1. Drugs Used in the
Management of
CONGESTIVE HEART
FAILURE

3. Aims and Objectives
Congestive Heart Failure is one of the
common causes of death and disability,
and is among the syndromes
commonly encountered in clinical
practice.

4. Decreased cardiac out-put, a salient
feature of heart failure, is associated
with edema, ascites, pericardial and
plural effusion, reflex sympathetic over
activity, oliguria and dyspnoea.

5. Different classes of drugs i.e. Diuretics,
Vasodilators, Renin Angiotensin system
blockers and β-Adrenergic agonists and
antagonists, which are used in the
management of congestive heart failure, will
be discussed.

6. This lecture deals with various aspects of
the Pharamacology of Digoxin and related
drugs (positive inotropic agents).

7. The role of other classes of drugs will be
briefly reviewed in context of the treatment of
heart failure.
_______________________________________
ETIOLOGY
Hypertension, Coronary Infarction; Congenital
Heart Disease. Cardiomyopathy

8. NOTE
Before initiating drug therapy for Heart
Failure, it is important to eliminate or mitigate
potentially reversible causes of cardiac
dysfunction i.e., Myocardial Ischemia, Valvular
heart disease, Hypertension, Intracardiac or
Intravascular Shunts, Cardiac Arrhythmias,
and Hyperthyroidism.

9. Cardiovascular
Consequences
of Heart Failure

10. PRELOAD
AFTERLOA

11. Signs and Symptoms
REDUCED STROKE VOLUME
(MAIN FEATURE)
1. BACKGROUND SYMPATHETIC
ACTIVITY INCREASED
I. Tachycardia
II. Constriction of peripheral arterioles and
veins (3 to 4 fold increase in peripheral
resistance)
2. OLIGURIA

12. 3. FLUID AND WATER RETENTION
i.
Peripheral Edema
ii. Ascities
iii. Pleural and pericardial effusion
4. PULMONARY EDEMA
i.
Dyspnoea
ii. Cyanosis
iii. Paroxysmal nocturnal dysponea

13. 5. VEINS
i.
Engorged
ii. Pulsations are visible in the jugular
veins in the neck

14. HEART
FAILURE:
Cyanosis,
Engorgement
of juglar veins,
enlargement of
liver, ascites,
dependent
edema,
elevated

15. WHAT TO DO UNDER THESE
CONDITIONS?
 INCREASE THE FORCE OF MYOCARDIAL
CONTRACTION
 DECREASE THE HEART RATE
 DECREASE THE AFTERLOAD
 DECREASE THE PRELOAD
 INDUCE DIURESIS

16. CLASSIFICATION
OF
DRUGS

20. DIGOXIN

22. CARDIAC-GLYCOSIDES
 Source
Digitalis purpurea (purple fox glove)
Digitoxin, Gitoxin, Gitalin
Digitalis lanata
Digoxin, Digitoxin, Gitoxin
Strophanthus kombe
Strophanthin, a glucoside
Strophanthus gratus
Ouabain:(Shortest acting, given I/V in emergency)

23. These cardiac-glycosides are also known as
cardinolides

Apart from digitalis, strophantus other plants
including, See onion (squill), Lilly of the valley,
Milk weed or also resource of cardiac glycosides

Chinese toad skin’s glands also secrete these
Glycosides (Bufadienolides).

25. MAJOR EFFECTS
 FORCE OF VENTRICULAR
CONTRACTION
 HEART RATE
DIGOXIN, THEREFORE, PRODUCES
POSITIVE INOTROPIC AND NEGATIVE
CHRONOTROPIC EFFECTS

26. Effects of Digoxin
in Congestive Heart Failure
FORCE OF VENTRICULAR CONTRACTION AND CARDIAC
OUTPUT INCREASE
I.
BACKGROUND SYMPATHETIC ACTIVITY
DECREASED
i.
HEART RATE
ii.
VASOMOTOR TONE
iii.
PRELOAD AND AFTERLOAD

27. II. RENAL CIRCULATION IMPROVED
i. RENIN, ANGIOTENSIN II, ALDOSTERONE
ii. Na+ and H2O RETENTION
iii. DIURESIS

28. III. HYDROSTATIC PRESSURE IN VEINS
DECREASED AND THE EXTRA FLUID
RESPONSIBLE FOR EDEMA IS DRAWN
BACK IN TO GENERAL CIRCULATION
PERIPHERAL EDEMA, ASCITIES AND
PULMONARY EDEMA

29. Negative Chrontropic Action
of Digoxin
I. CARDIAC OUTPUT INCREASED,
THEREFORE, DECREASE IN
BACKGROUND SYMPATHETIC
ACTIVITY

30. II. STIMULATION OF VAGAL CENTER
III. DEPRESSION OF SA NODE
IV. SLOWING OF AV CONDUCTION
___________________________________
INDIRECT EFFECT: I and II
DIRECT EFFECT: III and IV

31. DIRECT EFFECTS
1. SA NODE
Spontaneous activity (Automaticity)
2. AV NODE
i.
ERP
ii. Conductivity
iii. Excitability

32. 3. HIS PURKINJE SYSTEM
i. Excitability
ii. Automaticity
iii. ERP
iv. Conductivity
Ectopic Beats, Ventricular Tachycardia,
[SIDE EFFECTS]

33. 4. AURICLES
i. ERP
ii. Can lead to Fibrillations
iii. Flutter  Fibrillations

34. 5. VENTRICLES
ERP
EXCITABILITY: - Effect variable,
usually increases
Ventricular Arrhythmias

35. POSITIVE INOTROPIC
ACTION
(MECHANISM)
INHIBITION of Na+ / K+ ATPase

38. THERAPEUTIC USES
CONGESTIVE HEART FAILURE
ATRIAL FIBRILLATION
Even in the absence of congestive heart
failure, Digitalis may be indicated in many
cases of atrial fibrillation. The inappropriately
rapid ventricular rate in this disorder results
in great discomfort.

39. The aim of Digitalis therapy is to reduce the
ventricular rate.
It rarely halts atrial fibrillation. The dosage
should be adjusted to maintain the
ventricular rate in the range of 60-80/mint.
OTHER DRGUS: Propranolol, Verapamil

40. ATRIAL FLUTTER

To decrease the ventricular rate
AV Node:

ERP
Digitalis may convert flutter in to
fibrillation. This too facilitates control of
ventricular rate

41. 
If such conversion to fibrillation occurs,
withdrawal of Digitalis may result in the
return to Sinus Rhythm*.
*Danger of Embolism. A thrombus in auricles
may dislodge due to good contraction

42. PAROXYSMAL TACYHCARDIA
Atrial and AV nodal paroxysmal tachycardias
are the most common tachyarrhythmias next
to atrial fibrillation.
Digitalis is successful in terminating this
type of tachycardia by virtue of its vagal
effects (I/V administration).

43. Note: 1. Digoxin therapy is indicated in Severe Left
Ventricular Systolic Dysfunction.
2. Patients with mild to moderate heart failure
will often respond to ACE inhibitors and
Diuretics, and do not require Digoxin.

44. 3. It is no longer a first line agent in the
treatment of C.H.F. Reserved for patients
who are in atrial fibrillation or patients with
sinus rhythm who remain symptomatic
despite treatment with other drugs.

45. ADVERSE EFFECTS
HEART
Cardiac arrhythmias which under certain
circumstances are life threatening.
Sinus bradycardia, AV–block, Atrial
Fibrillation, Ventricular Extra Systoles,
Ventricular Fibrillation.

46. CNS DISTURBANCES
Characteristically altered color vision
(Xanthopsia). White borders or halos may
appear on dark objects.
Fatigue, disorientation, hallucinations,
delirium.
G.I.T
Anorexia, Nausea, Vomiting, Diarrhea.

47. OTHER EFFECTS:
Gynecomastia due to estrogenic effects; skin
rashes; hypokalaemia.
________________________________________
Delirium:- Fluctuating impairment of
consciousness and disorientation
Hallucinations:- False perceptions having no
external stimulus (visual, auditory)

51. TOXICITY MANAGEMENT
1) Discontinue the drug
2)Ventricular arrhythmias: Lidocaine, Phenytoin
3) AV conduction delay:
Atropine
4)Hypokalaemia:
K+

52. 5)Anti-digoxin Immuno Therapy: Injection (IV)
of antibody (fab) fragments that bind with,
and inactivate Digoxin.
________________________________________
CAUTION:- Diuretics which produce
hypokalaemia

53. Comparison
of
Digoxin
and
Digitoxin

54. Increased
Digitalis
concentration may
occur during
concurrent
therapy
1. Amiodarone
2. Erythromycin
3. Quinidine
4. Tetracycline
5. Verapamil
ENHANCED POTENTIAL FOR CARDIOTOXICITY
1. Corticosteroids
2. Thiazide
diuretics
3. Loop diuretics
Drug interactions with DIGOXIN

55. OTHER
INOTROPIC
AGENTS

56. I ) β-ADRENERGIC AGONIST
(Dobutamine)
ATP
cAMP
+
cAMP
Phosphorylation of Ca2+ Channels

57. II. PHOSPHODIESTARASE INHIBITORS
(AMRINONE; MILRINONE)
cAMP
AMP

58. Phosphodiesterase
Inhibitors

59. OVERVIEW

62. Steps in the Treatment of
Congestive Heart Failure
1. Reduce work load of the heart
a) Limit activity level
b) Reduce weight
c) Control hypertension
2. Restrict sodium
3. Restrict water (rarely required)

63. 4. Give ACE inhibitor or Digitalis *
5. Give β-blockers to selected patients
6. Give vasodilators
* Many clinicians use ACE inhibitors before
Digitalis.

64. Vasodilators for Use in Congestive
Heart Failure
DRUGS
Hydralazine
SITE OF DILATING
ACTION
Arterioles
Nitrates
Veins and Venules
Captopril and other
ACE inhibitors,
Angiotensin receptor
blockers
Both arterioles and
Veins

65. DRUG
PERLOAD
AFTERLOAD
I. Nitrovasodilators
Nitroglycerin
Isosorbide dinitrate
+++
+++
+
+
II. ACE inhibitors
Captopril
Enalapril
++
++
++
++
++
++
++
++
III. Angiotensin receptor
antagonist
(losartan)
IV. Phosphodiesterase
inhibitor
(Amrinone)

66. DRUG
V. Direct Vasodilators
(Hydralazine)
PERLOAD
AFTERLOAD
+
+++
+++
++
++
++
+
+++
VI. Adrenergic receptor
antagonists
Prazosin (α 1 antagonist)
Labetalol(α 1;
Nonselective β)
VII. Ca ++ channel blockers
Nifedipine

68. QUESTIONS

69. 1.
The drugs that have been found to be
least useful in congestive heart failure:
a)
Na+/K+ ATPase inhibitors
b)
Calcium channel blockers
c)
β-adrenoceptor agonists
d)
β-adrenoceptor antagonists
e)
ACE inhibitors

70. 2.
The mechanism of action of digoxin is
associated with
a)
Decrease in calcium uptake by the
sarcoplasmic reticulum
b)
Increase in ATP synthesis
c)
Modification of the actin molecule
d)
Increase in systolic cytoplasmic calcium
levels
e)
Blockade of cardiac β adrenoceptors

71. 3.
A 65- year old woman has been admitted to
coronary care unit with a left ventricular
myocardial infarction. If this patient develops
acute severe heart failure with marked
pulmonary edema, which one of the following
drugs would be most useful?
a)
Digoxin
b)
Furosemide
c)
Minoxidil
d)
Propranolol
e)
Spironolactone

72. 4.
Which of the following is most likely to
contribute to the arrhythmogenic effect of
digoxin?
a)
Increased vagal discharge
b)
Increased intracellular calcium
c)
Decreased sympathetic discharge
d)
Increased extracellular magnesium
e)
Increased extracellular potassium

73. Drugs used in chronic heart failure







Loop diuretics, for example furosemide.
Angiotensin-converting
enzyme
inhibitors
(e.g.
ramipril).
Angiotensin II subtype 1 receptor antagonists (e.g.
valsartan, candesartan).
β-adrenoceptor
antagonists
(e.g.
metoprolol,
bisoprolol, carvedilol), introduced in low dose in
stable patients.
Aldosterone
receptor
antagonists
(e.g.
spironolactone, and eplerenone).
Digoxin especially for heart failure associated with
established rapid atrial fibrillation. It is also indicated in
patients who remain symptomatic despite optimal
treatment.
Organic nitrates (e.g. isosorbide mononitrate) reduce
preload, and hydralazine reduces afterload. Used in
combination, these prolong life in African-Americans.

74. 
Approach
Recommendations
Sympto ms &
Signs of HF:
Fatigue (lo w card iac output), SOB,↑ VP, ra les , S3, ede ma , rad iologic conges tion,
J
cardio megaly. Elevated BNP. CX R to r/o infection, inters titial lung dis eas e & PPH
Ejec tion fr acti on
(obt ain ech o or
LV gate d s tu dy)
≤
40% = s ys tolic dys function
40-55% = mixed s ys tolic and dias tolic dys function
≥
55% = d ias tolic dys function - treat u nderlying dis or der (HPT/ is chaemia/pericard ial
cons triction/res trictive CM (card io myopathy)/infiltrative d is orders )
 Is che mic -CM HP T-CM  Valvu lar HD-CM (A S/AR/MR)  Metabolic :
hyper/hypo thyroidis m / he mochro matos is /pheochromocytoma  To xins : Alcohol/
anthracyclines /cocaine/amphetamines Vira l CM Id iopathic Dilated CM  Other:
Cons ider e tiolog y
Identi fy triggers
Acute -s udden ons et
Chr onic-gradual ons et
Is chaemia, arrhythmia , infection, pulmonary e mbolis m, acute valvula r pathology
Anemia , thyrotoxicos is , non-compliance, diet, Rx e .g. NSAID’s
Treatment:
Correct tr iggers and precipitants of acute and chronic Heart Failure
Ge neral me as ures
•
Low s odium d iet
•
D/C s moking
•
Regular e xe rcis e/activity
•
Treat lipid abnor ma lit ies
•
Treat is chemia
•
Treat and control diabetes
•
Control hypertens ion
•
Identify & Rx depres s ion
Diuretics -titrate to euvolemic s tate
•
Maintain Ideal Body Weight (dry weight = J VP norma l / trace pedal edema )
•
Furos emide 20 - 80 mg OD-BI D
•
HCT/Zaro xo lyn for refractory conges tion
Digoxin -for pers is ting s ymptoms in NS R (s ystolic dys function) or s ymptoms and rate
control in Afib. Dos e: 0.125 mg – 0.25 mg (Lower dos e in elderly: 0.0625 mg )
AC E In hi bi tor s - Ge n e ral Gu id el in e :
AC E In hi bi tor s - Ge n e ra l Gu id e l in e:
•
Tr a n dol a pr i l 1 ⇒ mg mg O D ‡
4
•
Tra n dol a pri l 1 ⇒ mg mg O D ‡
4
St a rt lo w a n d t it rat e t o t h e t a rg et d os e
St a rt lo w a n d t it ra t e t o t h e t a rg e t d os e
•
* Qu in ap ri l 10 mg ⇒ 0 mg
4
•
* Qu in a p ri l 10 mg ⇒ 0 mg O D
4
OD
u s ed in t h e clin ic a l t r ia ls o r t h e
u s ed in t h e c lin ic al t r ia ls o r t h e
•
* Ci la za p r il 0 .5 mg ⇒ 0 mg O D
1
* Ci la zap r il 0 .5 mg ⇒ 0 mg O D
1
MA X IMU M TO L ER A T ED DOS E:
MA X IMU M TO L ER A T ED DOS E:
•
* Fo s in o p ril 5 mg ⇒ 0 mg O D
4
* Fo s in o p ril 5 mg ⇒ 0 mg O D
4
•
Ca pt o pri l 6. 25 -1 2. 5 mg ⇒
•
Ca pt o pri l 6. 25 -1 2. 5 mg ⇒
•
*Perindopril 4 mg ⇒ mg O D
8
⇒ mg O D
8
5 0 mg B ID -TI D
5 0 mg B ID -TI D
* No larg e s ca le o u t c o me t ria ls
* No la rg e s ca le o u t c o me t ria ls
•
En al a pr i l 2. 5 mg ⇒0mg B ID†
10
•
En al a pri l 2. 5 mg ⇒ mg B ID†
1
† So LVD/ X -So LVD § A IR E / A I R EX ‡T RA C E
† So LVD/ X -So LVD § A IR E / A I R EX ‡T RA C E
•
Ra mi pri l 2. 5 mg ⇒ mg BI D §
5
•
Ra mi pr i l 2. 5 mg ⇒ mg BI D §
5
Cons ider IS DN 5-40mg QID+Hydrala zine 10•
Li s i no pri l 2 .5 mg ⇒0- 40 mg OD
3
•
Li s i no pr i l 2 .5 mg ⇒0- 40 mg OD
3
75mg QID for ACE-I/ARB intole rance VHeFT
Angiotens in II rece ptor antagonis ts (ARB ’s )
•
A C E- In h ib it o rs re ma in f irs t l in e t h erap y
•
A C E- In h ib it o rs re ma in f irs t l in e t h e ra p y
•
A RB ’s in d ic a t e d in A C E- I in t o lera n t p a t ie n t s
A RB ’s in d ic at ed in A C E- I in t o lera n t p a t ie n t s
•
(C HA RM c an d es a rt an 16-3 2 mg O D ) ( Va l- He FT / VA LIA NT v a ls a rt an 1 60 mg BI D)
(C HA RM ca n d e s a rt a n 16-3 2 mg O D ) ( Va l- He FT / VA LIA NT v als art a n 1 60 mg BI D)
S ymptomatic therapy
Therap y to
impro ve p ro gnosis
Cons ider A CE-I/A RB
Cons ider A CE-I/A RB
combinat ion in A CE-I
combinat ion in A CE-I
and /or βblocked
and /or βblocked
p at ients w it h w ors ening
p at ients w it h w ors ening
H F or hosp it aliz at ion
H F or hosp it aliz at ion
Cauti on:di abetics/renal
di sease /elderl y/ NSAIDs
& COX-2 inhi bitors
Anti-coagulant
anti-p latelet Rx
Beta-bl ock ers -Add Beta-blocker* to ACE-inhibitor/diuretic/ +/- d igo xin in s table Clas s
II-IV CHF/ LVEF ≤
40% (*No outcome data for other beta-blockers )
•
Bis oprolol* 1.25 →
10 mg OD (CIBIS II T rial)
•
Carvedilol* 3.125 mg BID →
25 mg BI D (50 mg BI D if we ight > 85 kg)
•
Metoprolol* 12.5 mg BID →
75 mg BID (M ERIT Tr ial)
Aldos terone antagonist (follow K/ Cr in 3-7 days /↓
furos emide to avoid a zotemia)
•
Spironolactone 12.5-25 mg OD added to ACE-inhib itor/diuretic/+/- digo xin in s table
Clas s III-IV CHF/ LVEF ≤35%/CR<220/K<5.0 ( RA LES Trial)
ASA if CA D ( ↓
dos e to ↓ CE inhib itor interaction)
A
Coumadin for Afib, LV thro mbus , ↓
LVEF ≤20%, DVT or pulmonary e mbolis m
Duration of A/C therapy: Indef inite fo r Afib/recurring s ys temic T E or DVT/ P E
Conside r Inte rnal Me dicine /Cardiology or He art Failure Clinic re fe rral for initiation/titration of β blocker. Consi der EPS
re ferral for symptomatic sustaine d or non-sustaine d ve ntricul ar arrhythmia (LVEF 30-40 %) or AICD: Pri or MI/C AD (LVEF ≤
30% with IVCD ≥ 0.12 se c: MADIT II) CHF: (NYH A II- III
& LVEF <35 % S CD-He FT) Cardi ac Re synchroniz ation
Therapy(CRT):(NYH A Class III- IV wi th re duced e je cti on fracti ons; LVEF < 35 %; Q RS duration ≥0.13 wi th IVCD or LBBB:
MIRAC LE / MUS TIC) or both CRT /AICD: (NYH A III-IV;Q RS ≥0.12:CO MPANIO N). EECP/Transplant for re fractory CHF.