Pharmacotherapy of congestive heart faliure

This PPT covers the pathophysiology, treatment protocol and details of individual drugs used and those drugs failed in clinical trials; taken from standard text books and articles as reference. This will be extremely useful for undergraduates ( MBBS, BDS,) and postgraduates (MD,MDS ,Phd).

1. PHARMACOTHERAPY OF CONGESTIVE HEART FALIURE GUIDE - DR REKHA PRESENTER - DR RAHUL VAISH

2. 2 DEFINITION Heart Failure define as a complex clinical syndrome that results from structural or functional impairment of ventricular filling or ejection of blood, which in turn leads to the cardinal clinical symptoms of dyspnea, fatigue and signs of HF, namely edema and rales . Many patients present without signs or symptoms of volume overload, the term “heart failure” is preferred over the older term “congestive heart failure.”

3. 3 EPIDEMIOLOGY Worldwide, with >20 million people affected. Developed countries is 2%. Affects 6–10% of people aged >65. HF is lower in women than in men. 5-year mortality rate said to be about 50. %. 5-year mortality rate said to be about 50%

4. 4 CLASSIFICATION OF HF The historical terms “systolic” and “diastolic” HF have been abandoned. HF patients are now broadly categorized into - HF with a reduced EF ( HFrEF formerly systolic failure) HF with a preserved EF ( HRpEF formerly diastolic failure)

5. 5 ETIOLOGY LV EF between 40 and 50% have been considered as having a borderline or mid-range EF.

6. 6 PATHOPHYSIOLOGY

7. 7 Heart failure Failure of C.O to meet the metabolic demand of body. CO= HR X SV INCREASED DEMAND PATHOPHYSIOLOGY

8. 8

9. 9 PATHOGENESIS

10. 10 PATHOPHYSIOLOGICAL MECHANISMS OF DIASTOLIC HEART FAILURE ( HFpEF )

11. 11 PATHOPHYSIOLOGIC MECHANISMS OF SYSTOLIC HEART FAILURE ( HFrEF )

12. 12 HF with a Reduced Ejection Fraction LV remodeling develops in response to a series of complex events that occur at the cellular and molecular levels .

13. 13 CLINICAL MANIFESTATIONS

14. 14

15. 15 New York Heart Association Classification

16. 16 DIAGNOSIS

17. 17 Treatment

18. 18 DRUGS USED IN SYSTOLIC HEART FAILURE ( HFrEF ) Treatment Principle I: Neurohumoral Modulation: ACEIs/ARB β blockers MINERALOCORTICOID RECEPTOR ANTAGONISTS

19. 19 Mechanism of Action Major cardiovascular actions that are all mediated by the AT1 receptor: Vasoconstriction. Stimulation of aldosterone release from the adrenal glands. Direct hypertrophic and proliferative effects on cardiomyocytes and fibroblasts, respectively. Stimulation of NE release from sympathetic nerve endings and the adrenal medulla.

20. 20 ACEIs act as vasodilators, reduces aldosterone levels (diuretic), have direct anti remodelling effects on the heart, and produce sympatholytic effects. Renal effects RPP Ang II constricts Renal Efferent Arterioles maintains GFP and GFR. ACEIs/ARB

21. 21 Thus RPP is compromised inhibition of ACE induces a sudden and marked decrease in GFR. So, ACEIs are contraindicated in bilateral renal artery stenosis . ACEIs should be initiated at very low doses. BP, blood creatinine, and K+ levels should be monitored. ACEI aldosterone levels normally mediates Na+ reabsorption and K+ excretion. Thus, ACEIs favour hyperkalaemia. ACE causes inactivation of bradykinin and substance P. ACEIs increase bradykinin and substance P levels, causes cough and angioedema. ARBs are competitive receptor antagonists at the AT1 receptor with the exception of not inducing cough.

22. 22 ACEIs/ARB

23. 23 ACEIs/ARB

24. The Candesartan in Heart Failure—Assessment of Mortality and Morbidity (CHARM) Preserved study showed a significant reduction in hospitalizations but no difference in all-cause mortality in patients with HFpEF who were treated with the angiotensin receptor blocker (ARB), candesartan. Irbesartan in Heart Failure with Preserved Systolic Function (I-PRESERVE) trial demonstrated no differences in meaningful endpoints in such patients treated with irbesartan. The Valsartan Heart Failure Trial (Val- HeFT ) suggested that addition of valsartan in patients already receiving treatment with ACEIs and beta blockers was associated with a trend toward worse outcomes. CLINICAL TRAILS 24

25. 25 They competitively reduce β receptor–mediated actions of catecholamines reduce heart rate and force, slow relaxation, slow AV conduction, suppress arrhythmias. It must be initiated in a clinically stable condition and at very low doses. β blockers paradoxically increases left ventricular EF after 3–6 months of therapy and reduces rate of arrhythmogenic sudden cardiac death. β ADRENERGIC RECEPTOR ANTAGONISTS

26. 26 β blockers protect the heart from the adverse long-term consequences of adrenergic overstimulation. The therapy with β blockers should be initiated only in clinically stable patients at very low doses, generally 1/8 of the final target dose, and titrated upward ever 4 weeks. Beta blockers with intrinsic sympathomimetic activity (xamoterol) and other agents, including bucindolol , have not demonstrated a survival benefit A large number of randomized trials including Metoprolol in dilated cardiomyopathy trial ( I993), US carvedilol trial (1996). MERIT-HF trial (1999), CIBIS-I1 trial (1999). CAPRICORN trial (2001), COPERNICUS trial (2002) have demonstrated subjective, objective, prognostic and mortality benefits or the above named beta blockers over and above that afforded by ACE inhibitors + diuretic ± digitalis.

27. 27 It should be given in low doses to all patients with symptomatic HFrEF . Aldosterone mediated Na+ and fluid retention, loss of K+ and Mg2+, sympathetic activation, parasympathetic inhibition, myocardial and vascular fibrosis, baroreceptor dysfunction, and vascular damage is prevented. Currently, two MRAs are available, spironolactone and eplerenone . Spironolactone is a nonspecific steroid hormone receptor antagonist with similar affinity for progesterone and androgen receptors ,it causes gynecomastia . MINERALOCORTICOID RECEPTOR ANTAGONISTS

28. 28 The most important ADR of both MRAs is hyperkalaemia. Administered not more than 50 mg/d. To be careful with diabetics, who carry a higher risk of hyperkalaemia. Do not combine with NSAIDs, which are contraindicated in heart failure. Do not combine with other K+-sparing diuretics. Aldosterone antagonism is associated with a reduction in mortality in all stages of symptomatic NYHA class II to IV HFrEF To large randomized trials (RALES, 1999 with spironolactone, and EPHESUS, 2003 with eplerenone) conducted on NYHA class Ill and IV heart failure have demonstrated the mortality and anti-remodeling benefit of these drugs over and above that of ACE inhibitors ± blockers. Aldosterone Antagonist Therapy in Adults with Preserved Ejection Fraction Congestive Heart Failure (TOPCAT) trial has been completed - hyperkalemia Pessimism has been generated by the negative outcome of the Aldosterone Receptor Blockade in Diastolic Heart Failure (ALDO-DHF ) study where in spironolactone improved echocardiographic indices of diastolic dysfunction but failed to improve exercise capacity, symptoms, or QOL measures

29. 29 The latest addition to standard combination therapy of heart failure is sacubitril + valsartan. Sacubitril inhibits Neprilysin , enzymatic degradation and inactivation of natriuretic peptides (ANP, BNP), bradykinin, and substance P are inhibited. The ARNI promote the beneficial effects natriuresis, diuresis, and vasodilation of arterial and venous blood vessels and to inhibit thrombosis, fibrosis, cardiac myocyte hypertrophy, and renin release. PARADIGM-HF trial as an alternate to optimally dosed ACEI and demonstrated an incremental improvement in survival when compared to ACEI alone ANGIOTENSIN RECEPTOR AND NEPRILYSIN INHIBITORS

30. 30 Treatment Principle II: Preload Reduction Fluid overload with increased filling pressures (increased preload) and dilation of the ventricles in heart failure is the consequence of decreased kidney perfusion and activation of the RAAS. The failing heart in congestion cannot generate sufficient force with increasing preload, leading to oedema in the lungs and the periphery.

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33. 33

34. 34 Treatment Principle III: Afterload Reduction Failing heart is sensitive to increased arterial resistance (i.e., afterload). Vasodilators, therefore, should have beneficial effects on patients with heart failure by reducing afterload and allowing the heart to expel blood against lower resistance.

35. 35 HYDRALAZINE–ISOSORBIDE DINITRATE Orally available organic nitrate preferentially dilates large blood vessels, venous capacitance and arterial conductance vessels. Sustained monotherapy is compromised by nitrate tolerance. It was suggested that hydralazine prevents nitrate tolerance by reducing ROS-mediated inactivation of NO, an action that could explain the efficacy of this drug combination. The fixed-combination formulation in use contains 37.5 mg hydralazine and 20 mg ISDN and is up titrated to a target dose of 2 tablets, thrice daily. Conferred a 43% survival benefit in African Americans. It was FDA-approved in 2006, the first ethnically restricted approval.

36. William Withering, a Birmingham physician, tried an extract of 'foxglove' (Digitalis) and found it to be remarkably effective in some cases of dropsy (edema). Cushney and Mackenzie, in the beginning of 20th century, established it action on the heart and its use in congestive heart failure (CHF). Digitalis lanata is the source or Digoxin Digitoxin (from Digitalis purpurea ) Treatment Principle IV: Increasing Cardiac Contractility 36 CARDIAC GLYCOSIDES:

37. MECHANISM OF ACTION 37

38. Positive inotropic action Systole is shortened, diastole is prolonged. Heart rate is decreased by digitalis. Vagal tone is increased reflex by sensitization of baroreceptors, as well as by stimulation of vagal centre. Extravagal - A direct depressant action on SA and A-V nodes. 38 PHARMACOLOGICAL ACTIONS Heart

39. Extracardiac : Anorexia, nausea, vomiting and abdominal pain, fatigue, malaise, Head ache, mental confusion, restlessness, hyperpnoea, disorientation, psychosis and visual disturbances. Cardiac: pulsus bigeminus , nodal and ventricular extrasystoles, ventricular tachycardia and terminally ventricular fibrillation, Partial to complete A-V block, Severe bradycardia, atrial extrasystoles, AF TOXICITY: steady-state plasma digoxin levels > 1.1 ng/ml Tachyarrhythmias I nfuse KCl 20 m.mol /hour, Ventricular Arrhythmias Lidocaine i.v. repeated as required is the drug of choice Supraventricular Arrhythmias Propranolol may be given i.v. or oral A-V Block And Bradycardia Atropine 0.6–1.2 mg i.m. ADVERSE EFFECTS 39

40. Ivabradine Ivabradine, an inhibitor of the I f current in the sinoatrial node, slows the heart rate without a negative inotropic effect. It has been approved recently for use in stable grade II to IV heart failure patients who are in sinus rhythm and have heart rate >70 per min with systolic dysfunction (ER <35%). It is given in addition to standard therapy with ACE inhibitor, diuretic, aldosterone antagonist, etc., and has been shown to decrease the composite end points of hospitalization and cardiovascular mortality (SHIFT trial 2010). 40 Treatment Principle V: Heart Rate Reduction

41. The therapy of acutely decompensated heart failure aims at fast symptom relief, short-term survival, fast recompensating, and reduction of readmission rates. . Diuretics Vasodilators Positive Inotropic Agents Increases the force of contraction and improves the CO. Dobutamine: β adrenergic agonist of choice for patients with acute CHF with systolic dysfunction is a potent agonist at α1 adrenergic receptors and a weak agonist at β1 and β2 receptors and no activity at dopamine receptors. DRUG TREATMENT OF ACUTELY DECOMPENSATED HEART FAILURE 41

42. Epinephrine: β1, β2, and α1 adrenergic agonist, Norepinephrine: potent β1 and α1 agonist, . Dopamine: The pharmacologic and hemodynamic effects of DA vary with concentration. Low doses (≤2 μg /kg lean body mass/min) induce cAMP dependent vascular smooth muscle vasodilation by direct stimulation of D2 receptors. This is used to increase renal blood flow and maintain an adequate GFR and diuresis in hospitalized patients with CHF with impaired renal function refractory to diuretics. 42

43. This inotropic drug acts by sensitizing myocardial troponin C to Ca , as well as by inhibiting PDE3 . It is ' inodilator ', Hemodynamic improvement in heart failure is both due to increase in cardiac contractility as well as reduction in preload and afterload. Levosimendan infused i.v. is primarily indicated for short-term treatment of acutely decompensated severe chronic heart failure. Evidences suggesting that symptomatic benefit and reductions in the length of stay in the hospital of levosimendan compared to catecholamines or classical PDE inhibitors. Myofilament Calcium Sensitizers ( Levosimendan , Pimobendan ) 43

44. The cAMP-PDE inhibitors decrease cellular cAMP degradation, resulting in elevated levels of cAMP. This results in positive inotropic and chronotropic effects in the heart and dilation of resistance and capacitance vessels, effectively decreasing preload and afterload. Milrinone ( PDE3) and Enoximone ( PDE3 and PDE4) are commonly used preparations. Phosphodiesterase Inhibitors 44

45. FISH OIL with long-chain omega-3 polyunsaturated fatty acids (ω-3 PUFAs) has been shown to be associated with modestly improved clinical outcomes in patients with HFrEF MICRONUTRIENTS ; thiamine and selenium deficiency EXERCISE ; Maximal changes in 6-min walk distance were evident at 3 months with significant improvements in cardiopulmonary exercise time and peak oxygen consumption persisting at 12 months. Other treatment strategies 45

46. 46 HEART FAILURE TREATMENT GUIDELINES

47. 47 FAILURES IN DRUG DEVELOPMENT FOR HEART FAILURE (OVERTURE) trial (ACCLAIM-HF) trial (CORONA)

48. Goodman and Gilman’s The pharmacological basis of therapeutics; Laurence N Brunton 13 th edition. Essentials of Medical Pharmacology by KD Tripathi 7 th edition. Harrison’s Principal of Internal Medicine 20 th edition. REFERANCE

49. Thank You

50. 50 Symptoms at rest

51. Bosentan ; endothelin antagonist ; associated with worsening heart failure in HFrEF despite demonstrating benefits in right-sided heart failure due to pulmonary arterial hypertension Moxonidine : centrally acting sympatholytic agent ; worsens outcomes left heart failure Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE) trial Infliximab and etanercept ; Nonspecific immunomodulation has been tested in the Advanced Chronic Heart Failure Clinical Assessment of Immune Modulation Therapy (ACCLAIM-HF) trial Two trials, Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) and Gruppo Italiano per lo Studio della Sopravvivenza nell’Insufficienza Cardiac (GISSI-HF), have tested low-dose rosuvastatin in patients with HFrEF and demonstrated no improvement in aggregate clinical outcomes NOVEL NEUROHORMONAL ANTAGONISM 51

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