It explains th mechanism of digitalis very nicely. It also explains the significance of other drugs being used in the treatment of CHF.

1. PHARMACOTHERAPY OF
CONGESTIVE CARDIAC
FAILURE
Mrs. Mayuri Padhye, Assistant professor,
Department of Pharmacology,
Saraswathi Vidya Bhavan’s College of
Pharmacy

2. CARDIAC GLYCOSIDES
 Have cardiac ionotropic property
 myocardial contractility & cardiac output in
a hypodynamic heart without a proportionate
in the O2 consumption
 Efficiency of failing heart is

3. CARDIAC GLYCOSIDES

4. CARDIAC GLYCOSIDES: CHEMISTRY
 Aglycone
1. Also c/a genin
2. Pharmacological
activity is confined
3. Short lived
4. Less potent in action
 Sugar
1. 1 0r more sugars
are attached to
genin
2. Important for
modification of
solubility & cell
permeability

5. CARDIAC GLYCOSIDES:
CHEMISTRY
 Cyclopentanoperhydrophenanthrene (steroid)
ring to which unsaturated lactone ring is
attached
 E.g Digoxin (Dig italis lanata ), Digitoxin
(Dig italis purpure a )
 Currently in market: Digoxin

6. PHARMACOLOGICAL ACTIONS
1. Heart:
 Direct effect on myocardial contractility &
electrophysiological properties

7. HEART
i. Force of contraction:
 Dose dependant increase & +ve ionotropic
action
 Systole is shortened, diastole prolonged
 Maintains stroke volume in case of normal
heart, but not with failing heart

8. HEART
ii. Tone:
 It is defined as the maximum length of the
fiber at a given filling pressure or the resting
tension in the muscle fiber
 Better ventricular emptying & reduction in
filling pressure
 Decrease in end diastolic volume

9. HEART
iii. Rate:
 Bradycardia is more marked
 Improves circulation & slows heart by vagal
action

10. HEART
iii. Rate:
 Vagal action is increased:
a. Direct stimulation of vagal centre
b. Sensitization of baroreceptors
 Extravagal action: Direct depression of SA &
AV node

11. HEART
iv. Electrophysiological properties:
a. Action potential:
 Resting membrane potential is with in
dose
 Excitability is enhanced at low doses, but
depressed at toxic doses
 Rate of 0 phase depolarization is reduced

12. HEART
iv. Electrophysiological properties:
a. Action potential:
 At therapeutic conc. Hyperpolarization of SA
& AV node

13. Electrophysiological properties
b. Effective Refractory Period:
 Atrium: increased by direct action &
decreased by vagal action
 A-V node & Bundle of His: increases by
direct, vagomimetic & antiadrenergic action
 Ventricles: increased by direct action

14. Electrophysiological properties
c. Conduction:
 A-V conduction is slowed at therapeutic
conc.
 At high doses:

15. Electrophysiological properties
d. ECG:
 At therapeutic doses: changes in ECG
 High doses: arrhythmias
 Changes are:
I. Decreased amplitude or Inversion of ‘T’
wave
II. Increased P-R interval [slowing A-V
conduction]
III. Shortening of Q-T interval [shortening of

16. PHARMACOLOGICAL ACTIONS
2. Blood vessels:
 Mild direct vasoconstrictor action
 Peripheral resistance is increased
 Venous tone is improved in normal & CHF
patients
 No prominent effect on BP; systolic may
diastolic may in CHF patients

17. PHARMACOLOGICAL ACTIONS
2. Blood vessels:
 At therapeutic doses, no significant effect on
the coronary circulation

18. PHARMACOLOGICAL ACTIONS
3. Kidneys:
 Diuresis in CHF patients
 Retained salt & water is gradually excreted
 No diuresis in normal individuals

19. PHARMACOLOGICAL ACTIONS
4. CNS:
Therapeutic dose Little apparent
Higher dose (CTZ
activation)
Nausea, vomiting
Much Higher dose Hyperapnoea,
central sympthetic
stimulation,
mental confusion, visual
disturbances

21. MOA

22. MOA

23. MOA

26. PHARMACOKINETICS

27. DIGITOXIN DIGOXIN
Lipid soluble Relatively polar
BA Will differW.R.T. manufacturers
VOD Very large, concentrated in heart,
skeletal muscles, liver, kidneys
Metaboli
sm
Liverpartly Enterohepatic
circulation
Excretio
n
Primarily unchanged
by kidneys
T1/2 Prolonged in elderly
Dose Not greatly
altered In renal
Needs to be
decreased

28. A/E
 Toxicity: High, Therapeutic index is very slow [1.5-
3]
 Margin of safety is low
1. Extracardiac
2. Cardiac

29. A/E
1. Extracardiac
 Gastric irritation, mesenteric
vasoconstriction, CTZ stimulation
 Anorexia, nausea, vomiting, abdominal pain
 Fatigue, no desire to walk, malaise,
headache, metal confusion, restlessness

30. A/E
1. Extracardiac
 Hyperpnoea, disorientation, psychosis,
visual disturbances
 Occasional diarrhea & rare skin rashes

31. A/E
2. Cardiac
 Arrhythmia: Pulsus bigeminus
Ventricular extrasystoles
Ventricular tachycardia
Terminal fibrillation
 Partial to complete AV block
 Severe bradycardia, atrial extrasystoles,
Atrial fibrillation

32. TREATMENT [(i)Tachyarrhythmia]

33. TREATMENT [(ii)Ventricular
Arrhythmia]
 Lignocaine i.v. : suppresses excessive
automaticity, but not accentuate A-V block
 Quinidine, procainamide c/i

34. TREATMENT
iii. Supraventricular arrythmias: Propranolol
i.v. /oral depending on urgency
iv. A-V block & Bradycardia : Atropine i.m.

35. PRECAUTIONS &
CONTRAINDICATIONS
 Hypokalemia: Enhances digitalis toxicity by
increasing its binding to Na+K+ATPase
 Elderly, renal or severe hepatic disease
 Myocardial Ischemia: shd be used only in
severe arrhythmia
 Myxodema: eliminates slowly

36. PRECAUTIONS &
CONTRAINDICATIONS
 Thyrotoxicosis: more prone to digitalis
arrythmia
 Ventricular tachycardia: c/i
 Partial A-V block: due to digitalis it may be
complete
 Acute myocarditis: ionotropic response to
digitalis is poor; more prone to arrythmias

37. INTERACTIONS
 Diuretics induces Hypokalemia: can precipitate
arrhythmia; potassium supplement
prophyalactically
 Ca++ may precipitate toxicity (synergism)
 Quinidine reduces binding of digoxin to tissue
proteins
 Absorption is reduced by sucralfate, antacids,

38. INTERACTIONS
 Absorption can be reduced by atropinic drugs,
TCA
 Propranolol, verapamil, diltiazem depresses A-
V conduction, opposes positive ionotropy
 Succinylcholine : can induce arrhythmia
[digitalized patients]
 Adrenergic drug: can induce arrhythmia &

39. USES
 CHF:
 Cardiac output is insufficient to meet the
demands
 10
due to systolic dysfunction
1. Systolic dysfunction
2. Diastolic dysfunction

40. USES
1. Systolic dysfunction
 In case of IHD, dilated cardiomyopathy,
tachyarrhythmia, myocarditis
i. Ventricles are dilated
ii. Unable to develop sufficient wall tension to
eject blood

41. USES: Diastolic dysfunction

42. USES: Cardiac Arrythmias
1. Atrial fibrillation:
 Controls ventricular rate in AF
 Increases ERP of A-V node by direct
vagomimetic action & antiadrenergic actions
 Decreases avg. atrial ERP
 Dose dependant decrease in avg.

43. USES: Cardiac Arrythmias
2. Atrial flutter:
 Atrial rate is 200-350/min, but atrial
contractions are regular & synchronous
 Reduces ventricular rate & prevents sudden
shift of A-V block to a lower degree

44. USES: Cardiac Arrythmias
3. Paroxysmal Supraventricular tachycardia:
 i.v. : increases vagal tone
 Depresses path through SA & AV node or
ectopic focus
 Terminates arrhythmia

45. TREATMENT FOR CHF
Two distinct goals in CHF:
a. Relief of congestive/ low output symptoms &
restoration of cardiac performance
b. Arrest/ reversal of disease progression &
prolongation of survival

46. TREATMENT FOR CHF
a. Relief of congestive/ low output symptoms &
restoration of cardiac performance
Ionotropic
Drugs
Digoxin, Dobutamine/Dopamine,
Amrinone/Milrinone
Diuretics Furosemide, Thiazides
RAS inhibitors ACE inhibitors, AT1 antagonist
(ARBs)
Vasodilators Hydralazine, Nitrates, Nitroprusside
β blockers Metoprolol, Bisoprolol, Carvediol

47. TREATMENT FOR CHF
b. Arrest/ reversal of disease progression &
prolongation of survival
 ACE inhibitors
 AT1 antagonists [ARBs]
 β blockers
 Aldosterone antagonists: Spironolactone

48. TREATMENT FOR CHF
1. Diuretics:
 High ceiling diuretics [Furosemide] are used
to mobilize edema fluid from the body but,
resistance may develop
 Hence, a combination is used
thiazide/metazolone/spironolactone

49. TREATMENT FOR CHF
1. Diuretics:
 Thiazide alone has a limited role
i. Decrease the preload & improve ventricular
efficiency by reducing circulating volume
ii. Remove peripheral edema & pulmonary
congestion

50. TREATMENT FOR CHF
1. Diuretics:
 I.V. furosemide increases systemic venous
capacitance & produces rapid symptomatic
relief. Hence, i.v. furosemide + vasodilator
 Diuretics may cause activation of Renin-
Angiotensin-Aldosterone system which may
lead to adverse cardiovascular
consequences

51. TREATMENT FOR CHF
1. Diuretics:
 Chronic diuretic therapy may lead to
hypokalemia, alkalosis, carbohydrate
intolerance
 Mild heart failure due to ACE inhibitors/
ARBs + β blockers
 If fluid retention : Stop diuretic therapy

52. TREATMENT FOR CHF
2. RAS inhibitors:
 ACE inhibitors/ ARBs: Symptomatic &
disease modifying benefits by
retarding/reversing ventricular hypertrophy,
myocardial cell apoptosis & remodelling
 Prognostic benefits has been observed

53. TREATMENT FOR CHF
 c/i if renal failure
 Renal insufficiency
a. ACE inhibitors
b. Hydralazine

54. TREATMENT FOR CHF
3. Vasodilators:
i. Preload reduction
 Nitrates causes pooling of blood in systemic
capacitance vessels & reduce ventricular
end-diastolic pressure & volume
 Controlled i.v. infusion of GTN gives rapid
relief in acute left ventricular failure

55. TREATMENT FOR CHF
3. Vasodilators:
i. Preload reduction
 A marked lowering of preload [vasodilators +
strong diuretics] may reduce the output of a
failing heart whose performance is
dependant upon elevated filling pressure

56. TREATMENT FOR CHF
3. Vasodilators:
ii. Afterload reduction
 Hydralazine dilates resistance vessels &
reduces aortic impedance so that with
weaker ventricular contraction is able to
pump more blood; Systolic wall stress is
reduced
 Long term use is limited because: Marked
tachycardia, worsening of myocardial
ischemia and fluid retention

57. TREATMENT FOR CHF
3. Vasodilators:
i. Pre & afterload reduction
 ACE inhibitors/ ARBs are orally active
medium efficacy non-selective arterio-
venous dilators, while sodium nitroprusside
is high efficacy i.v. dilator with equal action
on two types of vessels
 Loop diuretic + i.v. ionotropic drug + sod.
nitroprusside

58. TREATMENT FOR CHF
4. β blockers:
 Non-selective β + selective α [carvedilol] in
mild to moderate CHF
 Depress cardiac contractility; benefit is
maintained over long term, mortality is
reduced

59. TREATMENT FOR CHF
4. β blockers:
 The benefits appear to be due to
antagonism of ventricular wall stress
enhancing, apoptosis & pathologic
remodelling
 t/t should be stopped during acute heart
failure

60. TREATMENT FOR CHF
5. Aldosterone antagonist: effects of
aldosterone
 Expansion of E.C.F. volume --- increased
cardiac preload
 Fibrotic changes in the myocardium worsens
the systolic dysfunction & pathological
remodelling
 Hypokalemia & hypomagnesemia may
increase the risk of ventricular arrhythmias &

61. TREATMENT FOR CHF
5. Aldosterone antagonist:
 Enhancement of cardiotoxic effect
 Spironolactone antagonize the above
mentioned effects of aldosterone
 ACE inhibitors + Spironolactone + Other
drug

62. TREATMENT FOR CHF
5. Aldosterone antagonist:
 Retard disease progression will reduce the
occurrence of death due to cardiac failure
 Low doses to avoid hyperkalemia

63. TREATMENT FOR CHF
6. Sympathomimetic Ionotropic Drugs:
i. Dobutamine [2-8 μg/kg/min]:
 Relatively selective agonist with ionotropic
action. (Given as i.v. infusion)
 It is preferred because it does not raise
systemic vascularresistance
 In acute heart failure accompanying MI,
cardiac surgery

64. TREATMENT FOR CHF
6. Sympathomimetic Ionotropic Drugs:
ii. Dopamine [3-10 μg/kg/min]:
 Increases the after load at higher rates of
infusion
 At low dose, selective renal vasodilatation
 Improves renal perfusion & g.f.r. ; restores
diuretic response

65. TREATMENT FOR CHF
6. Sympathomimetic Ionotropic Drugs:
ii. Dopamine [3-10 μg/kg/min]:
 Benefits are short lasting
 Tolerance develops & not useful for long
termt/t
 Used in cardiogenic shock due to MI

66. TREATMENT FOR CHF
7. Phosphodiesterase III inhibitors:
i. Amrinone:
 A selective phosphodiesterase III [PDE III]
inhibitor
 PDE III is an isoenzyme specific for
intracellular degradation of cAMP in heart,
blood vessels & bronchial smooth muscles
 PDE III inhibitors: Increases myocardial

67. TREATMENT FOR CHF
7. Phosphodiesterase III inhibitors:
i. Amrinone:
 Does not bind with Na+K+ATPase; action is
independent of tissue catecholamines &
adrenergic receptors
 Two action: +ve ionotropy & Direct
vasodilatation
 Increases cardiac index & left ventricular

68. TREATMENT FOR CHF
7. Phosphodiesterase III inhibitors:
i. Amrinone:
 Decreases peripheral vascular resistance;
left ventricular end diastolic volume &
pressure accompanied by tachycardia &
slight fall in BP
 Action starts in 5 mins

69. TREATMENT FOR CHF
7. Phosphodiesterase III inhibitors:
i. Amrinone [A/E]:
 Thrombocytopenia: Prominent
 Nausea, Vomiting, Abdominal pain, fever,
arrhythmias

70. TREATMENT FOR CHF
7. Phosphodiesterase III inhibitors:
i. Amrinone [Uses]:
 Orally active; but oral use in maintenance
therapy has been abandoned
 Short term i.v. use in severe & refractory
CHF

71. TREATMENT FOR CHF
7. Phosphodiesterase III inhibitors:
ii. Milrinone:
 Related to amrinone; similar in action, but
more selective for PDE-III
 10 times more potent
 Short acting; t1/2: 40-80 mins

72. TREATMENT FOR CHF
7. Phosphodiesterase III inhibitors:
ii. Milrinone [A/E]:
 Thrombocytopenia: Not significant
 Preferred over amrinone for short term use

73. THANK YOU……