This document summarizes the properties and uses of drugs with cardiac inotropic effects for treating heart failure. It discusses how these drugs increase the force of cardiac contraction without proportionally increasing oxygen consumption. The document outlines the mechanisms of action, pharmacokinetics, therapeutic uses, and adverse effects of digitalis glycosides, which are commonly used inotropic drugs that work by inhibiting the sodium-potassium ATPase pump. Digitalis glycosides are used to treat both congestive heart failure and cardiac arrhythmias.

2. Introduction
• Drugs having the cardiac Inotropic property – increase in
force of contraction and cardiac output in a failing
(hypodynamic) heart.
• They increase the myocardial contractility and improves
cardiac output without proportionate increase in Oxygen
consumption - Cardio-tonic.
• Do not increase the heart rate.
• Present in several plants and in toad skin.

3. What is a failing Heart ???
Inability of the heart to pump sufficient blood to meet the
metabolic demands of the body.
 Systolic - In IHD, Valve incompetence,
cardiomyopathy and myocarditis etc.
 Diastolic - In Hypertension, aortic stenosis,
congenital heart disease and hypertrophic
cardiomyopathy
Reduced efficiency of the heart as a pump – reduced
Cardiac Output

4. Pharmacological actions
HEART:
• Direct effects - Myocardial contractility
• Vagomimetic effect
• CNS effects – altering sympathetic activity
Force of Contraction:
• Positive inotropic effect
• Systole is shortened and prolonged diastole
• In Normal Heart – what happens ??

5. Normal
Digitalis
Heart failure
Stroke
volume
Arterial impedance

6. Tone:
• Maximum length of fibre in a given filling pressure
(Resting tension)
• Not affected by digitalis
• Decreasing end diastolic size of failing ventricle
Rate:
• Rate decreased because of improved circulation, restored
vagal tone and abolished sympathetic over activity.
• Additionally decreases heart rate by vagal and extravagal
action.

7. Electrophysiological Properties:
• Action Potential: Excitability enhanced - RMP
progressively decreased, shifted towards isoelectric.
• SAN and AVN automaticity – reduced
• Conductivity: Slowed in AVN and Bundle of His fibres
• ECG:
 Increased PR interval
 Decreased QT (shortening of systole)
 Decreased - T wave

9. BP:
 No prominent action in Systolic and diastolic BP
KIDNEY:
 Diuresis due to the improvement of circulation in CHF
OTHER SMOOTH MUSCLES:
 Na+/K+ ATPase inhibition: increased spontaneous activity
CNS:
 Therapeutic doses: No major visible action
 High doses – stimulation of CTZ - nausea and vomiting
 Toxic doses – central sympathetic stimulation, mental
confusion, disorientation and visual disturbance

10. Mechanism of action
Inhibition of Na+K+- ATPase (the “sodium pump”)
Digoxin

12. Pharmacokinetics
Absorption and Distribution:
• Vary in their ADME
• Presence of food in stomach delays absorption
• Digitoxin is the most lipid soluble
Metabolism:
• Digitoxin is metabolized in liver partly to Digoxin and
excreted in bile.
• Enterohepatic circulation – long half life
• Digoxine primarily excreted unchanged in urine and rate
of excretion parallels creatinine clearance.
• All CGs are cumulative – steady state after 4 half lives.

13. Adverse effects
Extracardiac:
• GIT: nausea, vomiting and anorexia etc.
• CNS: Headache, blurring of vision, mental confusion etc.
• Fatigue, malaise
• Serum Electrolyte-
K+ : Digitalis competes for K+ binding at Na/K ATPase
 Hypokalemia: increase toxicity
 Hyperkalemia: decrease toxicity
Mg2+: Hypomagnesaemia: increases toxicity
Ca2+: Hypercalcaemia: increases toxicity

14. Cardiac: All Arrhythmias
• Tachyarrythmias
• Ventricular arrhythmia
• PSVT
• AV block
DIGOXIN ANTIBODY: DIGIBIND

15. Contraindications
• Hypokalemia: Toxicity
• Myocardial Infarction
• WPW syndrome: VF may occur (due to reduced ERP of
bypass)
• Elderly, renal or severe hepatic disease: more sensitive
• Ventricular tachyarrhythmias
• Partial AV block: Complete block
• Thyrotoxicosis

16. Common Drug interactions
• Diuretics: Hypokalaemia (K+ supplementation required)
• Calcium: synergizes with digitalis
• Adrenergic drugs: arrhythmia
• Propranolol and Ca++ channel blockers: depress
AV conduction and oppose positive ionotropic effects
• Metoclopramide, sucralfate and antacids –reduced
absorption

17. Therapeutic Uses
1. Congestive Heart Failure &
2. Cardiac Arrhythmias

18. Digitalization
• Low therapeutic window
• Therapeutic level of digoxin is 0.5 – 1.5 ng/ml
• Aim to achieve max benefits with minimal adverse effects.
• Slow digitalization: Digoxin 0.25 mg (or even 0.125mg) daily
in the evening – full response in 5-7 days
 If no improvement administer 0.375 for 1 week
 If still no improvement, administer 0.5 mg in next week.
 Monitor patient for blood levels.
 If bradycardia, stop the drug

19. • Rapid IV: Seldom used now: As desperate measure in
CHF and atrial fibrillation - 0.25 mg slow IV stat
followed by 0.1 mg every Hrly
• Rapid digitalization (oral): 0.5 to 1 mg stat then 0.25 mg
every 6 Hrly
- Monitor for toxicity - Patient is digitalized within 24 Hrs

20. Goals and Drugs of Therapy for CHF
• Relief of congestive/Low output symptoms and
restoration of Cardiac performance:
 Inotropic: Digoxin, Dopamine, Dobutamine,
Amrinone/Milrinone
 Diuretics: Furosemide, thiazides
 Vasodilators: ACE inhibitors/ARBs, Hydralazine,
Nitroprusside and Nitrates
 Beta-blockers: Metoprolol, Bisoprolol, Carvedilol

21. • Arrest/Reversal of disease progression and
prolongation of survival
 ACE inhibitors/ARBs, Beta-blockers
 Aldosterone antgonist: Spironolactone
• Non-pharmacological measures: Rest and salt
restriction (for all grades of CHF)

22. Diuretics
• Almost all cases of CHF are treated with diuretics
• High ceiling diuretics (furosemide, bumetanide) are
preferred –
• IV diuretics – rapid symptomatic relief
• Chronic cases – resistance to furosemide -
combination with thiazides/spironolactone

23. Benefits:
• Decrease in preload – Improved ventricular efficiency
• Relief from Oedema and pulmonary congestion
• Increases venous capacitance – relief of LVF
Drawbacks:
• No influence in disease process
• No Role in asymptomatic heart failure
• Activation of RAS
• Chronic therapy: hypokalaemia, alkalosis,

24. RAS Inhibitors
• ACE Inhibitors and ARBs
• Mainstay in treatment – orally effective, medium efficacy
• Symptomatic as well as disease modifying benefits:
 Vasodilatation – arterio-venous
 Retardation/Prevention of ventricular hypertrophy -
myocardial cell apoptosis, fibrosis and intercellular matrix
changes and remodeling.
• Starts with low dose and gradual increase
• Used in all grades of CHF– including asymptomatic cases

25. Vasodilators
• Used IV to treat acute CHF cases
• Preload reduction: Nitrates –controlled IV – rapid
relief of ALVF
• Afterload reduction: Hydralazine – dilate resistance
vessels – reduce aortic impedance
• Pre-and after load reduction: ACEIs/ARBs – medium
efficacy and Nitroprusside – high efficacy IV
• Used with loop diuretics + IV inotropics to tide over
crisis in severely decompensated patients

26. Beta-blockers
• Selective β1- receptor blockers – metoprolol and
bisoprolol in mild to moderate cases
• Mechanism: antagonism of sympathetic over activity –
ventricular wall stretching, remodeling, apoptosis etc.
prevented, also decreases RAS

27. Aldosterone antagonists - Spironolactone
• Rise in plasma aldosterone – worsens CHF
• Add-on therapy to ACE inhibitors + other drugs in mild to
moderate cases
• Retards disease progression and prevents sudden cardiac
death along with ACEIs and beta- blockers
• Low dose – to prevent hyperkalaemia (ACEIs)
• Restoration of furosemide refractoriness
• Contraindicated in renal insufficiency (hyperlkalaemia) –
K+ monitoring.

28. Phosphodiesterase (PDE III)
Inhibitors
• Inamrinone, Milrinone – positive inotropy and
vasodilataion (INODILATOR)
• PDE III is specific for degradation of intracellular cAMP and
cGMP
 Indicated only in short-term IV therapy in severe and
refractory cases and as an add-on drug.
 Oral maintenance therapy – NOT USED
• ADR: Thrombocytopenia, nausea, diarrhoea, abdominal
pain, liver damage and arrhythmia etc.

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