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Cardiac failure Heart failure (HF) is a complex, progressive disorder in which the heartis unable to pump sufficient blood to meet the needs of the body.Its cardinalsymptoms are dyspnea, fatigue, and fluid retention.

OVERVIEW 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*

OVERVIEWUnderlying causes of HF include arteriosclerotic heart disease, myocardial infarction, hypertensive heart disease, valvular heart disease, dilated cardiomyopathy, and congenital heart disease.*

COMPENSATORY MECHANISMSSYMPATHETIC ACTIVITY INCREASESBETA RECEPTORS STIMULATEDHR INCREASESFORCE OF CONTRACTION INCREASES

ALPHA RECEPTORS STIMULATEDVENOUS RETURN INCREASESPRE LOAD INCREASES*

CONSEQUENCES OF HEART FAILURE

CO DECREASESRBF DECREASES INCREASES ANGIOTENSIN IIINCREASES ALDOSTERONE*

CONSEQUENCES OF HEART FAILUREPERIPHERAL RESISTANCE INCREASESSODIUM AND WATER RETENTIONBLOOD VOLUME INCREASESMAY RESULT PERIPHERAL EDEMAPULMONARY EDEMA*

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COMPENSATORY PHYSIOLOGICAL RESPONSES IN HF1. Increased sympathetic activity: 2. Activation of the reninangiotensin aldosterone system: 3. Myocardial hypertrophy: *

ACUTE (DECOMPENSATED) HFIf the adaptive mechanisms adequately restore cardiac output, HF is said to be compensated. If the adaptive mechanisms fail to maintain cardiac output, HF is decompensated and the patient develops worsening HF signs and symptoms. Typical HF signs and symptoms include dyspnea on exertion, orthopnea, paroxysmal nocturnal dyspnea, fatigue, and peripheral edema.*

CHEST X-RAY- CHF*Note the enlarge Heart (greater than chest diameter on a PA film)

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The treatment of CHF aims to reduce preloadand afterload and to increase myocardialcontractility mainly by administration of:

1) angiotensin-converting enzyme inhibitors, 2) angiotensin-receptor blockers, 3) aldosterone antagonists, 4) -blockers, 5) diuretics, 6) direct vaso- and venodilators, and 7) inotropic agents CONGESTIVE HEART FAILURE (CHF)

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THERAPEUTIC STRATEGIES IN HF

Chronic HF is typically managed by fluid limitations (less than 1.5 to 2 L daily);REDUCE PHYSICAL ACTIVITYDECREASE SODIUM IN DIETVASODILATORSDIURETICSIONOTROPICSNote: Inotropic agents are reserved for acute HF signs and symptoms in mostly the inpatient setting. Drugs that may precipitate or exacerbate HF, such as nonsteroidal anti-inflammatory drugs (NSAIDs), alcohol, nondihydropyridine calcium channel blockers, and some antiarrhythmic drugs, should be avoided if possible.*

4 classes of drugs effective in reducing the symptoms and prolong life1. ACEIs reduce afterload and preload 2. Diuretics decrease extracellular fluid volume3. ARBs decrease preload and afterload4. Beta blockers.*

1. inhibitors

Angiotensin

Angiotensin I

Angiotensin II

AT1-receptor

AT2-receptor

Renin

ACE

ACEinhibitors

(-)

ACE

Kinins

Breakdown

(kininase II)

(-)

ACE INHIBITORSreduce pre- and afterload.They are administered in lower doses alone or together with diuretics, cardiac glycoside, anti-ischemic agents, etc. in all stages of CHF, due to systolic dysfunction. Adverse effects: These include postural hypotension, renal insufficiency, hyperkalemia, a persistent dry cough, and angioedema (rare).

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ANGIOTENSIN RECEPTOR BLOCKERAngiotensin II receptor blockers (ARBs) are medications that block the action of angiotensin II by preventing angiotensin II from binding to angiotensin II receptors on the muscles surrounding blood vessels. As a result, blood vessels enlarge (dilate) and blood pressureis reduced. Reduced blood pressure makes it easier for the heart to pump blood and can improveheart failure.*

In addition, the progression ofkidney diseasecaused by thehigh blood pressureor diabetesis slowed. ARBs have effects that are similar toangiotensin converting enzyme(ACE) inhibitors, butACE inhibitorsact by preventing the formation of angiotensin II rather than by blocking the binding of angiotensin II to muscles on blood vessels.ARBs do not affect bradykinin levels*

ALDOSTERONE ANTAGONISTSPatients with advanced heart disease have elevated levels of aldosterone due to angiotensin II stimulation and reduced hepatic clearance of the hormone. Spironolactone [spy-ro-no-LAC-tone] is a direct antagonist of aldosterone, thereby preventing salt retention, myocardial hypertrophy, and hypokalemia. Eplerenone [eh-PLEH-reh-none] is a competitive antagonist of aldosterone at mineralocorticoid receptors.*

IONOTROPIC AGENTSGLYCOSIDEDIGOXINDIGITOXIN

BETA AGONISTDOPAMINEDOBUTAMINE

PHOSPHO DIESTERASE INHIBITORSAMRINONEMILRINONE*

BETA AND ALPHA BLOCKING AGENTSCarvedilol is a blocker of - and -receptors. It also has antioxidant, vasodilating and cardioprotective effects. It decreases cardiac output, peripheral vascular resistance and afterload. Carvedilol lowers mortality with 2567%.The treatment begins with low doses (3.125 mg/12 h).

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Beta-blocking agentsCardioselective beta-blockers Bisoprolol andMetoprolol decrease with 31% mortality inpatients with CHF, if used in combination withdiuretics, ACE inhibitors and Digoxin.

THIAZIDES AND LOOP DIURETICSThey increase salt and water loss, reduce blood volume and lower excessive venous filling pressure, reduce circulating blood volume and preload. The congestive features of oedema, in the lungs and periphery, are alleviated, cardiac output is also increased.

Diuretics are administered together with ACE inhibitors and other drugs.

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VASO- AND VENODILATORSDilation of venous blood vessels leads to a decrease in cardiac preload by increasing venous capacitance. Nitrates are commonly used venous dilators to reduce preload for patients with chronic HF. Arterial dilators, such as hydralazine [hye-DRAL-a-zeen] reduce systemic arteriolar resistance and decrease afterload. If the patient is intolerant of ACE inhibitors or -blockers, or if additional vasodilator response is required, a combination of hydralazine and isosorbide dinitrate [eye-soe-SOR-bide dye-NYE-trate] may be used. hydralazine has been associated with drug-induced lupus.*

VASODILATORSVasodilator therapy with nitroprusside or nitroglycerin is often used for acute severe failure with congestion.Reduction in cardiac size and improved efficiency that can be realized with proper adjustment of venous return (preload) and reduction of resistance to ventricular ejection ( afterload)*

VASODILATORSThe natriuretic peptide nesiritide acts chiefly by causing vasodilation.Binds to natriuretic peptide receptors, thus increase cGMP, resulting in vasodilation.Used in acute decompensated CHF*

Cardiac glycosides (CGs)

Digitalis purpurea (Foxglove)

W. Withering (1785)

France, UK

Nativelle(1869)Digitoxin

MECHANISMDirect inhibition of Na+/K+ATPase Na+gradient results in indirect inhibition of Na+/Ca2+exchanger/antiport [Ca2+]i positive inotropyVagal stimulationresults in increased cardiac output via decreased heart rateincreased filling time

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CARDIAC GLYCOSIDESMECHANISM

INHIBIT SODIUM POTASSIUM PUMP

INTRACELLULAR SODIUM INCREASES

CALCIUM EXCHANGE DECREASE

CYTOPLASM Ca++ INCREASES

FORCE OF CONTRACTION INCREASES*

Na+/K+ATP-aseNa+/Ca2+exchangeCa2+3Na+3Na+2K+DIGOXINExIn()

PHARMACOKINETICSDIGOXINORAL AND IVLARGE VOL OF DISTRIBUTIONhas a long half-life of 30 to 40 hours. It is mainly eliminated intact by the kidney, requiring dose adjustment in renal dysfunction.

Digoxin is a substrate of P-gp, and inhibitors of P-gp, such as clarithromycin, verapamil, and amiodarone, can significantly increase digoxin levels, necessitating a reduced dose of digoxin.*

SIDE EFFECTS

Blurry yellow vision(xanthopsia),Nausea, vomiting, diarrheacholinergic effectsLife-threatening arrhythmias PR, QT, T-wave inversionHyperkalemiaRenal insufficiency causes digoxin toxicityHypokalemia causes digoxin toxicitywithout K+, digoxin can bind to Na+/K+ATPasedigoxin competes for excretion and competes for tissue-binding sites*

ANTIDOTESlowly normalize K+GivelidocaineGivedigoxin antibodies (anti-dig Fab fragments)GiveMg2+

Also remember:Digoxin should also be used with caution with other drugs that slow AV conduction, such as -blockers, verapamil, and diltiazem.*

-ADRENERGIC AGONISTSDOPAMINE DOBUTAMINE

Mostly slow IV route.-Adrenergic agonists, such as dobutamine [doe-BYOO-ta-meen] and dopamine [DOH-puh-meen], improve cardiac performance by causing positive inotropic effects and vasodilation.*

-ADRENERGIC AGONISTSDobutamine is the most commonly used inotropic agent other than digoxin. -Adrenergic agonists lead to an increase in intracellular cyclic adenosine monophosphate (cAMP), which results in the activation of protein kinase. Protein kinase then phosphorylates slow calcium channels, thereby increasing entry of calcium ions into the myocardial cells and enhancing contraction*

PHOSPHODIESTERASE INHIBITORSAMRINONEMILRINONEMech: cAMP INCREASESCYTOPLASM CALCIUM LEVELS Increase cardiac contractilitySE: THROMBOCYTOPENIA

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Alternative methods for treatment of severe CHFCardiac transplantaion

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