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  1. 1. Congestive Cardiac Failure Dr. R. Senthil Kumar
  2. 2. Introduction to Heart Failure <ul><li>Heart unable to provide adequate perfusion of peripheral organs to meet their metabolic requirements </li></ul><ul><li>Characterized by: </li></ul><ul><li>Reduction in cardiac output </li></ul><ul><li>Increased TPR </li></ul><ul><ul><li>Progressing to congestive heart failure (CHF) is accompanied by peripheral and pulmonary edema. </li></ul></ul>
  3. 3. Recent Advances Vs Reality <ul><li>Major advances in recent years in management of patients with CHF </li></ul><ul><li>In 2000 an estimated 4.7 million people in the United States had HF </li></ul><ul><li>The median survival after initial diagnosis is 1.7 years for men and 3.2 years for women. </li></ul><ul><li>Sudden cardiac death is common in patients with heart failure, contributing to 50% of all 287,000 deaths in the United States last year </li></ul>
  4. 4. Acute Vs Chronic HF <ul><li>In a patient with acute heart failure, the short-term aim is stabilization by providing symptomatic treatment through intravenous interventions. </li></ul><ul><li>Management of chronic heart failure is multifaceted, with the long-term aims of: </li></ul><ul><ul><li>relieving symptoms </li></ul></ul><ul><ul><li>improving hemodynamics </li></ul></ul><ul><ul><li>improving quality of life and </li></ul></ul><ul><ul><li>decrease mortality. </li></ul></ul>
  5. 5. Cardiac Vs Noncardiac targets <ul><li>Conventional belief that the primary defect in HF is in the heart </li></ul><ul><li>Reality is that HF involves many other processes and organs </li></ul><ul><li>Research has shown that therapy directed at noncardiac targets are more valuable than cardiac targets </li></ul>
  6. 6. Compensation in HF <ul><li>Heart failure is usually accompanied by an increase in: </li></ul><ul><li>Sympathetic nervous system (SNS) </li></ul><ul><li>Chronic up-regulation of the renin-angiotensin-aldosterone system (RAAS) and effects of aldosterone on heart, vessels, and kidneys. </li></ul><ul><li>CHF should be viewed as a complex, interrelated sequence of events involving hemodynamic, and neurohormonal events. </li></ul>
  7. 7. Compensation contd.. <ul><li>In a failing heart, the loss of contractile function leads to a decline in CO and a decrease in arterial BP. </li></ul><ul><li>Baroreceptors sense the hemodynamic changes and initiate countermeasures to maintain support of the circulatory system. </li></ul><ul><li>Activation of the SNS serves as a compensatory mechanism in response to the earlier </li></ul><ul><li>This helps maintain adequate cardiac output by: </li></ul><ul><li>Increasing myocardial contractility and heart rate (β 1 -adrenergic receptors) </li></ul><ul><li>Increasing vasomotor tone (α 1 -adrenergic receptors) to maintain systemic blood pressure </li></ul>
  8. 8. Consequences of hyperadrenergic state <ul><li>Over the long term, this hyperadrenergic state leads to irreversible myocyte damage, cell death, and fibrosis. </li></ul><ul><li>In addition, the augmentation in peripheral vasomotor tone increases LV afterload </li></ul><ul><li>This places an added stress upon the left ventricle and an increase in myocardial O 2 demand (ventricular remodeling). </li></ul><ul><li>The frequency and severity of cardiac arrhythmias are enhanced in the failing heart </li></ul>
  9. 9. <ul><li>Figure p.203 kat </li></ul>
  10. 10. Pathophysiology <ul><li>CHF pathophysiology animation </li></ul>
  11. 11. Therapeutic Overview <ul><li>Problem </li></ul><ul><li>Reduced force of contraction </li></ul><ul><li>Decreased cardiac output </li></ul><ul><li>Increased total peripheral resistance </li></ul><ul><li>Inadequate organ perfusion </li></ul><ul><li>Development of edema </li></ul><ul><li>Decreased exercise tolerance </li></ul><ul><li>Ischemic heart disease </li></ul><ul><li>Sudden death </li></ul><ul><li>Ventricular remodeling and decreased function </li></ul>
  12. 12. Goals and drug therapy <ul><li>Goals </li></ul><ul><li>Alleviation of symptoms, improve quality of life </li></ul><ul><li>Arrest ventricular remodeling </li></ul><ul><li>Prevent sudden death </li></ul><ul><li>Nondrug therapy </li></ul><ul><li>Reduce cardiac work; rest, weight loss, low Na+ diet </li></ul><ul><li>Drug therapy </li></ul><ul><li>Chronic heart failure </li></ul><ul><ul><li>ACE-I, β-blockers, ARB, aldosterone antagonists, digoxin, diuretics </li></ul></ul><ul><li>Acute heart failure </li></ul><ul><ul><li>Intravenous diuretics, inotropic agents, PDE inhibitors, vasodilator </li></ul></ul>
  13. 13. Signs and symptoms <ul><li>Tachycardia </li></ul><ul><li>Decreased exercise tolerance & SOB </li></ul><ul><li>Peripheral and pulmonary edema </li></ul><ul><li>Cardiomegaly </li></ul>
  14. 15. Diuretics <ul><li>Bottom line: they decrease fluid volumes </li></ul><ul><li>Four Flavours: </li></ul><ul><ul><li>Carbonic anhydrase inhibitors </li></ul></ul><ul><ul><li>Loop diuretics </li></ul></ul><ul><ul><li>Thiazide diuretics </li></ul></ul><ul><ul><li>K + -sparing </li></ul></ul>
  15. 16. Renin angiotensin system <ul><li>Baroreceptor mediated activation of the SNS leads to an increase in renin release and formation of angiotensin II </li></ul><ul><li>Angiotensin II acts through AT 1 and AT 2 receptors (most of its actions occur through AT 1 receptors) </li></ul><ul><li>This causes vasoconstriction and stimulates aldosterone production </li></ul><ul><li>RAS remains the most important target of chronic CHF therapy </li></ul>
  16. 17. Effects of AT-II
  17. 18. MOA <ul><li>ACE-Inhibitors and ARB animation </li></ul><ul><li>Blockade of ACE </li></ul><ul><li>Decreased AT-II </li></ul><ul><li>Decreased aldosterone </li></ul><ul><li>Decreased fluid retention </li></ul><ul><li>Vasodilation </li></ul><ul><li>Reduced preload and afterload </li></ul><ul><li>Slows cardiac remodeling </li></ul>
  18. 19. Advantages <ul><li>Improves symptoms significantly </li></ul><ul><li>Improves exercise tolerance </li></ul><ul><li>Slows progression of the disease </li></ul><ul><li>Prolong survival in established cases </li></ul>
  19. 20. ADR <ul><li>What are the ADR of ACEIs? </li></ul><ul><li>Cough (why?) </li></ul><ul><li>Postural hypotention (why?) </li></ul><ul><li>Hyperkalemia (possible Drug interactions?) </li></ul><ul><li>Contraindicated in pregnant women (1 st trimester) </li></ul><ul><li>Rare: angioedema </li></ul>
  20. 21. Other Vasodilators: <ul><li>Mechanism 2: </li></ul><ul><ul><li>Direct smooth muscle relaxants </li></ul></ul><ul><ul><li>Nitrates </li></ul></ul><ul><ul><ul><li>Venous dilators </li></ul></ul></ul><ul><ul><ul><li>Reduce preload </li></ul></ul></ul><ul><ul><ul><li>Eg: sodium nitropruside </li></ul></ul></ul>
  21. 22. Inotropes <ul><li>Increase force of contraction </li></ul><ul><li>All increase intracellular cardiac Ca ++ concentration </li></ul><ul><li>Eg: </li></ul><ul><ul><li>Digitalis (cardiac glycoside) </li></ul></ul><ul><ul><li>Dobutamine ( β -adrenergic agonist) </li></ul></ul><ul><ul><li>Amrinone (PDE inhibitor) </li></ul></ul>
  22. 23. Cardiac glycosides <ul><li>Digitalis </li></ul><ul><li>Sourced from foxglove plant </li></ul><ul><li>1785, Dr. William Withering’s monograph on digitalis </li></ul><ul><li>Has a profound effect on the cardiac contractility </li></ul>
  23. 25. Pck <ul><li>Two drugs (digoxin, digitoxin) </li></ul><ul><li>Well absorbed orally </li></ul><ul><li>10% of population have bacteria in the gut, which inactivate digoxin, needing an increased dose in such </li></ul><ul><li>Beware of using antibiotics in such patients </li></ul><ul><li>Digoxin has a very narrow ther. Margin </li></ul>
  24. 26. Pck <ul><li>Taken orally </li></ul><ul><li>Enters CNS (so what?) </li></ul><ul><li>Renal clearance proportional to CC </li></ul><ul><li>To be used with extreme caution in patients suffering from renal impairment </li></ul>
  25. 27. MOA <ul><li>Regulation of cytosolic Ca metabolism: </li></ul><ul><li>Reversibly combine with sodium-potassium ATPase of the cardiac cell membrane </li></ul><ul><li>Results in inhibition of pump activity </li></ul><ul><li>This leads to in intracellular Na conc. </li></ul><ul><li>This favors Ca ions in the cell </li></ul><ul><li>Ca levels result in increased systolic force of contraction </li></ul>
  26. 28. Digoxin MOA
  27. 29. Na/K ATPase inhibition
  28. 30. Additional MOA <ul><li>Force of contraction resembles to that of the normal heart </li></ul><ul><li>Improved circulation leads to reduced sympathetic activity </li></ul><ul><li>This reduces PVR </li></ul><ul><li>All this leads to reduction in HR </li></ul><ul><li>Vagal tone is enhanced </li></ul><ul><li>Finally myocardial O 2 demand is reduced </li></ul>
  29. 31. Electrophysiological effects on the heart
  30. 32. Uses <ul><li>Severe LV systolic dysfunction </li></ul><ul><li>Only after initiation of diuretics and vasodialtor therapy </li></ul><ul><li>Management of patients with chronic atrial fibrillation </li></ul><ul><li>Cannot arrest the progression of pathological changes causing heart failure, and does not prolong life in patients with CHF </li></ul>
  31. 33. ADR <ul><li>Digitalis toxicity is one among most commonest encountered (why?) </li></ul><ul><li>Therapeutic concentration- 0.5-1.5 ng/ml </li></ul><ul><li>Often the first step is discontinuation of Rx </li></ul><ul><li>Digoxin levels must be monitored closely </li></ul>
  32. 34. Signs of digoxin toxicity <ul><li>CNS: Malaise, confusion, depression, vertigo, vision (abnormalities in color vision) </li></ul><ul><li>GI: Anorexia, nausea, intestinal cramping, diarrhea </li></ul><ul><li>Cardiovascular: Palpitations, syncope, arrhythmias, bradycardia, AV node block, tachycardia </li></ul>
  33. 35. Factors increasing the possibility of digoxin toxicity <ul><li>Pharmacological and toxic effects are greater in hypokalemic patients. </li></ul><ul><li>K + -depleting diuretics are a major contributing factor to digoxin toxicity. </li></ul>
  34. 36. Management <ul><li>Arrhythmias may be converted to normal sinus rhythm by K + . when the plasma K + conc. is low or within the normal range. </li></ul><ul><li>When the plasma K + conc. is high, antiarrhythmic drugs, such as lidocaine, procainamide, or propranolol, can be used. </li></ul><ul><li>Severe toxicity treated with Digibind , an anti-digoxin antibody. </li></ul>
  35. 37. <ul><li>A 96-year-old AAF was admitted from a nursing home with complaints of abdominal pain, N/V, dizziness, confusion and double vision for 5 days. She was discharged from the hospital just 4 days ago. Digoxin was started during that previous hospitalization for control of tachycardia in atrial fibrillation. One day prior to discharge, digoxin level was 1.8 mg/mL and digoxin dose was decreased to 125 mcg PO Q 48 hr. PMH Hypertension, atrial fibrillation, coronary artery disease, stroke, congestive heart failure. Medications Metoprolol, Digoxin, ASA, lisinopril, Lasix, Coumadin, Nexium </li></ul>What could it be???
  36. 38. Dopamine <ul><li>Dopamine acts at a variety of receptors (dose dependant) </li></ul><ul><li>Rapid elimination- can only be administered as a continuous infusion </li></ul>
  37. 39. Dobutamine <ul><li>Stimulates beta-adrenergic receptors and produces a positive inotropic response </li></ul><ul><li>Unlike the vasoconstriction seen with high doses of dopamine, dobutamine produces a mild vasodilatation </li></ul>
  38. 40. MOA
  39. 41. PDE inhibitors <ul><li>Inamrinone (amrinone) and Milrinone (bipyridines) </li></ul><ul><li>Acts by inhibiting the enzyme Phosphodiesterase </li></ul><ul><li>Thus lead to increase of intracellular concentrations of cAMP </li></ul><ul><li>cAMP is responsible for the conversion of inactive protein kinase to active form </li></ul><ul><li>Protein kinases are responsible for phosphorylation of Ca channels </li></ul><ul><li>Thus causing increased Ca entry into the cell. </li></ul>
  40. 42. MOA <ul><li>Increase myocardial contractility by increasing the Ca influx during AP </li></ul><ul><li>Also have vasodilating effect </li></ul><ul><li>Selective for PDE isoenzyme-3 (found in cardiac and smooth muscle) </li></ul>
  41. 43. Current status <ul><li>Both are orally active </li></ul><ul><li>Only available in parenteral forms </li></ul><ul><li>Limited efficacy </li></ul><ul><li>Clinical trials- increased mortality (oral) </li></ul><ul><li>Still new drugs are under trial </li></ul>
  42. 44. ADR <ul><li>Inamrinone: nausea, vomiting, arrhythmias, thrombocytopenia and liver enzyme changes </li></ul><ul><li>Withdrawn in some countries </li></ul><ul><li>Milrinone: arrhythmias, less likely to cause other ADR </li></ul>
  43. 45. (BNP)-Niseritide <ul><li>Brain (B-type) natriuretic peptide (BNP) is secreted constitutively by ventricular myocytes in response to stretch </li></ul><ul><li>BNP binds to receptors in the vasculature, kidney, and other organs, producing potent vasodilation with rapid onset and offset of action by increasing levels of cGMP </li></ul><ul><li>Niseritide is recombinant human BNP approved for treatment of acute decompensated CHF. </li></ul>
  44. 46. BNP contd.. <ul><li>It reduces systemic and pulmonary vascular resistances, causing an indirect increase in cardiac output and diuresis. </li></ul><ul><li>Effective in HF because cause reduction in preload and afterload </li></ul><ul><li>ADR- hypotension </li></ul>
  45. 47. Beta blockers <ul><li>Overwhelming evidence to support the use of β-blockers in CHF, however </li></ul><ul><li>Mechanism involved remain unclear </li></ul><ul><li>Part of their beneficial effects may derive from slowing of heart rate and decrease myocardial O 2 consumption. </li></ul><ul><li>This would lessen the frequency of ischemic events and potential for development of a lethal arrhythmia. </li></ul>
  46. 48. Beta blockers <ul><li>Suggested mechanisms also include reduced remodeling </li></ul><ul><li>β-Blockers may be beneficial through resensitization of the down-regulated receptor, improving myocardial contractility. </li></ul><ul><li>Recent studies with bisoprolol, carvedilol and metoprolol showed a reduction in mortality in patients with these drugs </li></ul><ul><li>CI in unstable cases </li></ul>
  47. 49. Management of Chronic HF (combination of drugs) <ul><li>Limit physical activity </li></ul><ul><li>Reduce weight </li></ul><ul><li>Reduce water intake </li></ul><ul><li>Control HT </li></ul><ul><li>Na restriction </li></ul><ul><li>Diuretics </li></ul><ul><li>ACE-Is </li></ul><ul><li>Digitalis (ther. margin, DI with quinidine) </li></ul><ul><li>Beta blockers </li></ul><ul><li>Vasodilators </li></ul>
  48. 50. Management of acute HF <ul><li>Diuretics </li></ul><ul><li>Vasodilators </li></ul><ul><li>Inotropic drugs </li></ul><ul><li>Life support </li></ul><ul><li>Treating cause (surgery to correct valvular disorders) </li></ul>