1. أ. م. د. وحدة اليوزبكي Head of Department of Pharmacology- College of Medicine- University of Mosul-2014 Management of Heart Failure 2

2. Objectives - At the end of this lecture, students should be able to : 1- Define Heart failure (CHF) 2- State Underlying causes of CHF 3- Enumerate groups of Drug Therapy of CHF. 4- Identify action of diuretic in CHF. 5- Identify action, clinical uses and side effects of ACEIs in CHF. 6- Discuss Positive Inotropic Drugs - At a level accepted to the quality assurance standards for the College of Medicine/ University of Mosul.

3. Management of Heart Failure Definition: CHF: It is a condition in which the heart is unable to pump sufficient blood to meet the metabolic requirement of the body (peripheral system). Underlying causes of CHF include: 1- Atherosclerosis (most common). 2- Hypertension. 3- Valvular heart diseases. 4- Dilated cardiomyopathy. 5- Congenital heart diseases.

4. Compensatory physiological responses in CHF

5. Management of CHF I- General Measures: 1- Physical activity. 2- Low dietary intake of Na(<1500ug/day). 3- Avoid drugs that may precipitate CHF, E.g. NSAIDs, B Blocker, Calcium channel blocker, Some antiarrhythmic drugs, Alcohol. E.g. NSAIDs, B Blocker, Calcium channel blocker, Some antiarrhythmic drugs, Alcohol.

6. II- Drug Therapy 1- Vasodilators, include: ACE Inhibitors (captopril). ACE Inhibitors (captopril). 2- Diuretics. 3- Inotropic Drugs: a- Digitalis. b- B adrenergic agonist (Dobutamine). c- Phosphdiesterase inhibitors (Dipyridines) Eg. Amrinone, Milirinone.

7. I- Vasodilators in CHF -Vasodilators are useful in reducing excessive preload & afterload in CHF. - ACE Inhibitors (Captopril) are the agents of choice in CHF. Action: These drugs block the enzyme that cleaves angiotensin I to form the potent vasoconstrictor angiotensin II, this will lead to: 1- Vasodilatation of vascular sm.m, lead to reduction of peripheral resistance (PR) and thereby reduce afterload. 2- Reducing aldosterone secretion: This lead to reduce salt and water retention and in this way reduce the preload. 3- The reduction of the sympathetic output and activity. 4- Decrease the rate of Bradykinin degradationand so this will lead to increase bradykinin level ( which is potent vasodilator).

8. Action of ACE Inhibitors in CHF

9. Indication of ACE inhibitors 1- Single agent therapy in patient with mild dyspnea on exertion. 2- Patient with recent MI. 2- Patient with recent MI. Side Effects of ACE Inhibitors: - First dose postural hypotension, hyperkalaemia, renal insufficiency, persistent dry cough, skin rash, taste disturbance, leucopenia, angioneurotic edema & protein urea. Note: ACE Inhibitors should not be given to pregnant.

10. 2- Diuretic in CHF Action: Diuretic by plasma volume: 1- venous return to the heart (preload) & & this results in reduction of edema and its symptoms, and reduction of cardiac size, which leads to improved pump efficiency.. 2- Bdp & so afterload. 2- Bdp & so afterload. Note: Note: The diuretic used in CHF is Thiazide group which is mild & loose efficacy if patient creatinine clearance is less than 50 ml/ min in this case use loop diuretic (in case of renal insufficiency). The diuretic used in CHF is Thiazide group which is mild & loose efficacy if patient creatinine clearance is less than 50 ml/ min in this case use loop diuretic (in case of renal insufficiency).

11. 3-Positive Inotropic Drugs These drugs enhance & improve cardiac contractility & thus increase C.O. These drugs enhance & improve cardiac contractility & thus increase C.O. 2 Groups of inotropic drugs: A- Digitalis Glycosides. The cardiac glycosides are often called digitalis because most of the drug come from digitalis (foxglove plant). The cardiac glycosides are often called digitalis because most of the drug come from digitalis (foxglove plant).

12. Mechanism of Action of Digoxin Cardiac glycosides affect: A- Cardiac effect : 1- Directly: By inhibition of the membrane bound (Na-K activated Atpase). 2- In directly: By enhancement of vagal (PS) B- Extra cardiac effect:

14. Mechanism of Action of Digoxin 2- In directly: By enhancement of vagal (PS) by complex peripheral & central mechanism, & so slow the conducting tissue (SA &AV node) Negative chronotropic effect ( HR). B- Extra cardiac effect: Digitalis by increase cardiac output renal blood flow & urine volume ( diuretic effect) edema & preload.

15. Pharmacokinetic of Digitalis DigitoxinDigoxin 90-100%40-75%Absorption Up to 2 days 36 h t 1/2t 1/2t 1/2t 1/2 More rapid Onset of action < Vd > Protein binding Extensive in liver & excreted in faeces 85% excreted unchanged (kidney) Metabolism

16. Indications of Digoxin 1- CHF: mainly severe LV function. 2- Atrial fibrillation & some cases of Atrial Flutter. Dose (Digitalization): - Maintenance & slow loading (0.125-0.5 mg) - Rapid digitalization ( 0.5-0.75 mg / 8h for 3 doses).

17. Side Effects of Digoxin Digoxin has low therapeutic index ( 0.5-2 ng / ml), so has low margin of safety & toxicity occur if serum conc. of digoxin rise > 2 ng / ml: 1- GIT effect: 2- CNS effect: 3- Cardiac effects: 4- Gynaecomastia in men & breast enlargement in women with long use.

18. Factors predisposing to digitalis toxicity 1- Electrolyte Disturbance: a- Hypokalaemia ( K ). a- Hypokalaemia ( K ). b- Hypercalcaemia ( Ca). b- Hypercalcaemia ( Ca). c- Hypomagnesaemia ( Mg). c- Hypomagnesaemia ( Mg). 2- Diseases : a- Renal impairment ( excretion of digoxin). a- Renal impairment ( excretion of digoxin). b- Hypothyroidism ( metabolism of digoxin). b- Hypothyroidism ( metabolism of digoxin). c- Diarrhea ( K ). c- Diarrhea ( K ). 3- Drugs: a- diuretic therapy. a- diuretic therapy. b- Quinidin. c- Verapamil. b- Quinidin. c- Verapamil. d- NSAI drugs & Ca channel blocking agents. d- NSAI drugs & Ca channel blocking agents. e. Antibiotic. f- Steroids. e. Antibiotic. f- Steroids.

19. Management of Digoxin Toxicity 1- Discontinued digoxin & K depleting agents. 2- Kcl given orally or by slow IV infusion. 3- Mg replacing therapy may be given. 4- Phenytoin may be given for treatment of ectopic. 5- Lidocain for Ventricular tachycardia. 6- Atropin for sinus bradycardia. 7- In severe acute poisoning ( suicidal overdose), 8- (Digoxin immune fab) used. 9- Cardioversion (DC) reserved for VF.

20. B- Second Group of positive inotropic Phosphodiesterase inhibitors ( Amrinone & Milirinone) Action: These drugs by inhibiting phosphdiesterase enzyme prevent hydrolysis & decrease inactivation of CAMP to AMP CAMP level IC Ca improve cardiac muscle contractility. Side Effects: Cardiac arrhythmia < digitalis, BM & liver toxicity & even mortality.

21. C- B adrenergic agonist B stimulation improve cardiac performance by positive inotropic effects & vasodilatation. Dobutamin: Act by: IC cAMP by activation of adenyl cyclase & so IC Ca cardiac contractility. Note: Note: Dobutamine must be given IV infusion & used in treatment of HF in hospital setting. Dobutamine must be given IV infusion & used in treatment of HF in hospital setting.

22. Site of action of B agonist & Phosphodiesterase inhibitors on heart muscle