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.