This document discusses pharmacological approaches for treating heart failure. It describes how heart failure progresses and the sites where drugs can act. The main treatment approaches are positive inotropes like cardiac glycosides to improve contractility, diuretics to reduce edema, and ACE inhibitors to reduce preload and afterload. It then provides details on the mechanisms of action, pharmacokinetics, indications, interactions and side effects of various drug classes used to treat heart failure, including cardiac glycosides, beta agonists, phosphodiesterase inhibitors, diuretics and ACE inhibitors. It also discusses how drugs can modulate cardiac contractility dysfunction at the cellular level.

1. PHARMACOLOGYCAL
APPROACHES OF HEART
FAILURE
Dr. Jannatul Ferdoush
Assistant Professor
Department Of Pharmacology

2. • Pathophysiology of Heart Failure & site of drug action
Heart Failure
↓
↓ Myocardial contractility
↓
↓Renal perfusion ↓ Cardiac Output ↑ sympathetic outflow
↓ ↓ ↓
↓ ↓
↑Renin release ↑ Aldosterone ↑Residual volume Vasoconstriction
↓ ↓
Ang I Na- H2O retension ↓ ↓
↓ ↓ ↑Length of the muscle fibre ↑ Afterload
to follow Frank Starling Law
Ang II ↑ Plasma volume ↓
↓ ↓ ↑Residual Volume
Vasoconstriction ↑PreLoad ↓
↓ ↓ ↑↑Length of the muscle fibre
↑After load Oedema ↓
Cardiac Remodelling Occur
Heart dilated
↓
↑Peripheral venous Conjestion,
Pulmonary odema (shortness of breath)
↓
Detoriation of Heart Failure
(- ) POSITIVE INOTROPES
(- ) VASODILATOR
(- ) DIURETICS
(- ) ACEi

3. Treatment of Heart Failure
To Improve contractility: Positive inotropes
i) Cardiac Glycosides
ii) β1 agonists→ Dobutamine, Dopamine
iii) PDE inhibitors→ Amrinone, Milrinone
To reduce odema:
Diuretics – Thiazide & Frusemide
To reduce preload & after load:
ACE inhibitors

4. Cardiac glycoside
• These are the agents which have cardiotonic
property or action. Cardiotonic drugs increase
myocardial contractility without a corresponding
increase in O2 consumption.
Source Glycosides
Digitalis purpurea (leaf) Digitoxin
Gitoxin
Gitalin
Digitalis Lanata Digitoxin
Digoxin
Gitoxin
Strophanthus Gratus (seed) Strophanthin G (Ouabain)

5.  Clinically used –
 Digoxin (most commonly used)
 Digitoxin
 Ouabain.

6. • Chemistry of cardiac glycosides –
• All of the glycosides - of which digoxin is the
prototype – combine a steroid nucleus linked
to an unsaturated 5 membered lactone ring at
the 17 position and a series of sugars at
carbon 3 of the nucleus. Because they lack
an easily ionizable group, their solubility is not
pH dependent.

7. • It has both lipophilic (steroid nucleus) and hydrophilic
(lactone ring, hydroxyl group, sugar) groups. The
balance of these two has an important effect on
pharmacokinetics.
• Steroid nucleus with lactone ring is essential for
myocardial action. A sugar molecule present which is
important for pharmacokinetic property.

8. CVS effect of Cardiac Glycosides in Heart Failure
• (+ve) inotropic.
• (-ve) chronotropic→Binding to Na pumps in the plasma
membrane of central & peripheral nervous system → (-) of
symp. Nervous outflow → Stimulate Baroreceptor → ↑
Vagal tone of heart ( by acting on central vagal nucleus)
→↓ Firing of SA node → ↓ A-V Conduction → ↓ Heart rate.
• ↓Automaticity & Conduction Velocity at the AV nodal
tissue → Use in Heart failure with arrythmia. Chance of
Heart block.
• ↑ Automaticity- at high dose-cause Arrythmia.

9. Electrical activity of Cardiac Glycosides
No direct effect on SA node
↑ Refractory period of the AV node
↓Condution Velocity at the AV nodal Tissue
Stimulate vagal Nerve

10. Pharmacokinetics of different preparation of
cardiac Glycosides
Factor Digoxin Digitoxin Ouabain
Lipid solubility Less than digoxin
OH group- 2
More Lipid soluble
OH group- 1
H2O soluble
OH group- 5
Oral bioavailability 75% 80-90% Poor
Route Oral Oral Perenteral
Distribution Less More Poor
PPB Less More Negligible
Metabolism Partly in the liver Mainly LIver Not metabolized
Excretion Mainly by kidney By bile & stool Unchanged by
kidney
Half life 36 hours 7 days 24 hours
Onset 15- 20 min 25- 120min Immediate

11. • Indication:
• Heart failure
• Atrial arrythmia- Atrial flatter
Atrial fibrilation
• Paroxysmal supraventricular tachycardia
• Contraindication:
– Ventricular Tachycardia- because digitalis increase
autamaticity.
– Heart block.

12. Adverse effect
1.Extracardiac
 On GIT→ Anorexia, nausea,vomiting
 Fatigue ,weakness, diarrhoea
 Neurological problems-Blarring of vision, confusion
 Due to steroid nucleus- gynaecomastia in male
2.Cardiac effect:
i)All type of arrythmia (↑ Automaticity in high dose)
ii) Slowing A-V nodal Conduction-
Bradycardia
Heart block

13. Toxicity
• Anorexia is earliest symptom
bradycardia is earliest sign
( if <60 b/min, digitalis not given)
Low TI- 1-2.6nmol/L
Treatment: Rx is different in 2 different condition
i) Stop the drug
ii) Monitor K+ level( if hypokalemia administer K+ IV)
iii) If atrial arrythmia- digoxin not given because it slows
AV nodal conduction—use phenytoin which decrease
arrythmia but not slow AV nodal contraction.
iv) If ventricular arrythmia- lignocaine given,
it does not slows AV nodal conduction

14.  If heart block – give atropine to increase HR.
 If patient still refractory to treatment 
monoclonal antibody or digoxin binding specific
antibody (digibind) given to remove excess
digoxin from the body.

15. • Effect of administration of electrolyte on effect of
digoxin – K+, Ca++, Mg++  toxicity
 K+ and digitalis, interact in two ways-
 First –Hypokalemia increases the myocardial
localization of digoxin.reduction in extracellular
K+, cause phosphorylation cause increased
phosphorylation of Na pump. And digoxin has
higher affinity for the phosphorylated
form.increase K+, level can help to releive
symptos of digoxin by dephosphorylation of Na
pump.
 . Second – abnormal cardiac automaticity is
inhibited by hyperkalemia.

16.  Ca++ facilitates the toxic actions of cardiac
glycosides by accelerating the overloading of
intracellular Ca++ stores that appears to be
responsible for digitalis-induced abnormal
automaticity. Hypercalcemia therefore increases
the risk of digitalis induced arrhythmia.
 Decreased Mg++ concentration enhances
toxicities of cardiac glycosides.

17. Drug interaction
Pharmacodynamic interaction
• B –blocker + digoxin= ↓ AV Conduction –so Heart Block
• Verapamil+ digoxin= ↓ AV Conduction –so Heart Block
• Digitalis+ Diuretics(Thiazide/Frusemide)= cause K+ loss

18. • Pharmacokinetic interaction
• Verapamil+ digoxin→↑ plasma digitalis conc. by
competing with digoxin for renal excretion
→↑conc. of digoxin →toxicity
• Digitalis+Quinidine= displace digitalis from
tissue binding site→↑conc. of digitalis →↑toxicity

19. MODULATION OF
CARDIAC CONTRACTILITY
DYSFUNCTION AT CELLULAR
LEVEL BY DRUG

20. Fig:Sites of drug action

21. Cardiac Glycosides
• Selective inhibitor of the plasma membrane sodium pump.
• Mechanism of Action:
Inhibits Na+/K+ ATPase pump

Intracellular Na+concentration

Inhibits Na+/Ca2+ exchangers

Calcium efflux from the cell

 Intracellular calcium

 Cardiac Contractility

22. Beta-adrenergic receptor agonist
• Mechanism of action:
Acts on β1-adrenoceptor
Increase cAMP
↓
Activates protein kinase

activates sarcolemmal calcium channel

Increase cardiac contractility


23. Dopamine
 acts on β1 R at moderate dose → force of
contraction →CO
 At low dose act on D1 R-renal vasodilatation -
renal blood flow. So, it is a drug of choice.
Very short t ½ (2 – 3 minutes) due to metabolism
by COMT. So, we have to give in IV infusion.
1 – 5 μgm/kg/min  good β effect. > 5 μgm/kg/min
 α1 effect   PR.
dose  arrhythmia develop.

24. Dobutamine
• Act on β1 R
• ↑FC without increase in HR
• So, ↓ cardiac workload.

25. Phosphodiesterase inhibitors
• Mechanism of action
Inhibit enzymes that hydrolyzes cAMP

↑ intracellular cAMP

Activates protein kinase

activates sarcolemmal calcium channel

Increase cardiac contractility

26. • In Vessels  cAMP in arterial and venous
smooth muscle
• vasodilatation   PR   Afterload
• Venodilatation  ↑ venous capacitance  ↑
venous return   Preload
(the combination of (+Ve)chronotropic & mixed
arterial &venous dilatation leads to PDEi as
inodilator)

27. • Adverse effects –
• GIT – nausea and vomiting.
• Automaticity  arrhythmia
• Amrinone – thrombocytopenia

28. Diuretic
• Thiazide, frusemide.
• Beneficial effect both in acute and chronic HF.
• Role of diuretics in Heart Failure –
• Act on renal tubule  prevent reabsorption of
Na+ and H2O   Na+ and H2O excretion 
plasma volume   venous return   preload
 relieve of edema.

29. ACE inhibitors
 circulating angiotensin II level  less
vasoconstriction   PR   afterload.
  angiotensin II   aldosterone  less H2O
retention  plasma volume   venous return
  preload.
 No direct effect on heart. As  afterload  so 
forward pressure of heart  complete systolic
emptying of heart  so indirectly  CO. So, it is
a drug of choice.

30. • Only drug that ↓ PR ( after load) without causing
a reflex activation of the sympathetic system.
• Adverse Effects:
– Hypotension
– Dry persistent cough

31. β blockers
• Most patients with CHF respond favorably to certain
β blockers in spite of the fact that these drugs can
precipitate acute decompensation of cardiac
function.
• Trial of β blockers are based on the hypothesis that
excessive tachycardia and adverse effects of high
catecholamine levels on the heart contribute to the
downward course of HF patients.

32. • Suggested mechanism of beneficial action
include – attenuation of the adverse effects of
high concentration of catecholamines (including
apoptosis), up-regulation of β receptors,
decreased Heart Rate, and reduced remodelling
through inhibition of mitogenic activity of
catecholamines.
• They can improve symptoms, reduce the
frequency of hospitalization and reduce mortality
in CHF.