This document provides information on the treatment of congestive heart failure (CHF). It begins by defining CHF as a condition where the heart is unable to pump enough blood to meet the body's needs. It then discusses various contributing diseases and clinical features of CHF. The treatment of CHF involves restoring cardiac performance and arresting disease progression. Positive inotropic drugs discussed include cardiac glycosides like digitalis, beta-adrenergic agonists, phosphodiesterase inhibitors, and calcium sensitizers. Other treatments include diuretics, vasodilators, RAS inhibitors, and beta-blockers. The mechanisms of action and effects of cardiac glycosides like digitalis are explained in detail.

1. TREATMENT OF
CONGESTIVE HEART
FAILURE (CHF)
PREPARED BY-
MONIKA BHARDWAJ

2. CONGESTIVE HEART FAILURE
(CHF)
 Congestive heart failure (CHF) is a condition
in which the heart is unable to pump sufficient
blood to meet the needs of body.
 CHF can be increased workload imposed on
the heart.

3. CHF
 CHF = when the heart muscle weakens &
enlarges loss of ability to pump blood through
the heart & into the systemic circulation = heart
failure (or pump failure).
 peripheral & lung tissues become congested =
CHF

4. CHF
 CHF is accompanied by abnormal increases
in blood volume and interstitial fluid; the heart,
veins, and capillaries are therefore generally
dilated with blood.
 Hence the term “congestive” heart failure,
since the symptoms include pulmonary
congestion with left heart failure, and
peripheral edema with right heart failure.

5. Common Diseases
Contributing to CHF
- Cardiomyopathy
 Hypertension
 Myocardial ischemia & infarction
 Cardiac valve disease
 Coronary artery disease

6. Clinical Features of CHF
 Reduced force of
cardiac contraction
 Reduced cardiac
output
 Reduced tissue
perfusion
 Oedema (congestion)
 Increased peripheral
vascular resistance

7. Congestive Heart Failure Events

8. CHF
 CHF can be left sided or right sided
 Cardiac glycosides = digitalis glycosides
 inhibits the Na - K pump inc. intracellular Ca
cardiac muscle fibers contract more efficiently
 Digitalis = 3 effects on the heart
1) +se inotropic action (inc. myocardial contraction)
2) -se chronotropic action (dec. HR) #)
3) -se dromotropic action (dec. conduction of the
heart cells)

9. TREATMENT OF CHF
Classification
1. Relief of congestive/low output symptoms
and restoration of cardiac performance.
a. Positive inotropic drugs
-Cardiac glycosides- Digitalis
-β-adrenergic agonists (New dopamine receptor
agonist)- dobutamine/ Dopamine
-Phosphodiesterase inhibitors- Amrinone/Milrinone.
-Calcium sensitizers
b. Diuretics
-Furosemide, thiazide

10. Classification
c. Vasodilators
-Nitryl-vasodilators
-Hydralazine
-Nitropruside
d. RAS inhibitors
-Antiotensin converting enzyme inhibitor
-AT1 antagonist
e. β-receptor blocker
-metoprolol, carvedilol, nebivolol, bisoprolol

11. Classification
2. Arrest/Reversal of disease progression and
prolongation of survival
-ACE inhibitors
-ARBs
-β blockers
-Aldosterone antagonist K-sparing diuretics
Spironolactonee
Eplerenone

12. History and Sources of
Cardiac Glycosides
• Foxglove – William Withering (1785)
• Naturally in Plants and animals – Poisons
1. Cardenolides (Cardanolides):
1. Digitalis purpurea – Digitoxin, Gitoxin and Gitalin
2. Digitalis lanata - Digitoxin, Gitoxin and Digoxin
3. Strophanthus gratus – Ouabin
4. Thevetia nerifolia – Thevetin
5. Convallaria majalis – Convallotoxin
2. Bufadienolides:
• Bufo vulgris - Bufotoxin

13. CARDIOTONIC DRUGS
Cardiac glycosides
O
OOH
CH3
CH3
H
O
C18 H31O9
12
A
C
B
D
17
3
Digitoxin
Digoxin
= H at 12 C
= OH at 12 C
Sugars- 3 mols. of digitoxose
Aglycones
Unsaturated lactone
steroid nucleus
Convey the
pharmacological
activity
Convey cardiotonic
activity
Modulate potency and
pharmacokinetic distribution

14. Digitalis MOA – contd.
1. Depolarization
2. Release Ca++
3. Contraction
4. NCX
5. Blocked
6. Na+ more
X Ca++
Ca++<<
Depleted K+

15. Molecular mechanism of the +ve
inotropic effect
 Inhibition of the Na+-K+- pump (Na+-K+-ATPase) on the
cardiac myocyes sarcolemma
 A gradual increase in intracellular Na+ ([Na+]i) and a
gradual small fall in [K+]i
 An inhibitory effect on the non-enzymatic Na+- Ca2+-
exchanger, which exchanges extracellular Na+ for
intracellular Ca2+
 The net effect is the increase in intracellular Ca2+ [Ca2+]I
 The increased [Ca2+]I stimulates more Ca2+ ions to
influx via voltage gated Ca2+ channels and increase the
storage of Ca2+ into sarcoplasmic reticulum available
for release upon arrival of an action potential

16. Pharmacological Actions of
Digitalis Glycosides
 Inotropism. Digitalis exerts positive inotropic effect
both in the normal and failing heart via inhibition of
Na+-K+-ATPase at cardiac sarcolemma.
Cardiac output (CO)
 Digitalis increases the
stroke volume and hence
the CO
 No increase in oxygen
Consumption
 Decreased EDV

17. Pharmacological actions of Digitalis - HEART
Overall actions:
1. Direct Effects - Myocardial contractility and
electrophysiology
2. Vagomimetic effect
3. Reflex action – alteration of hemodynamic
4. CNS effects – altering sympathetic activity
Force of Contraction:
 Dose dependent increase in force of contraction in failing
heart – positive inotropic effect
 Increased velocity of tension development and higher peak
tension
 Systole is shortened and prolonged diastole

18. Contd.----
Normal
Digitalis
Heart failure
Strokevolume
Arterial impedance

19. Contd. ----
Tone:
• is Maximum length of fibre in a given filling pressure
(Resting tension)
• Not affected by digitalis
• Decreasing end diastolic size of failing ventricle
 Rate: bradycardia is more marked with digitalis.
- Rate decreased because of improved circulation
- restores vagal tone and abolished sympathetic over
activity
Additionally decreases heart rate by vagal and extravagal action

20. Electrophysiological actions - AP
• Qualitative and quantitative difference on different fibers
• Action Potential:
– Excitability enhanced - RMP progressively decreased.
– AV and BoH: Rate of “0 - phase” depolarization is reduced
– PF : Phase 4 slope is increased - latent pacemaking activity
(extrasystoles)
– SAN AND AVN AUTOMATICITY – REDUCED
– Higher doses: Oscillation at phase 4 – coupled beats.
– Amplitude of AP is diminished

22. Electrophysiological
actions – contd.
 AP duration reduced.
 ERP: (Minimum interval between 2 propagated action
potentials)- shorten
 Conductivity: Slowed in AVN and BoH fibres
- Depressed AV conduction.
 ECG:
 Increased PR interval
 Decreased QT (shortening of systole)
 A-V block at toxic doses
 Decreased/inversion of - T wave.

23. Digitalis action – Blood vessels
 Mild vasoconstrictor and increased PR in Normal
individuals
 In CHF – compensated by improvement of increased in cardiac output-
decrease in sympathetic overactivity – decrease in Peripheral
resistance occurs
 Improved venous tone in CHF
 BP: No significant effect on BP in CHF.
 Coronary vessels: No significant action on coronary
vessels – not contraindicated in patient with coronary
artery disease

24. Digitalis action – other tissues
 Kidney:
 Diuresis due to the improvement of circulation in CHF patients
 No diuresis in Normal persons.
 Other smooth muscles:
 Inhibition of Na+/K+ ATPase – increased spontaneous activity
– anorexia, nausea, vomiting and diarrhoea.
 CNS:
 No major visible action in therapeutic doses
 High doses – stimulation of CTZ - nausea and vomiting
 Toxic doses – central sympathetic stimulation, mental confusion,
disorientation and visual disturbance.

25. Cardiac glycosides - Pharmacokinetics
 Absorption and Distribution:
 Vary in their ADME
 Presence of food in stomach delays absorption of Digoxin and Digitoxin
 Digitoxin is the most lipid soluble
 Vd of Cardiac glycosides are high (heart, skeletal muscle, kidney -
concentrated) – 6-8 L/Kg (Digoxin).
 Metabolism:
 Digitoxin is metabolized in liver partly to Digoxin and excreted in bile
 Reabsorbed in gut wall - enterohepatic circulation – long half life
 No relation with renal impairment
 Digoxin is primarily excreted unchanged in urine and rate of excretion
parallels creatinine clearance
 So, renal impairment and elderly – long half life (dose adjustment)
 All CGs are cumulative – steady state is attain after 4 half lives (1 wk for
Digoxin and 4 weeks for digitoxin)

27. Digitalis – Adverse effects
• Cardiac and Extracardiac:
• Extracardiac:
1. GIT: nausea, vomiting and anorexia etc.
2. CNS: CTZ stimulation, headache, blurring of vision
(flashing light, altered color vision), mental confusion etc.
3. Fatigue, no desire to walk.
4. Serum Electrolyte K+ : Digitalis competes for K+ binding
at Na/K ATPase.
• Hypokalemia: increase toxicity
• Hyperkalemia: decrease toxicity
5. Gynecomastia - rare

28. Digitalis – Adverse effects
Cardiac: All Arrhythmias
 Tachyarrythmias: Heart rate abnormally increased due to
prolong diuretic and digitalis therapy (K depletion) –
Potassium chloride 20 m.mol IV/hr or orally is given in
case of toxicity
 Digitalis toxicity – don’t give K+
 Serum K+ estimation
 Ventricular arrhythmia: Excessive ventricular automaticity:
Lidocaine IV (or Phenyton)
 PSVT: Propanolol IV or Adenosine
 AV block: Atropine - 0.6 to 1.2 mg IM

29. Digitalis - contraindications
 Hypokalemia: Toxicity
 Myocardial Infarction
 WPW syndrome (wolff parkinson-white
syndrome): VF may occur (due to reduced ERP)
 Elderly, renal or severe hepatic disease: more
sensitive to digitalis
 Ventricular tachyarrhythmias
 Partial AV block: Complete block
 Thyrotoxicosis

30. Digitalis – Common Drug interactions
 Diuretics: diuretic therapy with digoxin induce
Hypokalaemia (K+ supplementation required)
 Calcium: synergizes with digitalis
 Adrenergic drugs: arrhythmia
 Succinylcholine: induce arrhythmia
 Propranolol and Ca++ channel blockers:
depress AV conduction and oppose positive
ionotropic effects
 Metoclopramide, sucralfate and antacids –
reduced absorption

31. Drugs that enhance digitalis toxicity
 Diuretics
 Calcium
 Quinidine
 Verapamil
 Methyldopa

32. Drugs that reduce digitalis toxicity
 Antacid
 Neomycin decrease absorption
 Metaclopramide
 Refampicin
 Phenobarbitone
Enzyme inducer – increase metabolic rate

33. Treatmentof DigitalisToxicity
 Digitalis should be immediately withdrawn, toxicity
symptoms may persist for some time due to slow elimination
 K+ Supplementation, Digitalis treatment usually results in
myocardial K+ loss
 Hence, intravenous administration of K+ salts usually
produces immediate relief, since K+ loss is the probable
cause of dysrhythmias
 K+ supplementation would raise the extracellular K+
decreasing the slope of phase-4 depolarization and
diminishing increased automaticity
 However K+ supplementation may lead to complete A-V
block in cases of depresses automaticity or decreased
conduction (contraindicated with digitalis-induced second-
and third-degree heart block)
 Lidocaine or phenytoin is effective against K+ digitalis-
induced dysryhthmias

34. ANTIDOTE-Digoxin-specific
Fab fragments
 Digoxin-specific Fab fragments (digitoxin speific
antibodies- DIGIBIND-38mg vial) are used safely for
the treatment of the life-threatening cardiac glycosides-
induced arrhythmias and heart block
 Digoxin-specific Fab fragments are produced by
purification of antibodies raised in sheep by
immunization against digoxin
 The crude antiserum from sheep is fractionated to
separate the IgG fraction, which is cleaved into Fab
and Fc fragments by papain digestion
 The Fab fragments are not antigenic and with no
complement binding
 They are excreted fairly rapidly excreted by the kidney
as a digoxin-bound complex

35. Selective ß1- Adrenergic
Agonists
 Dobutamine (and dopamine), at doses equal to or less
than 5 µg/kg/min, has a selective ß1- adrenergic agonistic
activity
 Beneficial effects in emergency treatment of acute CHF
and MI include the following:
o 1- Increased cardiac output as a result of enhanced
contractility without appreciably altering the heart
rate.
o 2- Reduction of mean arterial blood pressure.
o 3- Lowering of the total peripheral vascular resistance and
consequently decreasing the afterload
o 4- Reduction of ventricular filling pressure

36. Selective ß1- Adrenergic
Agonists
β-A
β-A
β-receptor

37. Phosphodiesterase III (PD-III) Inhibitors

38. Phosphodiesterase III (PD-III) Inhibitors
 Inhibition of myocardial phosphodiesterase III
(PD-III), the enzyme responsible for cAMP
degradation, results in +ve inotropism via
cAMP-PKC cascade in a similar way to the
selective ß1- adrenergic agonists
 Agents in this class include: Amrinone, and
milrinone
 PD-III inhibitors are suitable only for acute
CHF because they can induce life-
threatening arrhythmias on chronic use

39. Angiotensin Converting
Enzyme Inhibitors (ACEIs)
Captopril, ACEIs

40. Angiotensin Converting
Enzyme Inhibitors (ACEIs)
 the use of ACEIs produces the following actions:
 1. Reduced sympathetic nervous system tone
 2. Increased vasodilator tone of vascular smooth muscle
and hence total vascular resistance falls promptly via:
• Decreased circulating Ang-II
• Increased bradykinin
• Decreased catecholamines
 3. Reduced sodium and water retention as a result of the
reduced AngII-induced reduced aldosterone secretion
 Ultimately both preload and afterload are reduced
 Clinical trials showed that the use of ACEIs in CHF has
significantly reduced morbidity and mortality

41. OTHER DRUGS OF USE IN CHF
WITHOUT INOTROPIC EFFECT
Diuretics
 Diuretics reduce cardiac preload by inhibiting
sodium and water retention
 Cardiac pumping improves with the consequent
reduction in venous pressure relieving edema
 Thiazide (e.g., hydrochlothiazide) and loop
diuretics (e.g., frusemide) are routinely used in
combination with digitalis
 Potassium-sparing diuretics can be concurrently
used to correct hypokalemia
o Spironolactone+Digitalis+ACEI clinical trials:
improved survival for MI patients.

42. VASODILATORS
1. Arteriolar dilator- reduce after load
Eg. Hydralazine
2. Venodilator – reduce preload
Eg. Organic nitrates- nitroglycerine
3. Arteriolar and venular dilators- reduce both
pre load and afterload.
Eg. ACEi, ARBs, sodium nitroprusside, α-1
antagonist, calcium channel blocker.

43. Current status of digitalis.
 Before the introduction of high ceiling diuretics and
ACE inhibitors, digitalis was considered an
indispensible part of anti-CHF treatment.
 Now the standard treatment
ACEi/ARBs+ Diuretics+β-blockers
 if not patient not recovered with standard therapy
shift to DIGITALIS treatment.
 In MI patient β-agonist used at the place of digitalis.

44. Thank you