Congestive Heart Failure

(CHF)
 Heart Failure
O It is the inability of the heart to maintain an adequate COP
sufficient to meet tissue oxygen requirements.
O Heart failure is regarded to as "imbalance between COP and
tissue oxygen requirements".
O Main causes: Coronary artery disease, hypertension,
valvular heart disease and cardiomyopathy.
O Preload: Overfilling of the heart during diastole which
increases the work load, deterioration of ventricular function
and results in pulmonary congestion.
O Afterload: Elevated afterload cause the heart to work harder
to pump blood into the arterial system
 Heart Failure
Types of Heart Failure:
a) According to COP:
O Low COP failure: either due to systolic dysfunction or due to diastolic
dysfunction.
O High COP failure: due to hyperthyroidism, severe anemia, pregnancy, or severe
vitamin deficiency. Treatment of this type of heart failure is by treatment of the
cause.
b) According to Onset:
O Chronic heart failure.
O Acute heart failure.
c) According to Side affected:
O Right -sided heart failure: leads to systemic congestion.
O Left-sided heart failure: leads to pulmonary congestion.
O Combined heart failure: leads to both systemic and pulmonary congestion.
 Heart Failure
Compensatory Mechanisms in Heart Failure:
They try to increase COP but will eventually fail and heart failure
becomes "manifest" or "decompensated".
The compensatory mechanisms include:
1) Increase in cardiac size by hypertrophy and dilatation.
2) Reflex sympathetic stimulation: low COP → low ABP (except in
hypertensive heart failure) →
O Tachycardia.
O V.C. of both arteries and veins (↑afterload and preload).
O Increased renin-angiotensin activity → increased aldosterone synthesis and
release → sodium and water retention→ edema and increased blood volume.
 Heart Failure
The therapeutic goal for CHF:
O The treatment of CHF aims to reduce preload and afterload and to
increase myocardial contractility and cardiac output.
O Classes of drugs have been shown to be clinically effective in
reducing symptoms but DO NOT reverse the underlying pathologic
condition.
Classes of drugs:
1) Inhibitors of the renin-angiotensin system.
2) Diuretics; decease extracellular fluid volume.
3) Direct vasodilators; reduce the load on the myocardium.
4) Inotropic agents; increase the contraction of cardiac muscle
5) β-adrenoceptors blockers.
 Cardiac glycosides
Cardiac Glycosides (Digitalis Preparations):
Source: Plant origin (Digitalis purpurea, Digitalis lanata, Strophanthus).
Chemistry: each molecule is composed of:
O Non-sugar part (aglycone) formed of a steroid nucleus; it is responsible for the
pharmacodynamic properties.
O Sugar part (glycone) which is responsible for the degree of lipid solubility and
accordingly the pharmacokinetic properties.
Pharmacokinetics
 Cardiac glycosides
Pharmacodynamics:
Mechanism of action:
Cardiac glycosides partially inhibit membrane-bound Na+/K+ ATPase (Na+ pump)
in cardiac cells → increase intracellular Na+ → increase in intracellular Ca2+ by:
1) ↓ Ca2+/Na+ exchange.
2) ↑Release of Ca2+ from sarcoplasmic reticulum.
3) Opening of voltage-gated Ca2+ channels.
4) Elevation of free Ca2+ increases myocardial contractility.
Very important note:
Cardiac glycosides and K+, and to a lesser extent Mg2+ compete for
Na+/K+ ATPase; that is why hypokalemia is the most important predisposing
factor for digitalis toxicity. (K+ and Mg2+ activate but digitalis and Ca2+ inhibit the
enzyme).
 Cardiac glycosides
Pharmacological actions:
O Positive Inotropic action especially in left ventricular systolic
dysfunction.
O Increased COP in patients with congestive heart failure, but its
effect is insignificant in normal individuals.
O Increased mechanical efficiency of the heart as digitalis increases
contractility (work done) without marked increase in oxygen
consumption (energy consumed).
O Reduction of cardiac size to normal.
O Overall, the heart rate is decreased while stroke volume is increased,
resulting in a net increase in blood pressure, leading to increased
tissue perfusion.
 Cardiac glycosides
Heart rate:
O Digitalis decreases SAN automaticity; it has negative chronotropic
effect leading to decrease in heart rate. Remember that before digitalis
there is compensatory tachycardia.
O Reduction in heart rate is due to:
1) Vagal action: digitalis stimulates vagal C.I.C. both directly and
indirectly through stimulation of baroreceptors, and sensitizes SAN
to acetylcholine. This vagal action is the mechanism of bradycardia
in the beginning of treatment by digitalis (early digitalization).
2) Direct action (extra-vagal action): digitalis decreases SAN
automaticity directly and decreases sensitivity of SAN to
catecholamines (anti- adrenergic action). This action occurs after
full digitalization.
 Cardiac glycosides

Diuretic Action:
Digitalis has a diuretic action only in cases of congestive
heart failure as it increases COP → ↑renal blood flow
(RBF) →↑ GFR. In addition; improvement of COP
reduces sympathetic activity →↓ renin-angiotensin-
aldosterone system.
Coronary vessels:
O Therapeutic levels of digitalis have no effect on coronary
circulation and it can be used in patients with angina and
heart failure.
O In digitalis toxicity coronary vasospasm may occur.
 Cardiac glycosides

Therapeutic uses::
1) Congestive heart failure, especially left ventricular systolic
dysfunction. Digitoxin and digoxin can be used in chronic cases
whereas digoxin and ouabain can be used in acute heart failure
(acute LVF).
2) Atrial Fibrillation (AF): digitalis is useful in AF with or without
heart failure.
3) Atrial Flutter: digitalis protects the ventricles by reducing AV
conduction.
digitalis in many times convert atrial flutter into AF and its withdrawal
may restore normal sinus rhythm (remove the exciting cause)
 Cardiac glycosides
Adverse effects (Toxicity):
O CVS: (1-10%) Arrhythmia, conduction disturbances, bigeminy, trigeminy, PR
prolongation, sinus bradycardia.
Less common: Supraventricular tachyarrhythmia, atrial tachycardia, nodal tachycardia,
ventricular arrhythmia, ventricular premature contraction, ST segment depression,
atrioventricular block, ventricular fibrillation.
O GIT: anorexia, nausea, vomiting, colic, and diarrhea. Nausea is mainly due stimulation of
CTZ and less probably due to local GIT irritation.
O CNS: headache, drowsiness, confusion, hallucinations, and convulsions (rare but indicates
serious toxicity). depression
O Eye: Blurred vision or visual disturbances (chromatopsia), amblyopia, or diplopia.
Color vision deficiencies are a common sign of digoxin intoxication and color vision testing
can be used to diagnose digoxin toxicity. .Initial testing disclosed both red-green and blue-
yellow color vision deficiencies. These improved when digoxin levels diminished.
O Gynecomastia: may be due to steroid structure (remember spironolactone).
O Skin rashes of urticarial or scarlatiniform character
 Cardiac glycosides
Contraindications:
O Bradycardia (Carotid sinus hypersensitivity, an exaggerated response to carotid
sinus baroreceptor stimulation. It results in dizziness or syncope from transient
diminished cerebral perfusion).
O Partial AV block: It may lead to complete heart block.
O Ventricular arrhythmias: It convert ventricular tachycardia to ventricular
fibrillation.
O Recent myocardial infarction, it may induces serious dysrhythmias
O Hypertrophic obstructive cardiomyopathy (treated by β-blockers or CCBs).
O Constrictive pericarditis.
O Severe valve stenosis.
O Wolf-Parkinson-White syndrome (abnormal conducting fibers).
 Cardiac glycosides
Drug interactions:
A-Pharmacokinetic interactions:
1) Absorption:
a) Drugs that decrease digitalis absorption: Antacids (Mg2+ and Al3+
salts), Antiemetics (metoclopramide), Antidiarrheal drugs (kaolin
and pectin), Antibiotics (neomycin), and Antihyperlipidemic drugs
(cholestyramine).
b) Drugs that increase digitalis absorption: Antimuscarinic drugs as
atropine and propantheline. They may lead to digitalis toxicity.
2) Distribution:
O Many drugs displace digitalis from plasma proteins and may lead to
digitalis toxicity; as propranolol, NSAIDs as aspirin, CCBs as
verapamil and nifedipine, amiodarone, sulfonamides, and quinidine.
 Cardiac glycosides
Drug interactions:
A-Pharmacokinetic interactions:
3) Metabolism:
a) HME inducers as rifampicin, nicotine, phenytoin, and phenobarbitone
decrease bioavailability of digitalis.
b) HME inhibitors as contraceptives and erythromycin increase
bioavailability and may induce digitalis toxicity.
4) Excretion:
a) Quinidine and CCBs especially verapamil decrease renal clearance of
digoxin and may cause toxicity.
b) N.B. Quinidine induces digitalis toxicity by displacing digitalis from
plasma and tissue proteins, and decreasing its renal excretion.
 Cardiac glycosides
Drug interactions:
B-Pharmacodynamic interactions:
1) Diuretics increases K excretion as thiazides and loop diuretics
cause hypokalemia and hypomagnesemia which predispose to
digitalis toxicity.
2) K -sparing diuretics cause hyperkalemia which antagonizes
digitalis.
3) β-blockers and verapamil antagonize inotropic action of digitalis
but augment bradycardia and AV block.
4) Sympathomimetics acting as β1-agonists as adrenaline may lead to
ventricular arrhythmia.
5) Ca2+ salts increase the action of digitalis and may lead to toxicity.
 Cardiac glycosides
Treatment of digitalis toxicity:
1) Stop digitalis.
2) In case of hypokalemia: stop diuretics that cause loss of K and give
KCl (syrup, sustained release tablets, or slowly IV infusion) except in
case of renal impairment and AV block.
3) In case of hypercalcemia: Ca chelating agent as disodium edetate IV.
4) To treat AV block use atropine.
5) To treat ventricular arrhythmias
O With AV block: Phenytoin.
O Without AV block: Lidocaine or β-blockers.
6) In case of acute toxicity: Digoxin antibodies (Fab fragments, Digibind)
are given, and cholestyramine to decrease oral absorption of digitoxin.
 Other Positive inotropic agents
1 -β1-Agonists:
O Dobutamine →↑cAMP → activation of protein kinase → Ca+2 channel
phosphorylation → Ca+2 entry → enhancing contraction. It improves the cardiac
performance by both positive inotropic effects and vasodilation.
O Must be given by IV infusion and is primarily used in the treatment of acute heart
failure in hospital and in cardiogenic shock (Intraosseous infusion (IO) is the process of
injecting directly into the marrow of a bone.
2- Calcium sensitizers:
O Levosimendan: Levosimendan is a calcium sensitizer that can be administered
intravenously (IV) to patients with acute decompensated CHF. It enhances
myocardial contractility without increasing oxygen requirements, and causes
coronary and systemic vasodilation.
3- Phosphodiesterase inhibitors:
O Amrinone and milrinone →↑cAMP→↑intracellular Ca+2 → cardiac muscles
contraction and increase COP
Thank you