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Pharmacotherapy of heart failure

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gives an idea about the basics of heart failure, various management options and recent advances in the field of heart failure development

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Pharmacotherapy of heart failure

  1. 1. PHARMACOTHERAPY OF HEART FAILURE Presenter- Dr. Shivesh Gupta PG Guide- Dr. Shyamal Sinha
  2. 2. OUTLINE OF TODAY’S SEMINAR Introduction Epidemiology Classification Pathophysiology Management Recent advances Summary
  3. 3. INTRODUCTION A pathophysiologic state in which an abnormality of cardiac function is responsible for failure of the heart to pump blood at a rate commensurate with metabolic requirements of the tissues The current American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) guidelines define HF:- 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 and fatigue and signs of HF, namely edema and rales
  4. 4. EPIDEMIOLOGY Prevalance- 2% in developed countries and in India- 1.87 % Its prevalence is increasing worldwide, likely due to improved survival because of early diagnosis and better treatement More than 20 million people affected worldwide HF prevalence follows an exponential pattern, rising with age, and affects 6–10% of people over age 65 Approx 10% of patients with HF die each year
  5. 5. CLASSIFICATION BY EJECTION FRACTION:-  Reduced ejection fraction(<40-50%)- systolic heart failure  Preserved ejection fraction(>40-50%)- diastolic heart failure BY TIME COURSE:-  Chronic heart failure(CHF)  Acute heart failure BY OUTPUT:-  High output failure-Thyrotoxicosis, Paget's dis, Anemia, Pregnancy, A-V fistula  Low output failure- 95% of HF is this type
  6. 6. NYHA classification
  7. 7. Image Source:- Yancy CW, et al. 2016 ACCF/AHA/HFSA focused update on new pharmcological therapy for heart failure: an update of the 2013 guideline for the management of heart failure. Circulation, 2016, 135:e282–e293.
  8. 8. ETIOLOGY
  9. 9. PATHOPHYSIOLOGY The pathophysiology of heart failure is complex and involves four major interrelated systems:-  the heart itself  the vasculature  the kidney  neurohumoral regulatory circuits
  10. 10. COMPENSATORY MECHANISMS
  11. 11. SIGNS AND SYMPTOMS
  12. 12. MANAGEMENT Aims:- 1. Relief of signs and symptoms 2. Stabilization of haemodynamics 3. Prevention of disease progress 4. Treatment of risk factors 5. Improvement in Quality of Life and reduction in Mortality
  13. 13. CLINICAL TRIALS
  14. 14. NON-PHARMACOLOGICAL Activity  Routine modest exercise for class I-III, Graded over a period of time depending on the improvement  For euvolemic patients- regular isotonic exercise such as walking or riding a stationary-bicycle ergometer Diet  Restriction of sodium (2-3 g daily) is recommended in all patients, Extra < 2g reduction in moderate to severe cases.  Fluid restriction (<2 L/day) if hyponatremia (<130 meq/L)  Cessation of Smoking and alcohol consumption  Caloric supplementation- with advanced HF and unintentional weight loss or muscle wasting (cardiac cachexia)  Stop any drug contributing to HF
  15. 15. PHARMACOLOGICAL THERAPY Drugs with positive inotropic effects:-  Cardiac Glycosides:- Digoxin, Digitoxin  Phosphodiesterase Inhibitors:- Milrinone, Enoximone, Levosimendan  Beta- Agonists:- Dopamine, Dobutamine, Nor-adrenaline Drugs without positive inotropic effects:-  ACEIs:- Enalapril, Lisinopril, Captopril, Ramipril  ARBs:- Losartan, Candesartan, Irbesartan  Beta-Blockers:- Bisoprolol, Carvedilol, Metoprolol  Vasodilators:- Hydralazine, Isosorbide Dinitrate, Nitroprusside
  16. 16. TREATMENT PRINCIPLES I. Neurohumoral modulation II. Preload reduction III. Afterload reduction IV. Increasing Cardiac contractility V. Heart rate reduction
  17. 17. NEUROHUMORAL MODULATION Therapy consists of:- 1. Angiotensin Converting Enzyme Inhibitors 2. Angiotensin Receptor Blockers 3. β blockers 4. Mineralocorticoids Receptor Antagonists
  18. 18. ANGIOTENSIN-CONVERTING ENZYME INHIBITORS In the 1960s, Ferreira and colleagues:- Certain factors in venom extract from the Brazilian pit viper (Bothrops jararaca) intensify vasodilator responses to bradykinin Erdos and coworkers established that these factors inhibit ACE and kininase II This led to the synthesis of a series of carboxy alkanoyl and mercapto alkanoyl derivatives that are potent competitive inhibitors of ACE
  19. 19. Inhibits enzyme responsible for formation of Angiotensin II from Angiotensin I These are the drugs which reduce circulating levels of Angiotensin II Antagonises AT1 receptor effects of Angiotensin II:- 1. vasoconstriction 2. stimulation of aldosterone release from the adrenal glands 3. direct hypertrophic and proliferative effects on cardiomyocytes and fibroblasts, respectively 4. stimulation of NE release from sympathetic nerve endings and the adrenal medulla
  20. 20. Currently used as First line agents in symptomatic and asymptomatic Used as Combination with diuretics to make first line therapy in HF Slow : progress of ventricular dilatation Prolong survival : prevent pathological remodelling : heart & blood vessels
  21. 21. ANGIOTENSIN II RECEPTOR BLOCKERS Attempts to develop therapeutically useful AngII receptor antagonists date to the early 1970s In 1995, the orally active, potent, and selective nonpeptide AT1 receptor antagonist Losartan was developed and approved for clinical use in the U.S. Since then, seven additional AT1 receptor antagonists have been approved
  22. 22. The AngII receptor blockers competitively bind and block the AT1 receptor with high affinity More than 10,000-fold selective for the AT1 receptor over the AT2 receptor ARBs inhibit most of the biological effects of AngII, which include AngII-induced  Contraction of vascular smooth muscle  Vasopressin release & Aldosterone secretion  Release of adrenal catecholamines  Increases in sympathetic tone  Cellular hypertrophy and hyperplasia
  23. 23. They are therapeutic alternatives to ACEIs and second choice in all stages of heart failure in patients who do not tolerate ACEIs ARBs show the same pharmacological profile as ACEIs with the exception of not inducing cough However, the unopposed activity of AT2 receptor pathways in the presence of AT1 blockade by an ARB seems to confer no therapeutic advantage to ARBs over ACEIs
  24. 24. BETA BLOCKERS Heart Failure Raised epinephrine and non-epinephrine level Cardiac Hypertrophy, Remodelling, Apoptosis, Peripheral vasoconstriction The β blockers competitively reduce β receptor–mediated actions of Catecholamines:-  Reduce heart rate and force  Slow relaxation  Slow AV conduction  Suppress arrhythmias  Lower renin levels  And permit more or less bronchoconstriction, vasoconstriction, and lowering of hepatic glucose production
  25. 25. All patients with symptomatic heart failure (stage C, NYHA II–IV) and all patients with left ventricular dysfunction (stage B, NYHA I) with LVEF less than 35 % should be treated with a β blocker Used in mild-moderate (NYHA II/III) systolic dysfunction with cardiomyopathy Clinical improvements are slight rise in ejection fraction, reduction in HR, reduction in symptoms Initiate at low doses and up titrate to max dose 2-4 months therapy is required for clinical benefits Long term effect: maintain hemodynamic benefits and reduction in morbidity/mortality Not Indicated in:- HF after acute MI or with normal LVEF, AV block, Asthma, COPD
  26. 26. MINERALOCORTICOID RECEPTOR ANTAGONISTS •Drugs with a documented life-prolonging effect in patients with heart failure •Given in low doses to all patients in stage C (NYHA class II–IV), that is, with symptomatic HFrEF •The safety of a low-dose MRA (25 mg vs. a standard of 100 mg spironolactone) was demonstrated in a large randomized trial in a patient cohort with severe heart failure (NYHA III–IV), with the MRA added to ACEIs, diuretics, and digoxin
  27. 27. Antagonists of nuclear receptors of aldosterone They are K+-sparing diuretics but gained more importance for their additional efficacy in suppressing the consequences of neurohumoral activation. Aldosterone promotes Na+ and fluid retention, loss of K+ and Mg2+, sympathetic activation, myocardial and vascular fibrosis and vascular damage MRAs inhibit all these effects of aldosterone, of which the reduction in fibrosis is most pronounced in animal models. E.g. - Spironolactone and Eplerenone
  28. 28. Spironolactone:-  Dose: 12.5-25 mg/day  Add on with ACEI & others in moderate-severe CHF  In severe CHF: ACEI+ spironolactone+ digitalis: improves survival  Retard disease progression  Slow response  The most important ADR of both MRAs is hyperkalemia.  Spironolactone causes gynecomastia, not with Eplerenone
  29. 29. 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 drugs used here are Diuretics They increase Na+ and water excretion by inhibiting transporters in the kidney and thereby improve symptoms of CHF Diuretics are an integral part of the combination therapy of symptomatic forms of heart failure
  30. 30. Loop Diuretics:- E.g. Furosemide, Torasemide, Bumetanide  Inhibit the Na+-K+-2Cl symporter mediated reabsorption in the Ascending limb of the loop of Henle Thiazide Diuretics:- E.g.- Hydrochlorothiazide, Chlorthalidone  Mostly used as a combination therapy with loop  Inhibits Na+-Cl cotransporter in the distal convoluted tubule  Associated with a greater degree of K+ wasting per fluid volume reduction K+-Sparing Diuretics:- Amiloride, Triamterene, Spironolactone and Eplerenone  Inhibit apical Na+ channels in distal segments of the tubules directly (ENaC; e.g., amiloride, triamterene) or reduce its gene expression (spironolactone and eplerenone)  Used in the treatment of hypertension in combination with thiazides or loop diuretics to reduce K+ and Mg2+ wasting
  31. 31. Uses:-  Edema associated with congestive heart failure, liver cirrhosis, chronic kidney disease, and nephrotic syndrome  In severe CHF: ACEI+ spironolactone+ digitalis: improves survival  Hypertension with renal insufficiency  Nephrogenic diabetes insipidus  Acute pulmonary edema (intravenous)  Hyponatremia  Hypercalcemia
  32. 32. AFTERLOAD REDUCTION The failing heart is exquisitely sensitive to increased arterial resistance i.e., Afterload They have beneficial effects on patients with heart failure by reducing afterload and allowing the heart to expel blood against lower resistance Vasodilators:-  Venous Dilators:- Isosorbide Dinitrate, Nitroglycerin, etc  Arteriolar dilators:- Hydralazine  Mixed:- ACEI, ARBs, Nitroprusside
  33. 33. Hydralazine:- One of the first orally active Vasodiltator drugs to be marketed in the U.S. Combined with sympatholytic agents and diuretics with greater therapeutic success Hydralazine directly relaxes arteriolar smooth muscle with little effect on venous smooth muscle by reduction in intracellular Ca2+ concentrations thus reducing afterload The usual oral dosage of hydralazine is 25–100 mg twice daily Adverse effects:- headache, nausea, flushing, hypotension, palpitations, tachycardia, dizziness, lupus syndrome, hemolytic anemia, vasculitis, and rapidly progressive glomerulonephritis
  34. 34. Nitrates:- Sources of NO that increases cGMP and decreases cytosolic Ca2+ Isosorbide dinitrate:- Orally available organic nitrate, preferentially dilates large blood vessels (venous capacitance and arterial conductance vessels) The main effect is “venous pooling” and reduction of diastolic filling pressure (preload) The fixed-combination formulation 37.5 mg hydralazine + 20 mg ISDN and is uptitrated to a target dose of 2 tablets, thrice daily Particularly useful when ACEI are not tolerated Frequent adverse effects include dizziness and headache
  35. 35. INCREASING CARDIAC CONTRACTILITY The failing heart is unable to generate force sufficient to meet the needs of the body for perfusion of oxygenated blood Historically, physicians attempted to stimulate force generation with positive inotropic drugs The drugs included here are:- 1. Na+/K+ ATPase Inhibitors:- Cardiac Glycosides 2. cAMP-Dependent Inotropes:- Milrinone, Enoximone 3. Myofilament Ca2+ Sensitizers:- Levosimendan
  36. 36. CARDIAC GLYCOSIDES (CG) British botanist William Withering (1741–1799) •Described the actions of Digitalis purpurea in patients with heart failure (“dropsy”) and gave exact dosing recommendations (Skou 1986) Oswald Schmiedeberg (1833–1921) •Isolated the first chemical entities from foxglove leaves; one of these entities was digitoxin
  37. 37. Cardiac glycosides:- Inhibit the plasma membrane Na+/K+ ATPase that actively pumps Na+ out and K+ into the cell Inhibition of this enzyme slightly reduces the Na+ gradient across the myocyte membrane and thus reducing the driving force for Ca2+ extrusion by the NCX Thus provides more Ca2+ for storage in the SR and subsequent release to activate contraction Increase in Ca2+ permeability through voltage sensitive L type Ca2+ channels during plateau phase Release of more Ca2+ from SR & mitochondria by activating Ryr (ryanodine) receptors Inhibits SR- Ca2+ ATPase (reuptake channel)
  38. 38. Actions of Digoxin:- Positive Inotropic Effect by raising intracellular [Ca2+] and enhanced contractility This Increased cardiac output provides symptomatic relief in patients with heart failure Decreases in preload and afterload reduce chamber dilation and thereby ↓ in oxygen requirement Increased renal perfusion lowers renin production and increases diuresis, further decreasing preload Bradycardia, improved myocardial circulation and sense of well being but Does not substantially increase the survival Subside pulmonary congestion and edema
  39. 39. Currently given when ACEI & Diuretics fail to control symptoms Used in Low output heart failure due to HT, IHD & arrhythmias Dose: oOral route is preferred: 0.125-0.5mg/day. 1) Slow loading with 0.125-0.25 mg/day 2) Rapid method with 0.5-0.75 mg every 8hrs for 1 day followed by 0.125-0.25 mg/day( rare) oIV 0.5 to 1 mg but is seldom required No role in acute HF with acute MI, MR and papillary muscle dysfunction
  40. 40. I. Therapeutic efficacy - between 0.5 and 0.8 ng/mL II. Adverse effects:- Seen above 2 ng/mL  Cardiac effects like Bradycardia, AV Block, Atrial Fibrillation, Ventricular extrasystoles, bigeminy, etc  GI side effects like anorexia, vomiting, diarrhea  Neurotoxicity like mental confusion, delirium, loss of color perception, hyperkalemia, gynaecomastia
  41. 41. Treatment of toxicity:-  Cessation of CG medication normally suffices, estimate K levels  Extreme sinus bradycardia, sinoatrial block, or AV block grade II or III:- Atropine (0.5–1 mg) IV  Supraventricular tachyarrhytmias:- Oral Propranolol 10-40 mg every 6 hrs or IV 0.5 to 1 mg  Tachycardic ventricular arrhythmias and hypokalemia:- Lignocaine 1-2 mg/kg or K+ infusion (40–60 mmol/d)  Antidigoxin immunotherapy with Digibind as the antidote:- 40 mg neutralizes 0.6 mg digoxin ENHNACED digitalis toxicity:- Loop diuretics, steroids, Amiodarone, quinidine
  42. 42. CAMP-DEPENDENT INOTROPES The cAMP-PDE inhibitors decrease cellular cAMP degradation leading to elevated levels of cAMP This results in positive inotropic and chronotropic effects in the heart Also causes dilation of resistance and capacitance vessels, effectively decreasing preload and afterload The drugs included here are Milrinone and Enoximone
  43. 43. Milrinone Milrinone inhibits human heart PDE3 and PDE4 with similar potency The loading dose of milrinone is ordinarily 25–75 μg/kg, and the continuous infusion rate ranges from 0.375 to 0.75 μg/kg/min S/E:- less thrombocytopenia and liver effect, arrhytmogenic potential, headache, tremors Enoximone Congener of inamrinone, is a relative selective Inhibitor of PDE3 IV in acute heart failure Better tolerated and improves physical quality of life Bolus doses of enoximone at 0.5–1.0 mg/kg over 5–10 min are followed by an infusion of 5–20 μg/kg/min
  44. 44. MYOFILAMENT CA2+ SENSITIZERS In some countries, calcium sensitizers are approved for the short-term treatment of acutely decompensated heart failure Increase the sensitivity of contractile myofilaments to Ca2+ by binding to and inducing a conformational change in troponin C This causes an increased force for a given cytosolic Ca2+ concentration, theoretically without raising the [Ca2+]cytosol The drugs included are Levosimendan and Pimobendan Clinical data provide evidence for symptomatic benefit and reductions in the length of stay in the hospital Increased rates of arrhythmia and death are likely related to the PDE3 inhibitor activity of these compounds
  45. 45. POSITIVE INOTROPIC DRUGS These agents stimulate the heart’s force of contraction in a situation of critically diminished cardiac output Dobutamine:-  Dobutamine is the β adrenergic agonist of choice for the management of patients with acute CHF with systolic dysfunction  Dobutamine is a racemic mixture of (–) and (+) enantiomers  The (–) enantiomer - agonist at α1 adrenergic receptors, weak agonist at β1 and β2 receptors  The (+) enantiomer - potent β1 and β2 agonist, less activity at α1 adrenergic receptors (β1 - Normally Dominates)  Continuous infusions initiated at 2–3 μg/kg/ min and uptitrated  S/E:- tachycardia and supraventricular/ventricular arrhythmias
  46. 46. Dopamine:-  The pharmacologic and hemodynamic effects of DA vary with concentration  Low doses (≤2 μg/kg/min):- stimulation of D2 receptors and inhibits NE release and reduces α adrenergic stimulation of vascular smooth muscle, particularly in splanchnic and renal arterial beds  At intermediate infusion rates (2–5 μg/kg/min):-stimulation of cardiac β receptors to enhance myocardial contractility  At higher infusion rates (5–15 μg/kg/min):- Stimulation of α adrenergic receptor leading to peripheral arterial and venous constriction occurs  Other drugs are Epinephrine, Nor-epinephrine
  47. 47. VASOPRESSIN ANTAGONISTS Vasopressin receptors V1a : vasoconstriction and V2: antidiuretic Conivaptan (Vaprisol) V1a & V2 antagonist APPROVED for hyponatremia (SIADH) T1/2: 5-12 hrs Dose: 20 mg loading IV over 30 min followed by 20 mg IV over 24 hrs Potential use in heart failure: as ↓ afterload and S/E: infusion site reaction, headache, hypotension, pyrexia Tolvaptan:- V2 antagonist, Oral: 15-45 mg/day
  48. 48. VASOACTIVE PEPTIDES Released from the cardiac ventricles in response to increased wall tension ANP (Atrial Natriuretic Peptide) and BNP (Brain Natriuretic Peptide) diagnostic and prognostic marker in heart failure Rapid Measurement BNP →emergency diagnosis of heart failure
  49. 49. Nesiritide Recombinant form of human BNP Binds to surface4 receptors on vascular smooth muscle cells and endothelial cells and activates cGMP MOA:- o↓ arteriolar and venous tone (↑ cGMP in smooth muscle cells- smooth muscle relaxation) oAlso causes Natriuresis (Inhibits Na+ absorption in collecting duct) APPROVED for acute decompensated HF
  50. 50. VASOPEPTIDASE INHIBITORS Inhibition of neutral endopeptidases like ACE and NEP ↑ANP & ↑BNP Vasodilatation and Na+ & water excretion ↓Afterload and Preload E.g.: Omapatrilat, Sampatrilat, Fasidopatrilat  Omapatrilat:- Clinical status: in phase 3 trials
  51. 51. OTHER MEASURES CARDIAC RESYNCHRONIZATION THERAPY:- With placement of a pacing lead via the coronary sinus to the lateral wall of the ventricle, it enables a more synchronous ventricular contraction by aligning the timing of activation of the opposing walls. SURGICAL THERAPY IN HEART FAILURE like CABG in ischaemic cause of HF which can use the hibernating myocardium and improve the heart function STEM CELL THERAPY where either bone marrow–derived precursor cells or autologous cardiac-derived stem cells and programming them to develop and remodel into cardiac cells and improve the function of heart GENE THERAPY
  52. 52. Stage A Stage B Stage C Stage D
  53. 53. MANAGEMENT OF ACUTE HF Aims of therapy:- Reduction of afterload, CO & BP maintainance 1. Semiupright position and Tourniquet appliaction:- Raising head end of the bed or by backrest 2. Oxygen:- 6-8 L/min 3. Furosemide:- IV 40-60 mg, every 30 min till diuresis 4. Morphine:- IV 2-4 mg every 15 mins to a total of 15 mg 5. Aminophylline, in case there is bronchospasm 6. Sublingual NTG:- 0.4 mg, repeated every 5 mins for 3 doses, Monitor BP 7. ACEI:- Low dose is given to start with
  54. 54. MANAGEMENT OF CHRONIC HF
  55. 55. RECENT ADVANCES Medicines in development for heart disease & stroke, 2018. Available from:- http://phrma- docs.phrma.org/files/dmfile/midreport_heartstroke_2018_final.pdf
  56. 56. Recent data indicate that additional benefit may accrue via a drug combination called Angitensin Receptor- Neprilysin Inhibitor (ARNIs) In July 2015, the FDA approved a fixed-dose combination:- ARB (Valsartan) + Neprilysin Inhibitor (Sacubitril) {ENTRESTO} Sacubitril inhibits the degradation of the natriuretic peptides ANP and BNP Recommended dose of 100–400 mg daily, divided into two doses Approved for Chronic and stable but symptomatic HF Left ventricular ejection fraction (LVEF) of less than 40% Reduces the rates of hospitalization and death
  57. 57. IVABRADINE In April 2015, FDA approved Ivabradine (CORLANOR) from Amgen Ivabradine acts by reducing the heart rate via specific inhibition of the pacemaker current Used in combination with beta blockers in people with:-  Heart failure with LVEF lower than 35 %  Inadequately controlled by beta blockers alone  Heart rate exceeds 70 beats per minute Combination decreases the risk of hospitalization for heart failure
  58. 58. TRV027 A β-arrestin-based AT1 receptor blocker, TRV027 is being developed It binds AT1 receptor and blocks G protein– coupled signaling while engaging β-arrestin In animal models, it Increases myocyte contractility and protects against apoptosis In phase II clinical studies, TRV027 decreased mean arterial pressure and was well tolerated The safety and efficacy of TRV027 is being tested in the BLAST-HF study in patients with acute heart failure
  59. 59. SERELAXIN Serelaxin is a recombinant form of the human hormone relaxin Recent studies have shown that relaxin is also produced by the vasculature and failing myocardium Relaxin interacts with a G protein-coupled receptor, leading to increased cAMP that leads to nitric oxide production and thus relaxaton Increases cardiac output, arterial compliance, and renal blood flow, supporting important physiological changes during pregnancy Given its potent vasodilator properties as well as its ability to increase renal perfusion, Relaxin became of interest as a potential therapy for acute decompensated HF
  60. 60. SOLUBLE GUANYL CYCLASE ACTIVATORS Oxidative inactivation of sGC is believed to be a common pathology in cardiovascular disease and a reason for endothelial dysfunction sGC activators have maintained (or even enhanced) effects at sGC enzymes inactivated by oxidation Riociugat is a direct, heme-dependent stimulator of sGC and is approved for the treatment of pulmonary artery hypertension and chronic thromboembolic pulmonary hypertension Cinaciugat is a heme-independent activator of sGC and lowered pulmonary wedge pressure and increased cardiac output, but also markedly increased the rate of symptomatic hypotension, hence stopped
  61. 61. OMECAMTIV MECARBIL New Sarcomere directed drug Selective cardiac myosin activator Increases myocardial contractility and stroke volume without O2 consumption Currently under evaluation for the treatment of CHF caused by LV dysfunction
  62. 62. ADRENOMEDULLIN Potent vasodilator peptide Experimental therapeutic intervention in rats showed inhibition of progression of cardiac hypertrophy and remodeling Promotes maintenance or improvement in renal function Counter the activation or actions of vasoconstricting and sodium- retaining hormone systems Potential therapeutic agents for Heart failure
  63. 63. ISTAROXIME Investigational steroid derivative Inhibition of (Na+/K+ ATPase) Stimulation of the sarcoplasmic reticulum calcium ATPase (SERCA) isoform 2 (SERCA2) Enhances the heart’s relaxation phase, protects from arrhythmogenesis caused by calcium overload Improves ejection fraction, stroke volume and systolic blood pressure, while also enhancing ventricular filling Reduces heart rate and ventricular diastolic stiffness Wider margin of safety Drug is under phase 2 trial
  64. 64. ULARITIDE Recombinant peptide mimics activity of urodilatin Urodilatin was first isolated from human urine in 1988 as a modified version of pro-ANP produced mainly by distal renal tubule cells Route of administration- IV Under evaluation for acute heart failure Improve Cardiovascular parameter & promote diuresis without ↓ creatinine clearance In phase 3 clinical trail
  65. 65. OTHER MOLECULES SB207266, a 5HT4 receptor antagonist has been noted to improve cardiac function in heart failure rats, suggesting a possible beneficial effect of 5-HT4 receptor antagonist in heart failure PG-53072, a selective inhibitor of MMP has attenuated left ventricular dysfunction and cardiac remodeling in experimental heart failure CelacadeTM is an immune modulator which has prevented chronic inflammation and apoptotic cell death by activating IL-10 mediated anti-inflammatory process
  66. 66. SUMMARY oHeart failure is a significant clinical challenge associated with high morbidity, mortality and economic burden oThe prevalence of chronic heart failure is continuously increasing globally oDespite the fact that major advances in lifesaving treatment have been made; our ability to recognize and optimally treat heart failure is limited oThe short- and long-term morbidity and mortality in acute heart failure is still unacceptably high oFurther advances in understanding of pathophysiology of heart failure will probably help to identify novel therapeutic agents for patients with poor prognosis of heart failure
  67. 67. REFERENCES 1. Kasper, Fauci, Hauser, et.al. Harrison’s Principles of Internal Medicine. 19th Edition. New Delhi: McGraw Hill; 2015 2. Bruton LL, Dandan RH, et.al. Goodman & Gilamn’s The Pharmacological Basis of Therapeutics. 13th Edition. New Delhi: McGraw Hill; 2018 3. Satoskar RS, Rege NN, Tripathi RK, Bhandarkar SD. Pharmacology and Pharmacotherapeutics. 25th Edition. New Delhi: Elsevier; 2017 4. Sharma HL, Sharma KK. Principles of Pharmacology. 3rd Edition. New Delhi: Paras Medical Publisher; 2017 5. Yancy CW, et al. 2016 ACCF/AHA/HFSA focused update on new pharmcological therapy for heart failure: an update of the 2013 guideline for the management of heart failure. Circulation, 2016, 135:e282–e293 6. Pitchai Balakumar and Manjeet Singh , 2007. Recent Advances in Pharmacotherapy for Heart Failure: Future Directions. Trends in Medical Research, 2: 61-71 7. Balakumar, P. and M. Singh, 2006. Possible role of caspase-3 in pathological and physiological cardiac hypertrophy in rats. Basic Clin. Pharmacol. Toxicol., 99: 418-424 8. Balakumar, P. and M. Singh, 2006. Possible role of poly (ADP-ribose) polymerase in pathological and physiological cardiac hypertrophy. Meth. Find. Exp. Clin. Pharmacol., 28: 683-689 9. Birkeland, J.A., I. Sjaastad, T. Brattelid, E. Qvigstad and E.R. Moberg et al., 2007. Effects of

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