
• Vasodilation (able to “hold”
more blood, therefore less
returning to heart)

Afterload --Cardiac Output
– The resistance against which the ventricle must
pump. Excessive afterload = difficult to pump
blood → reduced CO/SV
– Afterload increased with:
• Hypertension
• Vasoconstriction
– Afterload decreased with:
• Vasodilation

Main causes
• Coronary artery disease
• Hypertension
• Valvular heart disease
• Cardiomyopathy
• Cor pulmonale

CHF Risk Factors
• CAD
• Age
• HTN
• DM
• Obesity
• Smoking
• High Cholesterol

Homeostatic Responses to Impaired Cardiac Performance (Due in part to activation
of the renin-angiotensin-aldosterone system (RAAS) and SNS.
Response Short-Term Effects* Long Term Effects
Salt and water retention Augments preload to
increase cardiac output
Pulmonary congestion and
peripheral edema
Vasoconstriction Maintains blood pressure
for perfusion of vital organs
Exacerbates pump
dysfunction (increased
cardiac afterload and
energy expenditure)
Sympathetic stimulation Increases heart rate and
ejection (increased output)
Increases energy
expenditure and causes
arrhythmias
Cardiac hypertrophy Adaptive: increased
sarcomere number with
increased cardiac output
Maladaptive: accelerated
cell death, arrhythmias
*Short-term effects occur in acute heart failure and are adaptive.
Long-term effects occur in chronic heart failure and are mainly maladaptive.

Treatment
Lifestyle changes
1. Salt restriction
2. Exercises
3. Smoking and alcoholism cessation
4. Body weight reduction
5. Supportive stockings

PHARMACOTHERAPY-- HEART FAILURE

Strategy of treatment of CHF
The therapeutic goal in CHF is to increase cardiac output.
1) Inotropic agents that increase the strength of contraction of
cardiac muscle
2) PDEI (Phosphodiesterase III inhibitors-Amrinone) agents that increase
cAMP to induce systoles and vasodilatation
3) Calcium sensitizers
4) b adrenergic agonist
5) b adrenergic antagonist
6) Vasodilators: Calcium channel blocker
7) Decreasing RAAS activity: ACEIs and AT1 antagonist
8) Diuretic agents

Drugs in congestive heart failure
1. Positive inotropic drugs
Cardiac glycosides
β-adrenergic agonists (New dopamine receptor agonist)
Phosphodiesterase inhibitors –Amrinone, Milrinone
Calcium sensitizers
2. Diuretics
3. Vasodilators
Calcium channel blocker
Nitryl-vasodilators
Hydralazine
4. RAAS inhibitors: ACE inhibitor and AT1 antagonist
5. β-receptor blocker

• Often called digitalis or digitalis glycosides
• Source: medicinal plants
– Digitalis purpurea and alba (purple and white foxglove) their medical use
goes 3000 years ago
– Oleander, Lilly of the Valley, Sea Squill (Scilla maritima)
o Chemically similar compounds that can increase the contractility of the heart
muscle and are therefore widely used in treating heart failure
• Pharmacodynamics: Na+
/K+
ATPase inhibition
o The drugs have a low therapeutic index
• Agents
– Digoxin = clinically used
– Digitoxin
– Oubain
Cardioselective Glycosides

DIGITALIS AND W. WITHERING
Digilis purpurea
Purple foxglove
William Withering (1741 - 1799)

O
O
OH
CH3
CH3
H
O
C18 H31O9
12
A
C
B
D
17
3
Digitoxin
Digoxin
= H at 12 C
= OH at 12 C
Sugars- 3 mols. of digitoxose
Aglycones
Unsaturated lactone
steroid nucleus
Convey the
pharmacological
activity
Convey cardiotonic
activity
Modulate potency and
pharmacokinetic distribution
The Indispensable parts of activity

 Potent and highly
selective reversible
inhibitors of cardiac
sodium pump, Na+-
K+ ATPase
 Inhibits movement of
Na+ and Ca2+ ions
across the
myocardial
membrane.

1. Mechanical effects - increase in cardiac contractility
  intracellular Na+
 increased intracellular Ca2+
content 
increased release of calcium from sarcoplasmic reticulum
2. Direct electrophysiological effects
· AP shortening (esp. the plateau phase) –  potassium
conductance that is caused by increased intracellular calcium
· Resting membrane potential is increased - made less negative
(due to the  Na+
, Ca2+
) in ↑ doses
· Delayed afterdepolarization (DAD) -  Ca2+
from stores - may
reach threshold - premature ventricular depolarization or
“ectopic beat“
CARDIOGLYCOSIDES- Effects on the heart

3. ANS system mediated effects
· significant parasympathomimetic effects
= central stimulation of vagus nerve
· decreased SA pacemaker activity
· decreased AV conductance
→ decreased HR !!!
· during intoxications - increased sympathetic outflow may be present
(sensitizing for other cardiac toxicity.)
CARDIOGLYCOSIDES-Effects on the heart

o Oral absorption: 65-80 %, parenteral administration for emergencies
o Wide distribution into the organ/tissues including CNS
o Excretion:
· 80% of drug – unchanged in the urine – mostly glom. filtration
Þdose individualisation in renal failure according GF
· small amount eliminated via active transport – renal tubules and bile –
interactions – importance  during renal failure
Digoxin Digitoxin
Half-life 40 hours 168 hours
Therapeutic plasma concentration 0.5 - 2 ng/mL 10 - 25 ng/mL
Toxic plasma concentration  2 ng/mL  35 ng/mL
Daily dose (slow loading or maintenance) 0.125 - 0.5 mg 0.05 - 0.2 mg
Rapid digitalizing dose 0.5 - 0.75 mg every 8 h
for 3 doses
0.2 - 0.4 mg every 12 h
for 3 doses
DIGOXIN-- Pharmacokinetics

• Congestive heart failure
– In association with atrial fibrillation/flutter (clear indication)
– Digoxin reduces hospitalizations and improves symptoms, however,
without improving survival (generally poor)
• indicated in severe forms of HF in combination with other treatment to
improve symptoms of HF and clinical status
– Not to be used in diastolic HF and acute MI related HF
• Antiarrhythmic indications
– Supraventricular arrhythmias
–  AV conduction will help control an excessively high ventricular rate -
improving ventricular filling and increasing cardiac output
!!! Contraindicated in Wolf-Parkinson-White syn (AVRT)
CARDIOGLYCOSIDES-Indications

Target organs: heart, CNS, GIT
Mechanisms: Na+
/K+
-ATPase inhibition, vagal mediated effects
o Cardiac effects
a) bradycardia, decreased or blocked AV conduction
b) AV junctional rhythm
c) premature ventricular depolarization, bigeminia rhythm (complex
of normal and premature ventricular beats) ventricular fibrillation
o GIT: Anorexia, nausea, vomiting (Nausea can be among the first
warning signs of toxicity !!!)
o CNS: headache, fatigue, confusion, agitation, blurred vision,
alteration of colour perception, and haloes on dark objects
o Gynecomastia in men upon prolonged use
CARDIOGLYCOSIDES-Adverse effects

Digitalization..
• The long half-life of digitalis compounds necessitates special
considerations when dosing.
• With a half-life of 40 hours, digoxin would require several days of
constant dosing to reach steady-state, therapeutic plasma levels
(Digitoxin with a half-life of 160 hours, would require almost a
month).
• Therefore, when initiating treatment, a special dosing regimen
involving "loading doses" is used to rapidly increase digoxin plasma
levels. This process is termed "digitalization.“
• For digoxin, the therapeutic plasma concentration range is 0.5 - 1.5
ng/ml. It is very important that therapeutic plasma levels are not
exceeded because digitalis compounds have a relatively narrow
therapeutic safety window.

Digitaliztion..
• Plasma concentrations above 2.0 ng/ml can lead to digitalis
toxicity, which is manifested as arrhythmias, some of which
may be life-threatening.
• If toxicity occurs with digoxin, it may take several days for the
plasma concentrations to fall to safe levels because of the
long half-life.
• There is available for digoxin toxicity an immune Fab
(Digibind) that can be used to rapidly reduce plasma digoxin
levels. Potassium supplementation can also reverse the toxic
effects of digoxin if the toxicity is related to hypokalemia.

Electrolytic disturbances
o Hypokalemia !!!
· K+
competes with digoxin for Na+
/K+
-ATPase binding site
→ hypokalemia facilitate digoxin binding and Na+
/K+
-ATPase inhibition, while
hyperkalemia has the opposite effects
· hypokalemia generally makes the heart more imbalanced and sensitive
to proarythmogenic stimuli
· SIGNIFICANT RISK
· patients heavily vomiting, GIT infections with diarrhoea
· patients receiving diuretics (loop/thiazides), dose effect
· PREVENTION
· co-administration of a potassium-sparing diuretic or
· supplementation with KCl
o Hypercalcemia !!! – increased Ca loading of cardiomyocytes
o hypernatremia, hypermagnesemia, and alkalosis
CARDIOGLYCOSIDES
Factors predisposing to digitalis toxicity

Drugs
• Quinidine - reduces the renal clearance of digoxin (competition for renal
excretion) and displaces digitalis from tissue protein  increases the toxicity of
digoxin
• Verapamil, amiodarone, spironolactone - displace digoxin from protein 
increase digoxin by 50-75 % (it may be necessary to
reduce dose)
• Potassium-depleting diuretics, corticosteroids
• other drugs
Diseases
• Hypothyroidism, hypoxia, renal failure, and myocarditis are predisposing factors to
digitalis toxicity
TDM to well individualize the therapy and avoid toxicity
CARDIOGLYCOSIDES
Factors predisposing to digitalis toxicity

• Fab-fragments (Digibind) against digoxin largely increase renal
excretion of digoxin (antidote)
• KCl administration
• Phenytoin may be used to suppress the ventricular extrasystoles
• Atropine may be used to antagonize concomitant bradycardia
CARDIOGLYCOSIDES
Treatment of severe acute intoxication (overdose)

Beta Receptor Agonists:
• Dopamine
• Dobutamine
• Positive inotropic agents most often used for the short-term
support of the circulation in advanced heart failure.
• Stimulate cardiac D1 receptor and b adrenergic receptor,
leading to stimulation of the Gs-adenylyl cyclase-cyclic AMP-
PKA pathway  Ca2+ dependent contraction and speed
relaxation.

Beta Receptor Antagonist
• Metoprolol approved for mild-to-moderate HF.
• Carvedilol  mild-to-moderate HF
• Bisoprolol
• Beta blockers should be initiated at very low doses, generally
less than one-tenth of the final target dose.
• Should be increased slowly, over the course of weeks, and
under careful supervision. The rapid institution of the usual
beta blocking doses used for HTN or CAD may cause
decompensation in many patients who otherwise would be
able to tolerate a slower titration of dose.

• Even when therapy is initiated with low doses of a
beta antagonist, there may be an increased tendency
to retain fluid that will require adjustments in the
diuretic regimen.
• In Class IIIB and IV patients  suggested that they
may tolerate beta blockers and benefit from their
use, this group of patients should be approached
with a high level of caution.

• There is almost no experience in patients with
new-onset, recently decompensated heart
failure. There are theoretical reasons for
caution in such patients, and at present they
should not be treated with beta blockers until
after they have stabilized for several days to
weeks.

Diuretics inhibit sodium and water retention, →reduce the volume of
blood, →venous pressure and the thus cardiac preload are reduced↓,
increasing the efficiency of the heart as a pump→ cardiac output ↑,
so reduce edema due to heart failure
Heart failure
• Low-grade : Thiazides hydrochlorothiazide
• Higher-grade : Acute left heart failure
loop diuretics --- furosemide
Spironolactone
Diuretics

Diuretics
• In sustained natriuresis and/or rapid decline in intravascular
volume  may progress CHF avoid use in asymptomatic LV
dysfunction.
• Aldosterone antagonists (Spironolactone) reduce mortalitity.
• Furosemide is started at 40 mg BID and dose is increased until
adequate diuresis occurs  decrease the dose to maintain
euvolemia.
• Higher dose may require in advanced CHF or with azotemia.
• Hypokalemia which is usually observed may be corrected with K+
supplements or K+ sparing diuretics to reduce S/E.

Vasodilators
• Angiotensin converting enzyme
inhibitor (ACEI) and AT1 antagonist
• Calcium channel blocker
• Nitryl-vasodilators
• Hydralazine

Vasodilators
• Although a number of vasodilators may
improve symptoms in heart failure, only the
hydralazine - isosorbide dinitrate
combination and antagonists of the renin-
angiotensin system (ACE inhibitors and AT1
receptor blockers) have been shown to
improve survival.

Vasodilators
• ACE Inhibitors:
• Used in treatment of HF of any severity.
• Must be initiated at low dose (6.25 mg Captopril, 5 mg
Lisinopril) to reduce chances of abrupt drop in BP.
• In patients with heart failure and reduced renal blood flow 
ACEI limit the kidney's ability to autoregulate glomerular
perfusion pressure  reduce the dose or substitute with
other vasodilators.
• ACEI induced angioedema  cessation of therapy.

Vasodilators
• Angiotensin Receptor Blockers:
• Suppress Ang II and aldosterone production,
decrease sympathetic nervous system activity,
and potentiate the effects of diuretics in heart
failure.

Amrinone and milrinone
o Phosphodiesterase inhibitors III (heart specific subtype)
· increase the intracellular concentration of cAMP  increase in
intracellular Ca, and therefore cardiac contractility
o Amrinone
· given only i.v. »»» mainly for short-term management of acute
congestive heart failure
· is associated with reversible thrombocytopenia (milrinone does
not affect platelets)
o Milrinone showed increased mortality and no beneficial effects,
amrinone did not reduced the incidence of sudden cardiac death or
prolong survival in patients with CHF !!!!!!
PHOSPHODIESTERASE III INHIBITORS

Levosimendan
• No increase intracellular Ca2+
- in contrast to previous agents
• Major effects – sensitizing troponin C to calcium and vasodilatation (also
some antiischemic effects)
• Increased contractility without worsening Ca2+
metabolism a increased O2
demands
• No major proarrhythmogenic effects
• Indication: i.v. for treatment acute decompensations of CHF
• Adverse reactions: hypotension, headache
• ↑ costs !!!
CALCIUM SENSITIZERS

10 Commandments of
Heart Failure Treatment
1. Maintain patient on 2- to 3-g sodium diet.
Follow daily weight. Monitor standing blood
pressures in the office, as these patients are
prone to orthostasis. Determine target/ideal
weight. Achieving target weight should mean no
orthopnea or paroxysmal nocturnal dyspnea.
2. Avoid all NSAIDs because they block the
effect of ACE inhibitors and diuretics. The only
proven safe calcium channel blocker in heart
failure is Amlodipine.

10 Commandments of
3. Use ACE inhibitors in all heart failure patients unless they have an
absolute contraindication or intolerance. Use doses proven to improve
survival and back off if they are orthostatic. In those patients who cannot
take an ACE inhibitor, use an angiotensin receptor blocker like Irbesartan.
4. Use loop diuretics (Furosemide) in most NYHA class II through IV
patients in dosages adequate to relieve pulmonary congestive symptoms.
Double the dosage (instead of giving twice daily) if there is no response
or if the serum creatinine level is > 2.0 mg per dL (180 µmol per L).
5. For patients who respond poorly to large dosages of loop diuretics,
consider adding 5 to 10 mg of Metolazone one hour before the dose of
Furosemide once or twice a week as tolerated.

6. Consider adding 25 mg spironolactone in most class III or IV
patients. Do not start if the serum creatinine level is > 2.5 mg per
dL (220 µmol per L).
7. Use Metoprolol , Carvedilol or Bisoprolol (beta blockers) in all
class II and III heart failure patients unless there is a
contraindication. Start with low doses and work up. Do not start if
the patient is decompensated.
8. Use digoxin in most symptomatic heart failure patients.
9. Encourage a graded exercise program.
10. Consider a cardiology consultation in patients who fail to
improve.
10 Commandments of

www.medipuzzle.com
Trusted by
10K + Students

CVS-_Congestive_Heart_Failure.pdf

CVS-_Congestive_Heart_Failure.pdf

More Related Content

What's hot

Similar to CVS-_Congestive_Heart_Failure.pdf

More from SanjayaManiDixit

Recently uploaded

In this document

CVS-_Congestive_Heart_Failure.pdf