2. Heart failure ?
• Definition: Heart failure is a clinical syndrome caused by the
inability of the heart to pump sufficient blood to meet the
metabolic needs of the body.
• Causes: Heart failure can result from any disorder that
reduces;
1. Ventricular filling (diastolic dysfunction)
2. Myocardial contractility (systolic dysfunction).
3. Coronary artery disease & hypertension.
3. Drug therapy for CHF or CCF
Relief of congestive/low output
symptoms & restoration of cardiac
performance
• Inotropic drugs: Digoxin,
Dobutamine/ Dopamine,
Amrinone/Milirinone
• Diuretics: Furosemide, Thiazides
• Vasodilators: Hydralazine, Nitrate,
Nitroprusside
• ACE inhibitors : Captopril, Enalapril
/AT1 antagonists : Losartan
• β- blockers: Metoprolol, Bisoprolol,
Carvedilol, Nabivolol
Arrest/reversal of disease
progression and prolongation of
survival
• ACE inhibitors: Captopril,
Enalapril /AT1 antagonists
(ARBs) : Losartan
• β- blockers: Metoprolol,
Bisoprolol, Carvedilol
• Aldostreone antagonist:
Spiranolactone, Eplerenone
4.
5. CARDIAC GLYCOSIDES
• These are glycosidic drugs having cardiac inotropic property.
• They increase myocardial contractility and output in a
hypodynamic heart without a proportionate increase in O2
consumption. Thus, efficiency of failing heart is increased.
6. • Cardiac glycosides are found in several plants
• Digitalis lanata is the source of Digoxin, the only glycoside that is
currently in use.
• Others like Digitoxin (from Digitalis purpurea) and Ouabain (from
Strophanthus gratus), etc. are no longer clinically used or marketed.
7. Pharmacology of Digoxin
Pharmacokinetics
• Absorption: Food delays absorption of digoxin tablet.
• Distribution: Vd is 6- 8 L/kg. Digoxin is concentrated in heart, Skeletal
muscle, liver and kidney.
• Metabolism: Metabolized in liver.
• Excretion: kidney
8. Pharmacological actions of Digoxin
1. Heart
a) Force of contraction
• Digoxin gives positive inotropic action in failing heart.
b) Tone
• Decrease end diastolic size of a failing heart.
c) Heart rate
• HR is decreased , bradycardia in CCF.
• Improved circulation (due to positive inotropic action)
9. d) Electrophysiological properties
1) Action potential (AP)
• The rate of 0 phase depolarization is reduced at AV node and bundle of His
• The slope of phase 4 depolarization increases in the purkinje fibers
• The SA and AV node automaticity is reduced at the therapeutic
concentration by vagal action
2) Excitability
• It increased by low dose and decreased by high dose
3) Conduction
• AV conduction is slowed at therapeutic dose by
decrease in rate of phase 0 depolarization
10. 4) Effective refractory period (ERP)
• Atrium: ERP is decreased by vagal action and increased by indirect action.
• AV node & bundle of His: ERP is increased by vagomimetic & anti-adrenergic
actions.
• Ventricle: ERP is increased by direct action.
5) ECG: At therapeutic doses
• Decreases amplitude or inversion of T wave.
• Shortening of Q-T interval
• Depression of ST segment due to interference with
repolarization
13. Pharmacological actions of digoxin (Contd…)
2. Blood vessels
• In normal individuals :Mild direct vasoconstrictor action.
• No prominent effect on BP: systolic BP may increase and diastolic may fall
in CHF patients.
3. Kidney
• In CHF patients: Diuresis, excretion of retained salt and water.
4. CNS
• Therapeutic dose- Little CNS effect.
• Higher doses - CTZ activation → nausea and vomiting. Also hyperapnoea,
central sympathetic stimulation, mental confusion, disorientation and visual
disturbances.
14. Adverse effects of Digoxin
• Extracardiac
Anorexia nausea, vomiting abdominal pain
Due to gastric irritation, mesenteric vasoconstriction andCTZ stimulation
Initially
headache mental confusion
hyperapnoea, psychosis visual disturbances
Others
15. Cardiac
• Every type of arrhythmia : pulsus bigeminus, nodal and ventricular
extrasystoles, ventricular tachycardia and terminally ventricular
fibrillation.
• Partial to complete A-V block.
• Severe bradycardia, atrial extrasystoles, AF.
16. Digoxin toxicity
Treatment
• Further dose must be stopped
• Tachyarrhythmias: Correction of K+ or
Mg2+Deficiency.
• Ventricular arrhythmias: Antiarrhythmic
Drugs eg, lidocaine or phenytoin.
• Supraventricular arrhythmias: Propranolol i.v
may me given
• A-V block & bradycardia: Atropine 0.6-1.2mg
i.m; otherwise cardiac pacing is recommended.
• Digoxin Antibodies: Digoxin antibodies (Fab
fragments; Digibind) are extremely effective.
17.
18. Drug interaction
• Quinidine causes reduction in digoxin clearance and can increase
the serum digoxin level if digoxin dosage is not adjusted.
• Digitalis toxicity, especially arrhythmogenesis, is increased by
hypokalemia, hypomagnesaemia
• Loop diuretics & thiazides, may significantly reduce serum
potassium and thus precipitate digitalis toxicity.
• Digitalis-induced vomiting may deplete serum magnesium and
similarly facilitate toxicity.
• Calcium: synergises with digitalis → precipitates toxicity.
• Adrenergic drugs: can induce arrhythmias in digitalized patients.
19. Precautions & Contraindications
• Hypokalemia: enhances digitalis toxicity.
• Elderly, renal or severe hepatic disease:
• Myocardial ischaemia: severe arrhythmias are more likely.
• Thyrotoxicosis: patients are more prone to develop digitalis
arrhythmias.
• Myxoedema: these patients eliminate digoxin more slowly; cumulative
toxicity can occur.
Therapeutic uses
• CHF
• Cardiac arrhythmias :Atrial fibrillation (AF), Atrial flutter (AFI) &
Paroxysmal supraventricular tachycardia (PSVT)
21. Phosphodiesterase 3 inhibitors
Inamrinone (amrinone) & Milrinone
Inamrinone (amrinone)
• Bipyridine derivative.
• A selective phosphodiesterase 3 (PDE3) inhibitor.
• The PDE3 isoenzyme is specific for intracellular degradation of cAMP in
heart, blood vessels and bronchial smooth muscles.
Pharmacological actions
• Heart: Myocardial contractility
• Peripheral vasculature: dilation of arteries & veins
Preload & afterload
22.
23. Pharmacokinetics
• In CHF patients i.v. amrinone action starts in 5 min and lasts 2–3 hours
• elimination t½ : 2–4 hours.
Adverse effects: Thrombocytopenia
Nausea, diarrhoea, abdominal pain
Liver damage, fever & arrhythmias
Use: short-term i.v. use in severe & refractory CHF,
as an additional drug to conventional therapy with digitalis, diuretics
and vasodilators
24. Milrinone
• it has similar action but is more selective for PDE3.
• 10 times more potent.
• It is shorter-acting with a t½ of 40–80 min.
• Thrombocytopenia is not significant.
• Milrinone is preferred over amrinone and should be
restricted to short-term use only.
26. At low dose, dobutamine has no significant effect on blood pressure. But
at high dose, dobutamine slightly increases BP due to action on α-
receptors.
