Congestive Heart Failure- Part II

Pharmacology: Drugs for CHF- Cardiac glycosides

1. Cardiac Glycosides and CHF

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 - Card io - t onic . 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. Nor m al Di g it a lis 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 , re stored 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

8. 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: T herapeutic doses: No major visible action High doses – stimulation of CTZ - nausea and vomiting Toxic doses – central sympathetic stimulation, mental confusion, disorientation and visual disturbance

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

10. 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. E nterohepatic circulation – long half life Digoxine p rimarily excreted unchanged in urine and rate of excretion parallels creatinine clearance. All CGs are cumulative – steady state after 4 half lives.

11. 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 Mg 2+ : Hypomagnesaemia: increases toxicity Ca 2+ : Hypercalcaemia: increases toxicity

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

13. 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

14. 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

15. Therapeutic Uses Congestive Heart Failure & Cardiac Arrhythmias

16. Digitalization L ow 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

17. 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

18. 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

19. 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)

20. 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

21. 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 N o Role in asymptomatic heart failure Activation of RAS Chronic therapy: hypokalaemia, alkalosis,

22. RAS Inhibitors ACE Inhibitors and ARBs M ainstay 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

23. Vasodi l ators 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

24. 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. p revented , also decreases RAS

25. 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 .

26. 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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