1. HEART FAILURE

2. Definition It is the inability of the heart to maintain an output sufficient to satisfy metabolic requirement of the body at all times.

3. Pathophysiology of Heart Failure The underlying abnormality in cardiac failure is inadequate cardiac output. Which is due to an increased preload. Increased after load. Or due to a disease of the myocardium itself. When the cardiac output decreases.→ leads to:

4. Pathophysiology of Heart Failure 1.Compensatory mechanisms: Hypertrophy and dilatation ↑sympathetic→↑after-load 2.↓R.B.F.→↓urine, ↑ renin 3.↑Residual blood in heart → venous congestion. 4.Remodeling of cardiac m.

5. Lines of Treatment General measures e.g. rest, sedatives, frequent small meals with salt restriction. Treatment of the cause. Angiotensin coverting enzyme inhibitors. Diuretics Spironolactone. Positive inotropic agents e.g. cardiac glycosides, dopamine, dobutamine, prenalterol,  2 agonist, and PDE inhibitors. Vasodilators. Beta blockers.

6. POSITIVE INOTROPIC DRUGS CARDIAC GLYCOSIDES Chemistry They are the combination of an aglycone or genin which is pharmacologically active portion. And sugar part that affects its physical properties.. They are obtained from dried leaves of the foxgloves. The most important cardiac glycosides is Digoxin

7. Pharmacokinetics Absorption: from duodenum Distribution: all over the body concentrated n heart(15-30 times). concentrated in sk.m.(10-15 times). bound to pl.pr(25%). Plasma concentration=0.5-2 ng/ml.

8. Pharmacodynamics A) Positive Inotropic Action It increases the contractile force of cardiac cells by increasing the free Ca++ concentration in the vicinity of contractile proteins during systole. Digioxin in large dose→ excess calcium→ Arrhythmia. B) Vagal effects. predominates n small dose. causes →↓ S,A.N., ↑ atrial Conductivity, ↓ A.V.N. conductivity.

9. Pharmacological Effects 1. Cardiovascular System Heart Contractility: It has a strong positive inotropic effectac output: It increases due to better filling of the heart and increases in the systolic force. Heart rate: It diminishes the heart rate due to: Vagal causes Extravagal causes

10. Heart Excitability: S.D.→↑ excitability, while L.D.→↓ excitability Automaticity: L.D.→↑ automaticity E.C.G. : ↓ H.R. Long P-R interval Short Q.R.S. and short Q-T interval Depressed S-T segment Arrhythmia.

11. Circulation COP: Increased in HF. A.B.P: Normalization. Venous pressure: decrease. Blood volume → decrease. Coronary circulation →Toxic dose → coronary V.C.

12. 2. Effects on the Kidney: In congestive heart failure, digitalis produces diuresis due to: Increase renal plasma flow and glomerular filtration rate. Inhibition of tubular sodium reabsorption. competitive antagonism with aldosterone.

13. 3. Effects on the Gastrointestinal Tract It causes nausea, vomiting anorexia and diarrhea. 4. Effects on the CNS It causes central stimulation, excitability and convulsions. Yellow vision. Stimulation of the chemoreceptor trigger zone.

14. Therapeutic Uses A. Absolute Indications: Chronic congestive heart failure associated with atrial fibrillation.

15. B. Relative Indications: 1. Treatment of heart failure failing to respond to diuretics. 2. Atrial fibrillation. 3. Atrial flutter. 4. Paroxysmal atrial tachycardia.

16. Contraindications A. Absolute Contraindications Heart block. Hypertrophic obstructive cardiomyopathy. In some cases of wolf-parkinson white syndrome. Paroxysmal ventricular tachycardia.

17. B. Relative Contraindications Cardiopulmonary disease Renal and hepatic insufficiency In hypertensive heart failure:The first line is antihypertensive with the emphasis on vasodilators. Sick sinus syndrome. Special caution is necessary when a patient is on other drugs which inhibit A.V. conduction e.g. beta-blockers. It is best avoided in patient likely to require cardioversion. Patient with hypersensitive carotid sinus.

18. Factors Modifying Response to Digitalisa Renal failure. Hepatic failure. Low body mass. Chronic pulmonary diseases, hypoxia, acid base imbalance. Cardiac disorders: A.Acute myocardial infarction leads to increase sensitivity B.Acute Rheumatic carditis increases the risk of heart block. C.Cardiomyopathy D.Constrictive pericarditis.

19. Dosage and Administration of Cardiac Glycosides It is necessary to establish and maintain an adequate concentration of digitalis in the heart “Digitalization”: 1. Digitalization can be achieved by one of the following schedules: Slow digtitalization “Cumulative method”: A maximum effect will be achieved in 4-5 elimination half-lives (i.e. about one week for digoxin and one month for digitoxin). Digitalization a can be also started with 0.5 mg twice per day for two days or 0.5 mg 3 times per day for one day followed by the maintenance dose.

20. Rapid digitalization “ Rapid loading method”: In emergency, we give a large initial loading dose “ digitalizing dose”. It is given in 3 or 4 divided doses at 6 hours intervals. Followed by maintenance doses. The main indications for urgent digitalization are AF with rapid ventricular response and severe acute left ventricular failure.

21. 2. Maintenance dose: 0.125 mg- 0.25 mg daily. One exception is A.F with fast ventricular response, which may require 0.125 daily in addition. N.B. Digitalis therapy involves the maintenance of an optimum concentration of the drug in the blood. (1-2 ng/ml for digoxin or 15-30 ng/ml for digitoxin).

22. Assessment of Response to Digitalis Relief of dyspnea and orthopnea. Disappearance of tachycardia. Increase urine volume. Disappearance of edema, congested neck veins and basal lung crepitations.

23. Precautions for Digitalis Therapy Never give I.V. digitalizing dose before being sure that the patient has not received any digitalis during previous 14 days to avoid digitalis toxicity. Make sure that K+ level is normal. With elderly people, one has to consider the digitalizing dose since toxic effects may be produced after administration of the normal adult dose.

24. DIGITALIS TOXICITY Manifestation of digitalis toxicity I- Cardiac:‏ Variable degree of A.V. block Sinus bradycardia; complete sinoatrial block. Paroxysmal and nonparoxysmal atrial tachycardia. Ventricular premature depolarization that appears as coupled beats (bigeminy and trigeminy) or ventricular tachycardia or fibrillation.

25. II- Extracardiac: ‏Anorexia, nausea, vomiting ‏Neurological effects: headache, muscle weakness, malaise, drowsiness and parasthesia disorientation, confusion, aphasia, delirium and hallucination “digitalis delirium” White borders or halos may appear on dark objects. Yellow and green. Transitory amblyopia, diplopia and scotoma due to retrobulbar neuritis. Skin rash, esinophilia, gynaecomastia, galactorrhea.

26. Management of digitalis toxicity Stop digitalis administration. Hypokalaemia can be corrected by slow IV infusion of K. Antiarrhythmic drugs: Lignocaine: Phenytoin Beta-blockers in tachyarrhythmia and ventricular ectopic beats. Atropine. Fab fragments of digitalis: specific antibodies it permits high renal clearance of digitalis complex by glomerular filtration.

27. OTHER POSITIVE INOTROPIC DRUGS DOPAMINE DOBUTAMINE It causes increase in cardiac output due to stimulation of  1 receptors. PRENALTEROL Similar to dobutamine but has longer duration of action and can be given orally.

28. PHOSPHODIESTERASE INHIBITORS CARDIO-ACTIVE BIPYRIDINES Amrinone, Milrinone It is a positive inotropic with vasodilatation properties. It increases myocardial contractility and reduction of peripheral resistance.

29. Mechanism Phosphodiesterase enzyme III inhibitors which lead to increase cAMP in cardiac tissues and smooth muscle. Increase inward Ca 2+ during the action potential. Side effects Thrombocytopenia Nausea, Vomiting Hepatic enzymes abnormalities. Cardiac arrhythmias: Less than digitalis. N.B.Milrinone is more potent with fewer side effects than amrinone.

30. Uses They are used in acute heart failure or acute exacerbation of chronic heart failure in patient who are not respond to other drugs. METHYLXANTHINES They act by translocation of intracellular calcium, increase concentration of cAMP and blockade of adenosine receptors e.g. aminophylline.

31. VASODILATORS The vasodilators are effective in heart failure because they provide a reduction in preload (venodilation), or reduction in after load (arteriolar dilation), or both. These include:Arteriodilators, venodilators, and mixed.

32. Vasodilators can be used in the Following Situations Pump failure-complicating AMI, valvular heart disease postoperative in cardiac surgery. Chronic congestive heart failure.

33. VASODILATORS 1.ACEIs. the, best, if not tolerated the second choice is → 2.ARBs. If contraindicated the choice is → 3.Nitrates, the oral preparations for CHF, and I.V. nitroglycerine for acute pulmonary edema.

34. DIURETICS They are used in order to: (1) Prevent fluid retention. (2) Relieve edema. (3) Decrease systemic pulmonary venous pressure. Thiazides: In mild and moderate heart failure. Frusemide: In server heart failure. Potassium retaining diuretics: In-patient with heart failure with secondary hyperaldosteronism.

35. RATIONAL FOR USE OF BETA-BLOCKERS IN HEART FAILURE The potential benefits of therapy with B-blockers are due to the ability of these drugs to reduce excessive sympathetic stimulation which cause. tachycardia and increased myocardial oxygen demand, cardiac hypertrophy, impaired myocyte function and myocyte death. increase renin release and angiotensin formation, and angiotensin II may have adverse effects on the heart.

36. RATIONAL FOR USE OF BETA-BLOCKERS IN HEART FAILURE A new  -blocker Carvedilol has considerable vasodilator activity. Antioxidant properties. Up-regulation of beta-receptors.

37. TREATMENT OF ACUTE PULMONARY EDEMA Hospitalization. Semisitting or sitting position. Treatment of the cause e.g. rapid atrial fibrillation, rapid rise of blood pressure. Morphine: I.V. in dose of 2-5 mg, because it produces the following: Relieving pain. Arteriolar dilatation. Venodilatation. Sedation which lead to decrease anxiety and work by breathing.

38. Oxygen : Oxygen increases the intra-alveolar pressure, decrease transudation and reduce pulmonary capillary pressure. Diuretics : Frusemide 40-60 mg. I.V. to relief of pulmonary edema. Vasodilators : I.V. Infusion with sodium nitroprusside or I.V. nitroglycerin or sublingual captopril. Rapid digitalization : Provided that the patient is not receiving digitalis. Aminophylline : I.V. 250 mg over 3-5 minutes because it: Diminishes bronchospasm. Increases renal plasma flow, increase sodium excretion and has diuretic effect. Increases myocardial contractility.