This document discusses pharmacotherapy for heart failure. It begins with the basic physiology of the cardiovascular system and compensatory mechanisms in heart failure. It then covers the classification, definition, causes, signs and symptoms of heart failure. The mainstay treatments discussed include ACE inhibitors, ARBs, beta blockers, diuretics, aldosterone antagonists, digoxin, and vasodilators. Specific drugs are described in each class with their mechanisms of action, dosages, side effects and drug interactions. Inotropic drugs for acute heart failure like dobutamine, dopamine, milrinone and levosimendan are also covered. The document provides a comprehensive overview of pharmacologic management of both chronic and acute

1. Pharmacotherapy
of
Heart Failure
Nidhi Maheshwari
Pharmacology

2. BASIC PHYSIOLOGY
MAP = CO X SVR
HR SV
ANS
PRELOAD
CONTRACTILITY
AFTERLOAD
ATRIAL CONTRACTION
VENOUS RETURN
LV VOLUME LV THICKNESS
AORTIC PRESSURE
SVR
BLOOD VOLUME
AT EJECTION

3. Questions covered
1) Describe recent advances in drug therapy of CCF/HF
2) Describe the present status of drugs used in management of CHF
3) Current and recent advances in treatment of CHF
SAQ
1) Role of beta blockers in HF & individual drugs

4. Background & incidence
• Incidence- 1.0-5.0 / 1000/ annum.
• Only cardiovascular disease : increasing in incidence and prevalence.
• Over 1 million patients hospitalized annually
• 50,000 deaths annually
• 5 yr mortality- 50%

5. Definition
Heart failure
• complex clinical syndrome
• from structural or functional cardiac disorder
• impairs the ventricular ability to fill with or eject blood sufficiently
required to meet body’s metabolic demands
Clinical manifestations
dyspnea (pulmonary congestion) and fatigue (reduced exercise tolerance)

8. Compensatory responses…
Myocardial disease
(decreased contractility)
(decreased stroke volume)
Decreased renal
perfusion
RAAS
activation
Vasoconstriction
Increased afterload
Sympathetic
activation
Increased heart
rate
vasoconstriction
Increased
after load
O2 demand
Cardiac
dilatation
Cardiac
hypertrophy
Increased
cardiac
contractility
Increased cardiac
O2 demand &
work

9. • Maintain Cardiac Output by compensatory mechanisms
• In long term, increase work load and worsens cardiac performance
• Compensatory mechanisms become exhausted and ineffective after a long time
• TPR and after load increases-> decreasing the ejection fraction
• Preload is increased due to increased blood volume and venous tone
• When adaptive mechanisms fail to maintain Cardiac Output-decompensated heart
failure
Signs and symptoms of decompensated HF : dyspnoea with cyanosis, hepatomegaly,
cardiomegaly, reflex tachycardia(?), decreased urine formation, decreased exercise
tolerance and muscle fatigue

10. Syndrome( multiple causes)
• MI/Angina
• HT
• Ventricular Tachycardia
• Hyperthyroidism
• Anaemia
• Berry-berry
Low CO
High
CO
Medications
Treat
Cause

12. Classification
ACC/AHA
Stage
NYHA Class Description
A Prefailure No symptoms but
risk factors present
B I Symptoms with
severe exercise
C II/III Symptoms with
marked (II) or mild
(III) exercise
D IV Severe symptoms
at rest

13. Treatment of Chronic
HF patients 4
ACC/AHA
Stage
NYHA Class Description Management
A Prefailure No symptoms but
risk factors present
Treat obesity, HT,
Diabetes,
Hyperlipidemia
B I Symptoms with
severe exercise
ACEI/ARB
Β blockers
diuretics
C II/III Symptoms with
marked (II) or mild
(III) exercise
Add
Aldosterone
antagonists, Digoxin,
CRT,
Hydralazine/nitrate
D IV Severe symptoms
at rest
Transplant
LVADCRT: cardiac resynchronization therapy; LVAD: left ventricular assisted device

15. Management of
acute heart failure4
1) IV furosemide
2) IV Dopamine/Dobutamine: in HF + severe hypotension
3) IV levosimendan (alternative to β agonist)
4) Vasodilators- IV nitroprusside, nitroglycerine, nesiritide
5) Vasopressin antagonists- Conivaptan, Tolvaptan: in HF with
hypovolemia( ? Is it hypervolemia)

16. Pharmacotherapy &
Pharmacology

17. Positive Inotropic Agent
a) Cardiac Glycosides: Digoxin
b) Bipyridines or PDE inhibitors: Inamrinone,
Milrinone, Levosimendan, Enoximone
χ) β Adrenergic Agonists: Dopamine,
Dobutamine, Dopexamine

18. Without Inotropic effects
a) Diuretics: Furosemide, Bumetanide,
Hydroclorothiazide, Metolazone,
Spironolactone, Eplerenone
b) ACEI: Enalapril, Lisinopril, Ramipril
c) AT1 receptor anatgonists: Losartan,
Valsartan

19. d) Β blockers: Carvedilol, Bisoprolol,
Metoprolol
e) Vasodilators: Hydralazine, Sodium
nitroprusside, Isosorbide di nitrate,
Nesiritide
f) Vasopressin Receptor Antagonists:
Conivaptan, Tolvaptan

20. ACE inhibitors
• First line agents in asymptomatic ventricular dysfunction
• Combination with diuretics make first line therapy in HF
Enalapril 2.5 mg BD ( max
10 mg BD)
Lisinopril 2.5-5 mg OD
( max 20 mg OD)
Ramipril 2.5 mg OD ( max
10 mg OD)

21. • Slow : progress of ventricular dilatation
• Prolong survival : prevent pathological remodeling : heart & blood vessels
• Beneficial in MI (stroke, arrhythmia)
• Use : asymptomatic to severe HF
• Side effects: hypotension, hyperkalaemia, cough, urticaria, angioedema,
altered taste, fetopathic
• Aldosterone escape is prevented by adding Spironolactone with ACEI.
combination also reduces mortality.

22. ARBs: (AT1 receptor blockers)
• Beneficial hemodynamic effects similar to ACEI
• Used when ACEI are Cx (excessive cough or angioedema) or not tolerated
• Side effects of ARBs : hypotension,hyperkalaemia, headache, dizziness,
fetopathic
Losartan:
Most common ARB s in CHF
T1/2: 2 hrs
B.A.: 33%
Dose: 50 mg OD/BD
Less first dose hypotension
Valsartan:
T1/2 : 6-9 hrs
B.A.: 23%
Dose: 80-160 mg OD

23. Heart Failure
↓
Raised epinephrine and non-epinephrine level
↓
Cardiac
Hypertrophy,
Remodeling,
Apoptosis
Peripheral
vasoconstriction

24. Heart Failure
↓
Raised epinephrine and non-epinephrine level
↓
Cardiac
Hypertrophy,
Remodeling,
Apoptosis
Peripheral
vasoconstriction
β blockers

25. Carvedilol
• α1 + β1 + β2 antagonist
• T1/2- 6-8 hrs
• Dose: 3.125 mg BD for 2 weeks, if well tolerated gradual ↑ to max 25
mg BD( max)
• Inhibits free radical induced lipid peroxidation, inhibits vascular smooth
muscle mitogenesis and also block L type voltage gated channels->
cardioprotective in CHF
β blockers

26. Metoprolol
• T1/2: 3-6 hrs
• Dose: 100 -200 mg (max)
Bisoprolol
• T1/2: 9-12 hrs
• OD is enough
• Dose: 2.5 -10 mg (max)
Nebivolol
• Also NO donor-vasodilatation and improve endothelial function
• Dose: 5mg OD
• Effective in systolic & diastolic function

27. • Use in mild-moderate (NYHA II/III) systolic dysfunction with cardiomyopathy
• Benefit seen in symptomatic
• Initiate at low doses and up titrate to max dose
• 2-4 months therapy is required for clinical benefits
• Do not start in decompensated HF
• Sustained released metoprolol or 2-3 times daily dosing should be preferred
• Clinical improvements are slight rise in ejection fraction, reduction in HR, reduction in
symptoms
• Long term effect: maintain hemodynamic benefits and reduction in
morbidity/mortality

28. Side effects:
• Accentuation of MI, CHF, edema (if started at high dose)
• Bradycardia
• Asthma/COPD precipitation
• Altered carbohydrate tolerance and lipid profile
• Rebound hypertension on withdrawal
• fluid retention

29. Diuretics

30. Loop Diuretics
Furosemide, Bumetanide
• preferred in HF (symptomatic esp:edema)
• Effective diuresis-> ↓ ECF -> ↓ venous return -> ↓ preload
a) ↓ edema
b) ↓ cardiac size(↑ CO)
• Do not influence primary disease process
• s/e: Hypokalaemia: precipitate digitalis toxicity & arrhythmia
• T1/2 : furosemide: 1-2 hr, bumetanide: 60 mins
• Dose: furosemide: 20-80 mg OD, Bumetanide: 1-5 mg OD

32. Aldosterone antagonists
Spironolactone
• Dose: 12.5-25 mg/day
• Add on with ACEI & others in moderate-severe CHF
• Retard disease progression (Aldosterone: fibroblast proliferation and
fibrotic changes in myocardium)
• Slow response
• Cx in renal failure (precipitate hyperkalemia)
• Eplerenone shows no gynaecomastia

33. Eplerenone
Search abt it

34. • With diuretcis. Reason a) Hypokalemia prevented
b) improve refractoriness of chronic diuretic use
c) also improves survival
• s/e: hyperkalemia, gynaecomastia
• In severe CHF: ACEI+ spironolactone+ digitalis: improves survival
Thiazides: Hydrochlorothiazide: used less frequently

35. Cardiac Glycosides
Digoxin
• Source: Digitalis Lanata
• Ix: Low output heart failure due to HT, IHD & arrhythmias
Dose:
Oral route is preferred: 0.125-0.5mg/day.
1) Slow loading with 0.125-0.25 mg/day
2) Rapid method with 0.5-0.75mgevery8hrs for1dayfollowedby0.125-0.25
mg/day(rare)
3) IVis seldomrequired
• Both are equally effective
• Given when ACEI & Diuretics fail to control symptoms
• Better results in HF with Atrial fibrillation

36. MOA
• Raises free cytoplasmic Ca2+
-> ↑FOC -> ↑ C.O. &↓ Cardiac systole
• Opposes compensatory sympathetic activity and vagal stimulation: ↓ H.R.
Effects
• No change or ↓ in oxygen requirement, ↓ heart size
• Protection of ventricles from atrial flutter or fibrillation
• ↓ in after load and preload
• Diuresis
• Bradycardia, improved myocardial circulation and sense of well being
Subside pulmonary
congestion and edema

37. Raised free cytosolic Ca2+
is due to
1) Main: Reversible inhibition of Na+
/K+
ATPase
2) Increase in Ca2+
permeability through voltage sensitive L type Ca2+
channels
during plateau phase
3) Release of more Ca2+
from SR & mitochondria by activating Ryr (ryanodine)
receptors
4) Inhibits SR- Ca2+
ATPase (reuptake channel)

39. DIGOXIN
Oral
absorption(
%)
75-90
Administrati
on
Oral, iv
aVd (L/kg) 6-7
Protein
binding
30
Plasma T1/2 38-40 hrs
Onset of
action
½ hr
Metabolized
(%)
20(liver)
Excretion Urine
(unchanged)
• Small mortality benefit at plasma
levels <1 ng/ml
• Preferred in conditions with dilated heart
(helpful in restoring cardiac compensation?)
• Reduces hospitalization and deaths from
progressive HF but increase in
sudden death4
• Shows cumulative effects: full therapeutic
effects after 4 x t ½: 6-7 days
• No effect on BP

40. Adverse effects from govind garg page 139
• Bradycardia, heart blocks. At toxic doses: extra systoles, pulsus bigeminus,
ventricular fibrillation & fatal arrhythmia
• Monitor serum level: digoxin & K+ and ECG
• In severe toxicity- temporary cardiac pacemaker catheter +digoxin immune fab
• Use of DIGIBIND Fab fragment: 40 mg neutralizes 0.6 mg digoxin
• Others: GI upset, blurred vision & loss of color perception, hyperkalemia,
gynaecomastiareduce dose
• Cx: Hypokalemia, children<10 yrs, elderly with renal or hepatic disease, MI,
hypothyroidism, WPW syndrome and myocarditis, hypercalcaemia,
hypomagnesemia, A-V block, renal failure, hypo-hyper thyroidism

41. A pt on chronic digoxin Rx develops ventricular
arrhythmia.
Steps:
• Withdraw digoxin
• Add oral K supplements slowly & cautiously
• Treat with lidocaine/B blocker
• DOC: iv digibind ovine antidigoxin Fab fragments; No
immunological reaction due to lack of Fc.

42. Drug Interactions
ENHNACED digitalis toxicity
1)Loop diuretics, steroids
2) Amiodarone, quinidine, verapamil, tetracyclines, erythromycin
3) Catecholamine, Sch
DECREASED digitalis effects
1) Antacids, Sucralfate, Neomycin
2)Enzyme inducers
3) Hyperthyroidism
4) Cholestyramine

43. • ACEI -> raised digitalis toxicity
• B blockers-> reduce av conduction
• Verapamil-> raised toxicity
• Nifedipine- safe
• Diuretics ( hypokalemia)-> raised toxicity
• Quinidine, amiodarone-> toxicity

44. • Cardiac-extracardiac se

45. Mx of side effects

46. Treatment of digitalis toxicity

47. Explain drug interaction
• Amiodarone/verapamil with digoxin

48. Vasodilators

50. Combination
• Given when ACEI are not tolerated or contraindicated
• Long term use can reduce damaging remodelling of the heart and prolong
survival ( less than ACEI)

51. β agonists

52. Dobutamine
• β1 selective
• T1/2: 2 min. Steady state concentration achieved in 10 mins
• IV 5-10 μg/kg/min
Uses:
• Short term management: acute HF
• HF with MI or cardiac surgery
Adverse effects
• Precipitation of angina/MI (as it increases myocardial O2 demand)
• Tolerance due to repeated use
• Caution in atrial fibrillation (↑AV conduction) and hypertensives(↑ BP)

53. Dopamine
• In acute HF
• HF with hypotension
• Low C.O. heart failure with compromised renal function
Effects
• ↑C.O. (β1 agonist)
• Renal & splanchanic vasodilatation (D1 agonist)
• Dose: 5-10 μg/kg/min
• Monitor BP, HR, urinary output

54. PDE Inhibitors
• Benefits is mostly from vasodilatation than positive inotropic effects
Inamrinone and Milrinone-PDE3 inhibitors
• Use in acute heart failure or severe exacerbations of chronic

55. Inamrinone
• T1/2- 2-4 hrs
• Action starts in 5 min and lasts for 2-3 hrs
• Dose: 0.5 mg/kg bolus full. by 5-10 μg/kg/min infusion
• s/e: thrombocytopenia, nausea, vomiting, arrhythmia, liver enzyme
changes: withdrawn in some countries
Milrinone
• T1/2- 40-80 min
• 10 times more potent than inamrinone. Preferred
• Dose: 50ug/kg iv bolus foll by 0.4-1.0 ug/kg/min
• s/e: less thrombocytopenia and liver effect. Same arrhytmogenic
potential, headache, tremors

56. Enoximone
• Congener of inamrinone
• IV in acute heart failure
• Better tolerated and improves physical quality of life (central stimulatory
effect of ↑c AMP)

57. Levosimendan
• Sensitizes troponin system to calcium & inhibits PDE
• May be useful in HF
• acutely decompensated congestive heart failure

58. Istaroxime4
• Investigational steroid derivative
MOA:
• Increases contractility by inhibiting Na+/K+ ATPase
• Facilitates sequestration of Ca2+ by saroplasmic reticulum (may render
drug less arrhythmogenic than digoxin)
• In phase 2 clinical trial

59. NON-Inotropic agents

60. Vasoactive Peptides
• ↑BNP (Brain Natriuretic Peptide): diagnostic and prognostic marker in
heart failure
• Rapid Measurement BNP →emergency diagnosis of heart failure
• released from the cardiac ventricles (response to increased wall tension)

62. Nesiritide
• Recombinant form of human BNP
• APPROVED for acute decompensated HF
MOA
• ↓ arteriolar and venous tone (↑ cGMP in smooth muscle cells --
smooth muscle relaxation)
• Natriuresis (Inhibits Na+ absorption in collecting duct)

63. • Dose: 2μg/kg bolus followed by continuous IV infusion of 0.01-0.03
μg/kg/min
• T1/2- 18 min
• s/e- excessive hypotension, renal damage
• No dose adjustment in renal insufficiency
(?)
C/I: syst BP< 70

64. he short- and long-term morbidity and mortality in acute heart failure is still unacceptably high.
There is an unmet need for new therapy options with new drugs with a new mode of action
Ularitide
• Recombinant peptide mimics activity of urodilatin
• Route of administration- IV
• Under Ix for acute heart failure
• Improve Cardiovascular parameter & promote diuresis without↓
creatinine clearance
• In phase 3

65. Vasopeptidase Inhibitors
MOA
• ↑ANP & ↑BNP inhibition of neutral endopeptidases (enzyme
metabolizing natriuretic peptides)
• ↓Ang II- inhibition of ACE
Effects
Vasodilatation and Na+ & water excretion
↓
↓total peripheral resistance and BP
E.g.: Omapatrilat, Sampatrilat, Fasidopatrilat

66. Omapatrilat
• Orally active long acting inhibitor of NEP
Studies suggest:
• ↓BP in Hypertensive animal models and in patients
• ↑ cardiac functions in heart failure patients
Side effects: angioedema (3 times more than ACEI), cough, dizziness
Clinical status: in phase 3 trials
Ecadotril:

67. Vasopressin Antagonists
V1a : vasoconstriction
V2: antidiuretic
• Conivaptan
• V1a & V2 antagonist
• APPROVED for hyponatremia (SIADH)
• Potential use in heart failure: as ↓ peripheral resistance and ↓ dilutional
hyponatremia
• T1/2: 5-12 hrs
• Dose: 20 mg loading IV over 30 min followed by 20 mg IV over 24 hrs
• Drug interactions present (CYP3A4 metabolism)
• s/e: infusion site reaction, headache, hypotension, pyrexia

68. Tolvaptan
• V2 antagonist
• Oral: 15-45 mg/day
• T1/2: 6-8 hrs
• APPROVED to treat hyponatremia (SIADH)
• Multiple drug interactions ( substrate and inhibitor of p-glycoprotein and CYP3
metabolism)
• Can cause rapid Na+ reduction & may prove fatal
1)Start only in hospital setting
2)Monitor sodium level

69. In heart failure clinical trials (patients of CHF with low ejection fraction)
Short term results:↓ body wt & ↓ dyspnoea
Long term results: ↓ body wt ( ↓edema)&↑Na+ conc (normalize Na+)
No effect on mortality & hospitalization
s/e: g I effects, hyperglycaemia, pyrexia, DVT, DIC, hemorrhage
Selective V1a antagonists
potential for raised TPR state like HT and HF

70. Renin inhibitor
Aliskiren
• Recently approved for HT
• In clinical trial for HF: may be efficacy similar to ACEI
• Exerts beneficial effect on myocardial remodeling by ↓ left ventricular
mass in HT patients--Showing salutary effects on CVS--- Trial done on
CHF patients
• In a trial 3
Aliskiren with β antagonist and ACEI in CHF did show no
hyperkalemia and hypotension and ↓ plasma BNP levels
↓
May improve symptoms and functional capacity in CHF

71. Endothelin antagonists
Bosentan
• Oral, non –selective
• Approved for use in pts with pulmonary hypertension.
• Not shown efficacy in heart failure
• Failed to show benefit in mortality and morbidity
Tezosentan
• nonselective ET receptor antagonist
Darunsentan

72. Adrenomedullin
• Potent vasodilator peptide
• Experimental therapeutic intervention in rats by transfer of the AM gene
or of recombinant AM inhibit the 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.

73. Steroids in HF

74. Statins

75. Allopurinol

76. Superscripts..
1- sharma& sharma
2-Tripathi
3-G&G
4-katzung