2. HEART FAILURE
Dfn:
Inability of the heart to provide sufficient COP to meet body
needs.
Congestive describes the engorgement of the venous system
and the associated tissue edema.
The central venous pressure that determines edema is called
the PRELOAD 2
3. The heart may failure to provide
sufficient COP due to:
Loss of viable myocytes due to
infarction, infection or exposure to
drugs/ chemicals.
Excessive resistance to cardiac out
put (after load) owing to arterial HT or
aortic stenosis.
Valvular defects (e.g. mitral
regurgitation) and tachycardia that
reduce cardiac stroke volume.
3
4. Common symptoms of CCF:
Dyspnea
Edema
Fatigue.
Types of HF
Left-sided heart failure
There are two types of left-sided heart failure
Systolic dysfunction
Diastolic dysfunction
Right-sided heart failure
4
6. COMPENSATORY REFLEXES
These initially alleviate the symptoms and then
later, exacerbate symptoms of HF.
They include:
Activation of extrinsic neurohumoral reflexes
Intrinsic cardiac compensation
6
7. COMPENSATORY CONT’D
Activation of SNS
Activation of RAS
Increased heart rate
Release of ADH
Release of atrial natriuretic peptide
Chamber enlargement
Myocardial hypertrophy
7
9. TREATMENT OF CHF
Non pharmacological treatment
Pharmacological treatment
9
10. NON PHARMACOLOGICAL APPROACH
Lifestyle change
1. Salt restriction
2. Exercises
3. Reduce on smoking and
alcoholism
4. Body weight (daily weight)
5. Supportive stockings 10
11. DRUGS USED IN MANAGEMENT OF HEART
FAILURE
A. POSTIVE INOTROPIC AGENTS
i. Cardiac glycosides
ii. Phosphodiesterase inhibitors
iii. β1 Adrenergic agonist
B. BETA BLOCKERS
C. RENIN- ANGIOTENSIN SYSTEM BLOCKERS
i. ACE Inhibitors
ii. Angiotensin II Receptor Blockers
D. DIURETICS
E. DIRECT VASODILATORS
11
12. POSTIVE INOTROPIC AGENTS
i. Cardiac glycosides
a. Digitoxin
b. Digoxin
ii. Phosphodiesterase inhibitors
a. Amrinone[AM-ri-none]
b. Milrinone[MIL-ri-none]
iii. β1 Adrenergic agonist
a. Dobutamine
b. Dopamine
12
13. CARDIAC GLYCOSIDES
Examples: Digoxin, Digitoxin, Ouabain e.t.c.
Prototype: Digoxin
Source:
Extracted from the leaves of purple (D.purpurea
) and white (digitalis lanata) Fox glove.
Structure:
Has aglycone steroid nucleus with unsaturated 5
membrane lactone ring and a series of sugars
linked to the C3 of the nucleus.
13
14. Aglycone steroid nucleus is essential for
pharmacological effects.
Unsaturated lactone ring confers the
cardiotoxic actions
C3 linked sugar moieties influence potency
and pharmacokinetics characteristics.
14
16. Pharmacological effects:
Increases the force of cardiac contractility and reduces heart
rate (HR).
Improvement in renal blood flow 0782547911
MOA:
a. Increasing the force of contractility
CG combine reversibly with the Na+-K+ ATPase of the
cardiac cell membrane, resulting in inhibition of pump activity
and this causes an increase in Na+ concentration inside the
cell which inhibits the transport of Ca+ out of the cell via Na+ -
Ca+ exchanger and thus an increase intracellular Ca+
concentration . The raised cytoplasmic Ca+ concentration is
then actively pumped into the SR and becomes available for
subsequent depolarization, resulting in an increase in the
force of contraction.
16
18. b. Alteration of electrical activity i.e. reduction in the heart
rate
CG alter the electric activity both directly and indirectly.
The Indirectly Activity:
CG alter HR by increasing the activity of the vagus nerve and a
reflex activity of the vagus nerve arcs. This increases
potassium outward and resting potential, reducing automaticity.
Increased vagal firing activity predominates in the
supraventricular regions.
This cause:
Slowing of SA node firing rate
Slowing of the AV node conduction velocity
Shortening of the atrial action potential
At toxic dosages, CG increase efferent cardiac sympathetic
tone. However the rate of neural discharge is not uniform for all
sympathetic nerves and this can result in a non uniform
myocardial excitability leading to arrhythmias
18
19. The Direct effect
The direct effect of cardiac glycosides are most
marked at high doses and relate to the loss of
cytoplasmic K+ due to inhibition of Na+/K+. This
reduces the resting membrane potential.
This results into enhanced automaticity,
decreased cardiac conduction velocity and
increased AV node refractory period
With increasing CG conc. Ca+ conc. reaches
toxic levels saturating the SR sequestration
mechanism resulting in oscillations in free Ca+.
This results in oscillations in membrane potential
leading to arrhythmias 19
21. Other MOA
CG increase PR by direct vasoconstriction and centrally
mediated increase in sympathetic tone. In CCF patients the
PR that is present falls as the treatment is maintained.
The improvement in the hemodynamics occurring as a result
of increased COP results in diuresis (due to increased renal
blood flow).
N.B:
All cardiac glycosides have a low therapeutic ratio because
their pharmacotherapeutics and toxic actions results from
increased cytoplasmic Ca+ conc.
CG are more beneficial on long term prognosis of the
Patients.
21
22. Therapeutic Uses:
Cardiac failure:
By the direct action on contractility, they are of great value in the
treatment of severe left ventricular systolic failure after initiation of
diuretics and ACE inhibitors, only if the patient has AF well it
becomes 1st choice.
Atrial fibrillation:
By the vagal effect on the AV node, it reduces conduction velocity,
thus slowing the ventricular rate (i.e. digoxin does not revert the
atrial fibrillation to the normal sinus rhythm).
Atrial flutter:
By the vagal action on the AV node; it reduces the rate, and by
shortening the refractory period of the atrial muscle; it convert
flutter to fibrillation in which the ventricular rate is more readily
controlled.
Paroxysmal Atrial Tachycardia (PAT)
Though adenosine, and Ca+ channels blockers are the best now.
22
23. PK of Digoxin
Administered orally and IV (but it's dangerous)
Well absorbed following oral administration with a high
bioavailability
Has a half life of 36hrs.
Cross barriers including BBB, PBB and is also found in breast
milk.
Highly binds to plasma protein
Eliminated unchanged by the kidneys.
Administration and Dosage:
You should not exceed the safety therapeutic range, the slow
approach of digitalization is the safest method.
If a more rapid effect is needed, then you can give a loading
dose divided into 3-4 doses over 24 hours then followed by
maintenance dose.
Slow digitalization or maintenance doses of digoxin is 0.125-
0.5 mg while loading dose is 0.5-0.75 mg every 8 hrs (3 daily)
then followed by maintenance dose.
23
24. Adverse effects:
CVS: Cardiac arrhythmias
GIT: Anorexia (earliest sign).
Nausea, vomiting, diarrhea (nausea and vomiting
due to stimulation of CTZ and vagal afferent).
CNS: Headache, malaise, fatigue, neuralgia,
confusion, agitation, and convulsions.
Vision change: include change in color perception, yellow
vision xanthopsia, hollows on dark objects.
Gynecomastia (rare) because of their peripheral estrogenic
action (it contains steroid nucleus)
24
25. Factors predisposing to digoxin toxicity:
Electrolyte disturbance:
a. Hypokalemia: may be produced by diuretics, steroids, vomiting
and diarrhea. It can precipitate serious arrhythmia and this can be
prevented by supplying K+ or the use of K+ sparing diuretics.
b. Hypercalcemia and hypomagnesemia: also predispose to digoxin
toxicity.
Drugs:
a. Quinidine and verapamil: By displacing digoxin from binding site.
Quinidine also competes with digoxin for renal excretion.
b. Other drugs may increase digoxin concentration and potential for
toxicity include: Amiodarone, tetracycline, erythromycin, and other
drugs that cause hypokalemia.
25
26. Principles of Rx of digitalis toxicity:
Cardiac glycosides and K+ depleting drugs are discontinued.
Oral administration of K+ supplements (KCl) to raise K+
concentration.
Monoclonal antibodies to bind cardiac glycosides.
Intravenous digoxin immune specific Ab fragment for antigen
binding (FAB), derived from specific antibodies to digoxin for
patients with life threatening toxicity.
NB:
CG toxicity can be minimized or prevented by monitoring of
serum electrolytes and CG blood concentration.
26
27. Rx of digoxin induced cardiac arrhythmias
Atropine to control sinus bradycardia.
Procainamide and Phenytoin to reverse CG induced arrhythmias.
Propranolol can be used for ventricular and supra ventricular
tachycardia unless there is AV block.
27
28. Digoxin toxicity treatment:
Toxicity can be treated with higher than normal
doses of potassium.
Digoxin antibody (digibind) is used specifically to
treat life-threatening digoxin overdose.
28
29. II. PHOSPHODIESTERASE INHIBITORS
Examples: Amrinone, milrinone , enoximone and vesnarinone.
Prototype: Milrinone
Is Amrinone analog but more potent (20 times)
MOA
Inhibit PDE 3 which breaks down cAMP and thus an increase in
its concentration. Increasing cAMP production results in a
cAMP-dependent phosphorylation of the L-type calcium channel
and a subsequent increase to the influx of a minute quantity of
calcium from outside the cell into the myocardium. 29
30. The entry of this small quantity of calcium causes the
release of the large reservoir of calcium stored in the
sarcoplasmic reticulum (SR) through the SR calcium
release channel (ryanodine receptor). Large reservoir
of calcium forms a complex with calmodulin which
plays a role in allowing the actin and myosin filaments
to overlap, resulting in systolic myocardial contraction.
cAMP break down is also inhibited in arterial and
venous smooth muscle resulting in marked
vasodilation.
30
32. Clinical uses:
Short term treatment of patients with digitalis and diuretics
Pharmacokinetics
Administered both as Intravenous infusions initial with a
loading followed by a continuous infusion, and orally.
Half-lives of Milrinone is 0.5 to 1 hour and are approximately
doubled in patients with severe heart failure.
10-40% is excreted in the urine unchanged
Adverse effects:
Liver function abnomalities
Thrombocytopnenia
Can precipitate lethal arrhythmias
32
33. III. BETA 1 ADRENERGERGIC AGONISTS
Examples: Dobutamine and Dopamine
Prototype: Dobutamine
Clinical use: Used in acute heart failure
MOA:
They bind to B1 adrenoceptors, leading to an increase in cAMP
levels accompanied by an elevated Ca 2+ intracellulary and, as a
consequence a postive inotropic response.
Note
High cardiac sympathetic tone produce B1 receptor down
regulation in a failing heart. Becoz of this they are never used for
long term management.
Other Beta 1 adrenergergic agonists; adrenaline, isoprenaline and
noradrenaline are not often used because they increase PR via
alpha 1 receptors.
See PK and Adverse effects under ANS Pharmacology 33
34. BETA ADRENERGIC ANTAGONIST
Example: Carvedilol
Pharmacological effect:
Reduce down regulation of B1 receptors that occurs in response to
high level of sympathetic tone.
Also inhibits GRK2 activity
MOA:
The G protein-coupled receptor kinase (GRK)- arrestin system is
involved in transduction of desensitization and down regulation of
myocardial B1 adrenoceptors. There several isoforms of GRK
among which is the myocardial GRK2 which is up-regulated in
patients with CHF. Inhibition of GRK2 activity may impair adverse
cardiac remodelling in CHF.
B1 adrenergic antagonists inhibit this enzyme.
34
35. Clinical significance:
They reduce death during long term treatment
NB:
All these agents may reduce HR and COP when the
treatment has just began and this may make the patient
to feel worse. However if the initial dose is low this is not
a problem.
As treatment is maintained COP increases and CHF
symptoms diminishes.
35
