A Global Problem HIGHLY LETHAL  5 yr Survival rate “50%” More M.I. cases now survive  More Incidence of CHF due to damaged myocardium Better options than before now available to treat CHF

1. Congestive Heart Failure
(CHF)
ANOOP KUMAR
ASSOCIATE PROFESSOR
DEPT. OF PHARMACOLOGY
ISF COLLEGE OF PHARMACY
MOBILE: 08587022854
WEBSITE: - WWW.ISFCP.ORG
EMAIL: anoopisf@gmail.com
ISF College of Pharmacy, Moga
Ghal Kalan, GT Road, Moga- 142001,
Punjab, INDIA
Internal Quality Assurance Cell - (IQAC)

2. • A Global Problem
• HIGHLY LETHAL  5 yr Survival rate “50%”
• More M.I. cases now survive  More
Incidence of CHF due to damaged
myocardium
• Better options than before now available to
treat CHF
What Happens in CHF 
Patho-
CHRONIC HEART FAILURE: 2

3. S=15-30 mm Hg
D= 0-5 mm Hg
S=90-140 mm Hg
D= 4-12 mm Hg
EDP=Av. 5 mm Hg
EDV=Normal 50 ml
Human Heart
•2 Pumps – in series
 Left & Right
•To Provide
Adequate Blood to
tissues
Venous
to Lungs
Arterial to
all other
organs-
incl.
Coronary
Physiology of HEART 3

4. Pathophysiology of CHF
Heart Failure defined as
“FAILURE of C.O. to MEET DEMANDS”
DECREASED
CARDIAC OUTPUT
(C.O.=S.V. x H.R.)
INCREASED
DEMAND
Thyrotoxicosis
Anemia
Beri Beri
4

5. STROKE VOLUME depends on
Extrinsic
Factors
Intrinsic
Contractility
Venous
(PRE-LOAD)
Arteriolar
(AFTER-LOAD)
Pathophysiology of CHF 5

6. 1. PRE-LOAD:
Defined as LOAD on Heart created by -
VOLUME of Blood entering the VENTRICLES
during DIASTOLE (& this volume must be
ejected during NEXT SYSTOLE) MORE the BLOOD
entering MORE the STRETCH of the Ventricular
Muscle  more Ventricular Volume EDP 
Work Stroke Volume (within Physiological
Limits Frank Starling’s Law)
☞Excess Pre-Load (e.g.Valve defects)
 HEART FAILURE
☞ VENODILATORS 
 PRE-LOAD  RELIEVE CHF
Pathophysiology of CHF 6

7. 2. AFTER-LOAD:
Defined as LOAD on the Contracting Ventricle exerted due
to -
RESISTANCE in ARTERIOLES against which HEART HAS TO
PUSH Blood during Systole (i.e. Peripheral Resistance – PR)
 MORE the PR  MORE the WORK-load on the
HEART  can be Handled only within Physiological Limits
(by a gradual Myocardial Hypertrophy)
☞Excess After-Load (e.g. Hypertension,
Arteriosclerosis)  HEART FAILURE
☞ ARTERIO-DILATORS  Pre-Load
 Relieve CHF
Pathophysiology of CHF 7

8. Pathophysiology of CHF 8

9. DECREASED CARDIAC OUTPUT
 RENAL BLOOD FLOW CAROTID SINUS
(Baro-receptor) Firing 
LESS INHIBITORY IMPULSES
 RENIN RELEASE
 ANGIOTENSIN II
 SYMPATHETIC
DISCHARGE

Heart
Rate
 Force of
Contraction
PRE-
Load (Veno
)

REMODELLING
 CARDIAC
Hyper-
trophy
Dilat-
ation
INITIALLY Compensatory
 in LV Ejection Fraction
LATER Decompen.
Stage   in LV
Ejection Fraction
Ej.
Fract.
Opposes
CHF
 AFTER-
Load
(Arteriolar
Constrict)

10. FORWARD FAILURE
EFFECTS
BACKWARD
FAILURE EFFECTS
 C. O.
 RENAL
FLOW
 VENOUS
PRESSURE
LUNGS
• Creps
• Dyspnea
LIVER
•Enlarged
•Palpable Less Urine
 Capillary
Filtration EDEMA
 Sympath
Activity
•  HR
•  PR
CONGESTION
 B. P.
FATIGUE
 Renin
 AngT-II
ALDO-
STERONE
 Na2 , H2O
Retention
MYOCARDIAL HYPERTROPHY
CARDIAC DILATATION
REMODELLING

11. HEART FAILURE can be –
• Acute: Myocardial Infarction (MI)
Acute Myocarditis (e.g. Viral)
• Chronic: as in Arteriosclerosis
Hypertension
Valvular Defects
Congenital Heart Defects
Myopathies
•Stages of CHF (N.Y. Heart Association):
•1. Minimal Dyspnea after Mild Exertion
•2. Dyspnea on Walking on Flat
•3. Dyspnea on getting in/out of BED
•4. Dyspnea while LYING IN BED
11

13. CARDIOTONIC GLYCOSIDES
(Cardenolides) - DIGITALIS
• DIGITALIS - Collective name of several Glycosides with
similar actions –but DIFFERENT Ph-Kinetics
• “Old Lady of Shropshire”  gave a Mixture of 18-20
Herbs for Rx of Dropsy
• Sir William Withering, a Physician (& a Botanist) studied the
Lady’s Herbal mixture & Published “AN ACCOUNT OF
FOXGLOVE” (Robinson, London,1785)
• *Identified PURPLE Foxglove as Active ingredient
*Identified types of Patients responding
*Standardized doses & preparations of Leaf
13

14. Sources of Digitalis - Many
•DIGOXIN  Digitalis lanata (White foxglove)
•DIGITOXIN D. lanata & D. purpurea
(Purple foxglove)
•Strophanthin  Strophanthus kombe
•Ouabain  S. gratus
14

15. Frank Starling Law & Effect of
Digoxin
5 10 15 20 25 mm
Hg Lt Ventr Filling Pressure
(EDP)
E
A
C
B
A
LtVStrokeWork(SV)
Symptoms of 
Venous Pressure
Inadequate
CO Effects
- Fatigue
Normal
Normal ≅
5 mm Hg
Compensated CHF
(but Raised Venous
Pressure
Symptoms)
CHF + Digoxin
Decompensated
CHF
15

16. Frank Starling Law & Effect of
Digoxin
A. Normal: in LV EDP (5 15 mm Hg)increased
Contractility   SV   CO within limits.
When EDP > 20 mm Hg  Heart can’t cope up
CO 
B. In CHF as SV  from ‘A’ to ‘B’ Signs of low CO
appear (Dyspnea, Fatigue) (Decompensated Heart
Failure)
C. Compensatory Mechanisms  SV from ‘B’ to ‘C’
 CO   Compensated CHF ; but Venous
Pressure remains  (5 to >15)  Neck Veins
engorge, Palpable Liver, Edema, Lung Creps
D. DIGITALIS Contractility SV  from ‘C’ to ‘D’
Carotid Buffer N firing again Symp. Tone
 BV Tone &  Vent EDP but Same SV & CO
16

17. Action Potential of Purkinje Fiber  Phase ‘0’
(Fast Upstroke)
•Fast Na+ Channels open
causing Fast Inward current
•Upstroke ends as Na+ channels
are rapidly inactivated
Net Ion Levels
inside Cell:
More Na+

18. Action Potential of Purkinje Fiber  Phase ‘1’:
Partial Repolarization
Initial Rapid Repolarisation is due to-
1) Inactivation of Na+
channels
2) Rapid opening & Closing of K+
channelsTransient outward
current
Net Ion Levels
inside Cell:
More Na+
&
Lesser K+

19. Action Potential of Purkinje Fiber  Phase ‘2’:
PLATEAU
Voltage Sensitive Ca++
channels open
 Slow Inward (Depolarising) Ca++
Current– Balancing Slow (Polarising)
K+
Outflow
Net Ions Level
inside Cell:
More Na+
Lesser K+
More
Ca++

20. Action Potential of Purkinje Fiber  Phase ‘3’:
REPOLARISATION
*Ca++
channels Close
*K+
channels open
Outward Repolarising K++
Current
Net Ions Levels
inside Cell:
More Ca++
More
Na+
Lesser K+
To be brought
to Normal by
Na+
/K+
-ATPase

21. Action Potential of Purkinje Fiber  Phase ‘4’:
FORWARD CURRENT
• Increasing Na+ permeability  Increasing
Depolarisation
• Next AP fires as threshold levels reach
• Myosite Cells don’t depolarise spontaneously

22. Phase 2
Ca++
Trigger Ca++
Ca++
3Na+
Ca++
3Na+
3Na+
2K+
3Na+
2K+
SR Ca++
Store
RY-R
+++++ACTIVATOR
Ca++
MYOFIBRILS CONTRACT
Na+
-K+
-ATPase (Na+
Pump) in Cardiac
Contractility
Na+-K-ATPase (Sodium Pump) –
•Corrects ionic changes of
Depolarisation-Repolarisation
•Maintains Resting Potential
•Occurs in many ISOFORMS in
Different Tissues;
•All Isoforms can be affected by
Drugs  Widespread Effects
22

23. Phase 2
Ca++
Trigger Ca++
Ca++
3Na+
Ca++
3Na+
3Na+
2K+
3Na+
2K+
SR Ca++
Store
RY-R
+++++ACTIVATOR
Ca++
MYOFIBRILS CONTRACT
Na+

Ca++

Activator
Ca++
CONTRACTILI
TY
D
I
G
I
T
A
L
I
S
Na+-
K+-
ATPase in Contractility MOA of DIGITALIS
23

24. contd
2. HEART RATE:
Digitalis  RATE - Specially in CHF
•  Contractility   CO Baro-receptor Reflex Restored
  Vagotonia &  Sympathotonia
• Digitalis Sensitizes Baro-receptors & RESETS it   
Parasympathetic effect on Heart
• Digitalis per-se at LOW Dose (1-2 ng/ml)  
Parasympathetic Tone 
• Baro-receptors More Sensitive
• SA Node (Pace Maker) More Sensitive to Ach
• Stimulates Vagal Center
 Bradycardia
 Affect Refractory Period & Conduction
 Sympathetic Activity
• Digitalis at HIGHER Dose: Direct (Extra-vagal)   of SAN
24

25. contd
3. REFRACTORY PERIOD & 4. CONDUCTION :
• Myocardial Tissue (Atria, Ventricles) &
• CONDUCTION Tissue (AVN, Purkinje fibers)
SHOW DIFFERENT RESPONSES to Digitalis
ANS mediated effects
Direct Digitalis effects
Property Atrial
Muscle
AVN, B. of
His/Purkin.
Fibers
Ventricle
Muscle
Refractory
Period
LD: -Vagal
HD: -Direct
-Vagal +
Direct
-Direct
(Less Vagal
Innervation)
Conduction
Velocity
LD: -Vagal
HD: -Direct
  PR
Interval
 - Direct
LD = LOW Dose; HD = HIGH Dose

26. contd
5. AUTOMATICITY: “Capacity to INITIATE a Heart
beat”
 At Therapeutic Dose (1-2 ng/ml)  Decreased
Due to  Vagal action & 
Sympathetic activity
 At HIGHER Dose: Increased Due to 
Sympathetic activity & Directly ( Cell Ca++)
 Atrial & Ventricular Arrhythmias
(TOXICITY)
26

27. contd
6. EXCITABILITY: “Capacity to RESPOND to a
Stimulus”
 At Therapeutic Dose (1-2 ng/ml)  Increased
 At HIGHER Dose: Decreased  Contributes
to Arrhythmias
7. ECG:
Early: ST depression T-wave inversion
Late: PR Interval  Prolonged QT Interval
 Shortened
27

28. contd
8. DIGITALIS & ELECTROLYTES:
 K+
:Digitalis binds to K+
-binding site of Na+
/K+
ATPase  Competitive Inhibition of Binding
of Each Other Hyperkalemia OPPOSES
Digitalis Action Hypokalemia POTENTIATES
Digitalis Action
 Ca++
: Accelerates Ca++
Overloading in Cells
Facilitates Digitalis–Induced
Automaticity & Excitability Arrhythmias
 Mg++
: Opposes Ca++
Actions HYPO-
Magnesemia  More Arrhythmias
28

29. Extra-cardiac Actions of Digitalis
A. VASCULAR: Indirect Effects due to  CO
 Blood Pressure (which is Low in CHF) Returns to
Normal   Coronary Blood Flow   Renal Blood
Flow  DIURESIS occurs  Relief of Pulmonary
Congestion
B. GIT: Nausea, Vomiting, Diarrhea Na+
/K+
ATPase  
of GIT   of CTZ (Hypothalamus)  Vomiting
(Adverse Reactions)
C. CNS : Visual & Psychic Effects (Adverse Reactions)
29

30. Dose of Digitalis
☞ Only DIGOXIN used (DIGITOXIN rarely).
Mild/Moderate CHF:
Slow Digitalisation & Maintenance: ORAL 0.125-0.75 mg
daily (Av. 0.25 mg)
Severe CHF (& with Atrial Flutter/Fibrillation):
Initial LOADING Dose I.V. 0.5-2 mg in 24 h
☞ INDICATORS of Digitalisation:
Bradycardia (Pulse) -to ~60/min Anorexia, Nausea
☞ Maintenance Dose: VARIABLE –Trial & Error  Desired
Plasma Levels ~ 1 ng/ml (0.5-1.5)
30

31. ADVERSE EFFECTS of DIGITALIS
MANY  LOW Therapeutic Index Drug
☞ CARDIAC ☞
Extra-CARDIAC
1. CARDIAC ADRs:
A) Disorders of IMPULSE FORMATION 
• Extrasystoles, Bigeminal Pulse
B) Disorders of IMPULSE CONDUCTION 
• Partial / Complete Heart Block
C) COMBINED Effects
Ventricular Tachycardia &
Ventricular Fibrillation
31

32. contd
2. EXTRA-CARDIAC ADRs:
A) GASTRO-INTESTINAL: COMMONEST
• ANOREXIA
• NAUSEA, VOMITING (also due to CTZ)
• Diarrhea
B) CNS & EYE:
COMMON: Headache, Fatigue, Drowziness
Confusion . Visual: Blurred Vision,
Yellow Vision (Xanthopsia),
Photophobia
RARE: Neuralgia, Paresthesia,
Optic Neuritis, Acute Psychoses,
Nightmares
C) MISCELLANEOUS: Gynecomastia
32

33. DRUG INTERACTIONS WITH DIGITALIS
• K+ Loss: (Diuretics)  More Digitalis Toxicity
• Beta-Blockers & Ca++ Channel Blockers:
More A-V Block
• Quinidine, Verapamil, Amiodarone & Erythromycin
  Digoxin levels   Toxicity
• Corticosteroids  Na+ retention  Antagonise the
beneficial effect of Digitalis in CHF
 K+ Loss   Digitalis Toxicity
• Antibiotics  in 10% patients, Gut
Bacteria normally destroy Digoxin  USE of
Antibiotics Destroys bacteria  Digoxin
Toxicity
☞ C.I.: Recent M.I., Ac. Myocarditis (
arrhythmia); Heart Block; Renal Dysfunction
(Use Digitoxin)

34. Therapeutic Uses of Digitalis
• Congestive Heart Failure (CHF)
• Acute Left Ventricular Failure
• Paroxysmal Supra-Ventricular Tachycardia
(PSVT)
• Atrial Flutter
• Atrial Fibrillation
34

35. 1. CONGESTIVE HEART FAILURE:
•Useful in Both Left & Right sided Heart Failure
•With other drugs- DIURETICS, VASODILATORS
•Digitalisation Dose: to be Individualized
MILD / MODERATE C.H.F:
 Digitalis may not be used at all as First Drug
 Diuretics & Vasodilators (ACE Inhibitors) may be
enough in most patients
 If not controlled by above DIGITALIS MUST
 Digitalis alone CORRECTS Decompensation &
Improves “Exercise Tolerance (ET)”
 Digitalis may be used for INITIAL CONTROL, not for
Maintenance Rx – but ET may worsen again after
stopping Digitalis
Severe CHF / CHF with ATRIAL FIBRILLATION: Digitalis
MUST be used
35

36. contd:
STATUS:
• Digitalis toxicity warrants use of other drugs in
Mild/Moderate cases
• However, Digitalis-
Reduces Episodes of Decompensation
Reduces Heart-Failure –related Mortality
But does not reduce Overall Mortality in CHF
• DIGOXIN GIVEN Initially I.V., Then Oral With  Oxygen
 I.V. Morphine, Diuretic (Furosemide)I.V.
Theophylline Other vasodilators (GTN, Nitroprusside)
2. Acute Left Ventricular Failure (LVF):
36

37. PSVT: SPONTANEOUS, COMMON, EPISODIC (PAROXYSMS)
• ATRIAL RATE 150-200/MIN WITH 1:1 A-V CONDUCTION
• DOC: *ADENOSINE TO ABORT ATTACK *DIGOXIN TO
PREVENT RECURRENCE  VAGAL TONE
CONDUCTION IN SAN  CAN BE GIVEN IV TO ABORT ATTACKS
ATRIAL FLUTTER : 200-350/MIN, SYNCHRONOUS RATE
• VARIABLE DEGREE OF A-V BLOCK  VENTR. RATE FASTER
• DIGOXIN   A-V CONDUCTION   VENTRICLE RATE
• DIGOXIN ALSO  INTRA-ATRIAL COND FLUTTER MAY CHANGE TO
FIBRILLATION  NOW WITHDRAW DIGITALIS SINUS RHYTHM
RETURNS IN 50% CASES
FIBRILLATION: DIGOXIN – DRUG OF CHOICE A-V BLOCK;
ATRIAL RATE NOT AFFECTED
3. Paroxysmal Supra-Ventricular Tachycardia
4. Atrial Flutter & Fibrillation
37

38. Other INOTROPIC Drugs
INAMRINONE(Imrinone) – {INO-DILATOR}
 Phosphodiesterase : Heart & BVPDE-3 isoform
 PDE-3    cAMP Contractility INO
 CO  (like Theophylline)
 Also BV dilatation  PR  DILATOR
 No effect on Na+
-K+
ATPase
ADRs: Nausea, Vomiting; Arrhythmia; Liver damage &
Thrombocytopenia
MILRINONE: 10x more Potent; More Selective; Shorter
Duration; Less ADRs
 Used IV for Severe Refractory CHF cases
Beta-1 AGONISTS: Dobutamine for Short Term use (Long
Term use  ?? Increase Workload of heart)
38

39. II: VASODILATORS in CHF
1. Drugs Lowering PRE-Load
2. Drugs Lowering AFTER-Load
3. Drugs Lowering BOTH
39

40. VASODILATORS in
CHF
In CHF:
 PRE-LOAD (Volume that fills Ventricles during
Diastole) is Increased due to OVER-FILLING
 Increased Work Load
 AFTER-LOAD (Peripheral Resistance that has to
be overcome by Heart to PUMP BLOOD during
SYSTOLE) is also Increased due to :
 Cardiac Output in CHF
Reflex Sympathetic Stimulation
Causing
*Tachycardia
*Vasoconstriction ( PR)
* Renin-Angiotensin Activity
 Increased Work Load
40

41. VASODILATORS in CHF
• To  PRE-LOAD Veno-dilators
Nitrites/Nitrates (Isosorbide di-NO3)
• To  AFTER-LOAD Arteriolar-dilators
Hydrallazine - Reflex Tachycardia,
SLE, Edema
Minoxidil
Calcium Channel Blockers
(Cardiac Depression +++)
K+
Channel Openers (Nicorandil)
• To  both PRE & AFTER loads
Arterio-Venous dilators
*ACE- Inhibitors- Ramipril
*AT1 -Antagonists: Losarten
*Alpha-1 Blockers: Prazosin
*Na- Nitroprusside

42. VASODILATORS & Other drugs in CHF
Angiotensinogen
Angiotensin-I
ANGIOTENSIN-II
Aldosterone
Na+
& H2O
Retention
Renin
Angiotensin
Converting
Enzyme (ACE)
Kininogen
BRADYKININ
Inactive BK
NO, PGs
VASODILATION
Kallikrein
Vaso Sympathotonia
•Cardiac 
• Renin
•Vaso
Spironolactone
DIURETICS
ACE-
Beta
Blockers
AT- R
Blockers

R


43. ACE-Inhibitors (e.g. Ramipril) in CHF
• Most Commonly Used Vasodilator in CHF
• Formation of ACE-product (AT- II) Reduced
 Effects of AT REDUCED
– Aldosterone Production  Na+
/H2O Retention
– Vasoconstriction
– Sympathotonia
– Myocardial Remodelling
• BK degradation 
 BK Effects Potentiated  Vasodilation
• Both Arteriolar & Venous Dilation occur
 Reduced PRE- & AFTER-load  Increased C.O.
• Reduced Long-term Mortality from MI, Stroke
• ADRs: Postural Hypotension, Dry Cough,
Hyperkalemia

44. DIURETICS in CHF
 ACT in 2 WAYS 
1. Excrete Na+
/H2O    VOLUME
OVERLOAD   PRE-Load & AFTER-
Load
2. LONG-TERM Use  Arteriolar Reactivity (due to 
Na+ content in arterial smooth muscle) Arteriolar
Dilation   AFTER-LOAD
  Congestion (Pulmonary), Edema &  C.O.
 Furosemide (Loop Diuretic) 20-40mg /d  Fast, Potent,
Shorter Acting  Used in Severe cases
 Thiazides Moderate Efficacy, Slower, Longer action
in Mild/Moderate cases
 ADRs: Hypokalemia mainly, but is lesser if ACE  also
44

45. BETA BLOCKERS in CHF
• Traditionally Beta Blockers were C.I. in CHF
• Current AIM of their use: to COUNTERACT effects
of Compen. Sympath , & raised NE levels
• MUST be STARTED in VERY LOW DOSES 
Gradually Increased
• Drugs used  Bisoprolol, Metoprolol, Carvidelol
• Bisoprolol: Start 1.25 mg/day  to 10 mg/d over
12 wks UNDER CAREFUL MONITORING
• Decreases Mortality in Stable CHF patients
Possible Mechanisms:
• Attenuate Adverse Effects of raised CA levels on
Myocardium–including Apoptosis
 Heart Rate
• Up-regulates β-receptors that get -regul. in CHF
 Myocardial Remodelling (by  CA-induced
Mitogenesis)

46. SPIRONOLACTONE in CHF
ALDOSTERONE Role in CHF:
 Na+
& H2O retentionEdema  Cardiac Load
K+
& Mg++
Loss  Risk of Arrhythmias & Sudden Cardiac death
 NE-Uptake  More NE-effects  Myocardial Remodelling &
Arrhythmogenesis
 Baro-receptor Sensitivity   Parasympath. Tone   Risk of
sudden Cardiac Death
Fibroblast ProlifernCardiac Fibrosis  Remod.
Alteration in Na+
- Channel Expression   Excitability &
Contractility of Myosites
SPIRONOLACTONE: Ald-R Blocker12.5-25 mg OD Opposes all above
effects + A Weak DIURETIC
Increases Survival on its own & Summates with Survival--Effects of
β-Blockers & ACE 
46

47. Rx of
C.H.F.
START Rx with ACE-
Control of Signs/Symptoms
No
Continue with
ACE 
Loop Diuretic
Beta-blocker
Add Spironolactone
ADD in following Order-
Digoxin I.V. Frusemide +
Metolazone Short Term
INOTROPE (Dobutamine)
or PDE-3  (Milrinone)
Add LOOP DIURETICS + β -Blockers
Yes
Continue Rx
Control of Signs/SymptomsNo Yes
Control of Signs/Symptoms
No Yes
Continue with
ACE 
Loop Diuretic
Spironolactone

48. THANKS
48