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Cardiac 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.

O VERVIEW 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 3

O VERVIEW Underlying causes of HF include arteriosclerotic heart disease, myocardial infarction, hypertensive heart disease, valvular heart disease, dilated cardiomyopathy, and congenital heart disease. 4

COMPENSATORY MECHANISMS SYMPATHETIC ACTIVITY INCREASES BETA RECEPTORS STIMULATED HR INCREASES FORCE OF CONTRACTION INCREASES ALPHA RECEPTORS STIMULATED VENOUS RETURN INCREASES PRE LOAD INCREASES 5

C ONSEQUENCES OF H EART F AILURE CO DECREASES RBF DECREASES INCREASES ANGIOTENSIN II INCREASES ALDOSTERONE 6

C ONSEQUENCES OF H EART F AILURE PERIPHERAL RESISTANCE INCREASES SODIUM AND WATER RETENTION BLOOD VOLUME INCREASES MAY RESULT PERIPHERAL EDEMA PULMONARY EDEMA 7

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C OMPENSATORY PHYSIOLOGICAL RESPONSES IN HF 1. Increased sympathetic activity: 2. Activation of the renin–angiotensin aldosterone system: 3. Myocardial hypertrophy: 9

A CUTE ( DECOMPENSATED ) HF If 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. 10

C HEST X- RAY - CHF 11 Note the enlarge Heart (greater than ½ chest diameter on a PA film)

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The treatment of CHF aims to reduce preload and afterload and to increase myocardial contractility mainly by administration of: 1) angiotensin-converting enzyme inhibitors, 2) angiotensin-receptor blockers, 3) aldosterone antagonists, 4) β-blockers, 5) diuretics, 6) direct vaso- and venodilators, and 7) inotropic agents CONGESTIVE HEART FAILURE (CHF)

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T HERAPEUTIC STRATEGIES IN HF Chronic HF is typically managed by fluid limitations (less than 1.5 to 2 L daily); REDUCE PHYSICAL ACTIVITY DECREASE SODIUM IN DIET VASODILATORS DIURETICS IONOTROPICS Note: 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. 15

4 classes of drugs effective in reducing the symptoms and prolong life 1. ACEIs– reduce afterload and preload 2. Diuretics – decrease extracellular fluid volume 3. ARBs – decrease preload and afterload 4. Beta blockers. 16

1. АСЕ inhibitors

ACE INHIBITORS reduce 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). 19

A NGIOTENSIN RECEPTOR BLOCKER Angiotensin 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 pressure is reduced. Reduced blood pressure makes it easier for the heart to pump blood and can improve heart failure. 20

In addition, the progression of kidney disease caused by the high blood pressure or diabetes is slowed. ARBs have effects that are similar to angiotensin converting enzyme (ACE) inhibitors, but ACE inhibitors act 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 21

A LDOSTERONE ANTAGONISTS Patients 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. 22

IONOTROPIC AGENTS GLYCOSIDE DIGOXIN DIGITOXIN BETA AGONIST DOPAMINE DOBUTAMINE PHOSPHO DIESTERASE INHIBITORS AMRINONE MILRINONE 23

B ETA AND ALPHA BLOCKING AGENTS Carvedilol is a blocker of β- and α- receptors. It also has antioxidant, vasodilating and cardioprotective effects. It decreases cardiac output, peripheral vascular resistance and afterload. Carvedilol lowers mortality with 25–67%. The treatment begins with low doses (3.125 mg/12 h). 24

Beta-blocking agents Cardioselective beta-blockers Bisoprolol and Metoprolol decrease with 31% mortality in patients with CHF, if used in combination with diuretics, ACE inhibitors and Digoxin.

T HIAZIDES AND LOOP DIURETICS They 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. 26

VASO- AND VENODILATORS Dilation 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 β- 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. 27

VASODILATORS Vasodilator 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 ) 28

VASODILATORS The natriuretic peptide nesiritide acts chiefly by causing vasodilation. Binds to natriuretic peptide receptors, thus increase cGMP, resulting in vasodilation. Used in acute decompensated CHF 29

Cardiac glycosides (CGs)

M ECHANISM Direct inhibition of Na + /K + ATPase ↓ Na + gradient results in indirect inhibition of Na + /Ca 2+ exchanger/antiport ↑ [Ca 2+ ] i → positive inotropy Vagal stimulation results in increased cardiac output via decreased heart rate increased filling time 31

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CARDIAC GLYCOSIDES MECHANISM INHIBIT SODIUM POTASSIUM PUMP INTRACELLULAR SODIUM INCREASES CALCIUM EXCHANGE DECREASE CYTOPLASM Ca++ INCREASES FORCE OF CONTRACTION INCREASES 34

Na + /K + ATP-ase Na + /Ca 2+ exchange Ca 2+ 3Na + 2K+2K+ DIGOXIN ExIn (–)(–)

PHARMACOKINETICS DIGOXIN ORAL AND IV LARGE VOL OF DISTRIBUTION has 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. 36

SIDE EFFECTS Blurry yellow vision(xanthopsia), Nausea, vomiting, diarrhea cholinergic effects Life-threatening arrhythmias ↑ PR, ↓ QT, T-wave inversion Hyperkalemia Renal insufficiency causes ↑ digoxin toxicity Hypokalemia causes ↑ digoxin toxicity without K +, digoxin can bind to Na + /K + ATPase digoxin competes for excretion and competes for tissue- binding sites 37

A NTIDOTE Slowly normalize K + Give lidocaine Give digoxin antibodies (anti-dig Fab fragments) Give Mg 2+ Also remember: Digoxin should also be used with caution with other drugs that slow AV conduction, such as β- blockers, verapamil, and diltiazem. 38

Β -A DRENERGIC AGONISTS DOPAMINE DOBUTAMINE Mostly slow IV route. β-Adrenergic agonists, such as dobutamine [doe- BYOO-ta-meen] and dopamine [DOH-puh-meen], improve cardiac performance by causing positive inotropic effects and vasodilation. 39

Β -A DRENERGIC AGONISTS Dobutamine is the most commonly used inotropic agent other than digoxin. β-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 40

PHOSPHODIESTERASE INHIBITORS AMRINONE MILRINONE Mech: cAMP INCREASES CYTOPLASM CALCIUM LEVELS ↑ Increase cardiac contractility SE: THROMBOCYTOPENIA 41

Alternative methods for treatment of severe CHF Cardiac transplantaion

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