Drugs used in treatment of heart failure

A presentation about the various drugs used in the treatment of heart failure

1. DRUGS USED IN THE TREATMENT OF HEART FAILURE

2. Introduction Heart is unable to provide adequate perfusion of peripheral organs to meet their metabolic requirements Previously – congestive HF Now - HF

3. Etiology Myocardial infarction Hypertension Diabetes Ventricular tachycardia Anemia Hyperthyroidism

4. The most important intrinsic compensatory mechanism is myocardial hypertrophy. H ypertrophy  ischemic changes, impairment of diastolic filling Remodeling is the term applied to dilation (other than that due to passive stretch) and other slow structural changes that occur in the stressed myocardium. It may include proliferation of connective tissue.

5. Pre load After load Further stress on V.wall  Deterioration of V.fn (Remodeling) Cardiac failure Cardiac output Sod.& water retention Activation of RAAS Activation of SNS Vasoconstriction, HR Contraction Angiotensin II Aldosterone

6. VD Pre load After load Further stress on V.wall  Deterioration of V.fn (Remodeling) Cardiac failure Cardiac output Sod.& water retention Activation of RAAS Activation of SNS VASOCONSTRICTION Angiotensin II Aldosterone ACEI DIURETICS INOTROPICS

7. Aims of treatment Drug management aims to provide symptomatic relief for the patient while also preventing further deterioration in cardiac function

8. DRUG THERAPY Relief of congestive symptoms & restoration of cardiac performance: 1.Inotropics-Digoxin,Dobutamine/Dopamine, Inamrinone / Milrinone 2.Diuretics-Furosemide,Thiazide 3.RAS inhibitors-ACE inhibitors/ARB 4.Vasodilators-Hydralazine,NITRATE, nitroprusside

9. 5.Synthetic BNP- Nesiritide 6.Beta blocker- Metoprolol,Bisoprolol II.Arrest / reversal if disease progression & prolong survival: 1.ACE inhibitors/ARB 2.Beta blockers 3.Aldosterone antagonist- Spironolactone,Eplerenone 4.Neprilysin inhibitor- Sacubitril

10. Anti-remodeling drugs ACE inhibitors AT1 receptors blockers Spironolactone Beta blockers: Carvedilol, Bisoprolol, Metoprolol e) Hydralazine + Isosorbide dinitrate

11. Cardiac glycosides History 1785 – William withering found that extract of Foxglove (Digitalis)is effective in dropsy 20 th century beginning established the action on heart & HF GLYCOSIDIC drugs Cardiac inotropic property

12. Source Digoxin - Digitalis lanata Digitoxin- D.lanata & purpurea Leaves Ouabain - Strophanthus gratus (seeds) Bufotoxin –Toad skin

13. CHEMISTRY Cardiac glycoside contain aglycon attached to sugar moiety AGLYCON consist of cycloperhydrophenanthrene (steroid ring) Attached to unsaturated lactone ring

14. MOA of Digitalis Reversible inhibition of Na + /K + /ATPase pump of myocardial cell membrane So Sodium accumulate intracellularly So more Calcium increase intracellularly More Calcium released from SR 3 intracellular Na ions exchanged for 2 extracellular K ions

15. Cardiac effects +ve inotropic ↑ CO, without ↑ O2 consumption -ve chronotropic vagal - Vagal stimulation extravagal – direct depressant action on SA & AV -ve dromotropic Slows conduction of AVN by direct & indirect action

16. PHAR. EFFECTS Cardiac effects : in CF patients +ve inotropic - By direct action ↑ CO, ↓ O2 demand  cardiotonic -ve chronotropic ↓ HR by vagomimetic & by direct action - ve dromotropic- Slows cond & ERP of AVN by direct &indirect action

17. Extra Cardiac effects 1.Kidney: Diuresis – I st prominent effect by ↑ Renal bld flow due to ↑ CO ↓ Venous pressure shifting Edema edema fluid into circulation Inhibit renin release 2.GIT: A,N,V due to CTZ stim.(early sympt) 3.↓sympathetic overactivity ↓ PVR

18. 4. CNS: Vagal centre stimulation CTZ stimulation

19. PK ROUTES : oral and i.v Steady state plasma levels in 7days Therapeutic conc .5-2ng/ml Toxic > 2.4ng/ml

20. PK DIGOXIN DIGITOXIN OUABAIN ORAL BA 75-90% 95-100% 0(nil) aVd (L/Kg) 6-7 0.6 18 PPB 30% 90% Neg Plasma ½ life 40 hrs 120hrs 20 hrs Onset of action ½ hrs 2 hrs Rapid ( I V) DOSE .125 -- .5Mg Very long Short Elimination Renal(unchanged) Hepatic(metabolized)

21. ADRs Narrow therapeutic index. Therapeutic Plasma conc is 1-2 ng /ml > 2ng/ml is toxic Monitor plasma conc & ECG ,HR , Electrolytes

22. Extra Cardiac ADR GIT : A ,N , V,abdominal pain rarely diarrhoea CNS :Head ache, Neuralgias Visual disturbance, vertigo Hallucinations, delusions Misc : Gynaecomastia

23. Cardiac ADRs Sinus Bradycardia C. Arrhythmia - ↑ automaticity partial or complete heart block atrial or ventricular extarsystole coupled beats( bigeminy) VF

24. Management of Digoxin over dosage Stop Digoxin Stop Diuretics causing hypokalemia Estimate serum K+: Mild to mod : Pot.salts 5g in div.dose, Oral Severe : Pot.chloride I/V 40mEq in 500ml of 5% glucose Pot.salts are CI if there is high degree AV block

25. V.arrhythmia : Lignocaine I/V PSVT : Adenosine, Propranolol AV block, Bradycardia : Atropine/ temporary pacemaker Specific treatment : Digibind I/V antidote in severe cases

26. DIGOXIN SPECIFIC ANTIBODY DIGIBIND Reverse cardiotoxicity Non immunogenic IV infusion

27. Drug interactions Diuretics steroids K+ levels Amiodarone Quinidine Verapamil Tetracycline Erythromycin Displace binding Ca2+ salts Synergism Digitalis toxicity

28. Drug interactions Antacids Sucralfate neomycin absorption Digitalis effects

29. Uses CHF pts with LV dysfunction in AF CHF pts in sinus rhythm who remain symptomatic despite max therapy with ACEI & Beta antagonists other uses AF, Atrial flutter PSVT

30. Drugs for heart failure

31. Diuretics - MOA in CF Control the symptoms, exercise capacity no reduction in CHF mortality Diuresis Preload Pulmonary & peripheral oedema Cardiac size Cardiac efficiency

32. Loop diuretics Furosemide, Bumetanide, torsemide Inhibit Na + K + 2Cl - symporter in the thick ascending limb of LH. delivery of Na & water to distal segments excretion of K + IV FUROSEMIDE : increases systemic venous capacitance Venodilation - decreases LV filling pressure

33. Thiazide diuretics Less frequently used May be added to loop diuretics to overcome loop diuretic resistance Inhibit Na+ Cl- co transporter in the DCT More hypokalemia , Hypercalcemia Hydrochlorothiazide only oral form, DOA : 5 to 15 hrs dose : 12.5 – 100 mg/day

34. Aldosterone antagonists Role of Aldosterone in HF Mechanism Effect Na & water retention Edema , elevated filling pressure K & Mg loss Arrhythmias, sudden cardiac death Fibroblast proliferation Myocardial fibrosis Remodeling Remodeling , arrhythmia

35. Mainly used as an add on therapy Retards disease progression Survival benefits Low doses of spironolactone ( 12.5-25mg/day) should be used to avoid hyperkalaemia May help restoration of diuretic response to furosemide when refractoriness has developed. Contraindicated in renal insufficiency Can cause gynaecomastia

36. Spironolactone & Eplerenone Weak diuretics Prevents - loop diuretic induced K+ loss ( arrhythmias & digitalis toxicity) Combination improves survival Prevents tolerance to loop diuretics Only oral form, DOA: 12 hrs, 25 mg/day ADR- Hyperkalemia, Gynaecomastia

37. ACE inhibitors

38. ACE inhibitors Symptomatic as well as disease modifying benefits Prolong the survival by preventing remodeling Reduce death due to arrhythmia, MI & stroke Recommended for all grades of HF Check renal function Differ only in PK parameters Agents of first choice Enalapril: 10 mg BD Lisinopril: 10 mg OD Ramipril : 5 mg BD Combination of spironolactone + ACEI provides more benefit

39. ACE inhibitors Indicated in all grades of HF ADRs Dry cough – use AT1 blockers Angioedema (can occur @ any time during tretment )– stop ACEI Hypotension Hyperkalemia – low K diet Dysguesia C/I – Pregnancy, B/L renal artery stenosis

40. AT receptor blockers Effects of AT activation Sympathetic activation vasoconstriction Aldosterone release Na retention Myocardial hypertrophy remodeling Myocardial fibrosis Myocyte apoptosis Endothelial dysfunction Endothelin synthesis Altered gene expression Cytokine release

41. AT receptor blockers Losartan, valsartan, candesartan Similar but limited effects compared to ACEI Considered in pts intolerant to ACEI AT1 blockers + spironolactone – more effective Hyperkalemia, angioneurotic edema

42. Direct Renin inhibitors ACE independent pathways for AngII production ACE inhibitors alone are not sufficient Aliskiren FDA approved Add on therapy to β blockers & ACEI or ARB Require large RCT 150mg/day.

43. Beta blockers Mechanism is not fully understood Attenuate the effects of CAs – apoptosis Prevents remodeling by inhibiting mitogenic activity of CAs Decrease HR - O2 consumption Decrease lethal arrhythmias

44. Beta blockers in CCF

45. Beta blockers cont.. Only metoprolol, Bisoprolol, Carvedilol shown usefulness Metoprolol & Bisoprolol – selective β 1 blockers Carvedilol- blocks β 1+ β 2 › + α 1 Antioxidant activity prevents cardiac + vascular s m mitogenesis

46. Beta blockers cont. Used in mild to moderate HF( NYHA class II & III) Stopped during an episode of acute heart failure Aim for round the clock beta blockade Contraindicated in decompensated HF Start with very low dose – titrate to target level Carvedilol – 50 mg/day Bisoprolol – 10 mg/day Metoprolol – 200 mg/day No benefit in asymptomatic HF

47. DIGOXIN in HEART FAILURE Routine oral digitalisation 0.25 mg Rapid oral digitalisation 0.75 mg loading dose IV digitalisation 0.5 to 1mg

48. INOTROPIC AGENTS USED in HF Cardiac glycosides Digoxin,Digitoxin Beta agonists Dobutamine,Dopamine PDE inhibitors Inamrinone,Milrinone

49. vasodilators Arteriolar dilators Ex : Hydralazine Venous dilators Ex : Isosorbide dinitrate Arteriolar & venous dilators ex: Na nitroprusside ACE inhibitors

50. Hydralazine MOA- unknown ( NO synthesis in endothelium) Dilates resistance vessels Reduces after load ADR - Tachycardia, lupus like reactions

51. Isosorbide dinitrate MOA- releases NO, activates Guanylyl cyclase Venodilation- preload & ventricular stretch Can be used in both acute and chronic HF ADR - Postural hypotension, tachycardia additive with other vasodilators synergistic with PDE inhibitors

52. Sodium nitroprusside MOA- Releases NO spontaneously activates Guanylyl cyclase Marked vasodilatation Both veno + arteriolar dilation Only IV, Short acting(1-2 min) ADR- hypotension, cyanide toxicity additive with other vasodilators    

53. Nesiritide Recombinant BNP Causes natriuresis Short acting ( t1/2-18 min) – IV bolus 2mg/kg Use- a/c decompensated HF with dyspnoea at rest No long term benefits ADR - hypotension

54. PDE inhibitors Non-glycoside non-adrenergic +ve inotropic agent Inodilator ( + inotropy and direct vasodilatation) Decreases preload and afterload . Does not arrest the progress, may ↑ mortality Eg: Amrinone (inamrinone) -rare use ,can cause thrombocytopenia, Hepatotoxicity Milrinone- more VD, < thrombocytopenia

55. AMRINONE GIVEN only IV Action starts in 5min . DOA – 3hrs Increases EF & decreases PVR Indicated as an add on drug to conventional drugs Thrombocytopenia, diarrhea, hepatotoxicity , arrhythmias etc

56. ADR Inamrinone : N , V , Arrhythmias Thrombocytopenia Liver enzyme changes Milrinone : Less likely – Hepatotoxicity & Thrombocytopenia Shorter elim t ½ Greater selectivity for PDE III Less S/E More potent

57. LEVOSIMENDAN Sensitises Troponin system to Ca2+ Cause VD Also appears to (-) PDE 3

58. DOBUTAMINE Selective β₁ agonist ↑CO – ↓Ventricular filling pressure Short t ½ Continued Infusion - Tachyphylaxis

59. β STIMULANTS Dopamine & Dobutamine DOPAMINE Low doses: 2ug/kg bwt/min  D : VD Interm: 2-5ug/kg bwt/min  β High : 5 – 15ug/kg bwt/min α SHOCK HR ↑

60. Newer drugs in use 1. ARNI Angiotensin receptor blocker and NEPRILYSIN INHIBITOR . FIRST IN ITS CLASS IS SACUBITRIL/VALSARTAN SACUBITRIL  Orally active NEPRILYSIN inhibitor Prevent degradation of endogenous ANP,BNP VD,natruresis & diuresis Combined with Valsartan in advanced heart failure

61. Contraindicated with concomitant use of ACE-. Contraindicated in patients with a history of angioedema Strictly contraindicated in pregnancy can cause oligohydramnios

62. Adverse effects Angioedema Hypotension hyperkalemia

63. IVABRADINE Bradycardia producing antianginal drug used in cardiac failure Selective blocker of If current ie Cardiac pacemaker f channels Used when Beta blockers are CI

64. PHARMACOKINETICS Bioavailability: 40% (because of first-pass elimination in the gut and liver) Ivabradine should be taken with meals Major metabolite: N- desmethylated derivative which is equipotent to IVABRADINE

65. Adverse Effects Bradycardia Hypertension Atrial fibrillation Luminous phenomena or phosphenes or visual brightness

66. TOLVAPTAN Orally active nonpeptide Vasopressin receptor V2 antagonist In advanced CHF

67. Management of acute HF Semi upright posture Oxygen Furosemide Morphine Aminophylline NTG/sodium nitroprusside Digoxin

68. 1. Reposition the patient : If it is safe to do so, support the patient in assuming an upright, sitting posture. Many patients will do this on their own to optimize their breathing efficiency 2) Oxygen therapy and/or ventilatory support 6 to 8 L/ mt 3) Diuretics : A) vasodilator properties and provide rapid decongestion and symptomatic relief. B)increase renal salt and water excretion. Intravenous furosemide is the first-line diuretic 

69. Furosemide 40 to 60 mg IV every 30 mts until diuresis sets in VENODILATION & DIURESIS

70. 4.MORPHINE IV 2 to 4 mg Every 15mts Allays anxiety ,pain Peripheral pooling of blood By central reduction in sympathetic activity

71. 5.AMINOPHYLLINE If bronchospam 250 to 500mg over 15 mts followed by infusion 6.SUBLINGUAL NITROGLYCERIN 0.4mg Decrease pulmonary capillary pressure Venodilator Repeated every 5 mts 3 times IV NTG 5 to 10 mcg/ mt

72. Sodium nitroprusside infusion both venodilators and arteriodilators , reducing both preload and afterload and as a result increasing stroke volume. Especially indicated in hypertensive AHF. Avoid vasodilators when SBP is <90 mmHg Vasodilators are contraindicated in shock, predominant right ventricular (RV) failure

73. 7.Low dose ACEI Acute MI with HF 8.Inotropes Dopamine/ Dobutamine / Digoxin IV Digoxin 0.5 mg over 15 mts Useful in AF /SVT CONTINUE managementof heart disease/HF after resolution of acute HF

74. NONPHARMACOLOGICAL MANAGT Salt & water restriction 2 to 3 gm/day Wt reduction Cessation of alcohol consumption & smoking STOP drugs: CCB,NSAIDS,GLUCOCORTICOIDS,SILDENAFIL

75. Management of Chronic HF (combination of drugs) ACE-Is/ ARB Beta blockers ARNIs Diuretics IVABRADIN Digitalis Vasodilators

76. Commonly asked Qs Classify drugs used in heart failure. Digoxin ( MOA,AE ,USES,NOTE ON DIGOXIN TOXICITY) Rationale :ACE/ARB IN HF FUROSEMIDE IN ACUTE HF SPIRONOLACTONE/EPLERENONE IN HF BETA BLOCKERS IN HF SN on ARNI NAMES OF BETABLOCKERS USED IN HF Inotropic agents Drug of choice in cardiogenic shock Treatment of Acute Heart Failure Names of drugs that inhibit remodeling process

77. Thank you