Role of physiologic compensatory mechanisms in the progression of hf

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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. Its cardinal symptoms are :dyspnea, fatigue, and fluid retention. HF is due to an impaired ability of the heart to adequately fill with and/or eject blood. It is often accompanied by abnormal increases in blood volume and interstitial fluid, hence the term a congestive HF because symptoms include dyspnea from pulmonary congestion in left HF, and peripheral edema in right HF.

causes of HF include :

1-arteriosclerotic heart disease: Left systolic dysfunction secondary to coronary artery disease is the most common cause of HF.

2-myocardial infarction 3-hypertension.

4- valvular heart disease.

5- dilated cardiomyopathy 6- congenital heart disease.



1-↑↑ preload :(preload is the venous return to the heart and the stretching of the myocardial muscle fibers).

2-↓↓myocardial contractility → ↓↓ cardiac output .

3-↑↑ afterload : (afterload is the resistance against which the heart must contract and eject blood when it↑↑ the cardiac performance ↓↓.

Role of physiologic compensatory mechanisms in the progression of HF

chronic activation of the sympathetic nervous system and the renin-angiotensin-aldosterone axis is associated with remodeling of cardiac tissue, characterized by loss of myocytes,hypertrophy, and fibrosis. The geometry of the heart becomes less elliptical and more spherical, interfering with its ability to efficiently function as a pump. This prompts additional neurohumoral activation, creating a vicious cycle that, if left untreated, leads to death. .

Goals of pharmacologic intervention in HF

The goals are to alleviate symptoms, slow disease progression, and improve survival. Accordingly, six classes of drugs have been shown to be effective: 1) inhibitors of the renin-angiotensin system, 2) β-adrenoreceptor blockers, 3) diuretics, 4) inotropic agents, 5) direct vasodilators, and 6) aldosterone antagonists . Depending on the severity of cardiac failure and individual patient factors, one or more of these classes of drugs are administered.

Beneficial effects of pharmacologic intervention include reduction of the load on the myocardium, decreased extracellular fluid volume, improved cardiac contractility, and slowing of the rate of cardiac remodeling.

Non drug measures : include restriction of fluid intake , ↓↓ body wt., dietary sodium restriction(<1500 mg/day), , avoidance of smoking,reduction of physical activity . Drugs that may precipitate or exacerbate HF, such as NSAIDs,alcohol, calcium-channel blockers, and some antiarrhythmic drugs, should be avoided if possible. .

Drug management


(ACE) inhibitors(like enalapril ,fosinopril,ramipril) are the agents of choice in HF. These drugs :

1-block the enzyme that cleaves ang. I to form the potent vasoconstrictor ang. II . These agents also diminish the rate of bradykinin inactivation.

[Vasodilation occurs as a result of the combined effects of lower vasoconstriction caused by diminished levels of ang. II and the potent vasodilating effect of increased bradykinin.]

2- By reducing circulating ang II levels, ACEIs also decrease the secretion of aldosterone,resulting in decreased sodium and water retention.

3-Actions on the heart: ACEIs decrease vascular resistance, venous tone, and blood pressure, resulting in an increased cardiac output .4- ACEIs also blunt the usual angiotensinII “mediated increase in epinephrine and aldosterone seen in HF.

5-ACEIs improve clinical signs and symptoms in patients also receiving thiazide or loop diuretics and/or digoxin. The use of ACEIs in the treatment of HF has significantly decreased both morbidity and mortality.

Adverse effects: These include postural hypotension, renal insufficiency, hyperkalemia, angioedema, and a persistent dry cough.

Angiotensin-receptor blockers

Angiotensin-receptor blockers (ARBs) are nonpeptide, orally active compounds that are extremely potent competitive antagonists of the angiotensin type 1 receptor. ARBs have the advantage of more complete blockade of angiotensin action, because ACE inhibitors inhibit only one enzyme responsible for the production of angiotensin II. Further, the ARBs do not affect bradykinin levels. their use in HF is as a substitute for ACE inhibitors in those patients with severe cough or angioedema.


several clinical studies have clearly demonstrated improved systolic functioning and reverse cardiac remodeling in patients receiving β -blockers. These benefits arise in spite of occasional initial exacerbation of symptoms. The benefit of β -blockers is attributed, in part, to their ability to prevent the changes that occur because of the chronic activation of the sympathetic nervous system, including decreasing the heart rate and inhibiting the release of renin. In addition, β -blockers also prevent the direct deleterious effects of norepinephrine on the cardiac muscle fibers, decreasing remodeling, hypertrophy and cell death. Two β -blockers have been approved for use in HF: carvedilol , and long-acting metoprolol . Carvedilol is a nonselective β-adrenoreceptor antagonist that also blocks α- adrenoreceptors, whereas metoprolol is a β 1-selective antagonist.


Diuretics relieve pulmonary congestion and peripheral edema. These agents are also useful in reducing the symptoms of volume overload, including orthopnea and paroxysmal nocturnal dyspnea. Diuretics decrease plasma volume and, subsequently, decrease venous return to the heart (preload). This decreases the cardiac workload and the oxygen demand. Diuretics may also decrease afterload by reducing plasma volume, thus decreasing BP thiazide diuretics are relatively mild diuretics and lose efficacy if patient creatinine clearance is less than 50 mL/min. Loop diuretics are used for patients who require extensive diuresis and those with renal insufficiency.

Direct Vasodilators

Dilation of venous blood vessels leads to a decrease in cardiac preload by increasing the venous capacitance; arterial dilators reduce systemic arteriolar resistance and decrease afterload. Nitrates are commonly employed venous dilators for patients with congestive HF. If the patient is intolerant of ACE inhibitors or β -blockers, the combination of hydralazine and isosorbide dinitrate is most commonly used.[Calcium-channel blockers should be avoided in patients with HF]

Inotropic Drugs

Positive inotropic agents enhance cardiac muscle contractility and, thus, increase cardiac output.


The cardiac glycosides are often called digitalis or digitalis glycosides, because most of the drugs come from the digitalis (foxglove) plant. These drugs have a low therapeutic index. The most widely used agent is digoxin.

DIGOXIN: it inhibits the Na-K ATPase activity resulting in an↑↑ of

Na ion inside the cell which facilitate the entry Ca ion inside the cell ,Ca ion is essential for the contractile proteins actin and myocin that present in the cell ,thus↑↑ the myocardial contractility producing positive inotropic effect ,it also stimulates the vagal nucleus centrally resulting in ↓↓ the conduction through the AV node so it is used to control the ventricular rate in patient with AF.

Therapeutic uses: Digoxin therapy is indicated in patients with severe left ventricular systolic dysfunction after initiation of ACE inhibitor and diuretic therapy. Digoxin is not indicated in patients with diastolic or right-sided HF. Digoxin's major indication is HF with atrial fibrillation .

Dobutamine, another inotropic agent, can be given intravenously in the hospital, but at present, no effective oral inotropic agents exist other than digoxin. Patients with mild to moderate HF will often respond to treatment with ACE inhibitors and diuretics, and they do not require digoxin.

Pharmacokinetics: All digitalis glycosides possess the same pharmacologic actions, but they vary in potency and ph.kinetics. Digoxin is very potent, with a narrow margin of safety and long half-life of around 36 hours. Digoxin is mainly eliminated intact

by the kidney, requiring dose adjustment based on creatinine clearance. Digoxin has a large volume of distribution, because it accumulates in muscle. A loading dose regimen is employed when acute digitalization is needed. Digitoxin has a much longer half-life and is extensively metabolized by the liver before excretion in the feces, and patients with hepatic disease may require decreased doses.

Adverse effects: Digitalis toxicity is one of the most commonly encountered adverse drug reactions. Side effects often can be managed by discontinuing cardiac glycoside therapy, determining serum potassium levels(decreased K+ enhances potential for cardiotoxicity), and if indicated, giving potassium supplements. In general, decreased serum levels of potassium predispose a patient to digoxin toxicity. Digoxin levels must be closely monitored in the presence of renal insufficiency, and dosage adjustment may be necessary. Severe toxicity resulting in ventricular tachycardia may require administration of antiarrhythmic drugs and the use of antibodies to digoxin (digoxin immune Fab), which bind and inactivate the drug.

Types of adverse effects include:

1-Cardiac effects: The common cardiac side effect is arrhythmias 2-GIT effects: Anorexia, nausea, and vomiting are common

3-CNS effects: headache, fatigue, confusion, blurred vision, alteration of color perception, and halos on dark objects.

Factors predisposing to digitalis toxicity:

1)Electrolytic disturbances: Hypokalemia can precipitate serious arrhythmia. 2) Hypercalcemia and hypomagnesemia.

3) Drugs: Quinidine, verapamil, and amiodarone, to name a few, can cause digoxin intoxication, both by displacing digoxin from tissue protein-binding sites and by competing with digoxin for renal excretion ,Potassium-depleting diuretics, corticosteroids, and a variety of other drugs can also increase digoxin toxicity.

4) Hypothyroidism, hypoxia, renal failure, and myocarditis are also predisposing factors to digoxin toxicity.

B -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 digitalis. Dobutamine leads to an increase in Intracellular (cAMP). Dobutamine must be given by intravenous infusion and is primarily used in the treatment of acute HF in a hospital setting.

Phosphodiesterase inhibitors

Amrinone and milrinone are phosphodiesterase inhibitors that increase the intracellular concentration of cAMP. This results in an↑↑of intracellular calcium and, therefore, cardiac contractility. Long-term amrinone or 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 increase mortality, and some symptomatic benefit may be obtained when it is used in patients with refractory HF.


Patients with advanced heart disease have elevated levels of aldosterone due to angiotensin II stimulation and reduced hepatic clearance of the hormone. Spironolactone is a direct antagonist of aldosterone, thereby preventing salt retention, myocardial hypertrophy,and hypokalemia. Spironolactone therapy should be reserved for the most advanced cases of HF. Because spironolactone promotes potassium retention, patients should not be taking potassium supplements. Adverse effects: include gastric disturbances, such as gastritis and peptic ulcer; central nervous system effects, such aslethargy and confusion; and endocrine abnormalities, such as gynecomastia, decreased libido, and menstrual irregularities.
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