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Heart failure
Heart failure (HF) is a complex, progressive disorder in which the heart is unable to pump sufficient blood to
meet the needs of the body. The primary signs and symptoms of all types of heart failure include tachycardia,
decreased exercise tolerance, shortness of breath, and cardiomegaly. Peripheral and pulmonary edema (the
congestion of congestive heart failure) are often but not always present. Decreased exercise tolerance with
rapid muscular fatigue is the major direct consequence of diminished cardiac output. The other manifestations
result from the attempts by the body to compensate for the intrinsic cardiac defect.
Underlying causes of HF include arteriosclerotic heart disease, myocardial infarction, hypertensive heart
disease, valvular heart disease, dilated cardiomyopathy, and congenital heart disease.
Pathophysiology:
Cardiac performance is a function of four primary factors:
1- Preload: mainly a measure of left ventricular filling pressure;
It is affected by venous blood pressure and volume of circulating
blood (venous return).
2-Afterload: is the resistance against which the heart must pump
blood and is represented by aortic and systemic vascular
resistance.
3- Contractility.
4-Heart rate: beats/ mint.
In heart failure, the C.O↓ so
B.p & renal blood↓ so
sympathetic activity & Renin secretion ↑ leading to
Tachycardia, sodium and water retention, edema, increase blood
volume, vasoconstriction
thus
Preload & Afterload ↑
these consequences
Further harm the heart and so further exacerbate H.F.
SO treatment of heart failure needs:
1- ↑ C.O: INOTROPIC DRUGS (Digitalis glycosides, β-Adrenergic agonists, Phosphodiesterase inhibitors).
2-↓ Sympathetic over activation: β-blocker (discussed previously)
3- ↓Renin angiotensin system overactivation: ACEI , ARB, Spironolacton (discussed previously)
4- Edema: Diuretics (discussed previously)
INOTROPIC DRUGS:
Positive inotropic agents enhance cardiac muscle contractility and, thus, increase cardiac output. Although
these drugs act by different mechanisms, in each case the inotropic action is the result of an increased
cytoplasmic calcium concentration that enhances the contractility of cardiac muscle.
A. Digitalis glycosides
Most of the drugs come from the digitalis (foxglove) plant. The cardiac glycosides influence the sodium and
calcium ion flows in the cardiac muscle, thereby increasing contraction of the atrial and ventricular
myocardium (positive inotropic action). The most widely used agent is digoxin .
Mechanism of action:
Cardiac glycosides increase contraction of the cardiac sarcomere by increasing the free calcium
concentration. This increase in calcium concentration is the result of a two-step process: first, an increase of
intracellular sodium concentration because of Na + /K + -ATPase inhibition; and second, a relative reduction
of calcium expulsion from the cell by the sodium calcium exchanger {NCX} caused by the increase in
intracellular sodium (Figure);
Pharmacokinetics
Digoxin, the only cardiac glycoside used in the USA, is 65–80% absorbed after oral administration. Once
present in the blood, all cardiac glycosides are widely distributed to tissues, including the central nervous
system. Digoxin is not extensively metabolized in humans; almost two thirds is excreted unchanged by the
kidneys. Its renal clearance is proportional to creatinine clearance, and the half-life is 36–40 hours in patients
with normal renal function.
Interactions with Potassium, Calcium, and Magnesium
Potassium and digitalis inhibit each other’s binding to Na + /K + -ATPase; therefore, hyperkalemia reduces
the enzyme-inhibiting actions of cardiac glycosides, whereas hypokalemia facilitates these actions
Calcium ion facilitates the toxic actions of cardiac glycosides by accelerating the overloading of intracellular
calcium stores that appears to be responsible for digitalis-induced abnormal automaticity.Hypercalcemia
therefore increases the risk of a digitalis-induced arrhythmia.
The effects of magnesium ion are opposite to those of calcium.
These interactions mandate careful evaluation of serum electrolytes in patients with digitalis-induced
arrhythmias.
Adverse effects:
a. Cardiac effects: The common cardiac side effect is arrhythmia, characterized by slowing of AV conduction
associated with atrial arrhythmias. A decrease in intracellular potassium is the primary predisposing factor in
these effects.
b. Gastrointestinal effects: Anorexia, nausea, and vomiting are commonly encountered adverse effects.
c. Central nervous system effects: These include headache, fatigue, confusion, blurred vision, alteration of
color perception, and halos on dark objects.
d- The digitalis glycosides show only a small difference between a therapeutically effective dose and doses
that are toxic or even fatal. Therefore, the drugs have a low therapeutic index.
e- Digoxin toxicity is one of the most commonly encountered adverse drug reactions. Severe toxicity
resulting in ventricular tachycardia may require administration of antiarrhythmic drugs and the use of
antibodies to digoxin (digoxin immune Fab).
Digoxin levels must be closely monitored in the presence of renal insufficiency, and dosage adjustment may
be necessary.
Drug-drug interactions: Fig;
B. β-Adrenergic agonists:
β-Adrenergic stimulation improves cardiac performance by causing positive inotropic effects and
vasodilation. Dobutamine is the most commonly used inotropic agent other than digoxin. Dobutamine leads
to an increase in intracellular cyclic adenosine monophosphate (cAMP), which results in the activation of
protein kinase. Slow calcium channels are one kind of important site of phosphorylation by protein kinase.
When phosphorylated, the entry of calcium ion into the myocardial cells increases, thereby enhancing
contraction (Figure↓).
Dobutamine must be given by intravenous infusion and is primarily used in the treatment of acute HF in a
hospital setting.
C. Phosphodiesterase inhibitors:
Inamrinone and milrinone are phosphodiesterase inhibitors that increase the intracellular concentration of
cAMP (Figure↓). This results in an increase of intracellular calcium and, therefore, cardiac contractility.Both
long-term inamrinone and milrinone therapy may be associated with a substantial increase in the risk of
mortality. However, short-term use of intravenous milrinone is not associated with increased mortality, and
some symptomatic benefit may be obtained when it is used in patients with refractory HF.