Congestive Heart Failure- Part II
- 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 ??
- 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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